JP2012046496A - Oral liquid medicine - Google Patents
Oral liquid medicine Download PDFInfo
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- JP2012046496A JP2012046496A JP2011160920A JP2011160920A JP2012046496A JP 2012046496 A JP2012046496 A JP 2012046496A JP 2011160920 A JP2011160920 A JP 2011160920A JP 2011160920 A JP2011160920 A JP 2011160920A JP 2012046496 A JP2012046496 A JP 2012046496A
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- Prior art keywords
- loxoprofen
- unpleasant taste
- pharmacologically acceptable
- acceptable salt
- salt
- Prior art date
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- 239000007788 liquid Substances 0.000 title claims abstract description 18
- 239000003814 drug Substances 0.000 title abstract description 9
- 229960002373 loxoprofen Drugs 0.000 claims abstract description 36
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000000178 monomer Substances 0.000 claims abstract description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 10
- BAZQYVYVKYOAGO-UHFFFAOYSA-M loxoprofen sodium hydrate Chemical compound O.O.[Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 BAZQYVYVKYOAGO-UHFFFAOYSA-M 0.000 claims abstract 8
- 150000002148 esters Chemical group 0.000 claims description 10
- 239000000470 constituent Substances 0.000 claims description 9
- -1 acrylate ester Chemical class 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 229920001577 copolymer Polymers 0.000 claims description 6
- 229940100688 oral solution Drugs 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 4
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical group CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 159000000000 sodium salts Chemical class 0.000 claims description 3
- 238000002156 mixing Methods 0.000 abstract description 5
- 229920003145 methacrylic acid copolymer Polymers 0.000 abstract description 4
- 125000004185 ester group Chemical group 0.000 abstract 1
- YMBXTVYHTMGZDW-UHFFFAOYSA-N loxoprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1CC1C(=O)CCC1 YMBXTVYHTMGZDW-UHFFFAOYSA-N 0.000 description 29
- 230000000052 comparative effect Effects 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000008213 purified water Substances 0.000 description 7
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 239000011248 coating agent Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 125000005210 alkyl ammonium group Chemical group 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 239000001103 potassium chloride Substances 0.000 description 3
- 235000011164 potassium chloride Nutrition 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- SOGAXMICEFXMKE-UHFFFAOYSA-N Butylmethacrylate Chemical compound CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 229920003067 (meth)acrylic acid ester copolymer Polymers 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- QIJIUJYANDSEKG-UHFFFAOYSA-N 2,4,4-trimethylpentan-2-amine Chemical class CC(C)(C)CC(C)(C)N QIJIUJYANDSEKG-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical class C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical class NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000003907 antipyretic analgesic agent Substances 0.000 description 1
- UPABQMWFWCMOFV-UHFFFAOYSA-N benethamine Chemical class C=1C=CC=CC=1CNCCC1=CC=CC=C1 UPABQMWFWCMOFV-UHFFFAOYSA-N 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical class C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- KXKPYJOVDUMHGS-OSRGNVMNSA-N chondroitin sulfate Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](OS(O)(=O)=O)[C@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](C(O)=O)O1 KXKPYJOVDUMHGS-OSRGNVMNSA-N 0.000 description 1
- 150000001868 cobalt Chemical class 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 150000005332 diethylamines Chemical class 0.000 description 1
- WPUMTJGUQUYPIV-JIZZDEOASA-L disodium (S)-malate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](O)CC([O-])=O WPUMTJGUQUYPIV-JIZZDEOASA-L 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 150000002301 glucosamine derivatives Chemical class 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- 239000012676 herbal extract Substances 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 159000000014 iron salts Chemical class 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000002780 morpholines Chemical class 0.000 description 1
- 150000002815 nickel Chemical class 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940109850 royal jelly Drugs 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019265 sodium DL-malate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001394 sodium malate Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本発明は、ロキソプロフェン又はその薬理上許容される塩を含有する内服液剤に関する。 The present invention relates to an internal liquid preparation containing loxoprofen or a pharmacologically acceptable salt thereof.
