JP5843873B2 - ビタミンb12の鼻内用組成物 - Google Patents
ビタミンb12の鼻内用組成物 Download PDFInfo
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- JP5843873B2 JP5843873B2 JP2013535525A JP2013535525A JP5843873B2 JP 5843873 B2 JP5843873 B2 JP 5843873B2 JP 2013535525 A JP2013535525 A JP 2013535525A JP 2013535525 A JP2013535525 A JP 2013535525A JP 5843873 B2 JP5843873 B2 JP 5843873B2
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- JP
- Japan
- Prior art keywords
- methylcobalamin
- aqueous composition
- formulation
- composition according
- sodium
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims description 131
- 229930003779 Vitamin B12 Natural products 0.000 title description 13
- 235000019163 vitamin B12 Nutrition 0.000 title description 13
- 239000011715 vitamin B12 Substances 0.000 title description 13
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 title 1
- 239000011585 methylcobalamin Substances 0.000 claims description 81
- 235000007672 methylcobalamin Nutrition 0.000 claims description 81
- JEWJRMKHSMTXPP-BYFNXCQMSA-M methylcobalamin Chemical compound C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O JEWJRMKHSMTXPP-BYFNXCQMSA-M 0.000 claims description 81
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 claims description 62
- 235000000639 cyanocobalamin Nutrition 0.000 claims description 31
- 239000011666 cyanocobalamin Substances 0.000 claims description 31
- 229960002104 cyanocobalamin Drugs 0.000 claims description 31
- 239000002904 solvent Substances 0.000 claims description 21
- 239000003961 penetration enhancing agent Substances 0.000 claims description 17
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol group Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000003755 preservative agent Substances 0.000 claims description 12
- OABYVIYXWMZFFJ-ZUHYDKSRSA-M sodium glycocholate Chemical group [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 OABYVIYXWMZFFJ-ZUHYDKSRSA-M 0.000 claims description 12
- 230000003232 mucoadhesive effect Effects 0.000 claims description 11
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 239000002738 chelating agent Substances 0.000 claims description 6
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 claims description 4
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical group [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 4
- NLEBIOOXCVAHBD-QKMCSOCLSA-N dodecyl beta-D-maltoside Chemical compound O[C@@H]1[C@@H](O)[C@H](OCCCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 NLEBIOOXCVAHBD-QKMCSOCLSA-N 0.000 claims description 4
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 4
- 125000001421 myristyl 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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 4
- CTPDSKVQLSDPLC-UHFFFAOYSA-N 2-(oxolan-2-ylmethoxy)ethanol Chemical group OCCOCC1CCCO1 CTPDSKVQLSDPLC-UHFFFAOYSA-N 0.000 claims description 3
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- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 claims description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 claims description 2
- 241000416162 Astragalus gummifer Species 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical class OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 2
- LVDKZNITIUWNER-UHFFFAOYSA-N Bronopol Chemical compound OCC(Br)(CO)[N+]([O-])=O LVDKZNITIUWNER-UHFFFAOYSA-N 0.000 claims description 2
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- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
