JPH0729930B2 - Composition containing minocycline in a stable manner - Google Patents
Composition containing minocycline in a stable mannerInfo
- Publication number
- JPH0729930B2 JPH0729930B2 JP61122488A JP12248886A JPH0729930B2 JP H0729930 B2 JPH0729930 B2 JP H0729930B2 JP 61122488 A JP61122488 A JP 61122488A JP 12248886 A JP12248886 A JP 12248886A JP H0729930 B2 JPH0729930 B2 JP H0729930B2
- Authority
- JP
- Japan
- Prior art keywords
- minocycline
- composition
- film
- weight
- sheet
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 239000000203 mixture Substances 0.000 title claims description 46
- 229960004023 minocycline Drugs 0.000 title claims description 26
- DYKFCLLONBREIL-KVUCHLLUSA-N minocycline Chemical compound C([C@H]1C2)C3=C(N(C)C)C=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O DYKFCLLONBREIL-KVUCHLLUSA-N 0.000 title claims 3
- 150000002681 magnesium compounds Chemical class 0.000 claims description 10
- 229920003169 water-soluble polymer Polymers 0.000 claims description 8
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 7
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 4
- 238000009472 formulation Methods 0.000 claims description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 4
- 239000004373 Pullulan Substances 0.000 claims description 3
- 229920001218 Pullulan Polymers 0.000 claims description 3
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 claims description 3
- 235000019423 pullulan Nutrition 0.000 claims description 3
- 229920002101 Chitin Polymers 0.000 claims description 2
- 229920001661 Chitosan Polymers 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 2
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 claims description 2
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 claims description 2
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 claims description 2
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 2
- 229940117841 methacrylic acid copolymer Drugs 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 235000010981 methylcellulose Nutrition 0.000 claims description 2
- 239000004584 polyacrylic acid Substances 0.000 claims description 2
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 description 23
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- WTJXVDPDEQKTCV-UHFFFAOYSA-N 4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydron;chloride Chemical compound Cl.C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2C1CC1C(N(C)C)C(=O)C(C(N)=O)=C(O)C1(O)C2=O WTJXVDPDEQKTCV-UHFFFAOYSA-N 0.000 description 9
- 229960002421 minocycline hydrochloride Drugs 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 229910001629 magnesium chloride Inorganic materials 0.000 description 8
- 235000011147 magnesium chloride Nutrition 0.000 description 8
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 208000028169 periodontal disease Diseases 0.000 description 7
- 235000002639 sodium chloride Nutrition 0.000 description 5
- 229940072172 tetracycline antibiotic Drugs 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000004098 Tetracycline Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 230000006641 stabilisation Effects 0.000 description 4
- 238000011105 stabilization Methods 0.000 description 4
- 229960002180 tetracycline Drugs 0.000 description 4
- 235000019364 tetracycline Nutrition 0.000 description 4
- 229930101283 tetracycline Natural products 0.000 description 4
- 150000003522 tetracyclines Chemical class 0.000 description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- FHHZOYXKOICLGH-UHFFFAOYSA-N dichloromethane;ethanol Chemical compound CCO.ClCCl FHHZOYXKOICLGH-UHFFFAOYSA-N 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 239000004014 plasticizer Substances 0.000 description 3
- 230000000087 stabilizing effect Effects 0.000 description 3
- 150000005846 sugar alcohols Polymers 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- SVTBMSDMJJWYQN-UHFFFAOYSA-N 2-methylpentane-2,4-diol Chemical compound CC(O)CC(C)(C)O SVTBMSDMJJWYQN-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000004100 Oxytetracycline Substances 0.000 description 2
- UYXTWWCETRIEDR-UHFFFAOYSA-N Tributyrin Chemical compound CCCC(=O)OCC(OC(=O)CCC)COC(=O)CCC UYXTWWCETRIEDR-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000001087 glyceryl triacetate Substances 0.000 description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 description 2
