JPWO2019153019A5 - - Google Patents
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- JPWO2019153019A5 JPWO2019153019A5 JP2019551639A JP2019551639A JPWO2019153019A5 JP WO2019153019 A5 JPWO2019153019 A5 JP WO2019153019A5 JP 2019551639 A JP2019551639 A JP 2019551639A JP 2019551639 A JP2019551639 A JP 2019551639A JP WO2019153019 A5 JPWO2019153019 A5 JP WO2019153019A5
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- JP
- Japan
- Prior art keywords
- amino
- preparation according
- edta
- chelating agent
- hec
- Prior art date
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- 239000002738 chelating agent Substances 0.000 claims description 34
- 239000000203 mixture Substances 0.000 claims description 30
- CWSZBVAUYPTXTG-UHFFFAOYSA-N 5-[6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxy-5-[4-hydroxy-3-(2-hydroxyethoxy)-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)OCCO)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 CWSZBVAUYPTXTG-UHFFFAOYSA-N 0.000 claims description 28
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 28
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 28
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 28
- -1 deferipron Chemical compound 0.000 claims description 24
- HHVIBTZHLRERCL-UHFFFAOYSA-N Methylsulfonylmethane Chemical group CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 claims description 22
- 229940016409 methylsulfonylmethane Drugs 0.000 claims description 22
- 238000009472 formulation Methods 0.000 claims description 20
- 229920000642 polymer Polymers 0.000 claims description 20
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 claims description 9
- ZGTMUACCHSMWAC-UHFFFAOYSA-L disodium;2-[2-[carboxylatomethyl(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetate Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000011780 sodium chloride Substances 0.000 claims description 8
- 208000002193 Pain Diseases 0.000 claims description 6
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 230000035807 sensation Effects 0.000 claims description 5
- URDCARMUOSMFFI-UHFFFAOYSA-N 2-[2-[bis(carboxymethyl)amino]ethyl-(2-hydroxyethyl)amino]acetic acid Chemical compound OCCN(CC(O)=O)CCN(CC(O)=O)CC(O)=O URDCARMUOSMFFI-UHFFFAOYSA-N 0.000 claims description 4
- FCKYPQBAHLOOJQ-UHFFFAOYSA-N 2-[[2-[bis(carboxymethyl)amino]cyclohexyl]-(carboxymethyl)amino]acetic acid Chemical compound OC(=O)CN(CC(O)=O)C1CCCCC1N(CC(O)=O)CC(O)=O FCKYPQBAHLOOJQ-UHFFFAOYSA-N 0.000 claims description 4
- YDONNITUKPKTIG-UHFFFAOYSA-N ATMP Chemical compound OP(O)(=O)CN(CP(O)(O)=O)CP(O)(O)=O YDONNITUKPKTIG-UHFFFAOYSA-N 0.000 claims description 4
- ZIUSSTSXXLLKKK-HWUZOJPISA-N Curcumin Natural products C1=C(O)C(OC)=CC(\C=C\C(\O)=C/C(=O)/C=C/C=2C=C(OC)C(O)=CC=2)=C1 ZIUSSTSXXLLKKK-HWUZOJPISA-N 0.000 claims description 4
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims description 4
- 206010013774 Dry eye Diseases 0.000 claims description 4
- VBIZUNYMJSPHBH-OQLLNIDSSA-N Salinazid Chemical compound OC1=CC=CC=C1\C=N\NC(=O)C1=CC=NC=C1 VBIZUNYMJSPHBH-OQLLNIDSSA-N 0.000 claims description 4
