JP5890599B2 - Stable fat emulsion containing prostaglandin E1 - Google Patents
Stable fat emulsion containing prostaglandin E1 Download PDFInfo
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- JP5890599B2 JP5890599B2 JP2009523535A JP2009523535A JP5890599B2 JP 5890599 B2 JP5890599 B2 JP 5890599B2 JP 2009523535 A JP2009523535 A JP 2009523535A JP 2009523535 A JP2009523535 A JP 2009523535A JP 5890599 B2 JP5890599 B2 JP 5890599B2
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- fat emulsion
- alprostadil
- prostaglandin
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- 239000002960 lipid emulsion Substances 0.000 title claims description 82
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 title claims description 35
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 title claims description 18
- 229960000711 alprostadil Drugs 0.000 title claims description 18
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 title description 4
- 239000011521 glass Substances 0.000 claims description 42
- 239000003708 ampul Substances 0.000 claims description 40
- 230000000694 effects Effects 0.000 claims description 28
- 230000001954 sterilising effect Effects 0.000 claims description 28
- 238000004659 sterilization and disinfection Methods 0.000 claims description 27
- BGKHCLZFGPIKKU-LDDQNKHRSA-N prostaglandin A1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1C=CC(=O)[C@@H]1CCCCCCC(O)=O BGKHCLZFGPIKKU-LDDQNKHRSA-N 0.000 claims description 16
- 238000003860 storage Methods 0.000 claims description 14
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- 235000012424 soybean oil Nutrition 0.000 claims description 7
- 239000003549 soybean oil Substances 0.000 claims description 7
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 claims description 6
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 6
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 6
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000005642 Oleic acid Substances 0.000 claims description 6
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 235000011187 glycerol Nutrition 0.000 claims description 6
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 6
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 6
- 229910052814 silicon oxide Inorganic materials 0.000 claims description 6
- 238000007789 sealing Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 4
- 239000008158 vegetable oil Substances 0.000 claims description 4
- 239000011248 coating agent Substances 0.000 claims description 3
- 238000000576 coating method Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims 2
- 239000007888 film coating Substances 0.000 claims 1
- 238000009501 film coating Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 16
- BGKHCLZFGPIKKU-UHFFFAOYSA-N (13E,15S)-15-hydroxy-9-oxo-prosta-10,13-dienoic acid Natural products CCCCCC(O)C=CC1C=CC(=O)C1CCCCCCC(O)=O BGKHCLZFGPIKKU-UHFFFAOYSA-N 0.000 description 14
- MYHXHCUNDDAEOZ-UHFFFAOYSA-N Prostaglandin A&2% Natural products CCCCCC(O)C=CC1C=CC(=O)C1CC=CCCCC(O)=O MYHXHCUNDDAEOZ-UHFFFAOYSA-N 0.000 description 14
- 239000000839 emulsion Substances 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 9
- 239000012086 standard solution Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 239000012488 sample solution Substances 0.000 description 4
- 239000000654 additive Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 description 2
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010040943 Skin Ulcer Diseases 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 230000003520 lipogenic effect Effects 0.000 description 2
- 238000007726 management method Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 231100000019 skin ulcer Toxicity 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000031104 Arterial Occlusive disease Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- QRDFZFLVKCRFHU-KHBONWNZSA-N CCCCCCC[C@@H]1[C@@H](\C=C\[C@@H](O)CCCCC)[C@H](O)CC1=O Chemical compound CCCCCCC[C@@H]1[C@@H](\C=C\[C@@H](O)CCCCC)[C@H](O)CC1=O QRDFZFLVKCRFHU-KHBONWNZSA-N 0.000 description 1
- 208000010159 IgA glomerulonephritis Diseases 0.000 description 1
- 206010021263 IgA nephropathy Diseases 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 208000021328 arterial occlusion Diseases 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000002296 dynamic light scattering Methods 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N hexane carboxylic acid Natural products CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 239000004533 oil dispersion Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 150000003165 prostaglandin E1 derivatives Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
Classifications
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- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- 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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
-
- 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
-
- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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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
- A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
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- Animal Behavior & Ethology (AREA)
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- General Chemical & Material Sciences (AREA)
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- Dispersion Chemistry (AREA)
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- Hematology (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Molecular Biology (AREA)
- Heart & Thoracic Surgery (AREA)
- Botany (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Description
本発明はプロスタグランジンE1を含む安定な脂肪乳剤に関する。The present invention relates to a stable fat emulsion containing prostaglandin E 1.