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 2
- 239000011654 magnesium acetate Substances 0.000 description 2
- 235000011285 magnesium acetate Nutrition 0.000 description 2
- 229940069446 magnesium acetate Drugs 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- -1 minocycline Chemical class 0.000 description 2
- 229960000625 oxytetracycline Drugs 0.000 description 2
- IWVCMVBTMGNXQD-PXOLEDIWSA-N oxytetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-PXOLEDIWSA-N 0.000 description 2
- 235000019366 oxytetracycline Nutrition 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 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 2
- 229960002622 triacetin Drugs 0.000 description 2
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 1
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- VRTNIWBNFSHDEB-UHFFFAOYSA-N 3,3-dichloroprop-1-ene Chemical compound ClC(Cl)C=C VRTNIWBNFSHDEB-UHFFFAOYSA-N 0.000 description 1
- HBTAOSGHCXUEKI-UHFFFAOYSA-N 4-chloro-n,n-dimethyl-3-nitrobenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 HBTAOSGHCXUEKI-UHFFFAOYSA-N 0.000 description 1
- 239000004099 Chlortetracycline Substances 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010014950 Eosinophilia Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000008431 aliphatic amides Chemical class 0.000 description 1
- 150000001341 alkaline earth metal compounds Chemical class 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- XMEVHPAGJVLHIG-FMZCEJRJSA-N chembl454950 Chemical compound [Cl-].C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H]([NH+](C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O XMEVHPAGJVLHIG-FMZCEJRJSA-N 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- CYDMQBQPVICBEU-UHFFFAOYSA-N chlorotetracycline Natural products C1=CC(Cl)=C2C(O)(C)C3CC4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-UHFFFAOYSA-N 0.000 description 1
- 229960004475 chlortetracycline Drugs 0.000 description 1
- CYDMQBQPVICBEU-XRNKAMNCSA-N chlortetracycline Chemical compound C1=CC(Cl)=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-XRNKAMNCSA-N 0.000 description 1
- 235000019365 chlortetracycline Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 229940031578 diisopropyl adipate Drugs 0.000 description 1
- SZXQTJUDPRGNJN-UHFFFAOYSA-N dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 description 1
- 229960003722 doxycycline Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940051250 hexylene glycol Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- VFQXVTODMYMSMJ-UHFFFAOYSA-N isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 description 1
- 239000005453 ketone based solvent Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- LZFFTXYPIUCBCO-UHFFFAOYSA-L magnesium;2-hydroxyacetate Chemical compound [Mg+2].OCC([O-])=O.OCC([O-])=O LZFFTXYPIUCBCO-UHFFFAOYSA-L 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- KSCKTBJJRVPGKM-UHFFFAOYSA-N octan-1-olate;titanium(4+) Chemical compound [Ti+4].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-] KSCKTBJJRVPGKM-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- UWJJYHHHVWZFEP-UHFFFAOYSA-N pentane-1,1-diol Chemical compound CCCCC(O)O UWJJYHHHVWZFEP-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960004989 tetracycline hydrochloride Drugs 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 229940066528 trichloroacetate Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 発明の分野 本発明はテトラサイクリン系抗生物質の一種であるミノ
サイクリンを安定に配合したフィルム状またはシート状
の、特に歯周疾患および粘膜疾患に有用な組成物に関す
る。Description: FIELD OF THE INVENTION The present invention relates to a film- or sheet-like composition containing minocycline, which is one of the tetracycline antibiotics, in a stable form, and particularly useful for periodontal diseases and mucosal diseases.
発明の背景 テトラサイクリン系抗生物質にはテトラサイクリンをは
じめ、ミノサイクリンなど数種の類縁化合物が包含され
るが、これらはいずれも非常に不安定な物質であり、従
来からテトラサイクリン系抗生物質を医薬組成物に安定
に配合するための検討が種々なされている。BACKGROUND OF THE INVENTION Tetracycline antibiotics include tetracycline and several related compounds such as minocycline, but these are all extremely unstable substances, and tetracycline antibiotics have been conventionally used in pharmaceutical compositions. Various studies have been conducted for stable blending.
