WO2001095912A1 - COMPOSITIONS CONTROLLING RELEASE pH RANGE AND/OR SPEED - Google Patents
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- WO2001095912A1 WO2001095912A1 PCT/JP2001/005151 JP0105151W WO0195912A1 WO 2001095912 A1 WO2001095912 A1 WO 2001095912A1 JP 0105151 W JP0105151 W JP 0105151W WO 0195912 A1 WO0195912 A1 WO 0195912A1
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
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- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
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- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
- A61K9/204—Polyesters, e.g. poly(lactide-co-glycolide)
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
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- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
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- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
Definitions
- the present invention relates to a composition for controlling the release pH range and / or the release rate that maximizes the therapeutic effect on inflammatory bowel diseases such as ulcerative colitis and Crohn's disease.
- R 1 is R 2 represents an alkyl having 1 to 4 carbon atoms an integer of a is 1-4 represents an alkyl having 1 to 4 carbon atoms:....
- R 3 is Alkyl having 1 to 4 carbon atoms, 'hydroxyalkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, phenyl which may have a substituent, or heteroaryl which may have a substituent Is shown.
- Inflammatory bowel disease is a refractory bowel disease that develops in the neutral region from the upper small intestine to the large intestine.
- Crohn's disease is observed from the duodenum to the small intestine, Colitis develops in the lower intestine of the large intestine.
- the present inventors have conducted various experiments using animal experiments. In these diseases, the drug (compound of the general formula (I)) is more likely to be absorbed into the lesion than to be absorbed into the blood from the gastrointestinal tract. It was found that it was important to release jewels and act directly on inflamed sites.
- this compound is a poorly soluble compound, and its solubility is extremely low, especially in the neutral region. Was. Therefore, in order to maximize the effect of this compound at a low dose, it is necessary to increase the dissolution rate in the neutral region and release the drug at the lesion site.
- Ji-Ji products are required to have various characteristics depending on the purpose of use, while ensuring their efficacy and safety.
- DDS a system that delivers a required amount of drug to a target site by a dosage form over a required period of time.
- the present invention focuses on controlling the rate of release of the drug from the composition in order to efficiently treat inflammatory bowel disease. Disclosure of the invention
- the present inventors have developed a solid preparation that can be orally administered by increasing the solubility of the compound of the general formula (1) in the neutral region in the gastrointestinal tract lumen and controlling the release rate.
- the present inventors have found that by dispersing the present compound in a polymer, the solubility of the present compound in the neutral region is improved, and that the release rate of the drug can be arbitrarily controlled.
- R 1 represents an alkyl having 1 to 4 carbons.
- R 2 represents an alkyl having 1 to 4 carbons.
- A represents an integer of 1 to 4.
- R 3 represents a carbon. Alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, phenyl optionally having substituent (s), or heteroaryl optionally having substituent (s) ) '
- a pharmaceutically acceptable salt thereof or a hydrate thereof and (ii) a water-soluble polymer, an enteric polymer, a permanent polymer and At least one base selected from the group consisting of porous polymers- Release PH and / or release rate controlling composition.
- composition for controlling the release pH range and / or the release rate according to (1) further comprising a surfactant.
- a composition for controlling a release pH range and / or a release rate comprising a compound of the general formula (I), a pharmaceutically acceptable salt or a hydrate thereof, and a surfactant.
- composition for controlling the release pH range and / or the release rate according to any of (4).
- the polymer is at least one selected from the group consisting of a water-soluble polymer, an enteric polymer, a water-insoluble polymer, and a porous high molecule.
- a release pH range comprising dissolving or dispersing a compound of the general formula (I), a pharmaceutically acceptable salt or a hydrate thereof, and a surfactant in a solvent, and distilling off the solvent. And / or a method for producing a release rate controlling composition.
- (12) a method comprising: melting a compound of the general formula (I), a pharmaceutically acceptable salt thereof or a hydrate thereof, and dissolving or dispersing the polymer to solidify by cooling; Alternatively, a method for producing a release rate controlling composition.
- polymer is at least one selected from the group consisting of a water-soluble polymer, an enteric polymer, a water-insoluble polymer, and a porous polymer.
- FIG. 1 shows the dissolution behavior of the composition for controlling the release pH range and the release rate according to the present invention (Examples 1 to 3) and the control solution of the Japanese Pharmacopoeia second liquid.
- FIG. 2 shows the dissolution behavior of the composition for controlling release pH and release rate (Examples 4 and 5) according to the present invention in the first liquid of JP.
- FIG. 3 is a graph showing the dissolution behavior of the composition for controlling release pH and release rate (Examples 4, 5) according to the present invention in the Japanese Pharmacopoeia second liquid.
