WO2011004799A1 - 中空構造を有する錠剤 - Google Patents
中空構造を有する錠剤 Download PDFInfo
- Publication number
- WO2011004799A1 WO2011004799A1 PCT/JP2010/061430 JP2010061430W WO2011004799A1 WO 2011004799 A1 WO2011004799 A1 WO 2011004799A1 JP 2010061430 W JP2010061430 W JP 2010061430W WO 2011004799 A1 WO2011004799 A1 WO 2011004799A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tablet
- component
- hydrophobic effect
- outer shell
- core
- Prior art date
Links
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 49
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- MGSRCZKZVOBKFT-UHFFFAOYSA-N thymol Chemical compound CC(C)C1=CC=C(C)C=C1O MGSRCZKZVOBKFT-UHFFFAOYSA-N 0.000 claims description 6
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- 238000002360 preparation method Methods 0.000 description 21
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- VEMKTZHHVJILDY-FIWHBWSRSA-N resmethrin Chemical compound CC1(C)[C@H](C=C(C)C)C1C(=O)OCC1=COC(CC=2C=CC=CC=2)=C1 VEMKTZHHVJILDY-FIWHBWSRSA-N 0.000 description 1
- 229960002477 riboflavin Drugs 0.000 description 1
- 235000019192 riboflavin Nutrition 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 229940080817 rotenone Drugs 0.000 description 1
- JUVIOZPCNVVQFO-UHFFFAOYSA-N rotenone Natural products O1C2=C3CC(C(C)=C)OC3=CC=C2C(=O)C2C1COC1=C2C=C(OC)C(OC)=C1 JUVIOZPCNVVQFO-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- VMSRVIHUFHQIAL-UHFFFAOYSA-M sodium;n,n-dimethylcarbamodithioate Chemical compound [Na+].CN(C)C([S-])=S VMSRVIHUFHQIAL-UHFFFAOYSA-M 0.000 description 1
- 229960003579 sotalol hydrochloride Drugs 0.000 description 1
- VIDRYROWYFWGSY-UHFFFAOYSA-N sotalol hydrochloride Chemical compound Cl.CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 VIDRYROWYFWGSY-UHFFFAOYSA-N 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- 229940012831 stearyl alcohol Drugs 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- JXHJNEJVUNHLKO-UHFFFAOYSA-N sulprofos Chemical compound CCCSP(=S)(OCC)OC1=CC=C(SC)C=C1 JXHJNEJVUNHLKO-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- UBCKGWBNUIFUST-YHYXMXQVSA-N tetrachlorvinphos Chemical compound COP(=O)(OC)O\C(=C/Cl)C1=CC(Cl)=C(Cl)C=C1Cl UBCKGWBNUIFUST-YHYXMXQVSA-N 0.000 description 1
- LITQZINTSYBKIU-UHFFFAOYSA-F tetracopper;hexahydroxide;sulfate Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Cu+2].[Cu+2].[Cu+2].[Cu+2].[O-]S([O-])(=O)=O LITQZINTSYBKIU-UHFFFAOYSA-F 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- 239000004308 thiabendazole Substances 0.000 description 1
- WJCNZQLZVWNLKY-UHFFFAOYSA-N thiabendazole Chemical compound S1C=NC(C=2NC3=CC=CC=C3N=2)=C1 WJCNZQLZVWNLKY-UHFFFAOYSA-N 0.000 description 1
- 229960004546 thiabendazole Drugs 0.000 description 1
- 235000010296 thiabendazole Nutrition 0.000 description 1
- BAKXBZPQTXCKRR-UHFFFAOYSA-N thiodicarb Chemical compound CSC(C)=NOC(=O)NSNC(=O)ON=C(C)SC BAKXBZPQTXCKRR-UHFFFAOYSA-N 0.000 description 1
- QGHREAKMXXNCOA-UHFFFAOYSA-N thiophanate-methyl Chemical group COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC QGHREAKMXXNCOA-UHFFFAOYSA-N 0.000 description 1
- 229960002447 thiram Drugs 0.000 description 1
- KUAZQDVKQLNFPE-UHFFFAOYSA-N thiram Chemical compound CN(C)C(=S)SSC(=S)N(C)C KUAZQDVKQLNFPE-UHFFFAOYSA-N 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- YWSCPYYRJXKUDB-KAKFPZCNSA-N tralomethrin Chemical compound CC1(C)[C@@H](C(Br)C(Br)(Br)Br)[C@H]1C(=O)O[C@H](C#N)C1=CC=CC(OC=2C=CC=CC=2)=C1 YWSCPYYRJXKUDB-KAKFPZCNSA-N 0.000 description 1
- REEQLXCGVXDJSQ-UHFFFAOYSA-N trichlopyr Chemical compound OC(=O)COC1=NC(Cl)=C(Cl)C=C1Cl REEQLXCGVXDJSQ-UHFFFAOYSA-N 0.000 description 1
- DQJCHOQLCLEDLL-UHFFFAOYSA-N tricyclazole Chemical compound CC1=CC=CC2=C1N1C=NN=C1S2 DQJCHOQLCLEDLL-UHFFFAOYSA-N 0.000 description 1
- HSMVPDGQOIQYSR-KGENOOAVSA-N triflumizole Chemical compound C1=CN=CN1C(/COCCC)=N/C1=CC=C(Cl)C=C1C(F)(F)F HSMVPDGQOIQYSR-KGENOOAVSA-N 0.000 description 1
- ZSDSQXJSNMTJDA-UHFFFAOYSA-N trifluralin Chemical compound CCCN(CCC)C1=C([N+]([O-])=O)C=C(C(F)(F)F)C=C1[N+]([O-])=O ZSDSQXJSNMTJDA-UHFFFAOYSA-N 0.000 description 1
- JARYYMUOCXVXNK-CSLFJTBJSA-N validamycin A Chemical compound N([C@H]1C[C@@H]([C@H]([C@H](O)[C@H]1O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)CO)[C@H]1C=C(CO)[C@@H](O)[C@H](O)[C@H]1O JARYYMUOCXVXNK-CSLFJTBJSA-N 0.000 description 1
- 229960000881 verapamil hydrochloride Drugs 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- WCJYTPVNMWIZCG-UHFFFAOYSA-N xylylcarb Chemical compound CNC(=O)OC1=CC=C(C)C(C)=C1 WCJYTPVNMWIZCG-UHFFFAOYSA-N 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
-
- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
-
- 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
Definitions
- the present invention relates to a tablet having a hollow structure having a hollow portion at a central portion and capable of floating in water, and a method for producing the tablet.
- the present invention relates to a tablet that stays in the stomach and has a sustained release effect.
- a stomach-retaining tablet is known as a tablet that continuously releases a drug in the stomach.
- These gastric retention tablets include gel swelling tablets that stay in the stomach by swelling in the stomach (Patent Documents 1 to 9), and foam tablets that float by foaming with acid in the stomach (Patent Documents). 10-13) Gastric floating tablets that are floated in the stomach by using a material with low specific gravity (Patent Documents 14 and 15) or having porous voids (Patent Documents 16 and 17) are known. Yes.
- As for granules preparations that are suspended in the stomach by providing a cavity inside the granules are known (Patent Documents 18 to 20, Non-Patent Document 1).