- ACTRVOBWPAIOHC-UHFFFAOYSA-N Succimer Chemical compound OC(=O)C(S)C(S)C(O)=O ACTRVOBWPAIOHC-UHFFFAOYSA-N 0.000 claims description 4
- 230000002776 aggregation Effects 0.000 claims description 4
- 238000004220 aggregation Methods 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 230000000873 masking Effects 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal Chemical compound CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 claims description 4
- 229950007671 salinazid Drugs 0.000 claims description 4
- 239000002562 thickening agent Substances 0.000 claims description 4
- PFNFFQXMRSDOHW-UHFFFAOYSA-N Spermine Chemical compound NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 claims description 3
- GKJQHSSYBJHANH-UHFFFAOYSA-N 1,1-bis(sulfanyl)propane-1-sulfonic acid Chemical compound CCC(S)(S)S(O)(=O)=O GKJQHSSYBJHANH-UHFFFAOYSA-N 0.000 claims description 2
- YDVODBIDDSGKAD-UHFFFAOYSA-N 1,4,7,11-tetrazacyclotetradecane Chemical compound C1CNCCCNCCNCCNC1 YDVODBIDDSGKAD-UHFFFAOYSA-N 0.000 claims description 2
- ROFVEXUMMXZLPA-UHFFFAOYSA-N 2,2'-bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 2
- SZGVJLCXTSBVKL-UHFFFAOYSA-H 2,4,6,8,10,12-hexaoxido-1,3,5,7,9,11-hexaoxa-2$l^{5},4$l^{5},6$l^{5},8$l^{5},10$l^{5},12$l^{5}-hexaphosphacyclododecane 2,4,6,8,10,12-hexaoxide Chemical compound [O-]P1(=O)OP([O-])(=O)OP([O-])(=O)OP([O-])(=O)OP([O-])(=O)OP([O-])(=O)O1 SZGVJLCXTSBVKL-UHFFFAOYSA-H 0.000 claims description 2
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 claims description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 2
- WHTVZRBIWZFKQO-UHFFFAOYSA-N Chloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 claims description 2
- 229960003677 Chloroquine Drugs 0.000 claims description 2
- 229940109262 Curcumin Drugs 0.000 claims description 2
- RPNUMPOLZDHAAY-UHFFFAOYSA-N DETA Chemical class NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 claims description 2
- RAABOESOVLLHRU-UHFFFAOYSA-N Diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 claims description 2
- QZKRHPLGUJDVAR-UHFFFAOYSA-K EDTA trisodium salt Chemical compound [Na+].[Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O QZKRHPLGUJDVAR-UHFFFAOYSA-K 0.000 claims description 2
- 229950002499 Fytic acid Drugs 0.000 claims description 2
- 206010061218 Inflammation Diseases 0.000 claims description 2
- IMQLKJBTEOYOSI-GPIVLXJGSA-N Inositol-hexakisphosphate Chemical compound OP(O)(=O)O[C@H]1[C@H](OP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@@H]1OP(O)(O)=O IMQLKJBTEOYOSI-GPIVLXJGSA-N 0.000 claims description 2
- 102000004895 Lipoproteins Human genes 0.000 claims description 2
- 108090001030 Lipoproteins Proteins 0.000 claims description 2
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 claims description 2
- 229940068041 Phytic Acid Drugs 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- 229960003581 Pyridoxal Drugs 0.000 claims description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-J Pyrophosphate Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims description 2