ロキソプロフェンは優れた解熱鎮痛作用を有する化合物であり、既に錠剤または細粒剤が上市されている。また、服用の容易性からロキソプロフェン含有液剤の提供が望まれているが、不快味を有するという問題がある。
これまでに、ロキソプロフェンと甘味剤とシクロデキストリンを含有するシロップ製剤が特許文献で報告されている（特許文献１）。また、ロキソプロフェンを起因とする胃粘膜障害を軽減したシロップ剤が知られているが、服用性に関する記載はない（特許文献２、３）。
Loxoprofen is a compound having an excellent antipyretic analgesic effect, and tablets or fine granules have already been marketed. Moreover, although provision of a loxoprofen containing liquid agent is desired from the ease of taking, there exists a problem that it has an unpleasant taste.
So far, a syrup preparation containing loxoprofen, a sweetener and cyclodextrin has been reported in Patent Literature (Patent Literature 1). Moreover, although the syrup agent which reduced the gastric mucosal disorder resulting from a loxoprofen is known, there is no description regarding ingestibility (patent document 2, 3).
一方、構成モノマーの少なくとも１つがエステル残基に窒素を含有する（メタ）アクリル酸エステルの共重合体は、固形製剤において、薬剤を被覆することにより薬物の不快味の遮蔽や薬物の安定性の確保ができるため、フィルム剤やコーティング剤として用いられている（特許文献４、５、６）。 しかし、内服液剤中に直接溶解して薬物の不快味を抑制することについては記載されていない。 On the other hand, a copolymer of (meth) acrylic acid ester, in which at least one of the constituent monomers contains nitrogen in the ester residue, is effective in shielding the unpleasant taste of the drug and stabilizing the drug by coating the drug in a solid preparation. Since it can ensure, it is used as a film agent or a coating agent (patent documents 4, 5, and 6). However, there is no description about suppressing an unpleasant taste of a drug by directly dissolving in an internal solution.
本発明は、不快味を抑制したロキソプロフェン含有内服液剤及びロキソプロフェンを含有する内服液剤の不快味抑制方法を提供することにある。 It is an object of the present invention to provide a loxoprofen-containing internal liquid that suppresses unpleasant taste and a method for suppressing the unpleasant taste of an internal liquid that contains loxoprofen.
本発明者らは、上記課題を解決するために鋭意検討を重ねた結果、ロキソプロフェン又はその薬理上許容される塩を含有する内服液剤に、構成モノマーの少なくとも１つがエステル残基に窒素を含有する（メタ）アクリル酸エステルの共重合体を配合することによりロキソプロフェン含有内服液剤の不快味を抑えられることを見出し、本発明を完成するに至った。 As a result of intensive studies in order to solve the above-mentioned problems, the present inventors have found that at least one of the constituent monomers contains nitrogen in the ester residue in the oral solution containing loxoprofen or a pharmacologically acceptable salt thereof. It has been found that the unpleasant taste of a loxoprofen-containing oral solution can be suppressed by blending a (meth) acrylic acid ester copolymer, and the present invention has been completed.
即ち本発明は、
（１）ａ）ロキソプロフェン又はその薬理上許容される塩、及びｂ）構成モノマーの少なくとも１つがエステル残基に窒素を含有する（メタ）アクリル酸エステルの共重合体を含有することを特徴とする内服液剤、
（２）ロキソプロフェン又はその薬理上許容される塩が、ロキソプロフェンのナトリウム塩である（１）に記載の内服液剤、
（３）ｐＨが2.5〜7.0である（１）〜（２）のいずれかに記載の内服液剤、
（４）ロキソプロフェン又はその薬理上許容される塩を含有する内服液剤に対して、構成モノマーの少なくとも１つがエステル残基に窒素を含有する（メタ）アクリル酸エステルの共重合体を配合することを特徴とする、ロキソプロフェン又はその薬理上許容される塩の不快味を抑制する方法、
である。
That is, the present invention
(1) a) loxoprofen or a pharmacologically acceptable salt thereof, and b) at least one of the constituent monomers contains a copolymer of (meth) acrylic acid ester containing nitrogen in the ester residue. Oral solution,
(2) The internal use liquid preparation according to (1), wherein loxoprofen or a pharmacologically acceptable salt thereof is a sodium salt of loxoprofen,
(3) The internal liquid preparation according to any one of (1) to (2), wherein the pH is 2.5 to 7.0,
(4) For a liquid preparation containing loxoprofen or a pharmacologically acceptable salt thereof, blending a copolymer of (meth) acrylate ester in which at least one of the constituent monomers contains nitrogen in the ester residue. A method for suppressing the unpleasant taste of loxoprofen or a pharmacologically acceptable salt thereof,
It is.