- composition for controlling the release pH range and / or the release rate” of the present invention comprises a compound represented by the general formula (I), a pharmaceutically acceptable salt thereof or a hydrate thereof (that is, the present compound) is a polymer It is provided as a solid dispersion dispersed therein, thereby improving the solubility of the present compound in the neutral region and arbitrarily controlling the release rate.
- release pH range control means that the dissolution rate of the present compound in the neutral pH range, that is, pH about 5 to about 9, is significantly higher than the dissolution rate in the dosage forms other than the present invention. It means that the compound is adjusted so that the compound is not substantially eluted in an acidic pH region, that is, at a pH of about 4 or less.
- substantially not eluted means that it is not eluted to such an extent that the therapeutic efficacy is impaired.
- control of the release rate means that the release rate of the compound from the preparation can be arbitrarily adjusted. If necessary, approximately 100% of the compound can be released in a short time. It can be designed to 'release' or to release it gradually and sustainably.
- halogen in X represents chlorine, bromine, fluorine or iodine, and chlorine is preferred.
- Alkyl having 1 to 4 carbon atoms in R 1 , R 2 and R 3 represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, and preferably methyl.
- the alkoxy having 1 to 4 carbon atoms in R 3 means methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and the like.
- the phenyl which may have a substituent in R 3 includes halogen (chlorine, bromine, fluorine and the like), alkyl having 1 to 4 carbons (such as methyl and ethyl), hydroxy, and 1 to 4 carbons as the substituent.
- the heteroaryl may have a substituent in R 3, halogen as a substituent (chlorine, bromine, fluorine, etc.), alkyl of 1 to 4 carbon atoms (methyl, etc. Echiru), hydroxy, amino, nitro, carbon Represents pyridyl, pyrazinyl, pyrimidinyl, chenyl, furyl, etc. which may have 1 to 2 alkoxys (eg, methoxy, ethoxy, etc.), 3-pyridyl, 2-methoxy-3-pyridyl, 4-medium Toxie 3-pyridyl and the like are exemplified.
- Pharmaceutically acceptable salts of the compound include inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and organic acids (acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, Acid addition salts with tartaric acid, cunic acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, ascorbic acid, etc., and inorganic bases (sodium hydroxide, potassium hydroxide, calcium hydroxide) Shim, magnesium hydroxide, zinc hydroxide, ammonium hydroxide, etc., organic bases (methylamine, getylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, trishydroxymethylaminomethane, quinine, guanidine, cinchonine, etc.
- inorganic acids hydro
- the compound of the general formula (I) is represented by (S) — 2— [4 _ '(4-cyclophenyl) -1, 2, 3,
- the composition of the present invention is obtained by dissolving or dispersing the present compound and a polymer and / or a surfactant in an appropriate organic solvent, and then subjecting the organic solvent to reduced pressure or normal pressure by a conventional method. It can be produced by dry distillation (dissolution method). Alternatively, the compound can be produced by melting the present compound by heating it to a temperature higher than its melting point, and then dissolving or dispersing the polymer and / or surfactant therein and quenching (melting method).
- the “polymer” used in the present invention is not particularly limited as long as it is capable of improving the solubility in the neutral region of the present compound and controlling the release rate by being compounded with the present compound. However, preferred are an enteric polymer, a water-insoluble polymer, a porous polymer or a permanent polymer, and examples thereof include the following polymers.
- water-soluble polymers examples include polyvinyl virolidone, polyvinyl alcohol, methylcellulose, hydroxypropylcellulose, and hydroxypropyl methylcellose 2208 (medium 90SH), and hydroxybutyl methylcellulose 2906 (metrorose 65SH). And hydroxypropyl methylcellulose 2910 (Metroze 60SH), carboxymethylethylcellulose, burlan, dextrin, sodium alginate, aminoalkyl methacrylate copolymer E, polyvinyl acetate methyl acetylamine, and the like.
- Preferred are polyvinylvirolidone, hydroxypropyl methylcellulose, carboxymethylethylcellulose, methylcellulose, and hydroxypropyl cellulose.
- Porous polymers include magnesium metasilicate aluminate, dimagnesium aluminate silicate, magnesium bismuth aluminate silicate, hydrous lucite, aluminum silicate, dried aluminum hydroxide gel, magnesium oxide, light anhydrous calcium acid and Special calcium silicate and the like can be mentioned.
- Preferred are light silicic anhydride, special calcium silicate, and magnesium aluminate metasilicate.
- Each of the above polymers can be used alone or in combination of two or more, if necessary.
- the ratio of mixing the present compound with the polymer is not particularly limited as long as the solubility of the present compound in the neutral region can be improved, and differs depending on the type of polymer, the usage, the film characteristics, and the like.