- the problem to be solved by the present invention is to obtain a tablet that can be produced by a simple production method and that is highly versatile and floats in water or stays in the stomach and can release the drug continuously. . Furthermore, it is to establish a technique that can be applied to various tablets suspended in water.
- the inventors of the present invention have made extensive studies on tablets that are easy to manufacture and that can float in water with high versatility.
- a core part containing a sublimable solid such as menthol is prepared, and after forming an outer shell containing an excipient on the outside of the core part so that the core part is located in the center part, heating is performed. It was found that a hollow tablet capable of floating in water can be obtained by removing a sublimable solid contained in the core portion and infiltrating a component exhibiting a hydrophobic effect, thereby completing the present invention.
- the present invention includes the following inventions.
- a tablet floatable in water obtained by a production method comprising at least the following steps (1) to (4).
- the component exhibiting a hydrophobic effect is at least one of a higher alcohol and a higher fatty acid glycerin ester.
- the component exhibiting a hydrophobic effect is at least one selected from stearyl alcohol, cetyl alcohol, hydrogenated castor oil, and stearic acid monoglyceride.
- the manufacturing method of the tablet which can float on the water which has a hollow structure including the following processes at least.
- a step of producing a core portion containing a sublimable solid (2) A sugar alcohol, a sugar, a cellulose derivative and Forming an outer shell containing at least one excipient selected from starches, and preparing a dry-coated tablet (3) Included in the core part by heating the dry-coated tablet obtained in step (2) Step 4 for obtaining a tablet having a hollow structure by removing the sublimable solid obtained (4) Step for immersing the tablet having a hollow structure obtained in step (3) in a component exhibiting a hydrophobic effect 11.
- the production method according to item 10 above, wherein the component showing a hydrophobic effect is a component showing a hydrophobic effect in the stomach. 12 12.
- the tablet of the present invention has a hollow structure and contains a component that exhibits a hydrophobic effect, it can float in water.
- the drug in the tablet of the present invention it is possible to float in water or stay in the stomach and to exert the sustained release effect of the main ingredient component.
- the tablet which has the hollow structure of this invention can be produced very simply compared with a prior art.
- Test Example 1 the change in mass when the dry-coated tablets of Reference Examples 1 to 5 are heated in an oven at 80 ° C. is shown.
- Test Example 2 the dissolution test results of Examples 1 to 7 and Comparative Example 1 are shown. It is the photograph which image
- the present invention has a hollow structure having a hollow portion in the central portion, and can float in water, including at least one excipient selected from sugar alcohol, sugar, cellulose derivatives and starches, and a component exhibiting a hydrophobic effect. It is a certain tablet.
- the tablet of the present invention has a hollow structure having a hollow portion in the central portion. By having the hollow structure, the tablet of the present invention can float in water.
- the tablet of the present invention having the hollow structure is a conventional effervescent tablet (Japanese Unexamined Patent Publication No. 62-283919, Japanese Unexamined Patent Publication No. 62-195323, Japanese Unexamined Patent Publication No. 62-207209, and Japanese And JP-A-61-43108 and International Publication No. 91/6281).
- the size of the hollow portion can be appropriately adjusted so that the tablet strength is ensured and the tablet has an appropriate size for floating in water. Further, the number of hollow portions is not necessarily one, but may be plural.
- the hollow portion is located at the center of the tablet from the viewpoint of tablet strength, but it is not always necessary to be accurately located at the center of the tablet, and can be appropriately adjusted within a range in which tablet strength is ensured.
- the size of the hollow portion is preferably adjusted as appropriate so that the tablet can float in water.
- the density of the entire tablet is 1 g / cm 3 or less, more preferably 0.95 g / cm 3 or less, 0.90 g / cm 3 It is particularly preferred that
- the density of the tablet can be roughly estimated by, for example, the following calculation method.
- the density of the tablet is estimated by calculating (B) ⁇ (A) using the volume (A) and the tablet mass (B) estimated from the tablet thickness and tablet diameter of the tablet. .
- the volume (A) is ⁇ (L ⁇ 2) 2 ⁇ ⁇ ⁇ D ⁇ .
- the density of the tablet can be calculated by the following formula 1. B / ⁇ (L ⁇ 2) 2 ⁇ ⁇ ⁇ D ⁇ (Formula 1)
- the weight of the tablet finally obtained for example, 0.25 g, density 0.250g ⁇ 0.20428cm 3 ⁇ 1.22g / cm 3 And it is larger than 1 g / cm 3 and does not float in water.
- the mass of the tablet is set to 200 mg, for example, by increasing the size of the cavity, the density becomes 1 g / cm 3 or less, so that it floats.
- the tablet of the present invention contains an excipient.
- filler refers to the additive mix
- the excipient is at least one selected from sugar alcohols, sugars, cellulose derivatives and starches.
- sugar alcohols examples include mannitol and xylitol.
- sugar examples include lactose, sucrose, and fructose.
- Examples of the cellulose derivative include crystalline cellulose.
- starches examples include corn starch.
- mannitol, lactose and crystalline cellulose are preferable.
- mannitol D-mannitol is preferable.
- the content of the excipient in the tablet can be adjusted as appropriate, but it is usually preferably 5 to 95% by mass, more preferably 10 to 80% by mass.
- “showing a hydrophobic effect” means having a low affinity to water, that is, having a property of being hardly dissolved in water or mixed with water.
- the tablet of this invention can release a medicinal ingredient gradually by containing the component which shows a hydrophobic effect. As a result, it can be expected that the effect relating to the medicinal component is sustained.
- the component showing the hydrophobic effect is preferably a low melting point oily substance that is solid at room temperature.
- the low melting point oily substance preferably has a melting point of 40 to 100 ° C., more preferably 50 to 90 ° C.
- components that exhibit a hydrophobic effect include higher fatty acid glycerin esters and higher alcohols, waxes, and organic acids that do not dissolve in gastric juice.
- the suspension and residence time of the tablet in water can be controlled.
- the release rate of the main ingredient component can be controlled by the kind of the component showing the hydrophobic effect.
- higher fatty acid glycerin esters examples include stearic acid monoglyceride, hydrogenated castor oil, palmitic acid stearic acid monoglyceride, oleic acid monoglyceride, stearic acid mono-diglyceride, and stearic acid oleic acid monoglyceride.
- higher alcohols examples include myristyl alcohol, cetyl alcohol, stearyl alcohol, 1-eicosanol, 1-docosanol, 1-tetracosanol, seryl alcohol, octacosan-1-ol and 1-triacontanol.
- stearic acid monoglyceride hydrogenated castor oil, stearyl alcohol, cetyl alcohol and stearic acid are preferable from the viewpoints of permeability and sustained release effect.
- a component exhibiting a hydrophobic action that can be used can be appropriately selected depending on the thermal stability of the component used for the excipient and the thermal stability of the main ingredient component.
- the content of the component showing the hydrophobic effect in the tablet of the present invention is preferably adjusted as appropriate depending on the type of the component and the density of the tablet, but is usually preferably 5 to 40% by mass, and preferably 10 to 30% by mass. More preferably, the content is 15 to 25% by mass.
- “being able to float in water” means that buoyancy is exhibited in a solvent such as water, and it can float on a liquid surface such as gastric juice for a long time.
- the time for which the tablet floats in water is preferably 1 hour or more after administration, more preferably 3 hours or more, and particularly preferably 5 hours or more.