例えば、特開昭52−90616号は２−ピロリドン水溶液中
でマグネシウム化合物のようなアルカリ土類金属化合物
を用いてオキシテトラサイクリン、ドキシサイクリン、
テトラサイクリン、クロルテトラサイクリンまたはそれ
らの塩をキレート化することにより、これらのテトラサ
イクリン系抗生物質の安定化を図った注射用の水溶液を
開示している。また、特開昭53−94028号はアルカリ土
類金属イオン、ポリビニルピロリドンおよび脂肪族アミ
ドを配合し、pH5.0〜7.5にすることにより、オキシテト
ラサイクリンの安定化を図った医薬組成物を開示してい
る。さらに、米国特許第3335055号はテトラサイクリン
をマグネシウムイオンおよびイソニコチン酸アミドなど
のピリジン誘導体を安定化する方法を開示している。For example, JP-A-52-90616 discloses the use of an alkaline earth metal compound such as a magnesium compound in an aqueous solution of 2-pyrrolidone for oxytetracycline, doxycycline,
Disclosed is an injectable aqueous solution for stabilizing these tetracycline antibiotics by chelating tetracycline, chlortetracycline or salts thereof. Further, JP-A-53-94028 discloses a pharmaceutical composition for stabilizing oxytetracycline by mixing alkaline earth metal ions, polyvinylpyrrolidone and an aliphatic amide and adjusting the pH to 5.0 to 7.5. ing. Further, US Pat. No. 3,350,555 discloses a method for stabilizing tetracycline with magnesium ions and pyridine derivatives such as isonicotinic acid amide.
しかしながら、テトラサイクリン系抗生物質の１種であ
るミノサイクリンについては従来その安定化を検討した
例は見当らない。However, no study has been found on the stabilization of minocycline, which is one of the tetracycline antibiotics.
また、最近にいたり、テトラサイクリンを含む歯周疾患
治療用薬物と水溶性高分子物質とからなるフィルム状も
しくはシート状の歯周疾患治療用製剤が患部に直接投与
でき、その効果も長時間にわたり発揮し得るものである
ことが報告されている（特開昭59−222406号）。しか
し、ミノサイクリンは、その安定化が困難なことから、
そのような製剤とすることが困難であった。In addition, recently, a film- or sheet-shaped preparation for treating periodontal disease, which comprises a drug for treating periodontal disease containing tetracycline and a water-soluble polymer, can be directly administered to the affected area, and its effect is exerted for a long time. It has been reported that it is possible (JP-A-59-222406). However, because minocycline is difficult to stabilize,
It was difficult to make such a preparation.
フィルム状またはシート状製剤は、患部へ直接適用で
き、持続的効果を発揮するなど種々の利点を有するもの
であり、ミノサイクリンについても、フィルム状または
シート状に製剤化することが要望されている。The film-form or sheet-form preparation has various advantages such that it can be directly applied to an affected area and exerts a sustained effect, and it is desired to formulate minocycline into a film-form or sheet-form.
本発明者らは先に、マグネシウム化合物を含有する多価
アルコールを基剤とすることにより、ミノサイクリンが
安定化されることを見出し、また、前記組成物に加え、
水溶性高分子物質、ある種のメタアクリル酸系コポリマ
ーおよびその可溶化剤を適宜組み合わせ配合した組成物
が、ミノサイクリンの安定性を損なうことなく、長時間
投与部位に滞留し、効果が持続的なものであることを見
出し、これらの点についてはすでに特許出願をした（特
願昭59−253788号および特願昭60−263318号）。その
後、さらにミノサイクリンを安定に配合したフィルム状
またはシート状組成物を得るべく鋭意研究を重ねた。そ
の結果、マグネシウム化合物を含有する水溶性高分子物
質を基剤とすることにより、ミノサイクリンが特異的に
安定化され、かつ、フィルム状またはシート状の組成物
が得られ、なおかつ歯周疾患および粘膜疾患の治療に有
効であることを見出し、本発明を完成するにいたった。The present inventors previously found that by using a polyhydric alcohol containing a magnesium compound as a base, minocycline is stabilized, and in addition to the composition,
A composition in which a water-soluble polymer, a certain methacrylic acid-based copolymer, and a solubilizing agent thereof are appropriately combined and mixed, stays at the administration site for a long time without impairing the stability of minocycline, and the effect is sustained. Therefore, we have already filed patent applications for these points (Japanese Patent Application No. 59-253788 and Japanese Patent Application No. 60-263318). After that, intensive studies were conducted in order to obtain a film-like or sheet-like composition in which minocycline was stably mixed. As a result, by using a water-soluble polymeric substance containing a magnesium compound as a base, minocycline is specifically stabilized, and a film- or sheet-shaped composition is obtained, and periodontal disease and mucosa They have found that they are effective in treating diseases, and have completed the present invention.
