JP2016020331A - Solid formulations - Google Patents
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- JP2016020331A JP2016020331A JP2015108405A JP2015108405A JP2016020331A JP 2016020331 A JP2016020331 A JP 2016020331A JP 2015108405 A JP2015108405 A JP 2015108405A JP 2015108405 A JP2015108405 A JP 2015108405A JP 2016020331 A JP2016020331 A JP 2016020331A
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- Prior art keywords
- sugar
- dimemorphan
- mass
- sucralose
- salt
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- 239000007787 solid Substances 0.000 title claims abstract description 29
- 239000000203 mixture Substances 0.000 title claims abstract description 13
- 238000009472 formulation Methods 0.000 title claims abstract description 12
- KBEZZLAAKIIPFK-NJAFHUGGSA-N dimemorfan Chemical compound C1C2=CC=C(C)C=C2[C@@]23CCN(C)[C@@H]1[C@H]2CCCC3 KBEZZLAAKIIPFK-NJAFHUGGSA-N 0.000 claims abstract description 32
- 229960001056 dimemorfan Drugs 0.000 claims abstract description 32
- 239000004376 Sucralose Substances 0.000 claims abstract description 19
- 235000019408 sucralose Nutrition 0.000 claims abstract description 19
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 15
- 239000008101 lactose Substances 0.000 claims abstract description 15
- 150000005846 sugar alcohols Chemical class 0.000 claims abstract description 12
- 150000001720 carbohydrates Chemical class 0.000 claims abstract description 10
- 229930091371 Fructose Natural products 0.000 claims abstract description 9
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000004386 Erythritol Substances 0.000 claims abstract description 7
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 claims abstract description 7
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims abstract description 7
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims abstract description 7
- 235000019414 erythritol Nutrition 0.000 claims abstract description 7
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 claims abstract description 7
- 229940009714 erythritol Drugs 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims description 27
- 239000008187 granular material Substances 0.000 claims description 9
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 8
- 239000005715 Fructose Substances 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 4
- 239000006187 pill Substances 0.000 claims description 3
- 235000019658 bitter taste Nutrition 0.000 abstract description 17
- 235000003599 food sweetener Nutrition 0.000 abstract description 6
- 239000003765 sweetening agent Substances 0.000 abstract description 6
- 235000019640 taste Nutrition 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 229960002737 fructose Drugs 0.000 abstract 1
- BJHIKXHVCXFQLS-UYFOZJQFSA-N keto-D-fructose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-UYFOZJQFSA-N 0.000 abstract 1
- 235000019605 sweet taste sensations Nutrition 0.000 abstract 1
- 229940074410 trehalose Drugs 0.000 abstract 1
- 238000011156 evaluation Methods 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 10
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 8
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 8
- 239000000796 flavoring agent Substances 0.000 description 8
- 235000019634 flavors Nutrition 0.000 description 8
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 8
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 8
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 5
- 229910019142 PO4 Inorganic materials 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 5
- 239000010452 phosphate Substances 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 4
- 229960002335 bromhexine hydrochloride Drugs 0.000 description 4
- 239000008120 corn starch Substances 0.000 description 4
- YRSGDLIATOURQO-UHFFFAOYSA-N ethyl 4-acetyl-5-oxohexanoate Chemical compound CCOC(=O)CCC(C(C)=O)C(C)=O YRSGDLIATOURQO-UHFFFAOYSA-N 0.000 description 4
- 239000003205 fragrance Substances 0.000 description 4
- 229960005489 paracetamol Drugs 0.000 description 4
- 229940085605 saccharin sodium Drugs 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 3
- 108010011485 Aspartame Proteins 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 241000544066 Stevia Species 0.000 description 3
- 235000010358 acesulfame potassium Nutrition 0.000 description 3
- 229960004998 acesulfame potassium Drugs 0.000 description 3
- 239000000619 acesulfame-K Substances 0.000 description 3
- 239000000605 aspartame Substances 0.000 description 3
- 235000010357 aspartame Nutrition 0.000 description 3
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 3
- 229960003438 aspartame Drugs 0.000 description 3
- 229940099112 cornstarch Drugs 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 229960001375 lactose Drugs 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000000954 anitussive effect Effects 0.000 description 2
- 229940124584 antitussives Drugs 0.000 description 2
- 229940124579 cold medicine Drugs 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 2
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- PVXPPJIGRGXGCY-DJHAAKORSA-N 6-O-alpha-D-glucopyranosyl-alpha-D-fructofuranose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@](O)(CO)O1 PVXPPJIGRGXGCY-DJHAAKORSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 206010049590 Upper respiratory tract inflammation Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000009477 fluid bed granulation Methods 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- INAXVFBXDYWQFN-XHSDSOJGSA-N morphinan Chemical group C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 239000004081 narcotic agent Substances 0.000 description 1
- 239000000820 nonprescription drug Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 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
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、ジメモルファン及び／又はその塩を含有する固形製剤に関するものである。 The present invention relates to a solid preparation containing dimemorphan and / or a salt thereof.