- the tablet of the present invention preferably contains a main ingredient component in a part other than the cavity part, that is, a part constituting the tablet. This makes it possible to release the main ingredient component while suspending the tablet in water.
- main ingredient component means a component having pharmacological activity.
- the main drug component is not particularly limited, but specific examples include the following drugs when used in gastric floating tablets.
- agents for the neuropsychiatric system such as barbitals, chlorpromazine, levodopa, diazepam and imipramine; antipyretic analgesics and anti-inflammatory agents such as acetaminophen, aspirin, ibuprofen, ketoprofen and indomethacin; antihistamines such as difuenhydramine hydrochloride; propranolol hydrochloride, etc.
- ⁇ -blockers diuretics such as spironolactone, acetazolamide and furosemide; antihypertensives such as captopril and bunazosin hydrochloride; coronary vasodilators such as diltiazem hydrochloride and isosorbide nitrate; and Ca antagonists such as nifedipine, nicardipine hydrochloride, nisoldipine and nitrendipine Agents; antihyperlipidemic agents such as pravastatin; antitussives such as theofylin and codeine phosphate; digestive agents such as pepsin and diastase; synthetic aluminum silicate Anti-ulcer agents such as cimetidine; vitamins such as riboflavin; various antibiotics such as tetracycline, penicillin and cefem; synthetic antibacterial agents such as ofloxacin and ciprofloxacin; thioconazole And antifungal agents such as griseo
- drugs that exert a direct effect in the stomach for example, acetohydroxamic acid
- drugs that are well absorbed in the stomach or upper intestine for example, ciprofloxacin and sotalol hydrochloride
- degraded by intestinal fluid Drugs or drugs that are unstable in intestinal fluid (for example, captopril), drugs that are difficult to dissolve in intestinal fluid or poorly soluble in intestinal fluid (for example, diazepam and verapamil hydrochloride) are preferred.
- any agrochemical used can be used as long as it is usually used in a paddy field, and one or two or more kinds may be used in combination.
- examples of such agricultural active ingredients include the following.
- insecticide examples include CYAP, MPP, MEP, ECP, pyrimifosmethyl, erythomfos, diazinon, quinalphos, isoxathion, pyridafenthione, chlorpyrifosmethyl, chlorpyrifos, ECP, bamidthione, profenofos, marathon, PAP, dimethoate, thiomethone, ethyl thione, Hosalon, PMP, DMTP, prothiophos, sulprophos, pyraclofos, DDVP, monocrotofos, BRP, CVMP, dimethylvinphos, CVP, propaphos, acephate, isofenphos, salicion, DEP, EPN, ethion, NAC, MTMC, MIPC, BPMC, PHC , MPMC, XMC, Ethiophene Carb, Bendio Carb, Pirimi curve, Carbosulfur fan
- the disinfectant examples include copper sulfate, slaked lime, basic copper calcium sulfate, basic copper sulfate, basic copper chloride, cupric hydroxide, copper ammonium complex, oxine copper, nonylphenol sulfonate copper, DBEDC, terephthalic acid Copper, sulfur, polysulfide lime, dineb, manneb, manzeb, ambum, polycarbamate, organic sulfur nickel salt, propineb, diram, thiuram, milneb, captan, diclofluuride, TPN, fusalide, IBP, EDDP, torquelophosmethyl, pyrazophos , Fosetyl, thiophanate methyl, benomyl, carbendazole, thiabendazole, iprodione, vinclozoline, procymidone, fluorimido, oxycarboxin, mepronil, flutolanil, teflophthalam, trichlamide,
- herbicides for example, 2,4-D, MCP, MCPB, MCPP, triclopyr, phenothiol, clomeprop, naproanilide, phenoxapropethyl, fluazihop, CNP, clomethoxynil, bifenox, MCC, IPC, fenmedefam, MBPMC , Vernarate, Beniocurve, Orthobencarb, Esprocarb, Molinate, Dimepiperate, DCPA, Arachlor, Butachlor, Pretilachlor, Metolachlor, Bromobutide, Mefenacet, Dimelon, Bensulfuron methyl, Cimetrine, Promethrin, Dimetamethrin, Bentazone, Oxadiazone, Pyrazolate Pyrazoxiphene, benzophenap, trifluralin, piperophos, butamifos, bensulide, DCBN Etc. and ACN, and the like.
- plant regulators include inabenfide, oxyethylene docosanol, nicotinamide and benzylaminopurine.
- the content of the main ingredient in the tablet varies depending on the excipient selected, the component showing the hydrophobic effect and the type of the main ingredient, but is usually preferably 5 to 95% by mass, more preferably 10 to 80% by mass, 70% by mass is particularly preferred.
- the tablet of the present invention can be appropriately mixed with a binder, a lubricant, a fragrance, a disintegrant, a colorant, a sweetener, a corrigent, an antiseptic and the like as necessary.
- sustained release effect means that a drug is gradually released from a preparation. Since the tablet of the present invention has a hollow structure, it floats in water, and since it contains a component showing a hydrophobic effect, it does not disintegrate in water, floats and stays for a long time, and releases the main ingredient component in water. , Can exert a sustained release effect.
- the tablet of the present invention includes a component that exhibits a hydrophobic effect in the stomach, so that it does not disintegrate in the stomach and floats and stays for a long time to release the active ingredient component, thereby allowing sustained release.
- the effect can be demonstrated. Therefore, drugs whose action site is the stomach, drugs that are fast absorbed in the stomach and slow in the intestinal tract, drugs whose absorption window is limited to the upper small intestine, drugs that are unstable in the intestinal environment, etc. By applying to, it is possible to exert a sustained release effect that maintains its medicinal effect.
- the release mode can be appropriately selected depending on the nature of the drug. Specific examples of the release mode include a release mode in which the drug release rate after 1 hour is about 20% and the release rate after 5 hours is 90% or more.
- the release mode can be appropriately adjusted depending on the excipient, the component showing the hydrophobic effect, the kind and content of the main ingredient, the density of the tablet, and the like.
- the tablet of the present invention can be produced by a production method including at least the following steps (1) to (4).
- a step of producing a core portion containing a sublimable solid (2) A sugar alcohol, a sugar, a cellulose derivative, and a cellulose derivative outside the core portion so that the core portion obtained in step (1) is located in the central portion Forming an outer shell containing at least one excipient selected from starches, and preparing a dry-coated tablet (3) Included in the core part by heating the dry-coated tablet obtained in step (2) Step (4) to obtain a tablet having a hollow structure by removing the sublimable solid to be immersed in a component having a hydrophobic effect, which is obtained in Step (3)
- Process of producing core part containing sublimable solid Process (1) is a process of tableting a sublimable solid and producing a core part.
- the sublimable solid is pulverized with a pestle in a mortar, and this is compression-molded with a mortar and pestle of a desired size using a tableting machine to produce a core part.
- “sublimable solid” means a substance having a melting point of 25 ° C. or higher and exhibiting sublimability.
- Specific examples include terpenes such as menthol, thymol and camphor, and aromatic hydrocarbons having sublimation properties such as naphthalene.
- Terpenes such as menthol, timolol and camphor are preferred when preparing a gastric floating oral sustained release preparation.
- sublimable solids that can be used can be appropriately selected depending on the thermal stability of the components used for the excipient and the thermal stability of the main ingredient component, but menthol is preferred among these.
- menthol either l-menthol or dl-menthol can be used.
- the “core part” means a partial structure obtained by tableting a sublimable substance.