発明の開示 本発明は、水溶性高分子物質と、ミノサイクリンまたは
その医薬上許容される塩およびマグネシウム化合物を配
合したフィルム状またはシート状を製剤形を有すること
を特徴とするミノサイクリンを安定に配合した組成物、
ことに、歯周疾患および粘膜疾患治療用組成物を提供す
るものである。DISCLOSURE OF THE INVENTION The present invention stably blends minocycline characterized by having a film-like or sheet-like formulation comprising a water-soluble polymer substance and minocycline or a pharmaceutically acceptable salt thereof and a magnesium compound. Composition,
In particular, the present invention provides a composition for treating periodontal disease and mucosal disease.
本発明のフィルム状またはシート状に調製されたミノサ
イクリンを安定に配合した組成物は、粘膜疾患部位また
は歯周疾患部位に直接適用することもでき、その効果も
長時間にわたり発揮し得るものである。The composition in which minocycline prepared in the form of a film or a sheet of the present invention is stably blended can be directly applied to a mucosal disease site or a periodontal disease site, and its effect can be exerted for a long time. .
特に、本発明の組成物を疾患部位に直接適用した場合、
これまで経口的にミノサイクリンを投与した時に見られ
た全身的な副作用、例えば、消化器系副作用である食欲
不振、悪心、下痢等の症状の発現、血小板減少、好酸球
増多等の生化学的副作用あるいは菌交代症等の発現が極
力防止されたものとなる。In particular, when the composition of the present invention is directly applied to the disease site,
Systemic side effects that have been observed when orally administered minocycline so far, for example, symptoms such as anorexia, nausea and diarrhea which are digestive system side effects, biochemistry such as thrombocytopenia, eosinophilia, etc. Side effects or the occurrence of bacterial alternations are prevented as much as possible.
本発明の組成物中に配合するミノサイクリンは遊離のも
のでも、たとえば、塩酸塩、硫酸塩、トリクロル酢酸塩
などの医薬上許容される酸付加塩いずれでもよく、組成
物全体に対して0.1〜10.0重量％の範囲で配合すること
ができる。The minocycline to be incorporated in the composition of the present invention may be a free minocycline, for example, any of pharmaceutically acceptable acid addition salts such as hydrochloride, sulfate, trichloroacetate, etc., and 0.1 to 10.0 based on the total composition. It can be blended in the range of wt%.
本発明の組成物において用いるマグネシウム化合物とし
ては、医薬上許容されるものであればいずれでもよく、
例えば、塩化マグネシウム、酢酸マグネシウム、硫酸マ
グネシウム、炭酸マグネシウム、グリコン酸マグネシウ
ムおよびこれらの水和物などが挙げられるが、特に塩化
マグネシウムが好ましい。一般に、マグネシウム化合物
は組成物全量に対して20重量％までの範囲で配合するミ
ノサイクリンの0.1〜10重量倍を用いることにより、ミ
ノサイクリンの良好な安定化が図れる。The magnesium compound used in the composition of the present invention may be any pharmaceutically acceptable one,
Examples thereof include magnesium chloride, magnesium acetate, magnesium sulfate, magnesium carbonate, magnesium glycolate and hydrates thereof, and magnesium chloride is particularly preferable. Generally, the magnesium compound is used in an amount of 0.1 to 10 times by weight that of minocycline to be blended in the range of up to 20% by weight based on the total amount of the composition, whereby good stabilization of minocycline can be achieved.