ジメモルファンは、モルヒナン骨格を有する鎮咳剤で、強力な鎮咳作用を有している。中枢性の依存性がない非麻薬性薬剤であり、上気道炎、急性気管支炎、肺炎に対して用いられており、一般用医薬品の咳止めシロップ剤としても使用されている。 Dimemorphan is an antitussive agent having a morphinan skeleton and has a strong antitussive effect. It is a non-narcotic drug with no central dependence, and is used for upper respiratory tract inflammation, acute bronchitis, and pneumonia. It is also used as a cough syrup for over-the-counter medicines.
しかし、ジメモルファンは味が苦く、顆粒剤等の固形製剤とした際に、風味の面から服用性が悪くなる。これまでも苦味等を呈する薬物を含有するために、味を改善する方法が開発されてきた。例えば、甘味剤や香料を添加するマスキング技術等が報告されている（特許文献１）。また、ジメモルファンを含有する内服用液剤の苦味を改善する技術が報告されている（特許文献２）。 However, dimemorphan has a poor taste, and when it is made into a solid preparation such as a granule, the ingestion is worse from the aspect of flavor. In the past, methods for improving taste have been developed in order to contain drugs that exhibit bitterness and the like. For example, a masking technique for adding a sweetener or a fragrance has been reported (Patent Document 1). Moreover, the technique which improves the bitterness of the liquid for internal use containing a dimemorphan has been reported (patent document 2).
しかし、固形製剤におけるジメモルファンの苦味改善に関する技術は知られていない。 However, a technique for improving the bitterness of dimemorphan in a solid preparation is not known.
本発明は、ジメモルファン由来の不快な味がマスキングされ、服用性が良好な固形製剤を提供することを課題とする。 An object of the present invention is to provide a solid preparation that is masked of unpleasant tastes derived from dimethylmorphane and has good dosing properties.
本発明者らは前記課題を検討した結果、ジメモルファンに、特定の糖類又は糖アルコールと、特定の甘味剤を組み合わせることによって、ジメモルファンの苦味が顕著に抑制され、しかも甘味剤の甘味の後引きがなく、服用性に優れた経口固形製剤が得られることを知見し、本発明を完成した。 As a result of studying the above problems, the present inventors have significantly reduced the bitter taste of dimemorphan by combining a specific sugar or sugar alcohol with a specific sweetener in addition to dimemorphan, and the sweetness of the sweetener is postponed. The present invention has been completed by discovering that an oral solid preparation excellent in dosing can be obtained.