本発明により、ロキソプロフェン又はその薬理上許容される塩の不快味を抑制することができる。 本発明中の（メタ）アクリル酸エステルの共重合体は、内服液剤中に直接溶解させるので、ロキソプロフェンをコーティング剤で被覆するなど煩雑な工程を経ずに、不快味を抑制したロキソプロフェン含有内服液剤を提供することができる。 According to the present invention, the unpleasant taste of loxoprofen or a pharmacologically acceptable salt thereof can be suppressed. Since the copolymer of (meth) acrylic acid ester in the present invention is directly dissolved in an internal solution, an internal solution containing loxoprofen that suppresses unpleasant taste without going through complicated steps such as coating loxoprofen with a coating agent. Can be provided.
ロキソプロフェンとは、2−［4−（2−オキソシクロペンタン−1−イルメチル）フェニル］プロピオン酸のことであり、その薬理上許容される塩とはナトリウム塩、カリウム塩、リチウム塩のようなアルカリ金属塩；カルシウム塩、マグネシウム塩のようなアルカリ土類金属塩、アルミニウム塩、鉄塩、亜鉛塩、銅塩、ニッケル塩、コバルト塩等の金属塩；アンモニウム塩のような無機塩；ｔ−オクチルアミン塩、ジベンジルアミン塩、モルホリン塩、グルコサミン塩、フェニルグリシンアルキルエステル塩、エチレンジアミン塩、Ｎ−メチルグルカミン塩、グアニジン塩、ジエチルアミン塩、トリエチルアミン塩、ジシクロヘキシルアミン塩、Ｎ，Ｎ’−ジベンジルエチレンジアミン塩、クロロプロカイン塩、プロカイン塩、ジエタノールアミン塩、Ｎ−ベンジル−フェネチルアミン塩、ピペラジン塩、テトラメチルアンモニウム塩、トリス（ヒドロキシメチル）アミノメタン塩のような有機塩等のアミン塩を挙げることができる。好ましくはナトリウム塩である。 Loxoprofen is 2- [4- (2-oxocyclopentan-1-ylmethyl) phenyl] propionic acid, and its pharmacologically acceptable salts are alkali salts such as sodium, potassium and lithium salts. Metal salts; alkaline earth metal salts such as calcium salts and magnesium salts, metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts and cobalt salts; inorganic salts such as ammonium salts; t-octyl Amine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N′-dibenzyl Ethylenediamine salt, chloroprocaine salt, procaine salt, diethanola Examples thereof include amine salts such as organic salts such as amine salts, N-benzyl-phenethylamine salts, piperazine salts, tetramethylammonium salts, and tris (hydroxymethyl) aminomethane salts. A sodium salt is preferable.
本発明におけるロキソプロフェン又はその薬理上許容される塩の配合量は目的に応じ適宜選択し使用できる。例えば１日当たり10〜180ｍｇ（フリー体・無水物に換算）配合することが好ましい。 The blending amount of loxoprofen or a pharmacologically acceptable salt thereof in the present invention can be appropriately selected and used according to the purpose. For example, it is preferable to blend 10 to 180 mg (converted into free form / anhydride) per day.