- the core portion containing the sublimable solid is removed by the heat treatment in step (3) after the outer shell is formed in step (2). Therefore, the shape of the core part itself becomes the hollow part of the tablet according to the present invention.
- the size and shape of the core portion can be appropriately selected according to the desired size and shape of the cavity. For example, if a disk-shaped core portion having a diameter of 6 mm and a thickness of 1 mm is produced, the finally obtained tablet cavity can be formed into a disk shape having a diameter of 6 mm and a thickness of 1 mm.
- a core part containing a sublimable substance When a core part containing a sublimable substance is produced, it may be produced by direct tableting, or may be granulated using dry granulation or wet granulation, etc. From the viewpoints of performance, operability and simplicity, the direct tableting method is preferred.
- a tableting machine When tablets are produced by the direct tableting method, as a tableting machine, a commonly used one such as a rotary tableting machine or a single-shot tableting machine can be used.
- the tableting pressure can be appropriately adjusted depending on the sublimable substance to be used, but is usually preferably 300 to 2000 kg, more preferably 100 to 1000 kg.
- Examples of the shape of the core portion containing the sublimable solid include various irregular shapes having a circular shape and a surface shape such as an elliptical shape, an oval shape, and a rectangular shape.
- step (2) At least one or more excipients selected from sugar alcohols, sugars, cellulose derivatives and starches are included outside the core portion so that the core portion obtained in the step (1) is located in the central portion.
- step (2) outer shell containing excipient is formed on the outer side of the core portion containing sublimable solid prepared in step (1), This is the process of making a lock.
- the “outer shell” usually means an outer layer of a tablet. In the tablet of the present invention, it means a solid portion located around the cavity.
- the outer shell may contain a main ingredient component.
- the outer shell is formed as follows. A part of the outer shell constituent material including the excipient is compressed with low compression. When the main ingredient is contained in the tablet of the present invention, the main ingredient is mixed with the outer shell constituent material.
- the low impact pressure is preferably 5 to 40 kg, more preferably 7 to 25 kg, and particularly preferably 10 to 15 kg. Further, a part of the outer shell constituting material when tableting at a low compression pressure is preferably 1/4 to 1/2 of the total amount of the outer shell constituting material, more preferably 1/3 of the total amount.
- a dry-coated tablet can be obtained by compression molding.
- the dry-coated tablet in this step can also be produced using a continuous dry tableting machine.
- the tableting pressure at the time of compression molding can be appropriately adjusted depending on the excipient used, but is preferably 300 to 2000 kg, more preferably 500 to 1500 kg.
- the shape of the outer shell for example, various irregular shapes having a circular shape and a surface shape such as an elliptical shape, an oval shape, and a rectangular shape can be cited.
- Step (3) Step of removing the sublimable solid contained in the core portion by heating the dry-coated tablet obtained in step (2) to obtain a tablet having a hollow structure
- Step (3) is step (2)
- the sublimable solid contained in the core portion located inside the outer shell of the dry-coated tablet obtained in the above step is removed by melting and sublimation by heating.
- the core part is removed by heat-treating the dry-coated tablet obtained in step (2), so that the sublimable solid contained in the core part flows out and sublimates through the inside of the outer shell.
- Examples of the heating method include a method in which the dry-coated tablet obtained in step (2) is left in a heated oven.
- the heating conditions can be appropriately selected depending on the thermal stability of the component used as the excipient, the thermal stability of the main ingredient component, and the properties of the sublimable solid, and are not particularly limited, but the heating temperature is usually 60 ° C. or higher. Is preferable, 70 ° C. or higher is more preferable, and 80 ° C. or higher is particularly preferable.
- the heating time is usually preferably 60 to 180 minutes, more preferably 80 to 120 minutes, and particularly preferably 90 to 100 minutes.
- the heating temperature is usually preferably 50 ° C or higher, more preferably 70 ° C or higher, and particularly preferably 80 ° C or higher.
- the heating time is usually preferably 60 to 180 minutes, more preferably 60 to 120 minutes, and particularly preferably 60 to 90 minutes.
- the tablet is heated at 80 ° C. for 1 hour. By doing so, a hollow tablet from which the core portion has been completely removed can be obtained.
- Step (4) is a step of heating the tablet having a hollow structure obtained in step (3) in advance. It is a step of immersing in a melted component exhibiting a hydrophobic effect.
- immersion time can be set suitably, a sufficient effect is shown in a short time. Specifically, it is usually preferably 30 seconds to 5 minutes, more preferably 1 to 3 minutes, and particularly preferably 1 minute.
- the tablet immersed in the component exhibiting the hydrophobic effect is taken out from the component exhibiting the hydrophobic effect that has been melted by heat and then cooled by being left below the melting point of the component that has been melted by heat.
- the cooling temperature can be appropriately selected, it is preferably left at room temperature from the viewpoint of ease of operation.
- stearyl alcohol when used as a “component that exhibits a hydrophobic effect in the stomach”, the tablet taken out from the hot melt of stearyl alcohol is allowed to stand at room temperature for about 10 seconds. The method of doing is mentioned.
- the production method in the present invention is very easy, and the sublimable solid can be completely removed in a very short time, and the tablet can have sufficient floating properties.
- the process of immersing the component showing the hydrophobic effect in the stomach is as short as about 1 minute, facilitating the production. It is also easy to produce tablets with different sustained-release effects by appropriately selecting ingredients that exhibit a hydrophobic effect in the stomach.
- Example 1 After l-menthol (Kanto Chemical Co., Ltd.) is crushed with a mortar, use a tableting machine (Hata Iron Works, HT-AP-18-SSII) to obtain a mass of 75 mg using a 6 mm diameter mortar and flat punch. The tablet of the core portion was obtained by tableting at a pressure of 500 kg.
- a tableting machine Haata Iron Works, HT-AP-18-SSII
- a powder was prepared by mixing 120 mg of mannitol (trade name: Mannit-P, Towa Kasei Kogyo Co., Ltd.) and 30 mg of famotidine as an outer shell component. Tableting was carried out with a pressure of 15 kg using a mortar having a diameter of 8.5 mm and a flat punch at Hatano Iron Works, HT-AP-18-SSII.
- the core part tablet prepared earlier is placed in the center part of the tablet in which the outer shell component is tableted, and the remaining outer shell ingredient 100 mg is filled over the core part tablet so as to cover the core part tablet.
- HT-AP-18-SSII was tableted using a mortar with a diameter of 8.5 mm and a flat punch at a pressure of 1000 kg to obtain a dry-coated tablet having a tablet weight of 225 mg.
- the obtained dry-coated tablets were heated in an oven at 80 ° C. for 90 minutes to melt and sublimate l-menthol to prepare a hollow preparation.
- the specific gravity of the obtained tablet by Formula 1 it was 0.740 ⁇ 0.002 g / cm 3 .
- the obtained hollow preparation is immersed in hardened castor oil (trade name Jardin Wax 101, Freund Sangyo) melted in a 90 ° C. water bath for 1 minute, then quickly removed, cooled and solidified at room temperature, and tableted. Got.
- hardened castor oil trade name Jardin Wax 101, Freund Sangyo
- Example 2 After l-menthol (Kanto Chemical Co., Ltd.) is crushed with a mortar, the weight is 75 mg using a 6 mm diameter mortar and flat punch with a tableting machine (Hatabe Iron Works, HT-AP-18-SSII). The tablet of the core portion was obtained by tableting at a pressure of 500 kg.