すなわち、本発明は、
（１）（ａ）ジメモルファン及び／又はその塩、（ｂ）乳糖、粉糖、砂糖、果糖、トレハロース、及びエリスリトールからなる群から選ばれる少なくとも１種の糖類又は糖アルコール、及び（ｃ）スクラロースを含有する固形製剤、
（２）（ｂ）乳糖、粉糖、砂糖、果糖、トレハロース、及びエリスリトールからなる群から選ばれる少なくとも１種の糖類又は糖アルコールの含有量が、（ａ）ジメモルファン及び／又はその塩１質量部に対して１５質量部〜１５０質量部である、（１）に記載の固形製剤、
（３）（ｃ）スクラロースの含有量が、（ａ）ジメモルファン及び／又はその塩１質量部に対して、０．５質量部以上である、（１）又は（２）に記載の固形製剤、
（４）固形製剤が、顆粒剤、散剤、丸剤又は錠剤である（１）〜（３）のいずれか記載の固形製剤、
である。
That is, the present invention
(1) (a) dimemorphan and / or a salt thereof, (b) at least one saccharide or sugar alcohol selected from the group consisting of lactose, powdered sugar, sugar, fructose, trehalose, and erythritol, and (c) sucralose. Containing solid formulations,
(2) (b) The content of at least one sugar or sugar alcohol selected from the group consisting of lactose, powdered sugar, sugar, fructose, trehalose, and erythritol is (a) 1 part by mass of dimemorphan and / or a salt thereof. The solid preparation according to (1), which is 15 to 150 parts by mass with respect to
(3) The solid preparation according to (1) or (2), wherein the content of (c) sucralose is 0.5 parts by mass or more with respect to 1 part by mass of (a) dimemorphan and / or a salt thereof,
(4) The solid preparation according to any one of (1) to (3), wherein the solid preparation is a granule, powder, pill or tablet,
It is.
本発明により、ジメモルファン及び／又はその塩の苦味が低減され、服用しやすいジメモルファン及び／又はその塩を含有する固形製剤を提供することが可能となった。 ADVANTAGE OF THE INVENTION According to this invention, the bitterness of dimemorphan and / or its salt was reduced, and it became possible to provide the solid formulation containing dimemorphan and / or its salt which is easy to take.
本発明のジメモルファンの塩としては、塩酸塩、硫酸塩、硝酸塩、リン酸塩、マレイン酸塩、フマル酸塩など内服固形剤として許容可能な塩が挙げられるが、最も好ましいのはジメモルファンリン酸塩である。 Examples of the salt of dimemorphan of the present invention include salts acceptable as an internal solid preparation such as hydrochloride, sulfate, nitrate, phosphate, maleate, and fumarate, and most preferred is dimemorphanline. Acid salt.
本発明における特定の糖類又は糖アルコールとは、乳糖、粉糖、砂糖、果糖、トレハロース、又はエリスリトールである。このうち特に好ましいのは、乳糖、果糖、粉糖である。本発明の特定の糖類又は糖アルコールの含有量は、発明の効果の点から、ジメモルファン及び／又はその塩１質量部に対して１５質量部以上が好ましく、より好ましくは３５質量部以上である。また、上限は１５０質量部までが好ましい。１５０質量部を超えると、固形製剤中のジメモルファン及び／又はその塩の含有量が低下して、十分な薬効が得られないばかりか、ジメモルファン及び／又はその塩の苦味を低減するための糖類又は糖アルコールの量が多くなり、固形製剤の服用全量が多くなり、錠剤が大型化し、服用コンプライアンスも低下するからである。 The specific saccharide or sugar alcohol in the present invention is lactose, powdered sugar, sugar, fructose, trehalose, or erythritol. Of these, lactose, fructose and powdered sugar are particularly preferred. The content of the specific saccharide or sugar alcohol of the present invention is preferably 15 parts by mass or more, more preferably 35 parts by mass or more with respect to 1 part by mass of dimemorphan and / or a salt thereof from the viewpoint of the effect of the invention. The upper limit is preferably up to 150 parts by mass. If it exceeds 150 parts by mass, the content of dimemorphan and / or a salt thereof in the solid preparation is reduced, and not only a sufficient medicinal effect is not obtained, but also a saccharide for reducing the bitter taste of dimemorphan and / or a salt thereof or This is because the amount of sugar alcohol is increased, the total dose of the solid preparation is increased, the size of the tablet is increased, and the compliance is decreased.