プロスタグランジンE1(以下、「PGE1」と略す場合がある。)、は一般名「アルプロスタジル」であり、強力な血管拡張作用及び血小板凝集抑制作用を有しており、慢性動脈閉塞症(バージャー病、閉塞性動脈硬化症)における四肢潰瘍及び安静時疼痛の改善、進行性全身性硬化症などにおける皮膚潰瘍の改善、糖尿病における皮膚潰瘍の改善などを効能として臨床的に用いられている。プロスタグランジンE1含有製剤としては微細な脂肪粒子中にPGE1を溶解したいわゆるリポ化製剤(例えば「リプル注」、田辺三菱製薬株式会社製造及び販売)が知られている。この製剤は、薬物の担体として利用された脂肪粒子が特に障害された血管に分布しやすい特性を有することを利用して、ドラッグデリバリーシステム(DDS)の考えにより病変部位に効率よくPGE1を集積させ、かつ生体内での有効成分の不活化を生じにくくした製剤であり、添加物として精製ダイズ油、高度精製卵黄レシチン、オレイン酸、濃グリセリン、及び水酸化ナトリウムを含み、pHが4.5から6.0に調整されている。Prostaglandin E 1 (hereinafter sometimes abbreviated as “PGE 1 ”) is a generic name “alprostadil”, which has a strong vasodilatory action and platelet aggregation inhibitory action, and chronic arterial occlusion Clinically used to improve limb ulcers and resting pain in patients with cervical disease (Berger disease, obstructive arteriosclerosis), skin ulcers in advanced systemic sclerosis, and skin ulcers in diabetes Yes. As a prostaglandin E 1- containing preparation, a so-called lipoformation preparation (for example, “ripple injection” manufactured by Mitsubishi Tanabe Pharma Corporation and sales) in which PGE 1 is dissolved in fine fat particles is known. This formulation utilizes the property that fat particles used as drug carriers are particularly easily distributed in damaged blood vessels, so that PGE 1 is efficiently accumulated at the lesion site based on the concept of a drug delivery system (DDS). In addition, it is a preparation that is less likely to cause inactivation of the active ingredient in vivo, and contains refined soybean oil, highly purified egg yolk lecithin, oleic acid, concentrated glycerin, and sodium hydroxide as an additive, and has a pH of 4.5 to 6.0 Has been adjusted.
しかしながら、上記のPGE1のリポ化製剤は有効成分であるPGE1が溶液中で分解しやすいため、凍結を避けて5℃以下の遮光下に保存する必要があり、有効期間は通常の製剤よりも短い1年間と定められている。このような製剤は流通段階や臨床現場における薬剤管理コストの増大を招く事から、薬剤管理コストの低減に繋がる有効期間の長い製剤の開発が切望されている。なお、プロスタグランジンE1の肺通過による失活を脂肪乳剤により抑制する手段は特開昭58-222014号公報(特許文献1)に開示されており、脂肪乳剤により化学的安定性を改善する手段は特開昭60-149524号公報(特許文献2)に開示されており、脂肪乳剤として調製された血管造影補助剤は特開平4-66540号公報(特許文献3)に開示されている。また、脂肪乳剤中のPGE1に対するpHの影響については、pH 5.0付近で最も安定であり、それ以上又はそれ以下のpHでは不安定化することが知られている(Pharmaceutical Research, 6, pp.210-215, 1989;非特許文献1)。
本発明の課題はより長い有効期間を持つプロスタグランジンE1活性を有する化合物を含有する製剤を提供することにある。より具体的には、プロスタグランジンE1含有製剤として市販されているリポ化製剤(例えば「リプル注」など)の有効期間を長期化する手段を提供することにある。An object of the present invention is to provide a preparation containing a compound having prostaglandin E 1 activity having a longer effective period. More specifically, an object of the present invention is to provide a means for prolonging the effective period of a lipogenic preparation (for example, “ripple injection”) marketed as a prostaglandin E 1- containing preparation.
本発明者らは上記の課題を解決すべく、鋭意研究した結果、製剤製造工程の最終段階において、ガラスアンプル中に密封された製剤(充填時にpHを約5.0に調整)をオートクレーブ(125℃)で加熱滅菌すると、ガラスアンプルの内部表面からアルカリ成分が溶出し、製剤のpHが滅菌前に比べて上昇することを見出した。この知見を基にして本発明者らはさらに研究を続けた結果、滅菌時のガラスアンプルからのアルカリ成分の溶出を抑制する手段を採用することにより、ガラスアンプルの特性(材質)の影響を受けずに容易に製造でき、長期間にわたって安定なリポ化製剤を提供できることを見出した。 As a result of diligent research to solve the above-mentioned problems, the inventors of the present invention obtained an autoclave (125 ° C.) of a preparation sealed in a glass ampoule (pH adjusted to about 5.0 at the time of filling) in the final stage of the preparation manufacturing process. It was found that when heat sterilization with, alkaline components were eluted from the inner surface of the glass ampule, and the pH of the preparation increased compared with that before sterilization. Based on this knowledge, the present inventors continued further research. As a result, by adopting a means for suppressing elution of alkali components from the glass ampule during sterilization, the present invention is influenced by the characteristics (material) of the glass ampule. It was found that a lipophobic preparation that can be easily produced and stable over a long period of time can be provided.
すなわち、本発明により、プロスタグランジンE1活性を有する化合物を含有する脂肪乳剤であって、ガラス製容器に密封された後に加熱滅菌されており、5℃で16ヶ月間保存後にプロスタグランジンE1活性の残存量が保存開始時の65%以上100%以下である脂肪乳剤が提供される。That is, according to the present invention, a fat emulsion containing a compound having prostaglandin E 1 activity, which is sealed in a glass container and then heat sterilized, and stored at 5 ° C. for 16 months, prostaglandin E 1 A fat emulsion in which the remaining amount of activity is 65% or more and 100% or less at the start of storage is provided.