- OFVLGDICTFRJMM-WESIUVDSSA-N Tetracycline Chemical compound C1=CC=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 OFVLGDICTFRJMM-WESIUVDSSA-N 0.000 claims description 2
- 229960002180 Tetracycline Drugs 0.000 claims description 2
- 239000004098 Tetracycline Substances 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 230000003115 biocidal Effects 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 235000012754 curcumin Nutrition 0.000 claims description 2
- 239000004148 curcumin Substances 0.000 claims description 2
- 229910000071 diazene Inorganic materials 0.000 claims description 2
- 235000011180 diphosphates Nutrition 0.000 claims description 2
- 239000003623 enhancer Substances 0.000 claims description 2
- 230000002708 enhancing Effects 0.000 claims description 2
- 229940005740 hexametaphosphate Drugs 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
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 2
- 230000004054 inflammatory process Effects 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 235000021317 phosphate Nutrition 0.000 claims description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 2
- 239000000467 phytic acid Substances 0.000 claims description 2
- 235000002949 phytic acid Nutrition 0.000 claims description 2
- 229920000768 polyamine Polymers 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 102000004169 proteins and genes Human genes 0.000 claims description 2
- 108090000623 proteins and genes Proteins 0.000 claims description 2
- 235000008164 pyridoxal Nutrition 0.000 claims description 2
- 239000011674 pyridoxal Substances 0.000 claims description 2
- 231100000486 side effect Toxicity 0.000 claims description 2
- 235000002639 sodium chloride Nutrition 0.000 claims description 2
- 235000019832 sodium triphosphate Nutrition 0.000 claims description 2
- 235000019364 tetracycline Nutrition 0.000 claims description 2
- AUMOSEQHACNXEW-UHFFFAOYSA-J tetrapotassium;[2-[bis[[hydroxy(oxido)phosphoryl]methyl]amino]ethyl-[[hydroxy(oxido)phosphoryl]methyl]amino]methyl-hydroxyphosphinate Chemical compound [K+].[K+].[K+].[K+].OP([O-])(=O)CN(CP(O)([O-])=O)CCN(CP(O)([O-])=O)CP(O)([O-])=O AUMOSEQHACNXEW-UHFFFAOYSA-J 0.000 claims description 2
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 claims description 2
- 239000003190 viscoelastic substance Substances 0.000 claims description 2
- 229960000958 Deferoxamine Drugs 0.000 claims 1
- 239000003961 penetration enhancing agent Substances 0.000 description 4
- 201000010874 syndrome Diseases 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 1
- 230000001627 detrimental Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 229940063675 spermine Drugs 0.000 description 1
Description
上記の発明は、理解を明確にする目的で、例示および実施例としてある程度詳細に記載されているが、添付の特許請求の範囲の精神または範囲から逸脱することなく特定の変更および修正を行うことができることは、本発明の教示に照らして、当業者には容易に明らかであろう。
本願は、以下の態様も包含する。
［態様１］
有害な眼状態の治療のための眼用製剤であって、
（ａ）キレート剤またはその塩；
（ｂ）電荷マスキング剤である輸送促進剤；
（ｃ）副作用の軽減および有効性の向上に十分な量の粘弾性材料である増粘剤の濃度；および
（ｄ）薬学的に許容される不活性ビヒクル
を含む製剤であり、
キレート剤および輸送促進剤が、適用される眼における高分子凝集の有意な減少をもたらすのに有効な割合で存在し、
組成物中の、キレート剤のパーセンテージが約０.１重量％～１５重量％であり、輸送のパーセンテージが約０.１重量％～４０重量％である、
製剤。
［態様２］
輸送促進剤がＭＳＭである、態様１記載の製剤。
［態様３］
ＭＳＭの量が５％未満である、態様１記載の製剤。