構成モノマーの少なくとも１つがエステル残基に窒素を含有する（メタ）アクリル酸エステルのエステル残基としては、例えばＣ1-8アルキルアミノエチル基またはＣ1-8アルキルアンモニウムエチル基等が挙げられる。Ｃ1-8アルキルアミノエチル基およびＣ1-8アルキルアンモニウムエチル基のＣ1-8アルキル基とは、炭素数１〜８の直鎖又は分岐アルキル基を示し、たとえばメチル基、エチル基、プロピル基、ブチル基、ヘキシル基、オクチル基、２−エチルヘキシル基が挙げられ、特にメチル基が好ましい。Ｃ1-8アルキルアミノエチル基またはＣ1-8アルキルアンモニウムエチル基としては例えばジメチルアミノエチル基、又はトリメチルアンモニウムエチル基が挙げられる。構成モノマーの少なくとも１つがエステル残基に窒素を含有する（メタ）アクリル酸エステルである共重合体の好ましい具体的例としては、メタアクリル酸メチル・メタアクリル酸ブチル・メタアクリル酸ジメチルアミノエチルコポリマー（アミノアルキルメタクリレートコポリマーＥ）、アクリル酸エチル・メタアクリル酸メチル・メタアクリル酸塩化トリメチルアンモニウムエチルコポリマー（アミノアルキルメタクリレートコポリマーＲＳ）などが挙げられる。 Examples of the ester residue of (meth) acrylic acid ester in which at least one of the constituent monomers contains nitrogen in the ester residue include a C 1-8 alkylaminoethyl group or a C 1-8 alkylammonium ethyl group. The C 1-8 alkyl groups C 1-8 alkyl amino ethyl group and C 1-8 alkyl ammonium ethyl group, a linear or branched alkyl group having 1 to 8 carbon atoms, such as methyl group, ethyl group, propyl Group, butyl group, hexyl group, octyl group and 2-ethylhexyl group, and methyl group is particularly preferable. C 1-8 alkylamino ethyl group or C as the 1-8 alkyl ammonium ethyl group such as dimethylaminoethyl group, and a trimethyl ammonium ethyl group. Preferable specific examples of the copolymer in which at least one of the constituent monomers is a (meth) acrylic acid ester containing nitrogen in the ester residue include methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer (Aminoalkyl methacrylate copolymer E), ethyl acrylate / methyl methacrylate / methacrylated trimethylammonium ethyl copolymer (aminoalkyl methacrylate copolymer RS), and the like.
本発明の内服液剤において、ロキソプロフェン又はその薬理上許容される塩と構成モノマーの少なくとも１つがエステル残基に窒素を含有する（メタ）アクリル酸エステルである共重合体の配合比は、ロキソプロフェン又はその薬理上許容される塩１質量部に対して通常0.01〜500質量部であり、好ましくは0.03〜133質量部であり、より好ましくは0.06〜16.7質量部であり、最も好ましくは0.08〜0.25質量部である。
本発明にかかる内服液剤のｐＨは、2.5〜7.0であり、好ましくは3.0〜7.0である。ｐＨ2.5未満の酸性域ではロキソプロフェン又はその薬理上許容される塩の溶解性の点で好ましくなく、ｐＨが7.0を越える塩基性域では、風味の点で好ましくないからである。また、ｐＨを酸性領域とすることで、内服液剤の防腐効果が得られることからも、上記範囲が好ましい。したがって、本発明の内服液剤のｐＨを上記範囲に保つために、本願発明では、必要に応じて塩酸、リン酸等の無機酸や、クエン酸、リンゴ酸等の有機酸，水酸化ナトリウム等の無機塩基やクエン酸ナトリウム、リンゴ酸ナトリウム等の有機塩基を配合しても良い。
In the internal use liquid preparation of the present invention, the blending ratio of loxoprofen or a pharmacologically acceptable salt thereof and a copolymer in which at least one of the constituent monomers is a (meth) acrylate ester containing nitrogen in an ester residue is loxoprofen or a mixture thereof. The amount is usually 0.01 to 500 parts by weight, preferably 0.03 to 133 parts by weight, more preferably 0.06 to 16.7 parts by weight, most preferably 0.08 to 0.25 parts by weight, based on 1 part by weight of the pharmacologically acceptable salt. It is.
The pH of the internal solution according to the present invention is 2.5 to 7.0, preferably 3.0 to 7.0. This is because the acidic range below pH 2.5 is not preferable in terms of the solubility of loxoprofen or a pharmacologically acceptable salt thereof, and the basic range above pH 7.0 is not preferable in terms of flavor. Moreover, the said range is preferable also from the antiseptic effect of an internal use liquid agent being acquired by making pH into an acidic region. Therefore, in order to keep the pH of the oral solution of the present invention in the above range, in the present invention, if necessary, inorganic acids such as hydrochloric acid and phosphoric acid, organic acids such as citric acid and malic acid, sodium hydroxide, etc. An inorganic base or an organic base such as sodium citrate or sodium malate may be blended.