上記発明の好ましい態様によれば、保存開始時においてプロスタグランジンE1活性を有する化合物を5μg以上含有しており、5℃で16ヶ月間保存後にプロスタグランジンE1活性を有する化合物の残存量が4μg以上である上記の脂肪乳剤;保存開始時においてプロスタグランジンE1活性を有する化合物を10μg以上含有しており、5℃で16ヶ月間保存後にプロスタグランジンE1活性を有する化合物の残存量が8μg以上である上記の脂肪乳剤が提供される。また、加熱滅菌後の保存開始時のpHが4.9から5.3の範囲である上記の脂肪乳剤が提供される。According to a preferred embodiment of the above invention, the amount of the compound having prostaglandin E 1 activity is contained at 5 μg or more at the start of storage, and the compound having prostaglandin E 1 activity after storage at 5 ° C. for 16 months. The above-mentioned fat emulsion having a content of 4 μg or more; containing 10 μg or more of a compound having prostaglandin E 1 activity at the start of storage, and remaining a compound having prostaglandin E 1 activity after storage at 5 ° C. for 16 months The above fat emulsion is provided in an amount of 8 μg or more. Also provided is the above fat emulsion having a pH in the range of 4.9 to 5.3 at the start of storage after heat sterilization.
さらに好ましい態様によれば、ガラス製容器が内部表面に皮膜コートが施された容器である上記の脂肪乳剤;ガラス製容器が内部表面に皮膜コートが施されたガラスアンプルである上記の脂肪乳剤;皮膜コートが酸化ケイ素皮膜コートである上記の脂肪乳剤;ガラス製容器がガラス表面のアルカリ成分を化学的処理により除去した容器である上記の脂肪乳剤;ガラス製容器がガラス表面のアルカリ成分を化学的処理により除去したガラスアンプルである上記の脂肪乳剤が提供される。また、脂肪乳剤全量に対して5〜50 w/v%の植物油を含む上記の脂肪乳剤が提供される。 According to a further preferred embodiment, the above-mentioned fat emulsion in which the glass container is a container having a film coat on its inner surface; the above fat emulsion in which the glass container is a glass ampoule having a film coat on its inner surface; The above fat emulsion in which the film coat is a silicon oxide film coat; the above fat emulsion in which the glass container is a container obtained by removing the alkali component on the glass surface by chemical treatment; the glass container chemically removes the alkali component on the glass surface. The above fat emulsion is provided which is a glass ampoule removed by processing. Also provided is the above fat emulsion comprising 5-50 w / v% vegetable oil based on the total amount of the fat emulsion.
別の観点からは、本発明により、プロスタグランジンE1活性を有する化合物を含有する脂肪乳剤の製造方法であって、プロスタグランジンE1活性を有する化合物を含有するpHが4.8から5.2の範囲に調節された脂肪乳剤をガラス製容器に密封して加熱滅菌する工程を含み、好ましくは当該容器が加熱滅菌後の当該脂肪乳剤のpH上昇を抑制する手段を備えている方法が提供される。From another aspect, the present invention provides a method for producing a fat emulsion containing a compound having prostaglandin E 1 activity, range pH containing a compound having prostaglandin E 1 activity of 5.2 from 4.8 The method includes the step of sealing the heat-adjusted fat emulsion in a glass container and sterilizing by heating, and the method is preferably provided with means for suppressing the increase in pH of the fat emulsion after heat-sterilization.
上記発明の好ましい態様によれば、当該ガラス製容器がガラスアンプルであり、pH上昇を抑制する上記手段がガラスアンプル内部表面の皮膜コート、好ましくは酸化ケイ素皮膜コートである上記の方法;当該ガラス製容器がガラスアンプルであり、pH上昇を抑制する上記手段がガラス表面のアルカリ成分の化学的処理による除去である上記の方法が提供される。また、加熱滅菌後の脂肪乳剤のpHが4.9から5.3の範囲である上記の方法;及び加熱滅菌後に各ガラスアンプル中の当該脂肪乳剤中に残存するPGE1活性を有する化合物の量の相対標準偏差が1.0%以下である上記の方法が提供される。なお、ここでPGE1活性を有する化合物の量とは、有効成分として「PGE1」を含有する脂肪乳剤にあっては有効成分である「PGE1」の量を、有効成分として「PGE1以外のPGE1活性を有する化合物」を含有する脂肪乳剤にあっては有効成分である「PGE1以外のPGE1活性を有する化合物」の量を意味する。According to a preferred aspect of the invention, the glass container is a glass ampoule, and the means for suppressing the increase in pH is a film coat on the inner surface of the glass ampoule, preferably a silicon oxide film coat; There is provided the above method, wherein the container is a glass ampoule and the means for suppressing the increase in pH is removal of an alkali component on the glass surface by chemical treatment. Also, the above method wherein the pH of the fat emulsion after heat sterilization is in the range of 4.9 to 5.3; and the relative standard deviation of the amount of the compound having PGE 1 activity remaining in the fat emulsion in each glass ampoule after heat sterilization The above method is provided wherein is 1.0% or less. Here, the amount of the compound having PGE 1 activity refers to the amount of “PGE 1 ” as an active ingredient in a fat emulsion containing “PGE 1 ” as an active ingredient, and “other than PGE 1 ” as an active ingredient. in the fat emulsion containing a compound "having a PGE 1 activity means an amount of an active ingredient" compound having PGE 1 activity other than PGE 1 ".