［態様４］
キレート剤対ＭＳＭの比率が約１０：１～１：２０の範囲である、態様２記載の製剤。
［態様５］
粘弾性ポリマーが、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、ヒドロキシエチルセルロース（ＨＥＣ）およびポリビニルアルコールから選択される、態様１記載の製剤。
［態様６］
粘弾性ポリマーがヒドロキシエチルセルロース（ＨＥＣ）である、態様１記載の製剤。
［態様７］
ＨＥＣの濃度が０.５％～５.０％である、態様６記載の製剤。
［態様８］
ＨＥＣの濃度が０.５％～１.０％である、態様６記載の製剤。
［態様９］
ＨＥＣの濃度が０.８％～０.８５％である、態様６記載の製剤。
［態様１０］
キレート剤が、エチレンジアミン四酢酸（ＥＤＴＡ）、エチレングリコール四酢酸（ＥＧＴＡ）、シクロヘキサンジアミン四酢酸（ＣＤＴＡ）、ヒドロキシエチルエチレンジアミン三酢酸（ＨＥＤＴＡ）、ジエチレントリアミン五酢酸（ＤＴＰＡ）、ジメルカプトプロパンスルホン酸（ＤＭＰＳ）、ジメルカプトコハク酸（ＤＭＳＡ）、アミノトリメチレンホスホン酸（ＡｒＰＡ）、クエン酸、酢酸およびそれらの許容される塩、ならびにそれらの組合せから選択される、態様１記載の製剤。
［態様１１］
ＥＤＴＡ塩が、ＥＤＴＡ二アンモニウム、ＥＤＴＡ二ナトリウム、ＥＤＴＡ二カリウム、ＥＤＴＡ三アンモニウム、ＥＤＴＡ三ナトリウム、ＥＤＴＡ三カリウム、ＥＤＴＡ四ナトリウム、ＥＤＴＡ四カリウム、ＥＤＴＡ二ナトリウムカルシウム、およびそれらの組合せから選択される、態様１０記載の製剤。
［態様１２］
キレート剤が、リン酸塩、ピロリン酸塩、トリポリリン酸塩およびヘキサメタリン酸塩から選択される、態様１記載の製剤。
［態様１３］
キレート剤が、キレート化抗生物質、クロロキンまたはテトラサイクリンである、態様１記載の製剤。
［態様１４］
キレート剤が、イミノ基内または芳香環中に２個以上のキレート化窒素原子を含有する窒素含有キレート剤、ジイミンまたは２,２'－ビピリジンである、態様１記載の製剤。
［態様１５］
キレート剤が、サイクラム（１,４,７,１１－テトラアザシクロテトラデカン）、Ｎ－(Ｃ
1
～Ｃ
30
アルキル)置換サイクラム（例えば、ヘキサデサイクラム、テトラメチルヘキサデシルサイクラム）、ジエチレントリアミン（ＤＥＴＡ）、スペルミン、ジエチルノルスペルミン（ＤＥＮＳＰＭ）、ジエチルホモスペルミン（ＤＥＨＯＰ）、デフェロキサミン（Ｎ'－{５－[アセチル(ヒドロキシ)アミノ]ペンチル}－Ｎ－[５－({４－[(５－アミノペンチル)(ヒドロキシ)アミノ]－４－オキソブタノイル}アミノ)ペンチル]－Ｎ－ヒドロキシサクシナミド、またはＮ'－[５－(アセチル－ヒドロキシ－アミノ)ペンチル]－Ｎ－[５－[３－(５－アミノペンチル－ヒドロキシ－カルバモイル)プロパノイルアミノ]ペンチル]－Ｎ－ヒドロキシ－ブタンジアミド）、デスフェリオキサミンＢ、デスフェロキサミンＢ、ＤＦＯ－Ｂ、ＤＦＯＡ、ＤＦＢ、デスフェラール、デフェリプロン、ピリドキサールイソニコチノイルヒドラゾン（ＰＩＨ）、サリチルアルデヒドイソニコチノイルヒドラゾン（ＳＩＨ）、エタン－１,２－ビス(Ｎ－１－アミノ－３－エチルブチル－３－チオール)から選択されるポリアミンである、態様１記載の製剤。。
［態様１６］
キレート剤が、([２－(ビス－エトキシカルボニルメチル－アミノ)－エチル]－{[２－(７－クロロ－キノリン－４－イルアミノ)－エチルカルバモイル]－メチル}－アミノ)－酢酸エチルエステル、([２－(ビス－エトキシカルボニルメチル－アミノ)－プロピル]－{[２－(７－クロロ－キノリン－４－イルアミノ)－エチルカルバモイル]－メチル}－アミノ)－酢酸エチルエステル、([３－(ビス－エトキシカルボニルメチル－アミノ)－プロピル]－{[２－(７－クロロ－キノリン－４－イルアミノ)－エチルカルバモイル]－メチル}－アミノ)－酢酸エチルエステル、([４－(ビス－エトキシカルボニルメチル－アミノ)－ブチル]－{[２－(７－クロロ－キノリン－４－イルアミノ)－エチルカルバモイル]－メチル}－アミノ)－酢酸エチルエステル、([２－(ビス－エトキシメチル－アミノ)－エチル]－{[２－(７－クロロ－キノリン－４－イルアミノ)－エチルカルバモイル]－メチル}－アミノ)－酢酸エチルエステル、([２－(ビス－エトキシメチル－アミノ)－プロピル]－{[２－(７－クロロ－キノリン－４－イルアミノ)－エチルカルバモイル]－メチル}－アミノ)－酢酸エチルエステル、([３－(ビス－エトキシメチル－アミノ)－プロピル]－{[２－(７－クロロ－キノリン－４－イルアミノ)－エチルカルバモイル]－メチル}－アミノ)－酢酸エチルエステル、([４－(ビス－エトキシメチル－アミノ)－ブチル]－{[２－(７－クロロ－キノリン－４－イルアミノ)－エチルカルバモイル]－メチル}－アミノ)－酢酸エチルエステルから選択されるＥＤＴＡ－４－アミノキノリン抱合体である、態様１記載の製剤。
［態様１７］
キレート剤が、クエン酸、フィチン酸、乳酸、酢酸およびそれらの塩、ならびにクルクミンから選択される天然キレート剤である、態様１記載の製剤。
［態様１８］
ビヒクルが水性である、態様１記載の製剤。
［態様１９］
製剤の投与が眼中の高分子凝集体を減少させる、態様１記載の製剤。
［態様２０］
高分子凝集体がペプチジル化合物である、態様１９記載の製剤。
［態様２１］
高分子凝集体がタンパク質である、態様１９記載の製剤。
［態様２２］
高分子凝集体がリポタンパク質である、態様１９記載の製剤。
［態様２３］
製剤が眼挿入物を含む、態様１記載の製剤。
［態様２４］
製剤が時限放出用である、態様１記載の製剤。
［態様２５］
高分子凝集体が
である、態様１９記載の製剤。
［態様２６］
製剤が、ＭＳＭ２.７％ｗ／ｗ；ＥＤＴＡ二ナトリウム１.３％ｗ／ｗ；およびＨＥＣ０.８５％ｗ／ｗを含む、態様１記載の製剤。
［態様２７］
有害な眼症候群の徴候の軽減を必要とする対象体の眼に態様１記載の製剤を投与することによる有害な眼症候群の徴候を軽減するための方法。
［態様２８］
有害な眼状態が眼における高分子凝集体の蓄積である、態様２７記載の方法。
［態様２９］
製剤が、粘弾性ポリマーの非存在下での有効性と比較して、粘弾性ポリマーの存在下で有効であるとして少なくとも７５％である量のキレート剤および浸透促進剤を含む、態様２７記載の方法。
［態様３０］
製剤が、浸透促進剤としてＭＳＭ、ＭＳＭおよび粘弾性ポリマーとしてＨＥＣを含む、態様２７記載の方法。
［態様３１］
使用される製剤が、ＭＳＭ２.７％ｗ／ｗ；ＥＤＴＡ二ナトリウム１.３％ｗ／ｗ；およびＨＥＣ０.８５％ｗ／ｗを含む、態様３０記載の方法。
［態様３２］
製剤が、粘弾性ポリマーの非存在下での刺痛感と比較して、粘弾性ポリマーの存在下で対象体の眼における刺痛感を有意に減少させる量のキレート剤、浸透促進剤および粘弾性ポリマーを含む、態様２７記載の方法。
［態様３３］
製剤が、浸透促進剤としてＭＳＭ、ＭＳＭおよび粘弾性ポリマーとしてＨＥＣを含む、態様２７記載の方法。
［態様３４］