- the polymer is suitably used in an amount of 0.1 to 999, preferably 0.2 to 500, more preferably 0.5 to 50, based on the present compound 1.
- a surfactant may be combined with the above polymer. By using a surfactant in combination, the release rate of the compound can be increased.
- the surfactant used in the present invention include polysorbate (40, 60, 65, 80), sodium lauryl sulfate, hydrogenated castor oil, and polyoxyethylene hydrogenated castor oil. Preferably, it is a polyoxyethylene hydrogenated castor oil.
- the release rate of the present compound in the composition of the present invention can be controlled by controlling the combination of the polymer and the surfactant and the compounding ratio of the present compound and the like. It can.
- Those skilled in the art can easily determine preferable polymers and surfactants, their blending ratios, and the like according to the purpose of use. For example, when it is desired to cause the * compound to act locally from the duodenum to the upper part of the small intestine, a dissolution rate of nearly 100% can be achieved in a short time by using a surfactant in combination. Conversely, when it is desired to continuously release the drug from the small intestine to the large intestine, it can be easily adjusted by combining a water-insoluble molecule as a polymer or increasing or decreasing the amount of the polymer added to the compound. .
- the composition of the present invention can be a composition in which the present compound and a surfactant are mixed.
- Surfactants improve the solubility and elution rate of the present compounds in the neutral pH region.
- a sustained release film such as ethyl cellulose, ethyl acrylate / methyl methacrylate / methacrylic acid trimethylammonium methacrylate copolymer
- an enteric film It is used as an enteric-coated product coated with hydroxymethyl pyrmethylcellulose phthalate (HP55), methyl acrylic acid.
- the organic solvent used dissolves the present compound and controls the release pH range and / or release rate of the present compound of a polymer or a surfactant.
- a polymer or a surfactant There is no limitation as long as it does not adversely affect the characteristics. Examples thereof include ethanol, acetone, and dichloromethane.
- the operating conditions such as the treatment temperature and the treatment time in the dissolution method vary depending on the compound used, the solvent and the like, but are usually from room temperature to 200 ° C. for several minutes to several tens of hours.
- the composition of the present invention is produced by a melting method, the polymer or the surfactant to be used is ⁇ controlling the release pH range and / or the release rate of the present compound '' at the melting point of the present compound. It is necessary to be able to maintain characteristics.
- the solid dispersion of the present compound obtained as described above can be used as it is, but it can be used in various forms such as fine granules, granules, tablets, capsules and the like which are generally known as pharmaceutical preparations.
- the dosage form may be formulated using a generally known manufacturing method.
- coloring agents eg, lactose, sucrose, starch, Disintegrants (eg, low-substituted hydroxypropylcellulose, croscarmellose sodium, crospovidone, carboxymethyl starch sodium), lubricants (eg, magnesium stearate), plasticizers
- a suitable additive such as an agent (triethyl citrate, polyethylene glycol, etc.) and a pH adjuster (such as citrate, ascorbic acid, magnesium aluminate, etc.) can be added.
- these additives may be added in an organic solvent (molten compound of the present invention) or may be added to a solid dispersion of the present compound.
- the CD composition of the present invention improves the dissolution rate of the present compound in the neutral region, and does not substantially elute the present compound in the acidic region (therefore, the elution of the present compound in the stomach upon oral administration) Therefore, it is useful as an oral administration preparation for the treatment of inflammatory diseases in the neutral region in the gastrointestinal tract lumen, that is, the region from the upper small intestine to the large intestine.
- the composition of the present invention can be effectively used for the treatment of inflammatory bowel diseases such as ulcerative colitis and Crohn's disease which are remarkably observed in the relevant region.
- the dosage of the oral preparation of the present invention varies depending on the type and severity of the disease, the drug receptivity of the patient, body weight, age, etc., but usually about 0.1 to about 1 as the amount of the compound per adult per day. Omg / kg, which can be administered once or in several divided doses. Next, the present invention will be described in detail with reference to Examples, Control Examples and Test Examples, but the present invention is not limited thereto.
- Test example 1 Dissolution test
- the solubility of the compound A contained in the compositions obtained in Examples 1 to 3 and the powder mixture obtained in Control Example 1 in the Japanese Pharmacopoeia second liquid (pH 6.8) was evaluated. That is, the samples of Example 13 and Control Example 1 (equivalent amount having 10 ⁇ ⁇ of compound A) were added to 900 mL of Japanese Pharmacopoeia No. 2 solution, and the dissolution test solution was collected temporarily at 37 ° C. Then, the test solution was filtered using a fine filter (pore size: 5 ⁇ : manufactured by Toyama Sangyo Co., Ltd.), and the amount of Compound ⁇ dissolved in the filtrate was measured by a spectrophotometer. The results are shown in Figure 1.
