JP2018531268A - ダントロレンを含む水性組成物 - Google Patents
ダントロレンを含む水性組成物 Download PDFInfo
- Publication number
- JP2018531268A JP2018531268A JP2018520391A JP2018520391A JP2018531268A JP 2018531268 A JP2018531268 A JP 2018531268A JP 2018520391 A JP2018520391 A JP 2018520391A JP 2018520391 A JP2018520391 A JP 2018520391A JP 2018531268 A JP2018531268 A JP 2018531268A
- Authority
- JP
- Japan
- Prior art keywords
- component
- cyclodextrin
- dantrolene
- aqueous composition
- aqueous
- 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.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 120
- 229960001987 dantrolene Drugs 0.000 title claims abstract description 67
- OZOMQRBLCMDCEG-CHHVJCJISA-N 1-[(z)-[5-(4-nitrophenyl)furan-2-yl]methylideneamino]imidazolidine-2,4-dione Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(O1)=CC=C1\C=N/N1C(=O)NC(=O)C1 OZOMQRBLCMDCEG-CHHVJCJISA-N 0.000 title claims abstract 4
- 239000000843 powder Substances 0.000 claims abstract description 41
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class 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 claims abstract description 17
- 238000001035 drying Methods 0.000 claims abstract description 6
- 229920000858 Cyclodextrin Polymers 0.000 claims description 35
- 238000009472 formulation Methods 0.000 claims description 31
- 239000003085 diluting agent Substances 0.000 claims description 23
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 18
- 239000001116 FEMA 4028 Substances 0.000 claims description 13
- 229960004853 betadex Drugs 0.000 claims description 13
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 11
- 229940097362 cyclodextrins Drugs 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 9
- -1 gelrantin Chemical compound 0.000 claims description 9
- 239000003002 pH adjusting agent Substances 0.000 claims description 9
- 239000002357 osmotic agent Substances 0.000 claims description 8
- 238000006467 substitution reaction Methods 0.000 claims description 8
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 6
- 229910052791 calcium Inorganic materials 0.000 claims description 6
- 239000011575 calcium Substances 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 239000011521 glass Substances 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- 229920000620 organic polymer Polymers 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 3
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 claims description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 3