本発明の脂肪乳剤はプロスタグランジンE1活性を有する化合物の安定性が従来の脂肪乳剤に比べて向上しており、長期間にわたって保存しても有効成分の含有量が低下しないという特徴がある。また、本発明の製造方法によれば、滅菌後のPGE1量についてガラス製容器の特性(材質)による影響を受けない(受け難い)製品を提供できるという特徴がある。The fat emulsion of the present invention is characterized in that the stability of the compound having prostaglandin E 1 activity is improved as compared with the conventional fat emulsion, and the content of the active ingredient does not decrease even when stored for a long period of time. . In addition, according to the production method of the present invention, it is possible to provide a product that is not influenced (not easily affected) by the characteristics (material) of the glass container with respect to the amount of PGE 1 after sterilization.
本発明の脂肪乳剤はプロスタグランジンE1活性を有する化合物を含有する脂肪乳剤であって、容器に密封された後に加熱滅菌されており、5℃で16ヶ月間保存後にPGE1活性の残存量が保存開始時の65%以上100%以下であることを特徴としている。PGE1活性を有する化合物としては、PGE1活性を有し、医薬の有効成分として適合するものであればいかなる化合物を用いてもよい。例えば、特開昭59-206349号公報や特開昭59-216820号公報などに開示されるPGE1誘導体が好適に使用される。これらのうち、例えば、7-{(1R,2R,3R)-3-ヒドロキシ-2-[(1E,3S)-3-ヒドロキシオクト-1-エン-1-イル]-5-オキソシクロペンチル}ヘプタン酸(一般名「アルプロスタジル」)が特に好ましい。The fat emulsion of the present invention is a fat emulsion containing a compound having prostaglandin E 1 activity, which is sealed in a container and then heat sterilized, and the remaining amount of PGE 1 activity after storage at 5 ° C. for 16 months Is characterized by being 65% or more and 100% or less at the start of storage. As the compound having PGE 1 activity, has a PGE 1 activity, as long as it fit as the active ingredient of the medicament of any compound may be used. For example, PGE 1 derivatives disclosed in JP-A-59-206349 and JP-A-59-216820 are preferably used. Of these, for example, 7-{(1R, 2R, 3R) -3-hydroxy-2-[(1E, 3S) -3-hydroxyoct-1-en-1-yl] -5-oxocyclopentyl} heptane The acid (generic name “alprostadil”) is particularly preferred.
本発明におけるプロスタグランジンE1活性を有する化合物として特に好ましいものは、前述の通り7-{(1R,2R,3R)-3-ヒドロキシ-2-[(1E,3S)-3-ヒドロキシオクト-1-エン-1-イル]-5-オキソシクロペンチル}ヘプタン酸(アルプロスタジル)であるが、当該化合物は脱水反応により7-{(1R,2S)-2-[(S,E)-3-ヒドロキシオクト-1-エニル]-5-オキソシクロペント-3-エニル}ヘプタン酸(プロスタグランジンA1)に変化しやすい。プロスタグランジンA1への変化により、本発明における脂肪乳剤の薬理活性が低下すると考えられる。本発明においては、5℃で16ヵ月間保存後の本発明の脂肪乳剤1ml中のプロスタグランジンA1量が3.0μg以下であることが望ましい。特に望ましいのは、0μg以上1.5μg以下である。 Particularly preferable as the compound having prostaglandin E1 activity in the present invention is 7-{(1R, 2R, 3R) -3-hydroxy-2-[(1E, 3S) -3-hydroxyoct-1 as described above. -En-1-yl] -5-oxocyclopentyl} heptanoic acid (alprostadil), but this compound was converted to 7-{(1R, 2S) -2-[(S, E) -3- Hydroxyoct-1-enyl] -5-oxocyclopent-3-enyl} heptanoic acid (prostaglandin A1). The change to prostaglandin A1 is considered to reduce the pharmacological activity of the fat emulsion in the present invention. In the present invention, it is desirable that the amount of prostaglandin A1 in 1 ml of the fat emulsion of the present invention after storage at 5 ° C. for 16 months is 3.0 μg or less. Particularly desirable is 0 to 1.5 μg.
PGE1活性を有する化合物を含有する脂肪乳剤は、例えば、特開昭58-222014号公報、特開昭60-149524号公報、及び特開平4-66540号公報などに記載されており、当業者は容易に脂肪乳剤を調製することが可能である。脂肪乳剤は、例えば、植物油、リン脂質、水、及びPGE1活性を有する化合物を含むように調製することができる。さらに、必要に応じて、乳化補助剤、安定化剤、高分子物質、等張化剤等を添加することもできる。Fat emulsions containing compounds having PGE 1 activity are described in, for example, JP-A-58-222014, JP-A-60-149524, and JP-A-4-66540. Can easily prepare a fat emulsion. Fat emulsions can be prepared to contain, for example, vegetable oils, phospholipids, water, and compounds having PGE 1 activity. Furthermore, if necessary, an emulsification aid, a stabilizer, a polymer substance, an isotonic agent and the like can be added.