用いる水溶性高分子物質は、メチルセルロース、ヒドロ
キシプロピルセルロース、ヒドロキシプロピルメチルセ
ルロース、カルボキシメチルエチルセルロース、ヒドロ
キシプロピルメチルセルロース・フタレート、ヒドロキ
シプロピルメチルセルロース・アセテート・サクシネー
ト、プルラン、キチン、キトサン、アミノアルキルメア
クリレートコポリマーRS、アミノアルキルメタアクリレ
ートコポリマーＥ、メタアクリル酸コポリマーＬ、ポリ
アクリル酸およびその塩、ポリビニルピロリドンから選
ばれ、これらは単独もしくは２種以上組み合わせて配合
することができる。とりわけ、ミノサイクリンの安定化
ならびに徐放効果のためにはビドロキシプロピルセルロ
ースが好ましい。The water-soluble polymer used is methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, pullulan, chitin, chitosan, aminoalkylmethacrylate copolymer RS, amino. It is selected from alkyl methacrylate copolymer E, methacrylic acid copolymer L, polyacrylic acid and salts thereof, and polyvinylpyrrolidone, and these may be blended alone or in combination of two or more. Above all, for the stabilization of minocycline and the sustained-release effect, bidroxypropylcellulose is preferable.
この水溶性高分子物質は、ミノサイクリンおよびマグネ
シウム化合物から規定されるが組成物全量に対して70.0
〜99.5重量％の範囲で配合する。This water-soluble polymer substance is defined by minocycline and magnesium compound, but is 70.0% based on the total amount of the composition.
It is mixed in the range of up to 99.5% by weight.
本発明の組成物は、フィルム状またはシート状に調製し
て投与される。フィルムまたはシートの形状は、その大
きさならびに厚さにおいてミノサイクリンの用量、投与
される部位および病態等により変化し、特に限定される
ものではなく、適宜の形状にすることができる。The composition of the present invention is prepared and administered in the form of a film or sheet. The shape of the film or sheet varies depending on the size and thickness of the minocycline, the site to which it is administered, the condition of the disease, and the like, and is not particularly limited and may be an appropriate shape.
しかしながら、一般的には本発明の組成物は歯周疾患あ
るいは粘膜疾患の治療を目的とするものであるため、長
さい５〜7mm、巾0.5〜70mm、厚さ0.01〜0.5mm程度にす
るのが望ましい。However, since the composition of the present invention is generally intended for the treatment of periodontal disease or mucosal disease, it should be about 5 to 7 mm long, 0.5 to 70 mm wide, and 0.01 to 0.5 mm thick. Is desirable.
本発明の組成物には、さらに必要に応じて可塑剤が配合
される。可塑剤としては、グリセリン、エチレングリコ
ール、ジエチレングリコール、プロピレングリコール、
ジプロピレングリコール、ヘキシレングリコール、1,5
−ペンタンジオール、1,3−ブチレングリコールなどの
多価アルコールおよびこれらの２種以上の混合物；トリ
アセチン、トリブチリン、ジアセチルエチレングリコー
ル、セバシン酸ジエチル、フタル酸ジエチル、フタル酸
ジブチル、アジピン酸ジイソプロピル、コハク酸ジブチ
ルなどの低級多価アルコールと低級脂肪酸のエステルお
よび低級アルコールとジカルボン酸のエステルおよびこ
れらの２種以上の混合物；および油脂等が挙げられる。
これらの配合量は、用いる水溶性高分子物質の種類によ
って異なるが、通常、組成物全量に対して20重量％まで
にするのが好ましい。可塑剤の添加により、本発明の組
成物は柔軟なものとなり、投与もより容易になる。The composition of the present invention may further contain a plasticizer if necessary. As the plasticizer, glycerin, ethylene glycol, diethylene glycol, propylene glycol,
Dipropylene glycol, hexylene glycol, 1,5
-Polyhydric alcohols such as pentanediol, 1,3-butylene glycol and mixtures of two or more thereof; triacetin, tributyrin, diacetylethylene glycol, diethyl sebacate, diethyl phthalate, dibutyl phthalate, diisopropyl adipate, succinic acid Examples thereof include esters of lower polyhydric alcohols such as dibutyl and lower fatty acids, esters of lower alcohols and dicarboxylic acids and mixtures of two or more thereof; and fats and oils.