- Example 1 As a result, in Control Example 1, the elution rate was 25% even after 360 minutes. On the other hand, by blending the high molecules, an elution rate of 50% or more was achieved after 360 minutes. Furthermore, from the results of Example 1, it can be seen that the release rate can be increased by increasing the blending ratio of the polymer, and when Examples 2 and 3 are compared, the addition of a surfactant, polyoxyethylene hydrogenated castor oil, was added. Found that 100 drugs could be released within 30 minutes. Test example 2: Dissolution test,
- the solubility in 1.2) and 2 solutions was evaluated. That is, the samples of Examples 4 and 5 (equivalent amounts containing 5 ni of compound A) were added to 900 mL of the dissolution test solution, and 37. In C The dissolution test solution is collected periodically, and the test solution is filtered using a fine filter (pore 5zm : manufactured by Toyama Sangyo Co., Ltd.), and the dissolved amount of Compound A in the filtrate is measured with a spectrophotometer did. The results are shown in FIGS.
- Example 3 Therapeutic effect in a TNBS induced rat enteritis model
- TNBS trinose benzenesulfonic acid
- the ratio in the preparation of Example 1 indicates the compounding ratio of compound A to polyvinyl bi-lidone.
- Table 2 MPO activity after oral administration
- Example 2 On the other hand, as a result of oral administration, the anti-inflammatory effect of Example 2, which had the highest solubility and the fastest release rate, was weaker than other release rate controlling compositions, and was controlled by controlling the release rate to sustained release. The effect was improved (Table 2). Industrial applicability
- the present invention relates to combining a compound of the general formula (I) with a water-soluble polymer, an enteric polymer, a water-insoluble high-molecular or porous polymer, and / or a surfactant.
- the present invention provides a controlled release composition capable of arbitrarily controlling the solubility and release rate of the compound in the gastrointestinal tract.
- the present technology it is possible to control ulcerative colitis and Crohn's disease. It was possible to achieve maximal anti-inflammatory effects at low doses in target organs. Therefore, the present composition is useful as a preparation for oral administration for treating the above diseases.
- This application is based on a patent application No. 2000-182,933 filed in Japan, the contents of which are incorporated in full herein.
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2002510090A JP4875277B2 (ja) | 2000-06-16 | 2001-06-15 | 放出pH域及び/又は速度制御組成物 |
CA2412776A CA2412776C (en) | 2000-06-16 | 2001-06-15 | Compositions controlling release ph range and/or speed |
EP01938708A EP1297836A4 (en) | 2000-06-16 | 2001-06-15 | COMPOSITIONS FOR CHECKING RELEASE, PH AREA AND / OR SPEED |
KR1020027017110A KR100838686B1 (ko) | 2000-06-16 | 2001-06-15 | 방출 pH 범위 및/또는 속도 제어 조성물 |
AU2001264303A AU2001264303A1 (en) | 2000-06-16 | 2001-06-15 | Compositions controlling release ph range and/or speed |
US10/319,568 US20030130268A1 (en) | 2000-06-16 | 2002-12-16 | Compositions controlling pH range of release and /or release rate |
US12/222,213 US20090012064A1 (en) | 2000-06-16 | 2008-08-05 | Compositions controlling pH range of release and/or release rate |
US13/448,538 US8883777B2 (en) | 2000-06-16 | 2012-04-17 | Compositions controlling pH range of release and/or release rate |
US14/522,983 US20150045352A1 (en) | 2000-06-16 | 2014-10-24 | COMPOSITIONS CONTROLLING pH RANGE OF RELEASE AND/OR RELEASE RATE |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000-182293 | 2000-06-16 | ||