脂肪乳剤は種々の方法により調製できるが、例えば、次の方法によって製造することができる。所定量の植物油(好ましくは大豆油)、リン脂質、PGE1活性を有する化合物、及びその他前記の添加剤などを混合し、必要に応じて加熱した後、常用のホモジナイザー(例えば、加圧噴射型ホモジナイザー、超音波ホモジナイザーなど)を用いて均質化処理することにより油中水型分散液を調製し、次いでこの分散液に必要量の水を加え、ホモジナイザーで均質化を行って水中油型乳剤に変換することにより脂肪乳剤を製造することができる。脂肪乳剤の調製後に安定化剤や等張剤などの添加剤をさらに加えてもよい。脂肪乳剤は、加熱滅菌の前にpHが4.8から5.2の範囲となるように調節される。pHの調整には水酸化ナトリウムなどの塩基性物質を適量用いればよい。浸透圧比は生理食塩水に対する比として約1となるように調整することができる。The fat emulsion can be prepared by various methods. For example, it can be produced by the following method. A predetermined amount of vegetable oil (preferably soybean oil), a phospholipid, a compound having PGE 1 activity, and other additives as described above are mixed, heated as necessary, and then a conventional homogenizer (for example, a pressure injection type) Prepare a water-in-oil dispersion by homogenization using a homogenizer, ultrasonic homogenizer, etc., then add the required amount of water to the dispersion and homogenize with a homogenizer to obtain an oil-in-water emulsion. A fat emulsion can be produced by conversion. Additives such as stabilizers and isotonic agents may be further added after the preparation of the fat emulsion. The fat emulsion is adjusted to a pH in the range of 4.8 to 5.2 prior to heat sterilization. An appropriate amount of a basic substance such as sodium hydroxide may be used to adjust the pH. The osmotic pressure ratio can be adjusted to be about 1 as a ratio to physiological saline.
本発明における脂肪乳剤の平均粒子径は、動的光散乱法を原理とした粒子径測定装置を用いて測定することができる。本発明における脂肪乳剤の好ましい平均粒子径は0.1μm以上0.4μm以下である。 The average particle size of the fat emulsion in the present invention can be measured using a particle size measuring device based on the dynamic light scattering method. The preferred average particle size of the fat emulsion in the present invention is 0.1 μm or more and 0.4 μm or less.
本発明の脂肪乳剤は、例えば上記のようにして調製した脂肪乳剤をガラス製容器に密封した後に加熱滅菌処理することにより製造することができる。ガラス製容器としては、密封に適しており、かつ加熱滅菌処理において内部に充填された脂肪乳剤中にアルカリ成分を溶出しない性質を有するものであれば任意のガラス製容器を使用することができるが、例えば、加熱滅菌後の当該脂肪乳剤のpH上昇を抑制する手段を備えているガラス製容器が好ましく、上記手段を備えているガラスアンプルが特に好ましい。 The fat emulsion of the present invention can be produced, for example, by sealing the fat emulsion prepared as described above in a glass container, followed by heat sterilization. As the glass container, any glass container can be used as long as it is suitable for sealing and has the property of not eluting alkaline components in the fat emulsion filled in the heat sterilization treatment. For example, a glass container provided with means for suppressing the increase in pH of the fat emulsion after heat sterilization is preferable, and a glass ampoule provided with the above means is particularly preferable.
加熱滅菌後の当該脂肪乳剤のpH上昇を抑制する手段は特に限定されず、例えば、加熱滅菌時において脂肪乳剤中にアルカリ成分の溶出を防止する手段、あるいは加熱滅菌時において脂肪乳剤中に酸性成分を溶出させる手段などを採用できるが、加熱滅菌時において脂肪乳剤中にアルカリ成分の溶出を防止する手段が好ましい。加熱滅菌時において脂肪乳剤中にアルカリ成分の溶出を防止する手段としては、例えば、容器内部表面に皮膜コートを施す手段が挙げられる。好ましくはガラスアンプルの内部表面に酸化ケイ素皮膜コートを施す手段を採用することができる。あるいは、pH上昇を抑制する手段として、ガラス表面のアルカリ成分を化学的処理により除去する手段を採用することも可能である。このような技術は、例えば特開平2-175630号公報などに記載されており、当業者が容易に採用することができる。 The means for suppressing the increase in pH of the fat emulsion after heat sterilization is not particularly limited, for example, means for preventing elution of alkaline components in the fat emulsion during heat sterilization, or acidic components in the fat emulsion during heat sterilization A means for preventing elution of alkaline components in the fat emulsion during heat sterilization is preferable. As means for preventing elution of alkali components in the fat emulsion during heat sterilization, for example, means for applying a film coat to the inner surface of the container can be mentioned. Preferably, means for applying a silicon oxide film coat to the inner surface of the glass ampoule can be employed. Alternatively, as a means for suppressing the increase in pH, a means for removing an alkali component on the glass surface by chemical treatment may be employed. Such a technique is described in, for example, Japanese Patent Application Laid-Open No. 2-175630, and can be easily adopted by those skilled in the art.