Although the blending amount of these varies depending on the type of the water-soluble polymer substance used, it is usually preferable to add up to 20% by weight based on the total amount of the composition. The addition of a plasticizer renders the compositions of the present invention flexible and easier to administer.
さらに、本発明の組成物は、着色剤、矯味矯臭剤等を本
発明の効果を損なわない範囲で添加してもよい。Further, the composition of the present invention may contain a colorant, a flavoring agent and the like within a range that does not impair the effects of the present invention.
本発明の組成物は、通常の製剤化技術に従って調製する
ことができる。The compositions of the present invention can be prepared according to conventional formulation techniques.
例えば、マグネシウム化合物および水溶性高分子物質を
有機溶媒に分散、溶解し、これにミノサイクリンまたは
その医薬上許容される塩を加え、均一に混合した後、常
法により、フィルム製造装置を用いるか、またはガラス
板、テフロンシート上等に流延し、風乾し、成形するよ
うな湿潤法により所望の形状および厚さを有するフィル
ム状またはシート状の組成物を得ることができる。For example, a magnesium compound and a water-soluble polymer are dispersed and dissolved in an organic solvent, minocycline or a pharmaceutically acceptable salt thereof is added to this, and after uniformly mixed, by a conventional method, using a film manufacturing apparatus, or Alternatively, a film-like or sheet-like composition having a desired shape and thickness can be obtained by a wet method such as casting on a glass plate or a Teflon sheet, air-drying, and molding.
用いられる溶媒としては、組成物の各成分に対し不活性
なものであるならばいずれでもよく、例えば；水；メタ
ノール、エタノール、イソプロパノールなどのアルコー
ル系溶媒；アセトン、メチルエチルケトンなどのケトン
系溶媒；塩化メチレン、ジクロロエタン、1,1,1−トリ
クロロエタンなどの塩素化炭化水素系溶媒などが挙げら
れ、単独でも、２種以上併用して用いてもよい。The solvent to be used may be any as long as it is inert to the components of the composition, for example: water; alcohol solvents such as methanol, ethanol and isopropanol; ketone solvents such as acetone and methyl ethyl ketone; Examples thereof include chlorinated hydrocarbon solvents such as methylene, dichloroethane, and 1,1,1-trichloroethane, which may be used alone or in combination of two or more kinds.
さらに、無溶媒下で各成分を粉体混合した後、圧縮成形
する方法によっても所望の組成物を得ることができる。Further, the desired composition can be obtained also by a method in which the respective components are powder-mixed in the absence of a solvent and then compression-molded.
実施例 つぎに実施例を挙げて本発明をさらに詳しく説明する。EXAMPLES Next, the present invention will be described in more detail with reference to Examples.
実施例１ 成 分 重量％ ミノサイクリン塩酸塩 2.0 塩化マグネシウム 2.0 ヒドロキシプロピルセルロース 96.0 成分全量の30重量倍のエタノールに塩化マグネシウムお
よびヒドロキシプロピルセルロースを分散、溶解し、こ
れにミノサイクリン塩酸塩を添加し、均一に混合した
後、常法により厚さ0.12mmのフィルム状組成物を得る。Example 1 Composition% by Weight Minocycline Hydrochloride 2.0 Magnesium Chloride 2.0 Hydroxypropyl Cellulose 96.0 Magnesium chloride and hydroxypropylcellulose were dispersed and dissolved in 30 weight times ethanol of the total amount of the components, and minocycline hydrochloride was added thereto to homogenize. After mixing, a film-like composition having a thickness of 0.12 mm is obtained by a conventional method.
