JP6987500B2 - インスリン分泌性ペプチドの安定な水性非経口医薬組成物 - Google Patents
インスリン分泌性ペプチドの安定な水性非経口医薬組成物 Download PDFInfo
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- JP6987500B2 JP6987500B2 JP2016533796A JP2016533796A JP6987500B2 JP 6987500 B2 JP6987500 B2 JP 6987500B2 JP 2016533796 A JP2016533796 A JP 2016533796A JP 2016533796 A JP2016533796 A JP 2016533796A JP 6987500 B2 JP6987500 B2 JP 6987500B2
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 1
- 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 description 1
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 description 1
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 102000002265 Human Growth Hormone Human genes 0.000 description 1
- 108010000521 Human Growth Hormone Proteins 0.000 description 1
- 239000000854 Human Growth Hormone Substances 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229920002535 Polyethylene Glycol 1500 Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 1
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 description 1
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2r)-2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000002547 anomalous effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000009615 deamination Effects 0.000 description 1
- 238000006481 deamination reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 230000000368 destabilizing effect Effects 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- HQPMKSGTIOYHJT-UHFFFAOYSA-N ethane-1,2-diol;propane-1,2-diol Chemical compound OCCO.CC(O)CO HQPMKSGTIOYHJT-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 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 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229920002523 polyethylene Glycol 1000 Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000003566 sealing material Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 235000011067 sorbitan monolaureate Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000003930 superacid Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- JADVWWSKYZXRGX-UHFFFAOYSA-M thioflavine T Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1C1=[N+](C)C2=CC=C(C)C=C2S1 JADVWWSKYZXRGX-UHFFFAOYSA-M 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000563 toxic property Toxicity 0.000 description 1
Classifications
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- 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
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/2278—Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/26—Glucagons
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/02—Inorganic compounds
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- 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