本発明における特定の甘味料とは、スクラロースである。本発明のスクラロースの含有量は、発明の効果の点から、ジメモルファン及び／又はその塩１質量部に対して０．５質量部以上であることが好ましく、より好ましくは１質量部以上、さらに好ましくは１．５質量部以上である。 The specific sweetener in the present invention is sucralose. The content of sucralose of the present invention is preferably 0.5 parts by mass or more, more preferably 1 part by mass or more, further preferably 1 part by mass with respect to 1 part by mass of dimemorphan and / or a salt thereof from the viewpoint of the effect of the invention. Is 1.5 parts by mass or more.
本発明の固形製剤の製造は、常法により製造することができ、その方法は特に限定されるものではない。例えば、ジメモルファン及び／又はその塩に、本発明の特定の糖類又は糖アルコール、及びスクラロースを混合し、必要に応じて他の公知の添加剤、例えば、賦形剤、崩壊剤、結合剤、滑沢剤、抗酸化剤、着色剤、矯味剤、界面活性剤、可塑剤等を混合して常法により、各種固形製剤に調製することができる。各種固形製剤としては、顆粒剤、散剤、丸剤、錠剤等を挙げることができる。 The solid preparation of the present invention can be produced by a conventional method, and the method is not particularly limited. For example, the specific sugar or sugar alcohol of the present invention and sucralose are mixed with dimemorphan and / or a salt thereof, and other known additives such as excipients, disintegrants, binders, lubricants are mixed as necessary. A variety of solid preparations can be prepared by a conventional method by mixing a bulking agent, an antioxidant, a coloring agent, a corrigent, a surfactant, a plasticizer and the like. Examples of various solid preparations include granules, powders, pills, tablets and the like.
以下に、本発明を実施例及び比較例に基づき、さらに詳細に説明する。尚、本発明の固形製剤の製造方法は実施例に記載された処方例に限定されるものではない。 Below, this invention is demonstrated in detail based on an Example and a comparative example. In addition, the manufacturing method of the solid formulation of this invention is not limited to the formulation example described in the Example.
（実施例１及び比較例１〜４）
（１）製造方法
ジメモルファンリン酸塩、アセトアミノフェン、ブロムヘキシン塩酸塩、乳糖、トウモロコシデンプン、軽質無水ケイ酸、黄色三二酸化鉄を以下表１に示す成分量秤量し、さらにヒドロキシプロピルセルロースを９０ｍｇ秤量し、混合した。これにヒドロキシプロピルセルロース６５ｍｇを精製水に溶解した結合液を用いて流動層造粒した後、スクラロース、アスパルテーム、アセスルファムカリウム、ステビア、サッカリンナトリウムを表１に示す成分量添加して、顆粒剤を得た。
(Example 1 and Comparative Examples 1 to 4)
(1) Manufacturing method Dimemorphan phosphate, acetaminophen, bromhexine hydrochloride, lactose, corn starch, light anhydrous silicic acid, yellow iron sesquioxide are weighed as shown in Table 1 below, and hydroxypropylcellulose is further added. 90 mg was weighed and mixed. After fluid bed granulation using a binding solution in which 65 mg of hydroxypropylcellulose was dissolved in purified water, sucralose, aspartame, acesulfame potassium, stevia, and saccharin sodium were added in the amounts shown in Table 1 to obtain granules. .
ここで、スクラロースの甘味度は、アスパルテーム、アセスルファムカリウムおよびステビアの３倍の甘味度を有するため、固形製剤中のこれら配合量はスクラロースの３倍量とした（比較例１〜３）。また、サッカリンナトリウムに比べてスクラロースは１．２倍の甘味度を有するため、サッカリンナトリウムを３６ｍｇ配合し、比較例４とした。 Here, since the sweetness of sucralose has a sweetness three times that of aspartame, acesulfame potassium and stevia, these blending amounts in the solid preparation were three times that of sucralose (Comparative Examples 1 to 3). Since sucralose has a sweetness 1.2 times higher than that of saccharin sodium, 36 mg of saccharin sodium was blended to obtain Comparative Example 4.