JP2000182293 | 2000-06-16 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/319,568 Continuation-In-Part US20030130268A1 (en) | 2000-06-16 | 2002-12-16 | Compositions controlling pH range of release and /or release rate |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2001095912A1 true WO2001095912A1 (en) | 2001-12-20 |
Family
ID=18683084
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2001/005151 WO2001095912A1 (en) | 2000-06-16 | 2001-06-15 | COMPOSITIONS CONTROLLING RELEASE pH RANGE AND/OR SPEED |
Country Status (7)
Country | Link |
---|---|
US (4) | US20030130268A1 (ja) |
EP (1) | EP1297836A4 (ja) |
JP (1) | JP4875277B2 (ja) |
KR (1) | KR100838686B1 (ja) |
AU (1) | AU2001264303A1 (ja) |
CA (1) | CA2412776C (ja) |
WO (1) | WO2001095912A1 (ja) |
Cited By (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004045586A1 (ja) * | 2002-11-15 | 2004-06-03 | Bioserentach Co., Ltd. | 薬物吸収促進を目的とする界面活性剤を含む固形化製剤 |
JP2007308480A (ja) * | 2006-04-20 | 2007-11-29 | Shin Etsu Chem Co Ltd | 腸溶性固体分散体を含んでなる固形製剤 |
WO2010095494A1 (ja) * | 2009-02-19 | 2010-08-26 | アサヒビール株式会社 | 難溶性物質を含有する顆粒、錠剤、及び難溶性物質の可溶化方法 |
JP2013047258A (ja) * | 2006-04-20 | 2013-03-07 | Shin-Etsu Chemical Co Ltd | 腸溶性固体分散体を含んでなる固形製剤 |
US8981083B2 (en) | 2010-05-14 | 2015-03-17 | Dana Farber Cancer Institute, Inc. | Compositions and methods for treating neoplasia, inflammatory disease and other disorders |
US9301962B2 (en) | 2010-05-14 | 2016-04-05 | Baylor College Of Medicine | Male contraceptive compositions and methods of use |
JP2016525563A (ja) * | 2013-08-01 | 2016-08-25 | オンコエシックス ゲーエムベーハー | チエノトリアゾロジアゼピン化合物を含む医薬製剤 |
JP2016529246A (ja) * | 2013-08-06 | 2016-09-23 | オンコエシックス ゲーエムベーハー | Betブロモドメイン阻害剤を用いるびまん性大細胞型b細胞性リンパ腫(dlbcl)の治療方法 |
US9815849B2 (en) | 2010-05-14 | 2017-11-14 | Dana-Farber Cancer Institute, Inc. | Compositions and methods for treating leukemia |
US9951074B2 (en) | 2014-08-08 | 2018-04-24 | Dana-Farber Cancer Institute, Inc. | Dihydropteridinone derivatives and uses thereof |
US9975896B2 (en) | 2013-07-25 | 2018-05-22 | Dana-Farber Cancer Institute, Inc. | Inhibitors of transcription factors and uses thereof |
US10124009B2 (en) | 2014-10-27 | 2018-11-13 | Tensha Therapeutics, Inc. | Bromodomain inhibitors |
US10150756B2 (en) | 2014-01-31 | 2018-12-11 | Dana-Farber Cancer Institute, Inc. | Diaminopyrimidine benzenesulfone derivatives and uses thereof |
US10308653B2 (en) | 2014-08-08 | 2019-06-04 | Dana-Farber Cancer Institute, Inc. | Diazepane derivatives and uses thereof |
US10702527B2 (en) | 2015-06-12 | 2020-07-07 | Dana-Farber Cancer Institute, Inc. | Combination therapy of transcription inhibitors and kinase inhibitors |
US10793571B2 (en) | 2014-01-31 | 2020-10-06 | Dana-Farber Cancer Institute, Inc. | Uses of diazepane derivatives |
US10881668B2 (en) | 2015-09-11 | 2021-01-05 | Dana-Farber Cancer Institute, Inc. | Acetamide thienotriazolodiazepines and uses thereof |
US10913752B2 (en) | 2015-11-25 | 2021-02-09 | Dana-Farber Cancer Institute, Inc. | Bivalent bromodomain inhibitors and uses thereof |
US10925881B2 (en) | 2014-02-28 | 2021-02-23 | Tensha Therapeutics, Inc. | Treatment of conditions associated with hyperinsulinaemia |
US11306105B2 (en) | 2015-09-11 | 2022-04-19 | Dana-Farber Cancer Institute, Inc. | Cyano thienotriazolodiazepines and uses thereof |
US11446309B2 (en) | 2013-11-08 | 2022-09-20 | Dana-Farber Cancer Institute, Inc. | Combination therapy for cancer using bromodomain and extra-terminal (BET) protein inhibitors |
Families Citing this family (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004339162A (ja) * | 2003-05-16 | 2004-12-02 | Shin Etsu Chem Co Ltd | 難溶性薬物を含む医薬用固形製剤とその製造方法 |