実施例２ 成 分 重量％ ミノサイクリン塩酸塩 2.0 塩化マグネシウム 2.0 ポリビニルピロリドン 96.0 成分全量の15重量倍のエタノールを用い、実施例１と同
様にして厚さ0.20mmのフィルム状組成物を得る。Example 2 Composition% by Weight Minocycline Hydrochloride 2.0 Magnesium Chloride 2.0 Polyvinylpyrrolidone 96.0 A 0.20 mm-thick film-like composition was obtained in the same manner as in Example 1 except that 15% by weight of ethanol was used.
実施例３ 成 分 重量％ ミノサイクリン塩酸塩 2.0 塩化マグネシウム 2.0 グリセリン 10.0 ポリビニルピロリドン 86.0 成分全量の５重量倍のエタノールを用い、実施例１と同
様にして厚さ0.4mmのフィルム状組成物を得る。Example 3 Composition% by Weight Minocycline Hydrochloride 2.0 Magnesium Chloride 2.0 Glycerin 10.0 Polyvinylpyrrolidone 86.0 A 0.4 mm-thick film-like composition was obtained in the same manner as in Example 1 using 5 parts by weight of ethanol.
実施例４ 成 分 重量％ ミノサイクリン塩酸塩 1.0 酢酸マグネシウム 1.0 ポリビニルピロリドン 98.0 成分全量の15重量倍の塩化メチレン−エタノール（1:
4）混液を用い、実施例１と同様にして厚さ0.02mmのフ
ィルム状組成物を得る。Example 4 Composition% by Weight Minocycline Hydrochloride 1.0 Magnesium Acetate 1.0 Polyvinylpyrrolidone 98.0 15% by Weight Methylene Chloride-Ethanol (1:
4) Using the mixed solution, a film-like composition having a thickness of 0.02 mm is obtained in the same manner as in Example 1.
実施例５ 成 分 重量％ ミノサイクリン塩酸塩 2.0 硫酸マグネシウム 5.0 ポリビニルピロリドン 93.0 成分全量の20重量倍の塩化メチレン−エタノール（1:
5）混液を用い、実施例１と同様にして厚さ0.15mmのフ
ィルム状組成物を得る。Example 5 Composition% by Weight Minocycline Hydrochloride 2.0 Magnesium Sulfate 5.0 Polyvinylpyrrolidone 93.0 20% by Weight Methylene Chloride-Ethanol (1:
5) Using the mixed solution, a film-like composition having a thickness of 0.15 mm is obtained in the same manner as in Example 1.
実施例６ 成 分 重量％ ミノサイクリン塩酸塩 0.5 塩化マグネシウム 0.5 プルラン 99.0 成分全量の20重量倍の30％エタノール溶液を用い、実施
例１と同様にして厚さ0.32mmのフィルム状組成物を得
る。Example 6 Component weight% minocycline hydrochloride 0.5 Magnesium chloride 0.5 Pullulan 99.0 Using a 30% ethanol solution in an amount 20% by weight of the total amount of the components, a film-like composition having a thickness of 0.32 mm is obtained in the same manner as in Example 1.
実施例７ 成 分 重量％ ミノサイクリン塩酸塩 2.0 塩化マグネシウム 2.0 トリアセチン 15.0 マミノアルキルメタアクリレート 81.0 コポリマーRS 成分全量の30重量倍の塩化メチレン−エタノール（1:
4）混液を用い実施例１と同様にして厚さ0.20mmのフィ
ルム状組成物を得る。Example 7 Component wt% Minocycline Hydrochloride 2.0 Magnesium Chloride 2.0 Triacetin 15.0 Maminoalkylmethacrylate 81.0 Copolymer RS 30% by weight of the total amount of methylene chloride-ethanol (1:
4) Using the mixed solution, a film-like composition having a thickness of 0.20 mm is obtained in the same manner as in Example 1.