使用される製剤が、ＭＳＭ２.７％ｗ／ｗ；ＥＤＴＡ二ナトリウム１.３％ｗ／ｗ；およびＨＥＣ０.８５％ｗ／ｗを含む、態様３０記載の方法。
［態様３５］
対象体における刺痛感を減少させながら有害な眼状態を治療するための製剤であって、
（ａ）キレート剤またはその塩；
（ｂ）メチルスルホニルメタン（ＭＳＭ）である電荷マスキング剤；
（ｃ）０.５％～５.０％の濃度のヒドロキシエチルセルロース（ＨＥＣ）である増粘剤；および
（ｄ）薬学的に許容される不活性ビヒクル
を含む製剤であって、
ＨＥＣの濃度が、眼におけるキレート剤／ＭＳＭの組合せの放出を減少させて、刺痛感が生じる濃度レベルよりも低い濃度レベルを維持するのに十分であり、
ＨＥＣの濃度が、有害な眼状態の有意な減少をもたらすのに有効な期間、眼中にキレート剤／ＭＳＭを保持するのに十分であり、
組成物中の、キレート剤のパーセンテージが約０.１重量％～３.０重量％であり、輸送のパーセンテージが約０.１重量％～６.０重量％である、
製剤。
［態様３６］
有害な眼状態が高分子凝集によって引き起こされる、態様３５記載の製剤。
［態様３７］
有害な眼状態がドライアイ症候群によって引き起こされる、態様３５記載の製剤。
［態様３８］
ドライアイ症候群が炎症によって引き起こされる、態様３７記載の製剤。
The above invention has been described in some detail as examples and examples for the purpose of clarifying understanding, but making specific changes and modifications without departing from the spirit or scope of the appended claims. It will be readily apparent to those skilled in the art in the light of the teachings of the present invention.
The present application also includes the following aspects.
[Aspect 1]
An ocular formulation for the treatment of harmful eye conditions
(A) Chelating agent or salt thereof;
(B) Transport promoter which is a charge masking agent;
(C) Concentration of thickener, which is a viscoelastic material sufficient to reduce side effects and improve efficacy;
(D) Pharmaceutically acceptable inert vehicle
Is a formulation containing
Chelating agents and transport enhancers are present in effective proportions to result in a significant reduction in macromolecular aggregation in the applied eye.
The percentage of chelating agent in the composition is from about 0.1% to 15% by weight and the percentage of transport is from about 0.1% to 40% by weight.
pharmaceutical formulation.
[Aspect 2]
The preparation according to embodiment 1, wherein the transport promoter is MSM.
[Aspect 3]
The preparation according to embodiment 1, wherein the amount of MSM is less than 5%.
[Aspect 4]
The preparation according to aspect 2, wherein the ratio of chelating agent to MSM is in the range of about 10: 1 to 1:20.
[Aspect 5]
The preparation according to embodiment 1, wherein the viscoelastic polymer is selected from hydroxypropylmethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose (HEC) and polyvinyl alcohol.
[Aspect 6]
The preparation according to embodiment 1, wherein the viscoelastic polymer is hydroxyethyl cellulose (HEC).
[Aspect 7]
The preparation according to embodiment 6, wherein the concentration of HEC is 0.5% to 5.0%.
[Aspect 8]
The preparation according to embodiment 6, wherein the concentration of HEC is 0.5% to 1.0%.
[Aspect 9]
The preparation according to embodiment 6, wherein the HEC concentration is 0.8% to 0.85%.
[Aspect 10]
Chelating agents include ethylenediaminetetraacetic acid (EDTA), ethyleneglycoltetraacetic acid (EGTA), cyclohexanediaminetetraacetic acid (CDTA), hydroxyethylethylenediaminetriacetic acid (HEDTA), diethylenetriaminetetraacetic acid (DTPA), and dimercaptopropanesulfonic acid (DMPS). ), Dimercaptosuccinic acid (DMSA), aminotrimethylenephosphonic acid (ArPA), citric acid, acetic acid and acceptable salts thereof, and the formulations according to embodiment 1.