（２）風味評価
得られた製剤について、表２の評価基準に従って、専門パネラー３名による風味評価を実施し、その結果を表３に示した。
(2) Flavor Evaluation According to the evaluation criteria shown in Table 2, the obtained formulations were evaluated by three professional panelists, and the results are shown in Table 3.
試験結果から明らかなように、アスパルテーム、アセスルファムカリウム、ステビア、サッカリンナトリウムを配合した製剤は、ジメモルファン由来の苦味を抑制することができなかった（比較例１〜４）。一方、スクラロースを用いた実施例１の製剤は、他の甘味剤と比較して、特に優れた苦味抑制効果が認められた（実施例１）。 As is clear from the test results, the preparations containing aspartame, acesulfame potassium, stevia, and saccharin sodium could not suppress the bitter taste derived from dimemorphan (Comparative Examples 1 to 4). On the other hand, the preparation of Example 1 using sucralose was found to have a particularly excellent bitterness suppressing effect as compared to other sweeteners (Example 1).
（実施例２〜６）
（１）製造方法
以下表４に占める各成分を秤量し、各成分を均一分散するように攪拌混合することによって散剤を得た。
(Examples 2 to 6)
(1) Manufacturing method Each component which occupies Table 4 below was weighed, and the powder was obtained by stirring and mixing so that each component might be uniformly disperse | distributed.
（２）風味評価
得られた製剤について、表２の評価基準に従って、専門パネラー３名による風味評価を実施し、その結果を表７に示した。
(2) Flavor Evaluation The obtained preparation was subjected to flavor evaluation by three professional panelists according to the evaluation criteria in Table 2, and the results are shown in Table 7.
試験結果から明らかなように、ジメモルファン１質量部に対して乳糖を１５質量部以上配合した製剤は、ジメモルファン特有の苦味の抑制効果が確認された（実施例２、３）。また、スクラロースを０．５質量部以上配合した製剤は、同様の苦味の抑制効果が確認された（実施例４〜６）。 As is clear from the test results, the preparation containing 15 parts by mass or more of lactose with respect to 1 part by mass of dimemorphan was confirmed to have an inhibitory effect on bitterness peculiar to dimemorphan (Examples 2 and 3). Moreover, the preparation which mix | blended 0.5 mass part or more of sucralose confirmed the same bitterness suppression effect (Examples 4-6).
（実施例７〜８、比較例５）
（１）製造方法
（実施例７)
ジメモルファンリン酸塩、アセトアミノフェン、ブロムヘキシン塩酸塩、乳糖、トウモロコシデンプン、軽質無水ケイ酸、黄色三二酸化鉄を以下表６に示す成分量秤量し、さらにヒドロキシプロピルセルロース２７ｍｇ、スクラロース３０ｍｇ秤量し、混合した。これにヒドロキシプロピルセルロース８１ｍｇを精製水とエタノールの混合液に溶解した結合液を用いて流動層造粒した後、スクラロース１５ｍｇ、香料２．４ｍｇ添加して、顆粒剤を得た。
(Examples 7-8, Comparative Example 5)
(1) Manufacturing method (Example 7)
Dimemorphan phosphate, acetaminophen, bromhexine hydrochloride, lactose, corn starch, light anhydrous silicic acid and yellow ferric oxide are weighed in the amounts shown in Table 6 below, and further weighed 27 mg of hydroxypropylcellulose and 30 mg of sucralose. , Mixed. Fluidized bed granulation was performed using a binding solution in which 81 mg of hydroxypropylcellulose was dissolved in a mixed solution of purified water and ethanol, and then 15 mg of sucralose and 2.4 mg of fragrance were added to obtain granules.