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 3
- 239000008121 dextrose Substances 0.000 claims description 3
- 229940050410 gluconate Drugs 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 239000003158 myorelaxant agent Substances 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- 229940097346 sulfobutylether-beta-cyclodextrin Drugs 0.000 claims description 3
- QGKBSGBYSPTPKJ-UZMKXNTCSA-N 2,6-di-o-methyl-β-cyclodextrin Chemical compound COC[C@H]([C@H]([C@@H]([C@H]1OC)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COC)[C@H]([C@@H]([C@H]3OC)O)O[C@H]3O[C@H](COC)[C@H]([C@@H]([C@H]3OC)O)O[C@H]3O[C@H](COC)[C@H]([C@@H]([C@H]3OC)O)O[C@H]3O[C@H](COC)[C@H]([C@@H]([C@H]3OC)O)O3)[C@H](O)[C@H]2OC)COC)O[C@@H]1O[C@H]1[C@H](O)[C@@H](OC)[C@@H]3O[C@@H]1COC QGKBSGBYSPTPKJ-UZMKXNTCSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- PHOQVHQSTUBQQK-SQOUGZDYSA-N D-glucono-1,5-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 claims description 2
- 229920002307 Dextran Polymers 0.000 claims description 2
- 239000005715 Fructose Substances 0.000 claims description 2
- 229930091371 Fructose Natural products 0.000 claims description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- 229920001612 Hydroxyethyl starch Polymers 0.000 claims description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- 239000001110 calcium chloride Substances 0.000 claims description 2
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 2
- 235000012209 glucono delta-lactone Nutrition 0.000 claims description 2
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- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 2
- 229940050526 hydroxyethylstarch Drugs 0.000 claims description 2
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims description 2
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- 229920001353 Dextrin Polymers 0.000 claims 1
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- 235000019425 dextrin Nutrition 0.000 claims 1
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 claims 1
- 238000005070 sampling Methods 0.000 claims 1
- OZOMQRBLCMDCEG-VIZOYTHASA-N 1-[(e)-[5-(4-nitrophenyl)furan-2-yl]methylideneamino]imidazolidine-2,4-dione Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(O1)=CC=C1\C=N\N1C(=O)NC(=O)C1 OZOMQRBLCMDCEG-VIZOYTHASA-N 0.000 description 70
- 239000000243 solution Substances 0.000 description 44
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- 238000002360 preparation method Methods 0.000 description 19
- 229960003710 dantrolene sodium Drugs 0.000 description 18