US20100319928A1 (en) * | 2009-06-22 | 2010-12-23 | Baker Hughes Incorporated | Through tubing intelligent completion and method |
US20110000674A1 (en) * | 2009-07-02 | 2011-01-06 | Baker Hughes Incorporated | Remotely controllable manifold |
US20110073323A1 (en) * | 2009-09-29 | 2011-03-31 | Baker Hughes Incorporated | Line retention arrangement and method |
WO2012075456A1 (en) | 2010-12-02 | 2012-06-07 | Constellation Pharmaceuticals | Bromodomain inhibitors and uses thereof |
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US9328117B2 (en) | 2011-06-17 | 2016-05-03 | Constellation Pharmaceuticals, Inc. | Bromodomain inhibitors and uses thereof |
WO2013184878A1 (en) | 2012-06-06 | 2013-12-12 | Constellation Pharmaceuticals, Inc. | Benzo [b] isoxazoloazepine bromodomain inhibitors and uses thereof |
TWI602820B (zh) | 2012-06-06 | 2017-10-21 | 星宿藥物公司 | 溴域抑制劑及其用途 |
CA2885944A1 (en) * | 2012-09-28 | 2014-05-08 | Oncoethix Sa | Pharmaceutical formulation containing thienotriazolodiazepine compounds |
WO2015018520A1 (en) * | 2013-08-06 | 2015-02-12 | Oncoethix Sa | A bet-brd inhibitor represents a novel agent for alk positive anaplastic large cell lymphoma |
WO2015018522A1 (en) * | 2013-08-06 | 2015-02-12 | Oncoethix Sa | Bet-bromodomain inhibitor shows synergism with several anti-cancer agents in pre-clinical models of diffuse large b-cell lymphoma (dlbcl) |
WO2015018523A1 (en) * | 2013-08-06 | 2015-02-12 | Oncoethix Sa | A novel bet-brd inhibitor for treatment of solid tumors |
WO2015078931A1 (en) * | 2013-11-27 | 2015-06-04 | Oncoethix Sa | Method of treating neuroblastomas using thienotriazolodiazepine compounds |
US9757385B2 (en) | 2013-11-27 | 2017-09-12 | Merck Sharp & Dohme Corp. | Method of treating leukemia using pharmaceutical formulation containing thienotriazolodiazepine compounds |
JP2016538307A (ja) * | 2013-11-27 | 2016-12-08 | オンコエシックス ゲーエムベーハー | チエノトリアゾロジアゼピン化合物を含む医薬製剤を使用する非小細胞肺癌の治療方法 |
KR20170002550A (ko) * | 2014-05-02 | 2017-01-06 | 온코에틱스 게엠베하 | 티에노트리아졸로디아제핀 화합물을 사용한 내성 비호지킨 림프종, 수아세포종, 및/또는 alk+ 비소세포 폐암의 치료 방법 |
WO2015168621A1 (en) | 2014-05-02 | 2015-11-05 | Oncoethix Sa | Method of treating acute myeloid leukemia and/or acute lymphoblastic leukemia using thienotriazolodiazepine compounds |
CA2947970A1 (en) | 2014-05-08 | 2015-11-12 | Oncoethix Gmbh | Method of treating triple-negative breast cancer using thienotriazolodiazepine compounds |
WO2015169953A1 (en) | 2014-05-08 | 2015-11-12 | Oncoethix Gmbh | Method of treating glioma using thienotriazolodiazepine compounds |
CN106852119A (zh) * | 2014-06-13 | 2017-06-13 | 翁科埃斯克斯有限公司 | 利用噻吩并三唑并二氮杂*化合物治疗非小细胞肺癌和/或小细胞肺癌的方法 |
JP6682522B2 (ja) | 2014-06-20 | 2020-04-15 | コンステレーション・ファーマシューティカルズ・インコーポレイテッドConstellation Pharmaceuticals,Inc. | 2−((4s)−6−(4−クロロフェニル)−1−メチル−4h−ベンゾ[c]イソオキサゾロ[4,5−e]アゼピン−4−イル)アセトアミドの結晶形態 |
CN107073011A (zh) * | 2014-08-19 | 2017-08-18 | 翁科埃斯克斯有限公司 | 利用噻吩并三唑并二氮杂*化合物治疗淋巴瘤的方法 |
EP3185871A1 (en) * | 2014-08-28 | 2017-07-05 | Oncoethix GmbH | Methods of treating acute myeloid leukemia or acute lymphoid leukemia using pharmaceutical compositions containing thienotriazolodiazepine compounds |
WO2016176335A1 (en) | 2015-04-27 | 2016-11-03 | Concert Pharmaceuticals, Inc. | Deuterated otx-015 |
Citations (5)
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EP0671167A1 (en) * | 1994-02-10 | 1995-09-13 | Tanabe Seiyaku Co., Ltd. | Pharmaceutical preparation controlled to release medicinal active ingredient at targeted site in intestinal tract |
JPH08143476A (ja) * | 1994-11-18 | 1996-06-04 | Japan Tobacco Inc | 薬物放出制御膜及び固形製剤 |