（実施例８）
ジメモルファンリン酸塩、アセトアミノフェン、ブロムヘキシン塩酸塩、乳糖、トウモロコシデンプン、粉糖、軽質無水ケイ酸、黄色三二酸化鉄を以下表６に示す成分量秤量し、さらにヒドロキシプロピルセルロース４５ｍｇ、スクラロース３０ｍｇ秤量し、混合した。これにヒドロキシプロピルセルロース５４ｍｇを精製水に溶解した結合液を用いて流動層造粒した後、スクラロース１５ｍｇ、香料２．３ｍｇ添加して、顆粒剤を得た。
(Example 8)
Dimemorphan phosphate, acetaminophen, bromhexine hydrochloride, lactose, corn starch, powdered sugar, light anhydrous silicic acid, yellow ferric oxide were weighed in the amounts shown in Table 6 below, and hydroxypropylcellulose 45 mg, sucralose 30 mg was weighed and mixed. Fluidized bed granulation was performed using a binding solution in which 54 mg of hydroxypropylcellulose was dissolved in purified water, and then 15 mg of sucralose and 2.3 mg of fragrance were added to obtain granules.
（比較例５）
ジメモルファンリン酸塩、アセトアミノフェン、ブロムヘキシン塩酸塩、Ｄ-マンニトール、トウモロコシデンプン、軽質無水ケイ酸、黄色三二酸化鉄を以下表６に示す成分量秤量し、さらにヒドロキシプロピルセルロース４５ｍｇ秤量し、混合した。これにヒドロキシプロピルセルロース１０５ｍｇを精製水に溶解した結合液を用いて流動層造粒した後、スクラロース４５ｍｇ、香料２．３ｍｇ添加して、顆粒剤を得た。
以下表６に処方を示す。
(Comparative Example 5)
Dimemorphan phosphate, acetaminophen, bromhexine hydrochloride, D-mannitol, corn starch, light silicic anhydride, yellow iron sesquioxide are weighed in the amounts shown in Table 6 below, and 45 mg of hydroxypropylcellulose is weighed. Mixed. Fluidized bed granulation was performed using a binding solution in which 105 mg of hydroxypropylcellulose was dissolved in purified water, and then 45 mg of sucralose and 2.3 mg of fragrance were added to obtain granules.
The prescription is shown in Table 6 below.
（２）風味評価
得られた製剤について、表２の評価基準に従って、専門パネラー３名による風味評価を実施し、その結果を表７に示した。
(2) Flavor Evaluation The obtained preparation was subjected to flavor evaluation by three professional panelists according to the evaluation criteria in Table 2, and the results are shown in Table 7.
試験結果から明らかなように、糖類としてマンニトールを用いた場合、ジメモルファン由来の苦味が強く感じられた（比較例５）。これに対し、乳糖を用いると、苦味を完全に抑えることができた（実施例７）。この効果は、乳糖を一部、粉糖に置き換えた場合においても発揮された（実施例８）。 As is apparent from the test results, when mannitol was used as the saccharide, a bitter taste derived from dimethylolphan was strongly felt (Comparative Example 5). On the other hand, when lactose was used, bitterness could be completely suppressed (Example 7). This effect was also exhibited when lactose was partially replaced with powdered sugar (Example 8).
（実施例９〜１４、比較例６〜９）
（１）製造方法
以下表８〜９に占める各成分を秤量し、各成分を均一分散するように混合した。これに精製水を添加して乳鉢造粒することによって顆粒剤を得た。
(Examples 9-14, Comparative Examples 6-9)
(1) Manufacturing method Each component which occupies Tables 8-9 below was weighed, and it mixed so that each component might be uniformly disperse | distributed. Granules were obtained by adding purified water thereto and granulating in a mortar.
（２）風味評価
得られた製剤について、表２の評価基準に従って、専門パネラー３名による風味評価を実施し、その結果を表１０に示した。
(2) Flavor Evaluation The obtained preparation was subjected to flavor evaluation by three professional panelists according to the evaluation criteria shown in Table 2, and the results are shown in Table 10.