本発明の脂肪乳剤は、pHが4.8から5.2の範囲に調節された上記脂肪乳剤を容器に密封して加熱滅菌することにより調製することができる。加熱滅菌は、例えばオートクレーブ中で125℃で数分間から10分程度行うことができるが、温度及び時間は特に限定されず、十分な滅菌が達成できる処理であれば任意の処理を採用することができる。加熱滅菌後の脂肪乳剤のpHは4.9から5.3の範囲であることが好ましい。加熱滅菌の前後におけるpHの上昇は0.3未満であることが好ましく、0.2未満であることがさらに好ましく、0.1未満であることが特に好ましい。また、滅菌後のPGE1量に関して、各アンプルごとのばらつきはPGE1量(μg)の相対標準偏差が1.0%以下であることが望ましく、さらに望ましくは0.5%以下である。The fat emulsion of the present invention can be prepared by sealing the above fat emulsion whose pH is adjusted to a range of 4.8 to 5.2 in a container and heat sterilizing. Heat sterilization can be performed, for example, in an autoclave at 125 ° C for several minutes to about 10 minutes, but the temperature and time are not particularly limited, and any treatment can be adopted as long as sufficient sterilization can be achieved. it can. The pH of the fat emulsion after heat sterilization is preferably in the range of 4.9 to 5.3. The increase in pH before and after heat sterilization is preferably less than 0.3, more preferably less than 0.2, and particularly preferably less than 0.1. In addition, regarding the amount of PGE 1 after sterilization, it is desirable that the relative standard deviation of the amount of PGE 1 (μg) is 1.0% or less, more preferably 0.5% or less.
本発明におけるプロスタグランジンE1活性を有する化合物を含有する脂肪乳剤は、例えばプロスタグランジンE1活性を有する化合物の重量として5μgまたは10μgを含有する製剤としてアンプルに充填して提供することができる。本発明においては、5μg充填されたアンプル中に、その量の80%〜125%の重量の当該化合物が充填されていることが望ましい。すなわちアンプル中に当該化合物が4μg以上6.25μg以下充填されていることを意味する。あるいは本発明においては、10μg充填されたアンプル中に、その両の80%〜125%の重量の当該化合物が充填されていることが望ましい。すなわちアンプル中に当該化合物が8μg以上12.5μg以下充填されていることを意味する。 The fat emulsion containing the compound having prostaglandin E1 activity in the present invention can be provided, for example, by filling an ampoule as a preparation containing 5 μg or 10 μg as the weight of the compound having prostaglandin E1 activity. In the present invention, it is desirable that an ampule filled with 5 μg is filled with the compound having a weight of 80% to 125% of the ampule. That is, it means that the compound is filled in an ampoule with 4 μg or more and 6.25 μg or less. Alternatively, in the present invention, it is desirable that an ampule filled with 10 μg is filled with the compound having a weight of 80% to 125% of both. That is, it means that the compound is filled in the ampoule with 8 μg or more and 12.5 μg or less.
なお、本発明の脂肪乳剤の適用疾患及び使用方法などについては、例えば「リプル注5μg」の添付文書(田辺三菱製薬株式会社、2008年4月改訂、第16版)に具体的かつ詳細に記載されている。 In addition, the applicable diseases and usage methods of the fat emulsion of the present invention are described specifically and in detail in, for example, a package insert of “Ripple Injection 5 μg” (Mitsubishi Tanabe Pharma Corporation, revised April 2008, 16th edition). Has been.
以下、実施例により本発明をさらに具体的に説明するが、本発明の範囲は下記の実施例に限定されることはない。
例1
精製ダイズ油に、アルプロスタジル(PGE1)、オレイン酸、及びホスファチジルエタノールアミン(PE)を除去した卵黄レシチンを溶解し、別途用意したグリセリンと注射用蒸留水との混合物を添加し、ホモミキサーで攪拌して懸濁液を調製した。得られた懸濁液をマントンゴーリン型乳化機(マントンゴーリン製)で乳化し、水酸化ナトリウム及び塩酸を用いてpHを4.90に調整した。調製した乳化物をシリコートアンプル(不二硝子製、アンプル内部に厚さ70〜100Åの酸化ケイ素皮膜コートを施したガラス製アンプル)に充填し、アンプルの空隙部分を窒素置換して熔閉することにより密封した。得られたアンプルを高圧蒸気滅菌機を用いて125℃で2.2分間滅菌して本発明の脂肪乳剤を得た。EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, the scope of the present invention is not limited to the following Example.