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- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 2
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- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
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- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 22
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- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- ZFLASALABLFSNM-UHFFFAOYSA-L carbanide;cobalt(3+);[5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] 1-[3-[2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2,7,12,17-tetrahydro-1h-corrin-24-id-3-yl]propanoylamin Chemical compound [CH3-].[Co+3].OCC1OC(N2C3=CC(C)=C(C)C=C3N=C2)C(O)C1OP([O-])(=O)OC(C)CNC(=O)CCC1(C)C(CC(N)=O)C2[N-]\C1=C(C)/C(C(C\1(C)C)CCC(N)=O)=N/C/1=C\C(C(C/1(CC(N)=O)C)CCC(N)=O)=N\C\1=C(C)/C1=NC2(C)C(C)(CC(N)=O)C1CCC(N)=O ZFLASALABLFSNM-UHFFFAOYSA-L 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical group C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
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- 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 description 1
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- 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
- DCQXTYAFFMSNNH-UHFFFAOYSA-M sodium;2-[bis(2-hydroxyethyl)amino]ethanol;acetate Chemical compound [Na+].CC([O-])=O.OCCN(CCO)CCO DCQXTYAFFMSNNH-UHFFFAOYSA-M 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- 230000001839 systemic circulation Effects 0.000 description 1
- 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 description 1
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Images
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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7135—Compounds containing heavy metals
- A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- 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
- A61K9/0043—Nose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
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Description
調製は全てナトリウム蒸気ランプの下で窒素を流しながら実施した。溶解した酸素濃度を可能な限り低く、好ましくはおよそ1から1.5ppmに保った。この方法は、
i)1バッチについてグリコフロールを水の80%v/vまで加えるステップと、
ii)塩化ベンザルコニウムおよびグリセリンを撹拌しながら溶解するステップと、
iii)クエン酸緩衝液を使用して溶液を緩衝するステップと、
iv)メチルコバラミンを溶解するまで撹拌して加えるステップと、
v)pHを酸/アルカリの添加により必要な値に調節するステップと、
vi)鼻スプレ溶液0.1ml当たり500μgの所望濃度を得るように溶液の容量を調整するステップと、
を含む。
薬物500μg/0.1mlから1500μg/0.1ml、
溶媒(合計)1〜35%、
保湿剤0〜5%、
粘膜付着剤5%以下、
浸透促進剤2.5%以下、
防腐剤4%以下
を含む。明細書でさらに説明するように、組成物は、使用される薬物に応じてpHを必要な値に調節するために緩衝成分をさらに含有する。
上記のようにして調製された500μg/0.1mLのメチルコバラミンを含有する鼻スプレのバイオアベイラビリティの検討を、絶食状態の健常なヒト被験者で実施した。試験計画は、6名の健常ヒト成人被験者における絶食状態で、非盲検、無作為化、3時期、3治療、3シーケンス、単回投与、3元クロスオーバー比較のバイオアベイラビリティ検討であった。
テスト製品(A):500μg/0.1mlのメコバラミン鼻スプレ
テスト製品(B):500μg/0.1mlのメコバラミン鼻スプレ
テスト製品(C):500μg/0.1mlのメコバラミン鼻スプレ
被験者は、製剤無作為化スケジュールに従って、各期間の間少なくとも7日の休薬期間を設けて、クロスオーバー方式で各治療(メコバラミン鼻スプレ)を受けた。
初回用量を投与する前に、ポンプをプライミングした。ポンプをプラミングするために、ボトルの底に親指を当ててノズルを第一指と第二指の間に置いた。スプレの最初の出現までユニットをしっかり且つ速やかにポンピングした。ポンプをさらに2回プライミングして、鼻スプレはいつでも使える状態にした。
被験者に、鼻スプレを投与しやすいように頭を少し後ろに傾けるように頼んだ。次に、外鼻孔中に深く3回噴霧した。用量が漏れ出さないように、被験者に同じ姿勢で2分間座っているように頼んだ。
血液試料の総数:1期間当たり20。
初期パラメータ:Cmax、AUC0−t、AUC0−inf
二次パラメータ:t1/2、ke、Tmax
メコバラミンの血清濃度は、予め検証した分析方法により測定した。
未変換および対数変換薬物動態学的パラメータCmax、AUC0−t、AUC0−infについて比較および比分析のためのANOVA、2つの片側検定を実施した。全てのパラメータが同様な結論を示していたので、治療の恩恵に最も関連のあるパラメータであるAUC0−t(pg.時間/ml)が、実例とされた製剤についての結果で提供される。
Claims (11)
- 水中で500μg/0.1mlから1500μg/0.1mlの濃度のメチルコバラミンと、補助溶媒/可溶化剤またはそれらの混合物とを、浸透促進剤、および場合により防腐剤、粘膜付着剤、キレート剤、湿潤剤、抗酸化剤またはそれらの組合せとともに含み、