試験結果から明らかなように、糖類又は糖アルコールとしてブドウ糖、パラチノース、キシリトール、ソルビトールを用いた場合、ジメモルファン由来の苦味が強く感じられた（比較例６〜９）。これに対し、乳糖、砂糖、果糖、粉糖、トレハロース、エリスリトールを用いると、苦味を抑えることができた（実施例９〜１４）。特に、乳糖、果糖、粉糖を用いると苦味の抑制効果は大きかった。 As is clear from the test results, when glucose, palatinose, xylitol, or sorbitol was used as the saccharide or sugar alcohol, a bitter taste derived from dimemorphan was strongly felt (Comparative Examples 6 to 9). On the other hand, when lactose, sugar, fructose, powdered sugar, trehalose, and erythritol were used, bitterness could be suppressed (Examples 9 to 14). In particular, when lactose, fructose, and powdered sugar were used, the effect of suppressing bitterness was great.
本発明により、ジメモルファンの苦味を改善した固形製剤を提供することができ、総合感冒薬、かぜ薬、又は鎮咳薬として有用である。 According to the present invention, it is possible to provide a solid preparation with improved bitter taste of dimemophane, which is useful as a general cold medicine, cold medicine, or antitussive.
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH1036292A (en) * | 1996-07-24 | 1998-02-10 | Taisho Pharmaceut Co Ltd | Liquid agent reduced in bitter taste |
| JP2000159691A (en) * | 1998-09-21 | 2000-06-13 | Taisho Pharmaceut Co Ltd | Solid preparation for oral administration |
| JP2000290199A (en) * | 1999-03-31 | 2000-10-17 | Taisho Pharmaceut Co Ltd | Oral medicinal composition |
| JP2001097856A (en) * | 1999-09-30 | 2001-04-10 | Taisho Pharmaceut Co Ltd | Antitussive |
| JP2001151677A (en) * | 1999-11-26 | 2001-06-05 | Taisho Pharmaceut Co Ltd | Composition for pharyngeal use |
| JP2010090142A (en) * | 2001-07-31 | 2010-04-22 | Wyeth | Sucralose formulation for masking unpleasant taste |
| WO2011148794A1 (en) * | 2010-05-27 | 2011-12-01 | 大正製薬株式会社 | Dimemorfan-containing liquid preparation for internal administration |
| JP2013253042A (en) * | 2012-06-07 | 2013-12-19 | Taisho Pharmaceutical Co Ltd | Transdermal absorption type preparation |
-
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Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH1036292A (en) * | 1996-07-24 | 1998-02-10 | Taisho Pharmaceut Co Ltd | Liquid agent reduced in bitter taste |
| JP2000159691A (en) * | 1998-09-21 | 2000-06-13 | Taisho Pharmaceut Co Ltd | Solid preparation for oral administration |
| JP2000290199A (en) * | 1999-03-31 | 2000-10-17 | Taisho Pharmaceut Co Ltd | Oral medicinal composition |
| JP2001097856A (en) * | 1999-09-30 | 2001-04-10 | Taisho Pharmaceut Co Ltd | Antitussive |
| JP2001151677A (en) * | 1999-11-26 | 2001-06-05 | Taisho Pharmaceut Co Ltd | Composition for pharyngeal use |
| JP2010090142A (en) * | 2001-07-31 | 2010-04-22 | Wyeth | Sucralose formulation for masking unpleasant taste |
| WO2011148794A1 (en) * | 2010-05-27 | 2011-12-01 | 大正製薬株式会社 | Dimemorfan-containing liquid preparation for internal administration |
| JP2013253042A (en) * | 2012-06-07 | 2013-12-19 | Taisho Pharmaceutical Co Ltd | Transdermal absorption type preparation |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP7499026B2 (en) | 2019-12-27 | 2024-06-13 | 小林製薬株式会社 | Internal pharmaceutical composition |
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