- LTWQNYPDAUSXBC-CDJGKPBYSA-L dantrolene sodium hemiheptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].[Na+].C1=CC([N+](=O)[O-])=CC=C1C(O1)=CC=C1\C=N\N1C(=O)[N-]C(=O)C1.C1=CC([N+](=O)[O-])=CC=C1C(O1)=CC=C1\C=N\N1C(=O)[N-]C(=O)C1 LTWQNYPDAUSXBC-CDJGKPBYSA-L 0.000 description 18
- 230000015556 catabolic process Effects 0.000 description 12
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
Abstract
Description
i)ダントロレンおよびダントロレンの医薬として許容される塩からなる群の1つ以上のメンバーから選択される成分(A);および
ii)シクロデキストリン誘導体からなる群の1つ以上のメンバーから選択される成分(B)
を含む水性組成物であり、ここで、組成物のpHが7よりも大きく、および成分(A)対成分(B)のモル比が1:2〜1:30、好ましくは1:3〜1:30の範囲である。
成分(A)は、本発明の水性組成物の必須成分である。
成分(A)は、ダントロレンおよびその医薬として許容される塩からなる群から選択される。
成分(A)は、以下の式(I)で表すことができ、式(I)はダントロレンを表す。
本発明の水性組成物のさらなる必須成分は、成分(B)である。
成分(B)は、シクロデキストリンおよびシクロデキストリン誘導体からなる群から選択される。
a)成分(A)および成分(B)を水性希釈剤に溶解して、成分(A)および成分(B)の水溶液を1:2〜1:30、好ましくは1:3〜1:30のモル比で得るステップ;
b)任意に、ステップa)の水溶液のpHを7より高く、好ましくは7.5から10.5の範囲に調整するステップ;
c)ステップa)またはb)で得られた水溶液を凍結乾燥して乾燥粉末を得るステップ;
d)水性希釈剤中でステップc)の粉末を再構成するステップ
を含む。
0.75mmol/l〜15.0mmol/lの範囲の量の成分(A);
5.0mmol/l〜250.0mmol/lの範囲の量の成分(B);
水性希釈剤;
任意に0.2mmol/l〜20.0mmol/lの範囲の量のpH調節剤;および
任意に25.0mmol/l〜250.0mmol/lの範囲の量の浸透圧剤
を含むまたはそれらからなり、ここで、濃度は、製剤または水性組成物の総体積に基づき、成分(A)対成分(B)のモル比は1:2〜1:30、好ましくは1:3〜1:30の範囲である。
1.5〜15mg/ml、好ましくは1.6〜11mg/mlの範囲の濃度のダントロレンナトリウム塩;
75〜350mg/ml、好ましくは80〜320mg/mlの範囲の濃度の2−ヒドロキシプロピル−β−シクロデキストリン;
水性希釈剤;
任意に最大25mmol/l、好ましくは0.1〜20mmol/lの濃度のpH調節剤;および
任意に最大200mmol/l、好ましくは20〜200mmol/lの濃度の浸透圧剤
を含み又はそれらからなり、ここで、水性希釈剤は、水、または水と生理学的に許容される溶液の混合物からなり、成分(A)対成分(B)の重量比は、1:2〜1:30、好ましくは1:3〜1:30の範囲である。
−驚くほど多量のダントロレン(塩)を溶解することができ、特に従来技術で可能であったよりも溶液中のダントロレン(塩)の著しく高い濃度に達することができる点、
−容易に濾過することができる透明な溶液を得ることができ、
−滅菌粉末製剤は、成分(A)透明な濾過された液体溶液から得られ、
−粉末製剤は、透明であり、粒子物質を含まず、即座に注射可能である非経口溶液をもたらす迅速な再構成時間を示し、
−粉末製剤から再構成された調製物は、規制濁度限界を考慮して規制要件を満たし(欧州PhamacopoeiaはNTU=3に濁度値の限界を設定する)、
−ダントロレン(塩)の溶液は非常に良好な安定性を示し、容易に非経口的に注射可能であり、
−この調製物は、初期溶液および再構成溶液の両方において、より多量のダントロレン(塩)を可溶化することができ、
−本発明の調製物(溶液および粉末)を使用しているときに、より少ない時間で大量の活性成分を注入することができ、治療用量に達するのに必要な時間が大幅に短縮され、
−ダントロレン(塩)のバイオアベイラビリティの増加が明らかに予期される
ことが挙げられる。
表1は、水性希釈剤が水であり、濃度が組成物の総体積を基準とする、本発明の例示的な組成物の内容を概要したものである。
A:対照(リン酸塩/トロメタミン溶液)
B:β−シクロデキストリン(CAS[7585−39−9])
F:スルホブチルエーテル−β−シクロデキストリンナトリウム塩(置換の程度6.0−7.1;CAS[182410−00−0])
D:2−ヒドロキシエチル−β−シクロデキストリン(モル置換率0.7;CAS[128446−32−2])
E:2−ヒドロキシプロピル−β−シクロデキストリン(モル置換率0.6;CAS[12446−35−5])
溶液1
10mgのダントロレンナトリウム塩を、水中pH9に調整したリン酸/トロメタミン緩衝液(25mM/25mM)中で調製した50mg/mlの2−ヒドロキシプロピル−β−シクロデキストリン溶液10mlに添加した。ダントロレンナトリウム対2−ヒドロキシプロピル−β−シクロデキストリンのモル比は約1:15である(分子量:ダントロレンナトリウムM=399,33g/molおよび2−ヒドロキシプロピル−β−シクロデキストリンM=1400g/molの分子量)。ダントロレンナトリウム対2−ヒドロキシプロピル−β−シクロデキストリンの重量比は1:50である。