WO1996036322A1 (en) * | 1995-05-17 | 1996-11-21 | The Procter & Gamble Company | Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery |
EP0754452A2 (en) * | 1995-07-20 | 1997-01-22 | Tanabe Seiyaku Co., Ltd. | Pharmaceutical preparation in form of coated capsule releasable at lower part of digestive tract |
WO1998011111A1 (fr) * | 1996-09-13 | 1998-03-19 | Yoshitomi Pharmaceutical Industries, Ltd. | Composes de thienotriazolodiazepine et leurs utilisations a des fins medicinales |
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JPS56110612A (en) * | 1980-02-08 | 1981-09-01 | Yamanouchi Pharmaceut Co Ltd | Readily disintegrable and absorbable compression molded article of slightly soluble drug |
US5264446A (en) | 1980-09-09 | 1993-11-23 | Bayer Aktiengesellschaft | Solid medicament formulations containing nifedipine, and processes for their preparation |
FR2525108B1 (fr) | 1982-04-19 | 1989-05-12 | Elan Corp Ltd | Medicaments a haut degre de solubilite et procede pour leur obtention |
JPS5914446A (ja) | 1982-07-13 | 1984-01-25 | Michio Yoshikawa | 過負荷検出装置 |
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US5773025A (en) * | 1993-09-09 | 1998-06-30 | Edward Mendell Co., Inc. | Sustained release heterodisperse hydrogel systems--amorphous drugs |
JPH07324086A (ja) * | 1994-05-31 | 1995-12-12 | Sankyo Co Ltd | チアゾリジン誘導体の固体分散体または固体分散体製剤 |
-
2001
- 2001-06-15 KR KR1020027017110A patent/KR100838686B1/ko active IP Right Grant
- 2001-06-15 WO PCT/JP2001/005151 patent/WO2001095912A1/ja active Application Filing
- 2001-06-15 EP EP01938708A patent/EP1297836A4/en not_active Withdrawn
- 2001-06-15 JP JP2002510090A patent/JP4875277B2/ja not_active Expired - Fee Related
- 2001-06-15 AU AU2001264303A patent/AU2001264303A1/en not_active Abandoned
- 2001-06-15 CA CA2412776A patent/CA2412776C/en not_active Expired - Lifetime
-
2002
- 2002-12-16 US US10/319,568 patent/US20030130268A1/en not_active Abandoned
-
2008
- 2008-08-05 US US12/222,213 patent/US20090012064A1/en not_active Abandoned
-
2012
- 2012-04-17 US US13/448,538 patent/US8883777B2/en not_active Expired - Fee Related
-
2014
- 2014-10-24 US US14/522,983 patent/US20150045352A1/en not_active Abandoned
Patent Citations (5)
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EP0671167A1 (en) * | 1994-02-10 | 1995-09-13 | Tanabe Seiyaku Co., Ltd. | Pharmaceutical preparation controlled to release medicinal active ingredient at targeted site in intestinal tract |
JPH08143476A (ja) * | 1994-11-18 | 1996-06-04 | Japan Tobacco Inc | 薬物放出制御膜及び固形製剤 |
WO1996036322A1 (en) * | 1995-05-17 | 1996-11-21 | The Procter & Gamble Company | Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery |
EP0754452A2 (en) * | 1995-07-20 | 1997-01-22 | Tanabe Seiyaku Co., Ltd. | Pharmaceutical preparation in form of coated capsule releasable at lower part of digestive tract |
WO1998011111A1 (fr) * | 1996-09-13 | 1998-03-19 | Yoshitomi Pharmaceutical Industries, Ltd. | Composes de thienotriazolodiazepine et leurs utilisations a des fins medicinales |
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Cited By (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004045586A1 (ja) * | 2002-11-15 | 2004-06-03 | Bioserentach Co., Ltd. | 薬物吸収促進を目的とする界面活性剤を含む固形化製剤 |
JP2007308480A (ja) * | 2006-04-20 | 2007-11-29 | Shin Etsu Chem Co Ltd | 腸溶性固体分散体を含んでなる固形製剤 |
JP2013047258A (ja) * | 2006-04-20 | 2013-03-07 | Shin-Etsu Chemical Co Ltd | 腸溶性固体分散体を含んでなる固形製剤 |
WO2010095494A1 (ja) * | 2009-02-19 | 2010-08-26 | アサヒビール株式会社 | 難溶性物質を含有する顆粒、錠剤、及び難溶性物質の可溶化方法 |
JP2010189337A (ja) * | 2009-02-19 | 2010-09-02 | Asahi Breweries Ltd | 難溶性物質を含有する顆粒、錠剤、及び難溶性物質の可溶化方法 |
US9301962B2 (en) | 2010-05-14 | 2016-04-05 | Baylor College Of Medicine | Male contraceptive compositions and methods of use |