[Aspect 11]
The EDTA salt is selected from EDTA diammonium, EDTA disodium, EDTA dipotassium, EDTA triammonium, EDTA trisodium, EDTA tripotassium, EDTA tetrasodium, EDTA tetrapotassium, EDTA disodium calcium, and combinations thereof. The preparation according to the tenth aspect.
[Aspect 12]
The preparation according to embodiment 1, wherein the chelating agent is selected from phosphate, pyrophosphate, tripolyphosphate and hexametaphosphate.
[Aspect 13]
The preparation according to embodiment 1, wherein the chelating agent is a chelated antibiotic, chloroquine or tetracycline.
[Aspect 14]
The preparation according to embodiment 1, wherein the chelating agent is a nitrogen-containing chelating agent containing two or more chelated nitrogen atoms in an imino group or an aromatic ring, diimine or 2,2'-bipyridine.
[Aspect 15]
Chelating agents include cycloms (1,4,7,11-tetraazacyclotetradecane), N- (C 1 to C 30 alkyl) substituted cycloms (eg, hexadecycrum, tetramethylhexadecylcyclum), diethylenetriamines (DETA). ), Spermine, diethylnorspermin (DENSPM), diethylhomosepermin (DEHOP), deferroxamine (N'-{5- [acetyl (hydroxy) amino] pentyl} -N- [5-({4-[(5-amino) Pentyl) (Hydroxy) Amino] -4-oxobutanoyl} Amino) Pentyl] -N-Hydroxysuccinamide, or N'- [5- (Acetyl-Hydroxy-Amino) Pentyl] -N- [5- [3 -(5-Aminopentyl-hydroxy-carbamoyl) propanoylamino] pentyl] -N-hydroxy-butanediamide), desferrioxamine B, desferroxamine B, DFO-B, DFOA, DFB, desferral, deferripron, pyridoxal A polyamine selected from isonicotinoylhydrazone (PIH), salicylaldehyde isonicotinoylhydrazone (SIH), and ethane-1,2-bis (N-1-amino-3-ethylbutyl-3-thiol), embodiment 1. The formulation described. ..
[Aspect 16]
The chelating agent is ([2- (bis-ethoxycarbonylmethyl-amino) -ethyl]-{[2- (7-chloro-quinoline-4-ylamino) -ethylcarbamoyl] -methyl} -amino) -acetic acid ethyl ester. , ([2- (Bis-ethoxycarbonylmethyl-amino) -propyl]-{[2- (7-chloro-quinoline-4-ylamino) -ethylcarbamoyl] -methyl} -amino) -acetic acid ethyl ester, ([ 3- (Bis-ethoxycarbonylmethyl-amino) -propyl]-{[2- (7-chloro-quinoline-4-ylamino) -ethylcarbamoyl] -methyl} -amino) -acetic acid ethyl ester, ([4- ( Bis-ethoxycarbonylmethyl-amino) -butyl]-{[2- (7-chloro-quinoline-4-ylamino) -ethylcarbamoyl] -methyl} -amino) -acetic acid ethyl ester, ([2- (bis-ethoxy) Methyl-amino) -ethyl]-{[2- (7-chloro-quinoline-4-ylamino) -ethylcarbamoyl] -methyl} -amino) -acetic acid ethyl ester, ([2- (bis-ethoxymethyl-amino)) -Propyl]-{[2- (7-Chloro-quinoline-4-ylamino) -ethylcarbamoyl] -methyl} -amino) -acetic acid ethyl ester, ([3- (bis-ethoxymethyl-amino) -propyl]- {[2- (7-Chloro-quinoline-4-ylamino) -ethylcarbamoyl] -methyl} -amino) -acetic acid ethyl ester, ([4- (bis-ethoxymethyl-amino) -butyl]-{[2- The preparation according to embodiment 1, which is an EDTA-4-aminoquinoline conjugate selected from (7-chloro-quinoline-4-ylamino) -ethylcarbamoyl] -methyl} -amino) -acetic acid ethyl ester.
[Aspect 17]
The preparation according to embodiment 1, wherein the chelating agent is a natural chelating agent selected from citric acid, phytic acid, lactic acid, acetic acid and salts thereof, and curcumin.
[Aspect 18]
The preparation according to embodiment 1, wherein the vehicle is aqueous.
[Aspect 19]
The preparation according to embodiment 1, wherein administration of the preparation reduces macromolecular aggregates in the eye.
[Aspect 20]
The preparation according to aspect 19, wherein the polymer aggregate is a peptidyl compound.
[Aspect 21]
The preparation according to aspect 19, wherein the polymer aggregate is a protein.
[Aspect 22]
The preparation according to aspect 19, wherein the polymer aggregate is a lipoprotein.
[Aspect 23]
The preparation according to aspect 1, wherein the preparation comprises an ocular insert.