- a powder was prepared by mixing 120 mg of mannitol (trade name: Mannit-P, Towa Kasei Kogyo Co., Ltd.) and 30 mg of famotidine as an outer shell component. Tableting was carried out with a pressure of 15 kg using a mortar having a diameter of 8.5 mm and a flat punch at Hatano Iron Works, HT-AP-18-SSII.
- the obtained dry-coated tablets were heated in an oven at 80 ° C. for 90 minutes to melt and sublimate l-menthol to prepare a hollow preparation.
- the obtained hollow preparation was immersed in stearyl alcohol (trade name NAA-45, Japanese fats and oils) melted in a 90 ° C. water bath for 1 minute, and then immediately removed and allowed to cool and solidify at room temperature. Obtained.
- stearyl alcohol trade name NAA-45, Japanese fats and oils
- Example 3 After l-menthol (Kanto Chemical Co., Ltd.) is crushed with a mortar, the weight is 75 mg using a 6 mm diameter mortar and flat punch with a tableting machine (Hatabe Iron Works, HT-AP-18-SSII). The tablet of the core portion was obtained by tableting at a pressure of 500 kg.
- a powder was prepared by mixing 120 mg of mannitol (trade name: Mannit-P, Towa Kasei Kogyo Co., Ltd.) and 30 mg of famotidine as an outer shell component. Tableting was carried out with a pressure of 15 kg using a mortar having a diameter of 8.5 mm and a flat punch at Hatano Iron Works, HT-AP-18-SSII.
- the core part tablet prepared earlier is placed in the center part of the tableted outer shell component, and the remaining outer shell component 100 mg is filled from above to cover the core part tablet.
- HT-AP-18-SSII Tablet-Litera®
- tableting was performed at a pressure of 1000 kg using a 8.5 mm diameter mortar and a flat punch to obtain a dry-coated tablet having a tablet weight of 225 mg.
- the obtained dry-coated tablets were heated in an oven at 80 ° C. for 90 minutes to melt and sublimate l-menthol to prepare a hollow preparation.
- the obtained hollow preparation was immersed in stearic acid monoglyceride (trade name: MGS-AMV, Nippon Surfactant Kogyo) melted in a 90 ° C. water bath for 1 minute, then immediately removed, cooled and solidified at room temperature. Tablets were obtained.
- stearic acid monoglyceride trade name: MGS-AMV, Nippon Surfactant Kogyo
- Example 4 After l-menthol (Kanto Chemical Co., Ltd.) is crushed with a mortar, the weight is 75 mg using a 6 mm diameter mortar and flat punch with a tableting machine (Hatabe Iron Works, HT-AP-18-SSII). The tablet of the core portion was obtained by tableting at a pressure of 500 kg.
- a powder was prepared by mixing 120 mg of mannitol (trade name: Mannit-P, Towa Kasei Kogyo Co., Ltd.) and 30 mg of famotidine as an outer shell component. Tableting was carried out with a pressure of 15 kg using a mortar having a diameter of 8.5 mm and a flat punch at Hatano Iron Works, HT-AP-18-SSII.
- Example 5 After l-menthol (Kanto Chemical Co., Ltd.) is crushed with a mortar, the weight is 75 mg using a 6 mm diameter mortar and flat punch with a tableting machine (Hatabe Iron Works, HT-AP-18-SSII). The tablet of the core part was obtained by tableting at a pressure of 500 kg.
- a powder was prepared by mixing 120 mg of mannitol (trade name: Mannit-P, Towa Kasei Kogyo Co., Ltd.) and 30 mg of famotidine as an outer shell component. Tableting was carried out with a pressure of 15 kg using a mortar having a diameter of 8.5 mm and a flat punch at Hatano Iron Works, HT-AP-18-SSII.
- the core part tablet prepared earlier is placed in the center part of the tableted outer shell component, and the remaining outer shell component 100 mg is filled from above to cover the core part tablet.
- HT-AP-18-SSII Tablet-Litera®
- tableting was performed at a pressure of 1000 kg using a 8.5 mm diameter mortar and a flat punch to obtain a dry-coated tablet having a tablet weight of 225 mg.
- the obtained dry-coated tablets were heated in an oven at 80 ° C. for 90 minutes to melt and sublimate l-menthol to prepare a hollow preparation.
- the resulting hollow preparation was melted in a 90 ° C. water bath with a 1: 1 mixture of stearyl alcohol (trade name NAA-45, Nippon Oil & Fats) and hydrogenated castor oil (trade name Surrey Wax 101, Freund Industries). After being immersed for 1 minute, it was quickly taken out and cooled and solidified at room temperature to obtain a tablet. As a result of calculating the specific gravity of the obtained tablet by the formula 1, it was 0.857 ⁇ 0.004 g / cm 3 .
- Example 6 After l-menthol (Kanto Chemical Co., Ltd.) is crushed with a mortar, the weight is 75 mg using a 6 mm diameter mortar and flat punch with a tableting machine (Hatabe Iron Works, HT-AP-18-SSII). The tablet of the core portion was obtained by tableting at a pressure of 500 kg.
- a powder was prepared by mixing 60 mg of mannitol (trade name: Mannit-P, Towa Kasei Kogyo Co., Ltd.) passed through a 850 ⁇ m sieve as the outer shell component and 90 mg of famotidine. Tableting was carried out with a pressure of 15 kg using a mortar having a diameter of 8.5 mm and a flat punch at Hatano Iron Works, HT-AP-18-SSII.
- mannitol trade name: Mannit-P, Towa Kasei Kogyo Co., Ltd.
- the core part tablet prepared earlier is placed in the center part of the tableted outer shell component, and the remaining outer shell component 100 mg is filled from above to cover the core part tablet.
- HT-AP-18-SSII tableting was performed at a pressure of 800 kg using a 8.5 mm diameter mortar and a flat punch to obtain a dry tablet having a mass of 225 mg.
- Example 7 After l-menthol (Kanto Chemical Co., Ltd.) is crushed with a mortar, the weight is 75 mg using a 6 mm diameter mortar and flat punch with a tableting machine (Hatabe Iron Works, HT-AP-18-SSII). The tablet of the core portion was obtained by tableting at a pressure of 500 kg.
- a powder was prepared by mixing 30 mg of mannitol (trade name: Mannit-P, Towa Kasei Kogyo Co., Ltd.) and 120 mg of famotidine as an outer shell component. Tableting was carried out with a pressure of 15 kg using a mortar having a diameter of 8.5 mm and a flat punch at Hatano Iron Works, HT-AP-18-SSII.
- the core part tablet prepared earlier is placed in the center part of the tableted outer shell component, and the remaining outer shell component 100 mg is filled from above to cover the core part tablet.
- HT-AP-18-SSII tableting was performed at a pressure of 800 kg using a 8.5 mm diameter mortar and a flat punch to obtain a dry tablet having a mass of 225 mg.
- the resulting dry-coated tablet was heated in an oven at 80 ° C. for 90 minutes to melt and sublimate l-menthol to prepare a hollow preparation.
- the specific gravity of the obtained tablet by Formula 1 it was 0.856 ⁇ 0.007 g / cm 3.
- mannitol trade name: Mannit-P, Towa Kasei Kogyo Co., Ltd.