本発明の内服液剤にはその他の成分として、ビタミン類、ミネラル類、アミノ酸又はその塩類、生薬、生薬抽出物、カフェイン、ローヤルゼリーなどを本発明の効果を損なわない範囲で適宜に配合することができる。 As other components, the internal liquid preparation of the present invention may appropriately contain vitamins, minerals, amino acids or salts thereof, herbal medicines, herbal extracts, caffeine, royal jelly and the like as long as the effects of the present invention are not impaired. it can.
さらに必要に応じて、抗酸化剤、着色剤、香料、矯味剤、界面活性剤、溶解補助剤、保存剤、甘味料、酸味料などの添加物を本発明の効果を損なわない範囲で適宜に配合することができる。 Furthermore, if necessary, additives such as antioxidants, colorants, fragrances, flavoring agents, surfactants, solubilizers, preservatives, sweeteners, acidulants are appropriately added within a range not impairing the effects of the present invention. Can be blended.
本発明の内服液剤は、常法により調製することができ、その方法は特に限定されるものではない。通常、各成分をとり適量の精製水で溶解した後、ｐＨを調整し、残りの精製水を加えて容量調製し、必要に応じてろ過、滅菌処理することにより得られる。 The internal liquid preparation of the present invention can be prepared by a conventional method, and the method is not particularly limited. Usually, after each component is taken and dissolved with an appropriate amount of purified water, the pH is adjusted, the remaining purified water is added to adjust the volume, and filtration and sterilization are performed as necessary.
本発明の内服液剤は、例えばシロップ剤、ドリンク剤などの医薬品や医薬部外品などに適用することができる。 The internal liquid preparation of the present invention can be applied to pharmaceuticals such as syrups and drinks, quasi drugs and the like.
以下に実施例、比較例及び試験例を挙げ、本発明をさらに詳しく説明する。
表１に実施例、表２に比較例を示した。実施例１〜６、比較例１〜４は、ロキソプロフェンナトリウム、塩化カリウム、酒石酸、及びアミノアルキルメタクリレートコポリマーＥを精製水に溶解し、塩酸、及び水酸化ナトリウムを用いてｐＨを調整し、精製水を加えて全量を30ｍＬとし、ガラス瓶に充填しキャップを施して内服液剤を得た。実施例７および比較例５は、ロキソプロフェンナトリウム、塩化カリウム、酒石酸、及びアミノアルキルメタクリレートコポリマーＥを精製水に溶解し、塩酸、及び水酸化ナトリウムを用いてｐＨを調整し、精製水を加えて全量を10ｍＬとし、ガラス瓶に充填しキャップを施して内服液剤を得た。実施例８はアミノアルキルメタクリレートコポリマーＲＳをエタノールに溶解し、ロキソプロフェンナトリウム、塩化カリウム、酒石酸を溶解した精製水と混合し、塩酸、及び水酸化ナトリウムを用いｐＨを調整し、精製水を加えて全量を30ｍＬとした。比較例６〜９はアミノアルキルメタクリレートコポリマーＥの代わりに高分子であるＰＶＰ、大豆多糖類、アルギン酸ナトリウム、コンドロイチン硫酸ナトリウムを用い、比較例１０はアミノアルキルメタクリレートコポリマーの代わりに砂糖を配合し、実施例１〜３と同様に調整した。
Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Test Examples.
Table 1 shows examples and Table 2 shows comparative examples. Examples 1 to 6 and Comparative Examples 1 to 4 were prepared by dissolving loxoprofen sodium, potassium chloride, tartaric acid, and aminoalkyl methacrylate copolymer E in purified water, adjusting the pH with hydrochloric acid and sodium hydroxide, Was added to make a total volume of 30 mL, filled into a glass bottle and capped to obtain an internal solution. In Example 7 and Comparative Example 5, loxoprofen sodium, potassium chloride, tartaric acid, and aminoalkyl methacrylate copolymer E were dissolved in purified water, pH was adjusted using hydrochloric acid and sodium hydroxide, and purified water was added to the total amount. Was filled in a glass bottle and capped to obtain an internal solution. In Example 8, aminoalkyl methacrylate copolymer RS is dissolved in ethanol, mixed with purified water in which loxoprofen sodium, potassium chloride, and tartaric acid are dissolved. The pH is adjusted with hydrochloric acid and sodium hydroxide, and purified water is added to the whole amount. To 30 mL. In Comparative Examples 6 to 9, PVP, soy polysaccharide, sodium alginate, and sodium chondroitin sulfate were used instead of aminoalkyl methacrylate copolymer E, and sugar was added in place of aminoalkyl methacrylate copolymer. Adjustments were made as in Examples 1-3.