ミノサイクリンの安定化試験 以下の第１表に示す処方の種々のミノサイクリン塩酸塩
およびテトラサイクリン塩酸塩配合フィルム状組成物を
調製し、調製直後と40℃で１ケ月保存後のそれら抗生物
質の力価を日本抗生物質基準解説（1982年版）に準じて
測定し、配合当初の力価に対する力価残存率（％）を算
出した。結果を第１表に示す。Stabilization test of minocycline Various minocycline hydrochloride and tetracycline hydrochloride mixed film-like compositions having the formulations shown in Table 1 below were prepared, and the titer of the antibiotics immediately after the preparation and after storage at 40 ° C for 1 month were evaluated. The measurement was performed according to the Japan Antibiotic Standards Commentary (1982 version), and the residual titer rate (%) relative to the initial titer was calculated. The results are shown in Table 1.
第１表に示すごとく、マグネシウム化合物と水溶性高分
子物質の組み合わせはミノサイクリンのみを特異的に安
定化する。 As shown in Table 1, the combination of the magnesium compound and the water-soluble polymeric substance specifically stabilizes only minocycline.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 喜多 一吉 大阪府高槻市朝日町３番１号 サンスター 株式会社内 (72)発明者 飯田 誠一 大阪府高槻市朝日町３番１号 サンスター 株式会社内 (56)参考文献 特公 平１−12728（ＪＰ，Ｂ２) ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Ikichi Kita No. 3 Asahi-cho, Takatsuki-shi, Osaka Sunstar Co., Ltd. (72) Seiichi Iida No. 3 Asahi-cho, Takatsuki-shi, Osaka Sunstar Co., Ltd. In-house (56) References Japanese Patent Publication 1-12728 (JP, B2)
Claims (1)
ルロース、ヒドロキシプロピルメチルセルロース、カル
ボキシメチルエチルセルロース、ヒドロキシプロピルメ
チルセルロース・フタレート、ヒドロキシプロピルメチ
ルセルロース・アセテート・サクシネート、プルラン、
キチン、キトサン、アミノアルキルメタアクリレートコ
ポリマーRS、アミノアルキルメタアクリレートコポリマ
ーＥ、メタアクリル酸コポリマーＬ、ポリアクリル酸お
よびその塩、ポリビニルピロリドンから選ばれる１種ま
たは２種以上の水溶性高分子物質と、ミノサイクリンま
たはその医薬上許容される塩およびマグネシウム化合物
を配合したフィルム状またはシート状の製剤形を有する
ことを特徴とするミノサイクリンを安定に配合した組成
物。1. Methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, pullulan,
One or more water-soluble polymer substances selected from chitin, chitosan, aminoalkylmethacrylate copolymer RS, aminoalkylmethacrylate copolymer E, methacrylic acid copolymer L, polyacrylic acid and its salts, and polyvinylpyrrolidone; A composition containing minocycline stably, which has a film-like or sheet-like formulation containing minocycline or a pharmaceutically acceptable salt thereof and a magnesium compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61122488A JPH0729930B2 (en) | 1986-05-27 | 1986-05-27 | Composition containing minocycline in a stable manner |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61122488A JPH0729930B2 (en) | 1986-05-27 | 1986-05-27 | Composition containing minocycline in a stable manner |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS62289518A JPS62289518A (en) | 1987-12-16 |
| JPH0729930B2 true JPH0729930B2 (en) | 1995-04-05 |
Family
ID=14837085
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61122488A Expired - Fee Related JPH0729930B2 (en) | 1986-05-27 | 1986-05-27 | Composition containing minocycline in a stable manner |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0729930B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11426351B2 (en) | 2019-12-26 | 2022-08-30 | Sunstar Inc. | Process for producing a pharmaceutical composition containing micro particles |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62298521A (en) * | 1986-06-18 | 1987-12-25 | Advance Co Ltd | Anti-periodontal substance |
| US20020187181A1 (en) * | 2001-05-14 | 2002-12-12 | 3M Innovative Properties Company | System for delivering cosmetics and pharmaceuticals |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6412728A (en) * | 1987-07-07 | 1989-01-17 | Fujitsu Ltd | Echo canceller |
-
1986
- 1986-05-27 JP JP61122488A patent/JPH0729930B2/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11426351B2 (en) | 2019-12-26 | 2022-08-30 | Sunstar Inc. | Process for producing a pharmaceutical composition containing micro particles |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS62289518A (en) | 1987-12-16 |
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