- a tableting machine Haata Iron Works, HT-AP-18-SSII
- mannitol trade name: Mannit-P, Towa Kasei Kogyo
- Tableting is performed with a tableting machine (Hata Iron Works, HT-AP-18-SSII) at a pressure of 600 kg using a mortar and flat plate with a diameter of 8.5 mm to obtain a dry tablet with a weight of 225 mg. It was. Thereafter, the dry-coated tablets were heated in an oven at 80 ° C. to melt and sublimate l-menthol.
- crystalline cellulose (trade name: Theolas PH-102, Asahi Kasei Chemicals) is used as the outer shell component with a diameter of 8.5 mm using a tableting machine (Hata Iron Works, HT-AP-18-SSII). Tableting was performed using a mortar and a flat punch at a pressure of 20 kg.
- lactose 200M, Fontera
- 50 mg of lactose 200M, Fontera
- a tableting machine Haataseko, HT-AP-18-SSII
- Tableting was performed at a pressure of 12 kg.
- hypromellose trade name: Metroise 90SH-4000SR, Shin-Etsu Chemical Co., Ltd.
- Tableting is performed with a tableting machine (Hata Iron Works, HT-AP-18-SSII) using a 8.5 mm diameter mortar and flat punch at a pressure of 900 kg to obtain a dry tablet with a weight of 225 mg. It was. Thereafter, the dry-coated tablets were heated in an oven at 80 ° C. to melt and sublimate l-menthol.
- an aminoalkyl methacrylate copolymer (trade name Eudragit RS PO, Degussa) as an outer shell component is 8.5 mm in diameter using a tableting machine (Hata Iron Works, HT-AP-18-SSII). Tableting was performed using a mortar and a flat punch at a pressure of 15 kg.
- a powder was prepared by mixing 120 mg of mannitol (trade name: Mannit-P, Towa Kasei Kogyo Co., Ltd.) and 30 mg of famotidine as an outer shell component. Tableting was carried out with a pressure of 15 kg using a mortar having a diameter of 8.5 mm and a flat punch at Hatano Iron Works, HT-AP-18-SSII.
- the core part tablet prepared earlier is placed in the center part of the tableted outer shell component, and the remaining outer shell component 100 mg is filled from above to cover the core part tablet.
- HT-AP-18-SSII HT-AP-18-SSII
- tableting was performed at a pressure of 1000 kg using a 8.5 mm diameter mortar and a flat punch to obtain a dry-coated tablet having a tablet weight of 225 mg. Thereafter, the dry-coated tablets were heated in an oven at 80 ° C. for 90 minutes to melt and sublimate l-menthol to prepare a hollow preparation.
- FIG. 1 shows the change in mass when the dry-coated tablets of Reference Examples 1 to 5 are heated in an oven at 80 ° C.
- mannitol Reference Example 1
- crystalline cellulose Reference Example 2
- lactose Reference Example 3
- a hollow preparation could be prepared.
- hypromellose Reference Example 4
- it took time to remove l-menthol it took time to remove l-menthol, and the hypromellose expanded slightly during sublimation, and the outer shell became brittle, which was not practical.
- the glass transition point of Eudragit RSPO is lower than 80 ° C. in the oven, so that the passage of l-menthol is blocked and almost l-menthol is formed. It was not removed and a hollow preparation could not be produced.
- Test Example 2 Dissolution test and buoyancy test Using 900 mL of 0.01 M hydrochloric acid as a test solution, a dissolution test was performed at 100 revolutions per minute by the paddle method. 1, 2, 3, 4, 5 and 6 hours after the start of the dissolution test, sampling was performed through a membrane filter having a pore size of 0.45 ⁇ m, and the dissolution rate was calculated by the liquid chromatography method under the following conditions. The buoyancy test was visually confirmed every 30 minutes after the start of the test.
- Table 1 shows the results of the floatability test. As shown in Table 1, Comparative Example 1 in which the fourth step and the fifth step were not performed floated immediately after the start of the test, but collapsed and sank in tens of seconds because mannitol was well dissolved in water. On the other hand, Examples 1 to 7 in which the fourth step and the fifth step were performed floated up to 6 hours after the start of the test. That is, the tablets of Examples 1 to 7 are expected to float and stay in the stomach for a long time. The tablet from which the core part was not removed did not float at all.
- the results of the dissolution test are shown in Table 2.