試験方法
25〜40歳までの4人をパネルとして、試験液約20ｍＬを服用し、調製直後のロキソ
プロフェンの不快味について評価した。なお、一つのサンプルを評価した後は、温湯
で口中をすすぎ、十分経過してから次の試験液の評価を行った。
評価基準
実施例１、２、比較例６〜９の評価はアミノアルキルメタクリレートコポリマーＥを配合していない比較例１との相対評価を行い、実施例３は比較例２、実施例４は比較例３、実施例５は比較例４、実施例６は比較例５との相対評価を行った。
実施例１、２、比較例６〜９は，比較例1に比べて「非常に弱く不快味を感じる」を−３点、「弱く不快味を感じる」を−２点、「やや弱く不快味を感じる」を−１点、「同等に不快味を感じる」を０点、「やや強く不快味を感じる」を1点、「強く不快味を感じる」を２点、「非常に強く不快味を感じる」を３点とし、結果を平均値で求めた。実施例３〜６はそれぞれの比較例の評価点を０点とし，比較例に比べ「非常に弱く不快味を感じる」を−３点、「弱く不快味を感じる」を−２点、「やや弱く不快味を感じる」を−１点、「同等に不快味を感じる」を０点、「やや強く不快味を感じる」を1点、「強く不快味を感じる」を２点、「非常に強く不快味を感じる」を３点とし、結果を平均値で求めた、表３および表４に評価点として示した。
Test method
Four persons from 25 to 40 years old took a panel and took about 20 mL of the test solution to evaluate the unpleasant taste of loxoprofen immediately after preparation. After evaluating one sample, the mouth was rinsed with warm water, and the next test solution was evaluated after sufficient time had passed.
Evaluation criteria Examples 1 and 2 and Comparative Examples 6 to 9 were evaluated relative to Comparative Example 1 in which no aminoalkyl methacrylate copolymer E was blended. Example 3 was Comparative Example 2 and Example 4 was Comparative Example. 3 and Example 5 were compared with Comparative Example 4 and Example 6 was compared with Comparative Example 5.
In Examples 1 and 2 and Comparative Examples 6 to 9, “very weak and unpleasant taste” is −3 points, “weak and unpleasant taste” is −2 points, “slightly unpleasant taste” -1 points for "feels uncomfortable", 0 points for "feeling uncomfortable taste equally", 1 point for "feeling slightly unpleasant taste", 2 points for "feeling strongly unpleasant taste", "very strong unpleasant taste" The result was obtained as an average value. In Examples 3 to 6, the evaluation score of each comparative example was set to 0, compared to the comparative example, “very weak and unpleasant taste” was −3 points, “weak and unpleasant taste” was −2 points, “slightly -1 points for "Weak and unpleasant taste", 0 points for "Equally unpleasant taste", 1 point for "Slightly unpleasant taste", 2 points for "Strongly unpleasant taste", "Very strong “I feel an unpleasant taste” was given 3 points, and the results were obtained as average values. Tables 3 and 4 show the evaluation points.
表３、４から明らかなように、アミノアルキルメタクリレートコポリマーＥを配合すると，ロキソプロフェンナトリウムの不快味が抑えられた。一方で、他の高分子を配合した比較例６〜９では不快味を改善する効果は得られなかった。また、砂糖を配合した比較例１０は不快味を改善する効果は得られなかった。 As apparent from Tables 3 and 4, when the aminoalkyl methacrylate copolymer E was blended, the unpleasant taste of loxoprofen sodium was suppressed. On the other hand, in Comparative Examples 6 to 9 containing other polymers, the effect of improving the unpleasant taste was not obtained. Moreover, the comparative example 10 which mix | blended sugar was not able to acquire the effect which improves an unpleasant taste.
本発明は、服用性良好なロキソプロフェン又はその薬理上許容される塩を含有した内服液剤の製造に利用可能である。 INDUSTRIAL APPLICABILITY The present invention can be used for the production of an internal liquid preparation containing loxoprofen or a pharmacologically acceptable salt thereof having good dosing properties.
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