[Aspect 24]
The preparation according to embodiment 1, wherein the preparation is for timed release.
[Aspect 25]
Polymer aggregates
The preparation according to aspect 19.
[Aspect 26]
The preparation according to aspect 1, wherein the preparation comprises 2.7% w / w of MSM; 1.3% w / w of EDTA disodium; and 0.85% w / w of HEC.
[Aspect 27]
A method for alleviating the signs of harmful eye syndrome by administering the preparation according to Embodiment 1 to the eyes of a subject in need of alleviation of the signs of harmful eye syndrome.
[Aspect 28]
27. The method of aspect 27, wherein the detrimental ocular condition is the accumulation of macromolecular aggregates in the eye.
[Aspect 29]
28. The embodiment 27, wherein the formulation comprises an amount of a chelating agent and a penetration enhancer that is at least 75% as effective in the presence of the viscoelastic polymer as compared to its effectiveness in the absence of the viscoelastic polymer. Method.
[Aspect 30]
28. The method of aspect 27, wherein the formulation comprises MSM, MSM as a penetration enhancer and HEC as a viscoelastic polymer.
[Aspect 31]
30. The method of aspect 30, wherein the formulation used comprises MSM 2.7% w / w; EDTA disodium 1.3% w / w; and HEC 0.85% w / w.
[Aspect 32]
The amount of chelating agent, penetration enhancer and stickiness that the formulation significantly reduces the stinging sensation in the subject's eye in the presence of the viscoelastic polymer as compared to the stinging sensation in the absence of the viscoelastic polymer. 27. The method of aspect 27, comprising an elastic polymer.
[Aspect 33]
28. The method of aspect 27, wherein the formulation comprises MSM, MSM as a penetration enhancer and HEC as a viscoelastic polymer.
[Aspect 34]
30. The method of aspect 30, wherein the formulation used comprises MSM 2.7% w / w; EDTA disodium 1.3% w / w; and HEC 0.85% w / w.
[Aspect 35]
It is a preparation for treating harmful eye conditions while reducing the feeling of stinging in the subject.
(A) Chelating agent or salt thereof;
(B) Charge masking agent, methylsulfonylmethane (MSM);
(C) Thickeners that are hydroxyethyl cellulose (HEC) at concentrations of 0.5% to 5.0%; and
(D) Pharmaceutically acceptable inert vehicle
It is a preparation containing
The concentration of HEC is sufficient to reduce the release of the chelating / MSM combination in the eye and maintain a concentration level lower than the concentration level at which the stinging sensation occurs.
The concentration of HEC is sufficient to retain the chelating agent / MSM in the eye for a period of time effective to bring about a significant reduction in harmful eye conditions.
The percentage of chelating agent in the composition is from about 0.1% to 3.0% by weight and the percentage of transport is from about 0.1% to 6.0% by weight.
pharmaceutical formulation.
[Aspect 36]
35. The formulation according to embodiment 35, wherein the harmful ocular condition is caused by macromolecular aggregation.
[Aspect 37]
35. The formulation according to embodiment 35, wherein the harmful eye condition is caused by dry eye syndrome.
[Aspect 38]
38. The formulation according to embodiment 37, wherein the dry eye syndrome is caused by inflammation.
Claims (28)
（ａ）キレート剤またはその塩；
（ｂ）電荷マスキング剤である輸送促進剤（ここで、輸送促進剤はＭＳＭである）；
（ｃ）副作用の軽減および有効性の向上に十分な量の粘弾性材料である増粘剤の濃度（ここで、粘弾性ポリマーは、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、ヒドロキシエチルセルロース（ＨＥＣ）およびポリビニルアルコールから選択される）；および
（ｄ）薬学的に許容される不活性ビヒクル
を含む製剤であり、
キレート剤および輸送促進剤が、適用される眼における高分子凝集の有意な減少をもたらすのに有効な割合で存在し、
組成物中の、キレート剤のパーセンテージが約０.１重量％～１５重量％であり、輸送のパーセンテージが約０.１重量％～４０重量％である、
製剤。 An ocular formulation for the treatment of harmful eye conditions
(A) Chelating agent or salt thereof;
(B) Transport promoter which is a charge masking agent (here, the transport promoter is MSM) ;
(C) Concentration of thickener, which is a viscoelastic material sufficient to reduce side effects and improve efficacy (where the viscoelastic polymers are hydroxypropylmethylcellulose, carboxymethylcellulose, hydroxyethylcellulose (HEC) and polyvinyl alcohol. ( Selected from) ; and (d) a formulation containing a pharmaceutically acceptable inert vehicle.
Chelating agents and transport enhancers are present in effective proportions to result in a significant reduction in macromolecular aggregation in the applied eye.