Example 1
Egg yolk lecithin from which alprostadil (PGE 1 ), oleic acid, and phosphatidylethanolamine (PE) have been removed is dissolved in purified soybean oil, and a mixture of glycerin and distilled water for injection are added separately. To prepare a suspension. The obtained suspension was emulsified with a Manton Gorin type emulsifier (manton Gorin), and the pH was adjusted to 4.90 using sodium hydroxide and hydrochloric acid. Fill the prepared emulsion into a siricoat ampoule (made by Fuji Glass, glass ampoule with a 70-100mm thick silicon oxide coating on the inside of the ampoule), and replace the ampoule gap with nitrogen and seal it. Sealed. The obtained ampule was sterilized at 125 ° C. for 2.2 minutes using a high-pressure steam sterilizer to obtain the fat emulsion of the present invention.
例2
例1と同様の方法で乳化物を調製し、水酸化ナトリウムを用いてpHを5.01に調整した後、例1と同様にしてシリコートアンプルに充填及び密封し、滅菌を行って本発明の脂肪乳剤を得た。
例3
例1と同様の方法で乳化物を調製し、水酸化ナトリウムを用いてpHを5.15に調整した後、例1と同様にしてシリコートアンプルに充填及び密封し、滅菌を行って本発明の脂肪乳剤を得た。Example 2
Prepare an emulsion in the same manner as in Example 1, adjust the pH to 5.01 using sodium hydroxide, fill and seal in a silicoat ampoule in the same manner as in Example 1, perform sterilization, and then the fat emulsion of the present invention Got.
Example 3
Prepare an emulsion in the same manner as in Example 1, adjust the pH to 5.15 using sodium hydroxide, fill and seal the silicoat ampoule in the same manner as in Example 1, sterilize, and then the fat emulsion of the present invention Got.
例4(比較例)
例1で調製した乳化物を通常のガラスアンプル(酸化ケイ素皮膜コートが施されていないガラス製アンプル)に充填し、アンプルの空隙部分を窒素置換して熔閉することにより密封した。得られたアンプルを高圧蒸気滅菌機を用いて125℃で2.2分間滅菌して脂肪乳剤を得た。Example 4 (comparative example)
The emulsion prepared in Example 1 was filled in a normal glass ampoule (a glass ampoule not coated with a silicon oxide film), and the gap of the ampoule was purged with nitrogen and sealed. The obtained ampule was sterilized at 125 ° C. for 2.2 minutes using a high-pressure steam sterilizer to obtain a fat emulsion.
例5
例1と同様の方法で乳化物を調製し、水酸化ナトリウムを用いてpHを5.09から5.15に調整した後、例1と同様にしてシリコートアンプルに充填および密封したサンプルを9例作製し、滅菌を行なって本発明の脂肪乳剤を得た。Example 5
Prepare an emulsion in the same manner as in Example 1, adjust the pH from 5.09 to 5.15 using sodium hydroxide, and then prepare 9 samples filled and sealed in a silicoat ampoule in the same manner as in Example 1. To obtain the fat emulsion of the present invention.
例6(比較例)
例5と同様の方法で、通常のガラスアンプルに充填したサンプルを10例作製し、例5と同様の方法で滅菌して脂肪乳剤を得た。
表1に加熱滅菌前のpHを変化させた脂肪乳剤を25℃で保存した場合におけるPGE1の安定性試験の結果を示す。PGE1の残存率はポストカラム反応を用いた高速液体クロマトグラフィーによって測定した(日本薬局方フォーラム(JP Forum), 15(3), pp.233-235, 2006に記載された方法に従って測定した)。表2に30℃、及び40℃で保存した場合におけるPGE1の安定性試験の結果を示す。この結果から明らかなように、30℃及び40℃で保存した場合にも、シリコートアンプルに密封充填された本発明の脂肪乳剤のPGE1安定性は、通常のガラスアンプルに密封充填された例5の脂肪乳剤よりも優れていた。上記の結果を用いて、pH 5.0付近に調製した脂肪乳剤を用いた場合の5℃でのPGE1安定性をアレニウスプロットを用いて計算した。表3に示すように、シリコートアンプルに密封充填された本発明の脂肪乳剤では16ヶ月目で開始時に対して65%以上の含有量を維持することができた。Example 6 (comparative example)
Ten samples filled in a normal glass ampoule were prepared in the same manner as in Example 5, and sterilized in the same manner as in Example 5 to obtain a fat emulsion.
Table 1 shows the results of the stability test of PGE 1 when fat emulsions with different pH prior to heat sterilization were stored at 25 ° C. The residual rate of PGE 1 was measured by high performance liquid chromatography using a post-column reaction (measured according to the method described in JP Forum, 15 (3), pp.233-235, 2006) . Table 2 shows the results of the stability test of PGE 1 when stored at 30 ° C. and 40 ° C. As is apparent from these results, the PGE 1 stability of the fat emulsion of the present invention sealed in a silicoat ampoule even when stored at 30 ° C. and 40 ° C. is shown in Example 5 in which a normal glass ampoule is hermetically sealed. It was superior to the fat emulsion. Using the above results, the PGE 1 stability at 5 ° C. when using a fat emulsion prepared near pH 5.0 was calculated using an Arrhenius plot. As shown in Table 3, the fat emulsion of the present invention sealed and filled in a silicoat ampoule was able to maintain a content of 65% or more with respect to the start at the 16th month.