US9320741B2 (en) | 2010-05-14 | 2016-04-26 | Dana-Farber Cancer Institute, Inc. | Compositions and methods for treating neoplasia, inflammatory disease and other disorders |
US10407441B2 (en) | 2010-05-14 | 2019-09-10 | Dana-Farber Cancer Institute, Inc. | Compositions and methods for treating neoplasia, inflammatory disease and other disorders |
US10676484B2 (en) | 2010-05-14 | 2020-06-09 | Dana-Farber Cancer Institute, Inc. | Compositions and methods for treating leukemia |
US9789120B2 (en) | 2010-05-14 | 2017-10-17 | Dana-Farber Cancer Institute, Inc. | Male contraceptive compositions and methods of use |
US9815849B2 (en) | 2010-05-14 | 2017-11-14 | Dana-Farber Cancer Institute, Inc. | Compositions and methods for treating leukemia |
US8981083B2 (en) | 2010-05-14 | 2015-03-17 | Dana Farber Cancer Institute, Inc. | Compositions and methods for treating neoplasia, inflammatory disease and other disorders |
US9975896B2 (en) | 2013-07-25 | 2018-05-22 | Dana-Farber Cancer Institute, Inc. | Inhibitors of transcription factors and uses thereof |
JP2016525563A (ja) * | 2013-08-01 | 2016-08-25 | オンコエシックス ゲーエムベーハー | チエノトリアゾロジアゼピン化合物を含む医薬製剤 |
JP2016529246A (ja) * | 2013-08-06 | 2016-09-23 | オンコエシックス ゲーエムベーハー | Betブロモドメイン阻害剤を用いるびまん性大細胞型b細胞性リンパ腫(dlbcl)の治療方法 |
US11446309B2 (en) | 2013-11-08 | 2022-09-20 | Dana-Farber Cancer Institute, Inc. | Combination therapy for cancer using bromodomain and extra-terminal (BET) protein inhibitors |
US10793571B2 (en) | 2014-01-31 | 2020-10-06 | Dana-Farber Cancer Institute, Inc. | Uses of diazepane derivatives |
US10150756B2 (en) | 2014-01-31 | 2018-12-11 | Dana-Farber Cancer Institute, Inc. | Diaminopyrimidine benzenesulfone derivatives and uses thereof |
US10730860B2 (en) | 2014-01-31 | 2020-08-04 | Dana-Farber Cancer Institute, Inc. | Diaminopyrimidine benzenesulfone derivatives and uses thereof |
US10925881B2 (en) | 2014-02-28 | 2021-02-23 | Tensha Therapeutics, Inc. | Treatment of conditions associated with hyperinsulinaemia |
US10308653B2 (en) | 2014-08-08 | 2019-06-04 | Dana-Farber Cancer Institute, Inc. | Diazepane derivatives and uses thereof |
US9951074B2 (en) | 2014-08-08 | 2018-04-24 | Dana-Farber Cancer Institute, Inc. | Dihydropteridinone derivatives and uses thereof |
US10124009B2 (en) | 2014-10-27 | 2018-11-13 | Tensha Therapeutics, Inc. | Bromodomain inhibitors |
US10702527B2 (en) | 2015-06-12 | 2020-07-07 | Dana-Farber Cancer Institute, Inc. | Combination therapy of transcription inhibitors and kinase inhibitors |
US10881668B2 (en) | 2015-09-11 | 2021-01-05 | Dana-Farber Cancer Institute, Inc. | Acetamide thienotriazolodiazepines and uses thereof |
US11306105B2 (en) | 2015-09-11 | 2022-04-19 | Dana-Farber Cancer Institute, Inc. | Cyano thienotriazolodiazepines and uses thereof |
US11406645B2 (en) | 2015-09-11 | 2022-08-09 | Dana-Farber Cancer Institute, Inc. | Acetamide thienotriazolodiazepines and uses thereof |
US10913752B2 (en) | 2015-11-25 | 2021-02-09 | Dana-Farber Cancer Institute, Inc. | Bivalent bromodomain inhibitors and uses thereof |
Also Published As
Publication number | Publication date |
---|---|
US8883777B2 (en) | 2014-11-11 |
EP1297836A1 (en) | 2003-04-02 |
US20150045352A1 (en) | 2015-02-12 |
CA2412776A1 (en) | 2001-12-20 |
AU2001264303A1 (en) | 2001-12-24 |
KR20030010724A (ko) | 2003-02-05 |
EP1297836A4 (en) | 2007-06-13 |
US20030130268A1 (en) | 2003-07-10 |
US20120202798A1 (en) | 2012-08-09 |
CA2412776C (en) | 2011-03-15 |
US20090012064A1 (en) | 2009-01-08 |
JP4875277B2 (ja) | 2012-02-15 |
KR100838686B1 (ko) | 2008-06-16 |
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