pHが6から6.5であり、粘度が1から200Cpsであり、
前記浸透促進剤が、グリココール酸ナトリウム、タウロコール酸ナトリウム、デオキシコール酸ナトリウム、テトラデシルマルトシド、ドデシルマルトシドまたはそれらの組合せであることを特徴とする、安定な鼻腔内水性組成物。 - 水中で補助溶媒/可溶化剤またはそれらの混合物の存在下または不在下で、500μg/0.1mlから1500μg/0.1mlの濃度のシアノコバラミンと、少なくとも1種の浸透促進剤と、場合により防腐剤、粘膜付着剤、キレート剤、湿潤剤、抗酸化剤またはそれらの組合せとを含み、
pHが4から6であり、粘度が1から200Cpsであり、
前記浸透促進剤が、グリココール酸ナトリウム、タウロコール酸ナトリウム、デオキシコール酸ナトリウム、テトラデシルマルトシド、ドデシルマルトシドまたはそれらの組合せであることを特徴とする、安定な鼻腔内水性組成物。 - 請求項1または2に記載の安定な鼻腔内水性組成物であって、前記補助溶媒/可溶化剤が、グリコフロール、プロピレングリコール、ポリエチレングリコール、またはそれらの混合物から選択されることを特徴とする組成物。
- 請求項1〜3のいずれか1項に記載の安定な鼻腔内水性組成物であって、前記補助溶媒/可溶化剤が1から35%w/vの範囲内にあることを特徴とする組成物。
- 請求項1〜4のいずれか1項に記載の安定な鼻腔内水性組成物であって、前記浸透促進剤またはそれらの組合せの量が組成物の2.5%w/v以下であることを特徴とする組成物。
- 請求項1〜5のいずれか1項に記載の安定な鼻腔内水性組成物であって、前記粘膜付着剤が、セルロース誘導体;カルボポールを含むポリ(アクリル酸)ポリマ;ポリ(ヒドロキシエチルメタクリレート);ポリ(エチレンオキシド);ポリ(ビニルピロリドン);ポリ(ビニルアルコール)ポリマを含む合成ポリマ、またはトラガカント、アルギン酸ナトリウム、カラヤガム、グアーガム、キサンタンガム、レクチン、可溶デンプン、ゼラチン、ペクチンおよびキトサンを含む天然ポリマまたは任意のそれらの組合せから選択されることを特徴とする組成物。
- 請求項1〜6のいずれか1項に記載の安定な鼻腔内水性組成物であって、前記粘膜付着剤が組成物の5重量%以下であることを特徴とする組成物。
- 請求項1〜7のいずれか1項に記載の安定な鼻腔内水性組成物であって、前記防腐剤が、塩化ベンザルコニウム、メチルパラベン、エチルパラベン、プロピルパラベン、安息香酸、ベンジルアルコール、ブロノポール、ブチル化ヒドロキシルアニソール、ブチル化ヒドロキシルトルエン、クロロクレゾール、またはイソプロピルアルコールまたはそれらの組合せから選択されることを特徴とする組成物。
- 請求項8に記載の安定な鼻腔内水性組成物であって、前記防腐剤が組成物の4重量%以下であることを特徴とする組成物。
- 請求項1〜9のいずれか1項に記載の安定な鼻腔内水性組成物であって、前記湿潤剤が、グリセリン、乳酸ナトリウム、ソルビトール、キシリトール、ブチレングリコールから選択されることを特徴とする組成物。
- 請求項10に記載の安定な鼻腔内水性組成物であって、前記湿潤剤が組成物の5重量%であることを特徴とする組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN2169MU2010 | 2010-10-29 | ||
IN2169/MUM/2010 | 2010-10-29 | ||
PCT/IB2011/002546 WO2012056299A1 (en) | 2010-10-29 | 2011-10-28 | Nasal compositions of vitamin b12 |
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JP5843873B2 true JP5843873B2 (ja) | 2016-01-13 |
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JP2013535525A Active JP5843873B2 (ja) | 2010-10-29 | 2011-10-28 | ビタミンb12の鼻内用組成物 |
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EP (1) | EP2632430B1 (ja) |
JP (1) | JP5843873B2 (ja) |
CN (1) | CN103384513B (ja) |
AP (1) | AP3814A (ja) |
AR (1) | AR083658A1 (ja) |
BR (1) | BR112013010049B1 (ja) |
CO (1) | CO6801717A2 (ja) |
CU (1) | CU24142B1 (ja) |
DK (1) | DK2632430T3 (ja) |
EA (1) | EA024475B1 (ja) |
ES (1) | ES2686299T3 (ja) |
HU (1) | HUE039349T2 (ja) |
MX (1) | MX337365B (ja) |
MY (1) | MY163106A (ja) |
PE (1) | PE20131137A1 (ja) |
PL (1) | PL2632430T3 (ja) |
PT (1) | PT2632430T (ja) |
UA (1) | UA111342C2 (ja) |
WO (1) | WO2012056299A1 (ja) |
ZA (1) | ZA201303024B (ja) |
Families Citing this family (5)
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AU2017281941A1 (en) * | 2016-06-24 | 2019-02-07 | Aegis Therapeutics Llc | Compositions, devices, and methods for the treatment of alcohol use disorder |
CA3044221A1 (en) | 2016-11-18 | 2018-05-24 | Opiant Pharmaceuticals, Inc. | Intranasal nalmefene compositions and methods for the treatment of opioid overdose |
WO2018142358A1 (en) * | 2017-02-06 | 2018-08-09 | Torrent Pharmaceuticals Ltd. | Intranasal composition of methylcobalamin |
US11504362B2 (en) | 2017-06-09 | 2022-11-22 | Exelixis, Inc. | Liquid dosage forms to treat cancer |
GB202013645D0 (en) | 2020-08-31 | 2020-10-14 | Innotesto Bvba | Pharmacetical compositions for the nasal administration of a colbalamin compound |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
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AT376879B (de) * | 1982-10-27 | 1985-01-10 | Gerot Pharmazeutika | Verfahren zur herstellung einer injektionsloesung |