表4に、滅菌後の各サンプル中に残存するPGE1量と、それらの平均値、標準偏差値および相対標準偏差値を示す。シリコートアンプルに密封充填された本発明の脂肪乳剤残量の標準偏差値は、通常のガラスアンプルに密封充填された例7の脂肪乳剤量の相対標準偏差値よりも小さく、サンプルごとのばらつきが小さい均一な製品であることが示された。Table 4 shows the amount of PGE 1 remaining in each sample after sterilization, and the average value, standard deviation value, and relative standard deviation value thereof. The standard deviation value of the remaining amount of the fat emulsion of the present invention hermetically sealed in a silicoat ampule is smaller than the relative standard deviation value of the amount of the fat emulsion of Example 7 hermetically sealed in a normal glass ampule, and the variation among samples is small. It was shown to be a uniform product.
例7
例2と同様の方法で調製した乳化物を1 ml採取し、1 mlの内標準溶液(1-ナフトール50 mgを99.5%エタノール20 mlに溶解し、この溶解液3 mlに移動相を加えて100 mlとしたもの)を加えて混合し、試料溶液とした。別にアルプロスタジル標準液をデシケーターで乾燥し、10 mgを量り取り正確に秤量し、99.5%エタノールに溶解して100 mlとして標準原液(E1)とした。また、プロスタグランジンA1標準液をデシケーターで乾燥し、10 mgを量り取り、99.5%エタノールに溶解して100 mlとして標準原液(A1)とした。E1およびA1を2.5 mlずつ採取し、移動相を加えて50 mlとし、この混合液1 mlを採取して内標準液1 mlと混合して標準溶液とした。試料溶液および標準溶液それぞれ40μlにつき、液体クロマトグラフィーを実施した。Example 7
Take 1 ml of the emulsion prepared in the same manner as in Example 2, dissolve 1 ml of internal standard solution (50 mg of 1-naphthol in 20 ml of 99.5% ethanol, add the mobile phase to 3 ml of this solution, 100 ml) was added and mixed to obtain a sample solution. Separately, the alprostadil standard solution was dried with a desiccator, 10 mg was weighed and accurately weighed, and dissolved in 99.5% ethanol to make 100 ml as a standard stock solution (E1). Further, the prostaglandin A1 standard solution was dried with a desiccator, 10 mg was weighed and dissolved in 99.5% ethanol to make 100 ml as a standard stock solution (A1). 2.5 ml each of E1 and A1 was collected, and the mobile phase was added to make 50 ml. 1 ml of this mixed solution was collected and mixed with 1 ml of the internal standard solution to obtain a standard solution. Liquid chromatography was performed on 40 μl each of the sample solution and the standard solution.
内標準物質のピーク面積に対するプロスタグランジンA1のピーク面積の比を求めた。試料溶液におけるプロスタグランジンA1の面積比はQTとし、標準溶液におけるプロスタグランジンA1の面積比はQSとした。これら面積比を用いて、次式によりアルプロスタジルに換算したプロスタグランジンA1の量を求めた。
プロスタグランジンA1の量(μg)=(プロスタグランジンA1の正確な秤取量(mg))× QT/QS × 0.5 × 1.054The ratio of the peak area of prostaglandin A1 to the peak area of the internal standard was determined. The area ratio of prostaglandin A1 in the sample solution was QT, and the area ratio of prostaglandin A1 in the standard solution was QS. Using these area ratios, the amount of prostaglandin A1 converted to alprostadil was determined by the following formula.
Prostaglandin A1 amount (μg) = (Accurate prostaglandin A1 weighed (mg)) × QT / QS × 0.5 × 1.054
例2と同様の方法で調製した乳化物については、プロスタグランジンA1の正確な秤量は10.05 mg、試料溶液の内標準物質のピーク面積に対するプロスタグランジンA1のピーク面積の比(QT)は0.180931、標準溶液の内標準物質のピーク面積に対するプロスタグランジンA1のピーク面積の比(QT)は0.778099であった。これを上記式にあてはめて計算したところ、当該乳化物中のプロスタグランジンA1の量は1.23μgであった。 For the emulsion prepared in the same manner as in Example 2, the exact weight of prostaglandin A1 was 10.05 mg, and the ratio of the peak area of prostaglandin A1 to the peak area of the internal standard substance in the sample solution (QT) was 0.180931. The ratio of the peak area of prostaglandin A1 to the peak area of the internal standard substance in the standard solution (QT) was 0.778099. When this was applied to the above equation and calculated, the amount of prostaglandin A1 in the emulsion was 1.23 μg.
本発明の脂肪乳剤はプロスタグランジンE1活性を有する化合物の安定性が従来の脂肪乳剤に比べて向上しており、長期間にわたって保存しても有効成分の含有量が低下しないので、プロスタグランジンE1含有製剤として極めて有用である。In the fat emulsion of the present invention, the stability of the compound having prostaglandin E 1 activity is improved as compared with the conventional fat emulsion, and the content of the active ingredient does not decrease even when stored for a long time. It is extremely useful as a preparation containing gin E 1 .
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