- the dissolution rate was calculated by “amount of main ingredient components released from tablets at each elution time” ⁇ “content of main ingredient components in one tablet” ⁇ 100. Since famotidine, which is the main ingredient used in this study, decomposes under acidic conditions, the "amount of main ingredient released from the tablet at each dissolution time" in the above formula is the amount of famotidine and its degradation product. The total was calculated.
- a highly versatile tablet capable of sustained release of a drug can be obtained by floating and staying in water by a simple production method, which is useful.
- the tablet of the present invention is a gastric retention preparation, a water purification agent, a floating pesticide preparation, a floating chlorine agent for pools, a floating detergent for pools, a floating dealgae for pools, floating It can be applied to a slow-dissolving bath, a floating feeding agent for ornamental fish, a floating fishing bait, and the like.
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Abstract
Description
1.中心部分に空洞部を有する中空構造を有し、糖アルコール、糖、セルロース誘導体およびスターチ類から選ばれる少なくとも1の賦形剤並びに疎水効果を示す成分を含む、水に浮遊可能である錠剤。
2.以下の(1)~(4)の工程を少なくとも含む製造方法により得られる水に浮遊可能である錠剤。
(1)昇華性固体を含むコア部分を作製する工程
(2)工程(1)で得られたコア部分が中心部分に位置するように、該コア部分の外側に糖アルコール、糖、セルロース誘導体およびスターチ類から選ばれる少なくとも1以上の賦形剤を含む外殻を形成し、有核錠を作製する工程
(3)工程(2)で得られた有核錠を加熱することによりコア部分に含まれる昇華性固体を除去して、中空構造を有する錠剤を得る工程
(4)工程(3)で得られた中空構造を有する錠剤を、疎水効果を示す成分に浸漬させる工程
3.疎水効果を示す成分が、胃内で疎水効果を示す成分である、前項1または2に記載の錠剤。
4.密度が1g/cm3以下である前項1~3のいずれか1項に記載の錠剤。
5.空洞部以外の部分に主薬成分を含有する前項1~4のいずれか1項に記載の錠剤。
6.徐放性効果を有する前項1~5のいずれか1項に記載の錠剤。
7.賦形剤が、マンニトール、結晶セルロースおよび乳糖並びにそれらの混合物から選ばれる少なくとも1である前項1~6のいずれか1項に記載の錠剤。
8.疎水効果を示す成分が、高級アルコールおよび高級脂肪酸グリセリンエステルの少なくとも1である前項1~7のいずれか1項に記載の錠剤。
9.疎水効果を示す成分が、ステアリルアルコール、セチルアルコール、硬化ヒマシ油およびステアリン酸モノグリセライドから選ばれる少なくとも1である前項1~8のいずれか1項に記載の錠剤。
10.以下の工程を少なくとも含む中空構造を有する水に浮遊可能である錠剤の製造方法。
(1)昇華性固体を含むコア部分を作製する工程
(2)工程(1)で得られたコア部分が中心部分に位置するように、該コア部分の外側に糖アルコール、糖、セルロース誘導体およびスターチ類から選ばれる少なくとも1以上の賦形剤を含む外殻を形成し、有核錠を作製する工程
(3)工程(2)で得られた有核錠を加熱することによりコア部分に含まれる昇華性固体を除去して、中空構造を有する錠剤を得る工程
(4)工程(3)で得られた中空構造を有する錠剤を、疎水効果を示す成分に浸漬させる工程
11.疎水効果を示す成分が、胃内で疎水効果を示す成分である、前項10に記載の製造方法。
12.昇華性固体がテルペン類および昇華性を有する芳香族炭化水素の少なくとも1である前項10または11に記載の製造方法。
13.テルペン類が、メントール、チモールおよびカンファーから選ばれる少なくとも1である前項12に記載の製造方法。
14.工程(2)における外殻部に主薬成分を含有させる前項10~13のいずれか1項に記載の製造方法。
15.賦形剤が、マンニトール、結晶セルロースおよび乳糖並びにそれらの混合物から選ばれる少なくとも1である前項10~14のいずれか1項に記載の製造方法。
16.疎水効果を示す成分が、高級アルコールおよび高級脂肪酸グリセリンエステルの少なくとも1である前項10~15のいずれか1項に記載の製造方法。
17.疎水効果を示す成分が、ステアリルアルコール、セチルアルコール、硬化ヒマシ油およびステアリン酸モノグリセライドから選ばれる少なくとも1である前項10~16のいずれか1項に記載の製造方法。
18.前項1~9のいずれか1項に記載の錠剤を用いることによる、錠剤の胃内滞留方法。
19.前項1~9のいずれか1項に記載の錠剤を用いることによる、胃内での持続的な薬物放出方法。
B/{(L÷2)2×π×D} (式1)
(0.85÷2)2×π×0.36=0.20428cm3
となる。
0.250g÷0.20428cm3≒1.22g/cm3
となり、1g/cm3より大きいため水に浮遊しない。
(1)昇華性固体を含むコア部分を作製する工程
(2)工程(1)で得られたコア部分が中心部分に位置するように、該コア部分の外側に糖アルコール、糖、セルロース誘導体およびスターチ類から選ばれる少なくとも1以上の賦形剤を含む外殻を形成し、有核錠を作製する工程
(3)工程(2)で得られた有核錠を加熱することによりコア部分に含まれる昇華性固体を除去して、中空構造を有する錠剤を得る工程
(4)工程(3)で得られた中空構造を有する錠剤を、疎水効果を示す成分に浸漬させる工程
工程(1)は、昇華性固体を打錠してコア部分を作製する工程である。昇華性固体を乳鉢中で乳棒を用いて粉砕し、これを打錠機にて目的とする大きさの臼と杵を用いて圧縮成型し、コア部分を作製する。
工程(2)は、工程(1)で作製した昇華性固体を含むコア部分の外側に、賦形剤を含む外殻を形成し、有核錠とする工程である。本明細書において「外殻」とは、通常、錠剤の外層を意味する。本発明の錠剤においては、空洞部の周囲に位置する固体部分を意味する。なお、外殻は主薬成分を含有してもよい。
工程(3)は、工程(2)で得られた有核錠の外殻の内側に位置するコア部分に含まれる昇華性固体を、加熱することにより溶融・昇華させて除去する工程である。工程(2)で得られた有核錠を加熱処理することで、コア部分に含有される昇華性固体が外殻の内部を通って外部に流出・昇華することでコア部が除去される。
工程(4)は、工程(3)で得られた中空構造を有する錠剤を、あらかじめ加熱溶融させた疎水効果を示す成分に浸漬させる工程である。また、浸漬時間は適宜設定できるが、短時間で十分な効果を示す。具体的には、通常30秒間~5分間が好ましく、1~3分間がより好ましく、1分が特に好ましい。本工程を経ることにより、薬物放出速度が劇的に変化し、即溶性の薬物放出の徐放化が可能となる。
以下に実施例及び比較例を挙げて本発明を詳細に説明するが、本発明がこれらに限定されるわけではない。
l-メントール(関東化学,特級)を乳鉢ですりつぶした後、打錠機(畑鉄工所、HT-AP-18-SSII)にて直径6mmの臼及び平面杵を用いて質量75mgとなるように、圧力500kgで打錠することでコア部分の錠剤を得た。
l-メントール(関東化学、特級)を乳鉢ですりつぶした後、打錠機(畑鉄工所、HT-AP-18-SSII)にて直径6mmの臼及び平面杵を用いて質量75mgとなるように、圧力500kgで打錠することでコア部分の錠剤を得た。
l-メントール(関東化学、特級)を乳鉢ですりつぶした後、打錠機(畑鉄工所、HT-AP-18-SSII)にて直径6mmの臼及び平面杵を用いて質量75mgとなるように、圧力500kgで打錠することでコア部分の錠剤を得た。
l-メントール(関東化学、特級)を乳鉢ですりつぶした後、打錠機(畑鉄工所、HT-AP-18-SSII)にて直径6mmの臼及び平面杵を用いて質量75mgとなるように、圧力500kgで打錠することでコア部分の錠剤を得た。
l-メントール(関東化学、特級)を乳鉢ですりつぶした後、打錠機(畑鉄工所、HT-AP-18-SSII)にて直径6mmの臼及び平面杵を用いて質量75mgとなるように、圧力500kgで打錠することでコア部の錠剤を得た。
l-メントール(関東化学、特級)を乳鉢ですりつぶした後、打錠機(畑鉄工所、HT-AP-18-SSII)にて直径6mmの臼及び平面杵を用いて質量75mgとなるように、圧力500kgで打錠することでコア部分の錠剤を得た。
l-メントール(関東化学、特級)を乳鉢ですりつぶした後、打錠機(畑鉄工所、HT-AP-18-SSII)にて直径6mmの臼及び平面杵を用いて質量75mgとなるように、圧力500kgで打錠することでコア部分の錠剤を得た。
l-メントール(関東化学、特級)を乳鉢ですりつぶした後、打錠機(畑鉄工所、HT-AP-18-SSII)にて直径6mmの臼及び平面杵を用いて質量75mgとなるように、圧力500kgで打錠することでコア部分の錠剤を得た。
l-メントール(関東化学、特級)を乳鉢ですりつぶした後、打錠機(畑鉄工所、HT-AP-18-SSII)にて直径6mmの臼及び平面杵を用いて質量75mgとなるように、圧力500kgで打錠することでコア部分の錠剤を得た。