US4724231A (en) | 1985-04-16 | 1988-02-09 | Nastech Pharmaceutical, Inc. | Nasel compositions containing vitamin B12 |
ES2074396B1 (es) * | 1993-03-24 | 1996-04-01 | Farmalider Sa | Sistema de administracion nasal de cianocobalamina (vitamina b12). |
BE1007839A6 (nl) * | 1993-12-20 | 1995-10-31 | Merkus Franciscus W H M Prof | Farmaceutische compositie voor de nasale toediening van hydroxocobalamine. |
US7229636B1 (en) * | 2003-03-04 | 2007-06-12 | Nastech Pharmaceutical Company Inc. | Cyanocobalamin low viscosity aqueous formulations for intranasal delivery |
ES2356242T3 (es) * | 2003-05-07 | 2011-04-06 | EISAI R&D MANAGEMENT CO., LTD. | Preparación liofilizada conteniendo metilcobalamina y procedimiento de producción de esta preparación. |
US20070111964A1 (en) * | 2005-08-17 | 2007-05-17 | Fleming And Company, Pharmaceuticals | Vitamin B12 nasal spray and method of use |
CN101600729A (zh) * | 2006-06-23 | 2009-12-09 | 帕尔医疗公司 | 用于鼻内递送的氰钴胺低粘度水性制剂 |
US20090012039A1 (en) * | 2007-03-16 | 2009-01-08 | Stan Kurtz | Use of methylcobalamin nasal spray to treat disorders |
DE102007012644A1 (de) * | 2007-03-16 | 2008-09-18 | Bayer Healthcare Ag | Stabilisierung von Vitamin B12 |
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2011
- 2011-10-28 ES ES11797111.9T patent/ES2686299T3/es active Active
- 2011-10-28 WO PCT/IB2011/002546 patent/WO2012056299A1/en active Application Filing
- 2011-10-28 PL PL11797111T patent/PL2632430T3/pl unknown
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- 2011-10-28 CU CU20130062A patent/CU24142B1/es unknown
- 2011-10-28 MX MX2013004846A patent/MX337365B/es active IP Right Grant
- 2011-10-28 PT PT11797111T patent/PT2632430T/pt unknown
- 2011-10-28 UA UAA201306483A patent/UA111342C2/uk unknown
- 2011-10-28 AP AP2013006837A patent/AP3814A/en active
- 2011-10-28 BR BR112013010049-4A patent/BR112013010049B1/pt active IP Right Grant
- 2011-10-28 JP JP2013535525A patent/JP5843873B2/ja active Active
- 2011-10-28 HU HUE11797111A patent/HUE039349T2/hu unknown
- 2011-10-28 EA EA201390623A patent/EA024475B1/ru unknown
- 2011-10-28 DK DK11797111.9T patent/DK2632430T3/en active
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- 2011-10-28 PE PE2013000547A patent/PE20131137A1/es active IP Right Grant
- 2011-10-31 AR ARP110104028A patent/AR083658A1/es not_active Application Discontinuation
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2013
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Also Published As
Publication number | Publication date |
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DK2632430T3 (en) | 2018-09-17 |
MX2013004846A (es) | 2013-10-01 |
UA111342C2 (uk) | 2016-04-25 |
ZA201303024B (en) | 2014-01-29 |
MX337365B (es) | 2016-02-29 |
EA201390623A1 (ru) | 2013-09-30 |
PE20131137A1 (es) | 2013-10-03 |
WO2012056299A1 (en) | 2012-05-03 |
MY163106A (en) | 2017-08-15 |
JP2013540805A (ja) | 2013-11-07 |
BR112013010049A2 (pt) | 2018-01-09 |
CO6801717A2 (es) | 2013-11-29 |
ES2686299T3 (es) | 2018-10-17 |
AP3814A (en) | 2016-09-30 |
BR112013010049B1 (pt) | 2021-07-13 |
EA024475B1 (ru) | 2016-09-30 |
PT2632430T (pt) | 2018-10-19 |
CU20130062A7 (es) | 2013-10-29 |
HUE039349T2 (hu) | 2018-12-28 |
PL2632430T3 (pl) | 2018-11-30 |
CU24142B1 (es) | 2015-12-23 |
AP2013006837A0 (en) | 2013-04-30 |
CN103384513A (zh) | 2013-11-06 |
CN103384513B (zh) | 2016-01-13 |
AR083658A1 (es) | 2013-03-13 |
EP2632430A1 (en) | 2013-09-04 |
EP2632430B1 (en) | 2018-06-06 |
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