溶液2
実施例1と同様に調製した;ダントロレンナトリウム対2−ヒドロキシプロピル−β−シクロデキストリンの重量比は1:10である。
溶液3−シクロデキストリンを含まない対照溶液
10mgのダントロレンナトリウム塩を、pH9に調整したリン酸塩/トロメタミン緩衝液(25mM/25mM)10mlに加えた。
溶液4−比較
溶液1のように調製したが、非置換シクロデキストリン(すなわち、β−シクロデキストリン)を使用した。
溶液5−比較
WO2010/126818の実施例3に記載されるように調製したが、ダントロレン:2−ヒドロキシプロピル−β−シクロデキストリン=2.5:1の比(w/w)を有する。
Claims (15)
- i)ダントロレンおよびダントロレンの医薬として許容される塩からなる群の1つ以上のメンバーから選択される成分(A);ならびに
ii)シクロデキストリン誘導体からなる群の1つ以上のメンバーから選択される成分(B)
を含む水性組成物であって、ここで、組成物のpHが7よりも大きく、および成分(A)対成分(B)のモル比が1:2〜1:30の範囲である水性組成物。 - 成分(A)対成分(B)のモル比が1:3〜1:30、好ましくは1:5〜1:18の範囲である、請求項1に記載の水性組成物。
- 組成物のpHが7.5〜10、好ましくは8.0〜9.5、より好ましくは8.5〜9.5である、請求項1または2に記載の水性組成物。
- 成分(B)が、β−シクロデキストリン、2,6−ジメチル−β−シクロデキストリン、2−ヒドロキシエチル−β−シクロデキストリン、2−ヒドロキシエチル−β−シクロデキストリン、2−ヒドロキシエチル−γ−シクロデキストリン、2−ヒドロキシプロピル−γ−シクロデキストリン、(2−カルボキシメトキシ)プロピル−β−シクロデキストリン、スルホブチルエーテル−β−シクロデキストリン、および2−ヒドロキシプロピル−β−シクロデキストリンからなる群から選択される、請求項1〜3のいずれか1項に記載の水性組成物。
- 成分(B)が、0.05〜10、好ましくは0.2〜2、とりわけ0.25〜1.0、特に0.5〜0.5の範囲のモル置換度(MS)を有するシクロデキストリン誘導体である、請求項1〜4のいずれか1項に記載の水性組成物。
- タミン、ヒスチジンおよびそれらの混合物からなる群から選択されるpH調節剤をさらに含む、請求項1〜5のいずれか1項に記載の水性組成物。
- pH調整剤に対する成分(A)のモル比が、20:1〜1:20、好ましくは10:1〜1:10、より好ましくは8:1〜1:5である、請求項6に記載の水性組成物。
- 組成物が、好ましくはマンニトール、フルクトース、グルコース、グルコノラクトン、グルコン酸塩、スクロース、ラクトース、トレハロース、デキストロース、デキストラン、ヒドロキシエチルスターチおよびそれらの混合物、グリシン、ゲランチン、グルコノグルコヘプタン酸カルシウム、塩化カリウム、塩化カルシウム、塩化ナトリウムおよびそれらの混合物からなる群から選択される浸透圧剤をさらに含む、請求項1〜7のいずれか1項に記載の水性組成物。
- 請求項1〜8の1つ以上に記載の水性組成物を乾燥させることによって得られる粉末。
- a)請求項9に記載の粉末を含む少なくとも1つの第1のコンパートメント;および
b)水性希釈剤を含む少なくとも1つの第2のコンパートメント
を含むキット。 - キットまたは少なくとも第1のおよび/もしくは少なくとも第2のコンパートメントが、ガラス、有機ポリマーおよびそれらの混合物からなる群から選択される材料で作製される、請求項10に記載のキット。
- i)成分(A)および成分(B)を水性希釈剤中に1:2〜1:30、好ましくは1:3〜1:30のモル比で溶解するステップ;
ii)ステップa)の水溶液のpHを7より大きく、好ましくは7.5から10の範囲に調整するステップ - 医薬として試料するための請求項1〜8の1つ以上に記載の組成物または請求項9に記載の粉末を含む製剤。
- 筋弛緩薬として使用するための、請求項13に記載の製剤。
- 粉末の組成物が非経口的に、好ましくは静脈内に投与される、請求項13または14の1つ以上に記載の使用のための製剤。
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US10532102B2 (en) * | 2016-08-19 | 2020-01-14 | Foresee Pharmaceuticals Co., Ltd. | Pharmaceutical composition and methods of uses |
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WO2019064185A1 (en) * | 2017-09-27 | 2019-04-04 | Novartis Ag | PARENTERAL FORMULATION COMPRISING SITOMOD |
CN112770744A (zh) * | 2018-09-06 | 2021-05-07 | 希米科控股有限公司 | 丹曲洛林水性制剂及其制备方法 |
WO2022169582A1 (en) * | 2021-02-05 | 2022-08-11 | Uswm, Llc | Compositions and methods for clear concentrated parenteral delivery of dantrolene therapeutic agents |
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