The percentage of chelating agent in the composition is from about 0.1% to 15% by weight and the percentage of transport is from about 0.1% to 40% by weight.
pharmaceutical formulation.
である、請求項１７記載の製剤。 The preparation according to claim 17 , wherein the polymer aggregate is.
（ａ）キレート剤またはその塩；
（ｂ）メチルスルホニルメタン（ＭＳＭ）である電荷マスキング剤；
（ｃ）０.５％～５.０％の濃度のヒドロキシエチルセルロース（ＨＥＣ）である増粘剤；および
（ｄ）薬学的に許容される不活性ビヒクル
を含む製剤であって、
ＨＥＣの濃度が、眼におけるキレート剤／ＭＳＭの組合せの放出を減少させて、刺痛感が生じる濃度レベルよりも低い濃度レベルを維持するのに十分であり、
ＨＥＣの濃度が、有害な眼状態の有意な減少をもたらすのに有効な期間、眼中にキレート剤／ＭＳＭを保持するのに十分であり、
組成物中の、キレート剤のパーセンテージが約０.１重量％～３.０重量％であり、輸送のパーセンテージが約０.１重量％～６.０重量％である、
製剤。 A formulation for treating harmful eye conditions while reducing the stinging sensation in the eye .
(A) Chelating agent or salt thereof;
(B) Charge masking agent, methylsulfonylmethane (MSM);
(C) A thickener which is hydroxyethyl cellulose (HEC) at a concentration of 0.5% to 5.0%; and (d) a preparation containing a pharmaceutically acceptable inert vehicle.
The concentration of HEC is sufficient to reduce the release of the chelating / MSM combination in the eye and maintain a concentration level lower than the concentration level at which the stinging sensation occurs.
The concentration of HEC is sufficient to retain the chelating agent / MSM in the eye for a period of time effective to bring about a significant reduction in harmful eye conditions.
The percentage of chelating agent in the composition is from about 0.1% to 3.0% by weight and the percentage of transport is from about 0.1% to 6.0% by weight.
pharmaceutical formulation.
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|---|---|---|---|
| JP2024053723A Pending JP2024079810A (en) | 2018-02-05 | 2024-03-28 | Formulations comprising chelators, permeation enhancers and hydroxyethyl cellulose for treating ophthalmic disorders |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US20210085696A1 (en) |
| EP (1) | EP3749294A4 (en) |
| JP (2) | JP2021512847A (en) |
| KR (1) | KR20210127872A (en) |
| AU (1) | AU2019215521A1 (en) |
| WO (1) | WO2019153019A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114712026A (en) * | 2022-05-12 | 2022-07-08 | 温州医科大学附属眼视光医院 | Method for constructing total turbid cataract animal model |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060166879A1 (en) * | 2002-12-20 | 2006-07-27 | Chakshu Research Inc | Treatment of conditions associated with the presence of macromolecular aggregates, particularly ophthalmic disorders |
| US20060177430A1 (en) * | 2002-12-20 | 2006-08-10 | Chakshu Research Inc | Treatment of ocular disorders with ophthalmic formulations containing methylsulfonylmethane as a transport enhancer |
| CA2511217A1 (en) * | 2002-12-20 | 2004-07-15 | Chakshu Research, Inc. | Ophthalmic formulation for the prevention and treatment of ocular conditions |
| US20060172972A1 (en) * | 2002-12-20 | 2006-08-03 | Chakshu Research Inc | Formulation and method for administration of ophthalmologically active agents |
| US20100069335A1 (en) * | 2005-07-15 | 2010-03-18 | Rajiv Bhushan | Prevention and Treatment of Ophthalmic Complications of Diabetes |
| EA200800338A1 (en) * | 2005-07-15 | 2008-08-29 | Чакшу Рисерч Инк. | PREVENTION AND TREATMENT OF OPHTHALMOLOGICAL COMPLICATIONS OF DIABETES |
| AU2013363984B2 (en) * | 2012-12-20 | 2018-02-15 | Rajiv Bhushan | Antimicrobial compositions |
-
2019
- 2019-03-13 WO PCT/US2019/022077 patent/WO2019153019A1/en unknown
- 2019-03-13 EP EP19747269.9A patent/EP3749294A4/en not_active Withdrawn
- 2019-03-13 US US16/967,634 patent/US20210085696A1/en not_active Abandoned
- 2019-03-13 JP JP2019551639A patent/JP2021512847A/en active Pending
- 2019-03-13 KR KR1020207025665A patent/KR20210127872A/en not_active Application Discontinuation
- 2019-03-13 AU AU2019215521A patent/AU2019215521A1/en active Pending
-
2024
- 2024-03-28 JP JP2024053723A patent/JP2024079810A/en active Pending
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