l-メントール(関東化学、特級)を乳鉢ですりつぶした後、打錠機(畑鉄工所、HT-AP-18-SSII)にて直径6mmの臼及び平面杵を用いて質量75mgとなるように、圧力500kgで打錠することでコア部分の錠剤を得た。
l-メントール(関東化学、特級)を乳鉢ですりつぶした後、打錠機(畑鉄工所、HT-AP-18-SSII)にて直径6mmの臼及び平面杵を用いて質量75mgとなるように、圧力500kgで打錠することでコア部分の錠剤を得た。これとは別に、外殻成分としてヒプロメロース(商品名 メトローズ90SH-4000SR、信越化学工業)50mgを打錠機(畑鉄工所、HT-AP-18-SSII)にて直径8.5mmの臼及び平面杵を用いて、圧力25kgで打錠した。
l-メントール(関東化学、特級)を乳鉢ですりつぶした後、打錠機(畑鉄工所、HT-AP-18-SSII)にて直径6mmの臼及び平面杵を用いて質量75mgとなるように、圧力500kgで打錠することでコア部分の錠剤を得た。
l-メントール(関東化学、特級)を乳鉢ですりつぶした後、打錠機(畑鉄工所、HT-AP-18-SSII)にて直径6mmの臼及び平面杵を用いて質量75mgとなるように、圧力500kgで打錠することでコア部分の錠剤を得た。
図1は、参考例1~5の有核錠を80℃のオーブン中で加熱したときの質量変化を示したものである。外殻にマンニトール(参考例1)、結晶セルロース(参考例2)、乳糖(参考例3)を用いたものはl-メントールが容易に除去され、中空製剤が作製できた。外殻にヒプロメロース(参考例4)を用いたものは、l-メントールの除去に時間がかかり、且つ、昇華する際にヒプロメロースが若干膨張し、外殻がもろくなり実用的ではなかった。
試験液に0.01M塩酸900mLを用い、パドル法により毎分100回転で溶出試験を行った。溶出試験開始後1、2、3、4、5及び6時間後に孔径0.45μmのメンブランフィルターを通してサンプリングを行い、以下の条件で液体クロマトグラフ法にて溶出率を算出した。浮遊性試験は試験開始後30分おきに目視にて確認した。
カラム:Inertsil ODS-3、内径4.6mm、長さ250mm、粒径5μm、ジーエルサイエンス製
移動相:20mMリン酸二水素ナトリウム水溶液/液体クロマトグラフィー用メタノール混液(4:1)
検出器:紫外可視吸光光度計(測定波長:254nm)
Claims (19)
- 中心部分に空洞部を有する中空構造を有し、糖アルコール、糖、セルロース誘導体およびスターチ類から選ばれる少なくとも1の賦形剤並びに疎水効果を示す成分を含む、水に浮遊可能である錠剤。
- 以下の(1)~(4)の工程を少なくとも含む製造方法により得られる水に浮遊可能である錠剤。
(1)昇華性固体を含むコア部分を作製する工程
(2)工程(1)で得られたコア部分が中心部分に位置するように、該コア部分の外側に糖アルコール、糖、セルロース誘導体およびスターチ類から選ばれる少なくとも1以上の賦形剤を含む外殻を形成し、有核錠を作製する工程
(3)工程(2)で得られた有核錠を加熱することによりコア部分に含まれる昇華性固体を除去して、中空構造を有する錠剤を得る工程
(4)工程(3)で得られた中空構造を有する錠剤を、疎水効果を示す成分に浸漬させる工程 - 疎水効果を示す成分が、胃内で疎水効果を示す成分である、請求項1または2に記載の錠剤。
- 密度が1g/cm3以下である請求項1~3のいずれか1項に記載の錠剤。
- 空洞部以外の部分に主薬成分を含有する請求項1~4のいずれか1項に記載の錠剤。
- 徐放性効果を有する請求項1~5のいずれか1項に記載の錠剤。
- 賦形剤が、マンニトール、結晶セルロースおよび乳糖並びにそれらの混合物から選ばれる少なくとも1である請求項1~6のいずれか1項に記載の錠剤。
- 疎水効果を示す成分が、高級アルコールおよび高級脂肪酸グリセリンエステルの少なくとも1である請求項1~7のいずれか1項に記載の錠剤。
- 疎水効果を示す成分が、ステアリルアルコール、セチルアルコール、硬化ヒマシ油およびステアリン酸モノグリセライドから選ばれる少なくとも1である請求項1~8のいずれか1項に記載の錠剤。
- 以下の工程を少なくとも含む中空構造を有する水に浮遊可能である錠剤の製造方法。
(1)昇華性固体を含むコア部分を作製する工程
(2)工程(1)で得られたコア部分が中心部分に位置するように、該コア部分の外側に糖アルコール、糖、セルロース誘導体およびスターチ類から選ばれる少なくとも1以上の賦形剤を含む外殻を形成し、有核錠を作製する工程
(3)工程(2)で得られた有核錠を加熱することによりコア部分に含まれる昇華性固体を除去して、中空構造を有する錠剤を得る工程
(4)工程(3)で得られた中空構造を有する錠剤を、疎水効果を示す成分に浸漬させる工程 - 疎水効果を示す成分が、胃内で疎水効果を示す成分である、請求項10に記載の製造方法。
- 昇華性固体がテルペン類および昇華性を有する芳香族炭化水素の少なくとも1である請求項10または11に記載の製造方法。
- テルペン類が、メントール、チモールおよびカンファーから選ばれる少なくとも1である請求項12に記載の製造方法。
- 工程(2)における外殻部に主薬成分を含有させる請求項10~13のいずれか1項に記載の製造方法。
- 賦形剤が、マンニトール、結晶セルロースおよび乳糖並びにそれらの混合物から選ばれる少なくとも1である請求項10~14のいずれか1項に記載の製造方法。
- 疎水効果を示す成分が、高級アルコールおよび高級脂肪酸グリセリンエステルの少なくとも1である請求項10~15のいずれか1項に記載の製造方法。
- 疎水効果を示す成分が、ステアリルアルコール、セチルアルコール、硬化ヒマシ油およびステアリン酸モノグリセライドから選ばれる少なくとも1である請求項10~16のいずれか1項に記載の製造方法。
- 請求項1~9のいずれか1項に記載の錠剤を用いることによる、錠剤の胃内滞留方法。
- 請求項1~9のいずれか1項に記載の錠剤を用いることによる、胃内での持続的な薬物放出方法。
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JP2011521914A JP5594484B2 (ja) | 2009-07-06 | 2010-07-05 | 中空構造を有する錠剤 |
EP10797110.3A EP2457561A4 (en) | 2009-07-06 | 2010-07-05 | TABLET HAVING A HOLLOW STRUCTURE |
CA2767143A CA2767143A1 (en) | 2009-07-06 | 2010-07-05 | Tablet having hollow structure |
US13/382,666 US20120100212A1 (en) | 2009-07-06 | 2010-07-05 | Tablet having hollow structure |
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EP (1) | EP2457561A4 (ja) |
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WO2022195476A1 (en) | 2021-03-15 | 2022-09-22 | Clexio Biosciences Ltd. | Gastroretentive devices for assessment of intragastric conditions |
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Title |
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EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, vol. 57, 2004, pages 235 - 243 |
See also references of EP2457561A4 |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2020230089A1 (en) | 2019-05-14 | 2020-11-19 | Clexio Biosciences Ltd. | Treatment of nocturnal symptoms and morning akinesia in subjects with parkinson's disease |
US11389398B2 (en) | 2019-05-14 | 2022-07-19 | Clexio Biosciences Ltd. | Gastroretentive treatment of nocturnal symptoms and morning akinesia in subjects with parkinson's disease |
WO2022195476A1 (en) | 2021-03-15 | 2022-09-22 | Clexio Biosciences Ltd. | Gastroretentive devices for assessment of intragastric conditions |
Also Published As
Publication number | Publication date |
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JP5594484B2 (ja) | 2014-09-24 |
EP2457561A1 (en) | 2012-05-30 |
CA2767143A1 (en) | 2011-01-13 |
JPWO2011004799A1 (ja) | 2012-12-20 |
EP2457561A4 (en) | 2014-03-05 |
US20120100212A1 (en) | 2012-04-26 |
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