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- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- Peptides Or Proteins (AREA)
Description
好ましくは、GLP−1及びGLP−1類似体は:
8位は:A、GまたはVであり;
22位は:GまたはEであり;
26位は:K、R、QまたはNであり;
34位は:K、R、QまたはNであり;
36位は:R、R−NH2、KまたはK−NH2であり;及び
37位は:Gまたは欠失である)
の配列を有する。
好ましくは、エキセンジン−4及びエキセンジン−4類似体は:
XXXGTXXXXX SKQXEEEAVX LXXXXLKNGG XXXXXXXXX
(式中、1位は、H、RまたはYであり;
2位は、S、G、AまたはTであり;
3位は、DまたはEであり;
6位は、FまたはYであり;
7位は、T、YまたはSであり;
8位は、SまたはYであり;
9位は、DまたはEであり;
10位は、LまたはIであり;
14位は、L、I、VまたはMであり;
20位は、RまたはKであり;
22位は、FまたはYであり;
23位は、I、V、LまたはMであり;
24位は、EまたはDであり;
25位は、W、FまたはYであり;
31位は、Pまたは欠失であり;
32位は、Sまたは欠失であり;
33位は、Sまたは欠失であり;
34位は、Gまたは欠失であり;
35位は、Aまたは欠失であり;
36位は、Pまたは欠失であり;
37位は、Pまたは欠失であり;
38位は、Pまたは欠失であり;及び
39位は、S、Rまたは欠失である)
の配列を有する。例えば、エキセンジン−4及びエキセンジン−4類似体は:
HGEGTFTSDL SKQMEEEAVR LFIEWLKNGG PSSGAPPPS
の配列を有し得る。
好ましい態様の詳細の説明
GLP−1の安定性に対するpH値及びイオン性強度の影響
処方物医薬組成物の調製
GLP−1 2mg/mL
マンニトール 40mg/mL
フェノール 2.6mg/mL
NaAC−HAC 10mmol/L
pH 3.5〜4.5
であった。
GLP−1の物理的安定性に対する緩衝系及び抗菌剤の影響
計画及び結果は、表4に示す通りである:
GLP−1の安定性に対するアジュバント(添加剤)の影響
医薬組成物の処方物:
エキセンジン−4の類似体Emは、次の配列:
HGEGTFTSDL SKQLEEEAVK LFIEWLKNGG PSSGAPPPR
を有した。
(1)Emの合成
(2)医薬組成物の処方方法
(3)HPLC検出方法
Claims (16)
- 長期間貯蔵可能な安定で注射可能なインスリン分泌性ペプチド水性非経口医薬組成物であって、
前記水性非経口医薬組成物が、GLP−1、薬剤的に許容可能な等張剤、及び薬剤的に許容可能な緩衝塩溶液を含み;前記等張剤が、 (i) マンニトール、ソルビトール、イノシトール、キシリトール、グリセリン、およびプロピレングリコールからなる群から選択されるポリオール;(ii) 塩化ナトリウム;(iii) ショ糖、トレハロース、ラクトース、フルクトース、およびグルコースからなる群から選択される糖、並びにそのいずれかの組み合わせからなる群から選択され;前記緩衝塩が、ヒスチジン−塩酸(ヒスチジン−HCl)、クエン酸ナトリウム−クエン酸、リン酸水素二ナトリウム−クエン酸、NaOH−クエン酸、酢酸ナトリウム−酢酸(NaAC−HAC)、コハク酸塩−コハク酸、乳酸塩−乳酸、グルタミン酸塩−グルタミン酸、リンゴ酸塩−リンゴ酸、安息香酸塩−安息香酸、酒石酸塩−酒石酸およびグリシン−塩酸(Gly−HCl)およびそのいずれかの組み合わせからなる群から選択され;フェノールを含み;
前記水性非経口医薬組成物が、3.6〜4.2のpH値を有し;
前記インスリン分泌性ペプチドが、0.1mg/mL〜20mg/mLの濃度を有する、
前記水性非経口医薬組成物。 - GLP−1が、1mg/mL〜5mg/mLの濃度を有する、請求項1記載の水性非経口医薬組成物。
- GLP−1が、2mg/mL〜4mg/mLの濃度を有する、請求項1または2記載の水性非経口医薬組成物。
- 前記ポリオールが、10mg/mL〜100mg/mLの濃度を有し;前記塩化ナトリウムが、1mg/mL〜30mg/mLの濃度を有し;前記糖が、10mg/mL〜100mg/mLの濃度を有する、請求項1記載の水性非経口医薬組成物。
- 前記ポリオールが、30mg/mL〜50mg/mLの濃度を有する、請求項4記載の水性非経口医薬組成物。
- 前記塩化ナトリウムが、1mg/mL〜15mg/mLの濃度を有する、請求項4記載の水性非経口医薬組成物。
- 前記塩化ナトリウムが、5mg/mL〜15mg/mLの濃度を有する、請求項4記載の水性非経口医薬組成物。
- 前記塩化ナトリウムが、7mg/mL〜9mg/mLの濃度を有する、請求項4〜6のいずれか一項に記載の水性非経口医薬組成物。
- 前記糖が、30mg/mL〜50mg/mLの濃度を有する、請求項4〜6のいずれか一項に記載の水性非経口医薬組成物。
- フェノールが、1mg/mL〜20mg/mLの濃度を有する、請求項1記載の水性非経口医薬組成物。
- 前記緩衝塩が、2〜200mmol/Lの濃度を有する、請求項1記載の水性非経口医薬組成物。
- 前記緩衝塩が、5〜50mmol/Lの濃度を有する、請求項1記載の水性非経口医薬組成物。
- 前記緩衝塩が、5〜20mmol/Lの濃度を有する、請求項1記載の水性非経口医薬組成物。
- 前記緩衝塩が、7.5〜10mmol/Lの濃度を有する、請求項1記載の水性非経口医薬組成物。
- 糖尿病治療用医薬製造のための請求項1〜14のいずれか1項に記載の水性非経口医薬組成物の使用。
- 脂肪過多症治療用医薬製造のための請求項1〜14のいずれか1項に記載の水性非経口医薬組成物の使用。
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PCT/CN2014/083370 WO2015021861A1 (zh) | 2013-08-13 | 2014-07-31 | 稳定的促胰岛素分泌肽水针药物组合物 |
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