JPH02286625A - Sustained release pharmaceutical for injection - Google Patents
Sustained release pharmaceutical for injectionInfo
- Publication number
- JPH02286625A JPH02286625A JP1109691A JP10969189A JPH02286625A JP H02286625 A JPH02286625 A JP H02286625A JP 1109691 A JP1109691 A JP 1109691A JP 10969189 A JP10969189 A JP 10969189A JP H02286625 A JPH02286625 A JP H02286625A
- Authority
- JP
- Japan
- Prior art keywords
- human
- component
- ingredient
- oil
- long
- 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.)
- Pending
Links
- 238000002347 injection Methods 0.000 title claims abstract description 5
- 239000007924 injection Substances 0.000 title claims abstract description 5
- 238000013268 sustained release Methods 0.000 title abstract description 3
- 239000012730 sustained-release form Substances 0.000 title abstract description 3
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 19
- 108010002352 Interleukin-1 Proteins 0.000 claims abstract description 13
- 102000000589 Interleukin-1 Human genes 0.000 claims abstract description 13
- 239000003921 oil Substances 0.000 claims abstract description 13
- 235000019198 oils Nutrition 0.000 claims abstract description 13
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 9
- 239000003381 stabilizer Substances 0.000 claims abstract description 9
- 239000008159 sesame oil Substances 0.000 claims abstract description 7
- 235000011803 sesame oil Nutrition 0.000 claims abstract description 7
- 240000001090 Papaver somniferum Species 0.000 claims abstract description 6
- 235000008753 Papaver somniferum Nutrition 0.000 claims abstract description 6
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 claims abstract description 6
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 6
- 229930195729 fatty acid Natural products 0.000 claims abstract description 6
- 239000000194 fatty acid Substances 0.000 claims abstract description 6
- 108010010803 Gelatin Proteins 0.000 claims abstract description 5
- 239000008273 gelatin Substances 0.000 claims abstract description 5
- 229920000159 gelatin Polymers 0.000 claims abstract description 5
- 235000019322 gelatine Nutrition 0.000 claims abstract description 5
- 235000011852 gelatine desserts Nutrition 0.000 claims abstract description 5
- 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 abstract description 4
- 102000009027 Albumins Human genes 0.000 claims abstract description 4
- 108010088751 Albumins Proteins 0.000 claims abstract description 4
- 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 abstract description 4
- 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 abstract description 4
- 229940063655 aluminum stearate Drugs 0.000 claims abstract description 4
- 239000003549 soybean oil Substances 0.000 claims abstract description 4
- 235000012424 soybean oil Nutrition 0.000 claims abstract description 4
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 claims abstract description 3
- 229940042585 tocopherol acetate Drugs 0.000 claims abstract description 3
- 238000002360 preparation method Methods 0.000 claims description 24
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- 201000011510 cancer Diseases 0.000 claims description 4
- 230000017074 necrotic cell death Effects 0.000 claims description 4
- 239000004359 castor oil Substances 0.000 claims description 3
- 235000019438 castor oil Nutrition 0.000 claims description 3
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000011859 microparticle Substances 0.000 claims 1
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 abstract description 18
- 102000057041 human TNF Human genes 0.000 abstract description 15
- 239000004615 ingredient Substances 0.000 abstract description 10
- 239000008280 blood Substances 0.000 abstract description 4
- 210000004369 blood Anatomy 0.000 abstract description 4
- 230000003902 lesion Effects 0.000 abstract description 4
- 210000002751 lymph Anatomy 0.000 abstract description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 abstract description 2
- 229910052782 aluminium Inorganic materials 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 20
- 238000009472 formulation Methods 0.000 description 19
- 239000000843 powder Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 7
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- CUNWUEBNSZSNRX-RKGWDQTMSA-N (2r,3r,4r,5s)-hexane-1,2,3,4,5,6-hexol;(z)-octadec-9-enoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O CUNWUEBNSZSNRX-RKGWDQTMSA-N 0.000 description 3
- 101001002634 Homo sapiens Interleukin-1 alpha Proteins 0.000 description 3
- 102100040247 Tumor necrosis factor Human genes 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000010419 fine particle Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229960005078 sorbitan sesquioleate Drugs 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 230000002601 intratumoral effect Effects 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 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 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical class CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
- 108010044091 Globulins Proteins 0.000 description 1
- 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 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 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
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 210000004880 lymph fluid Anatomy 0.000 description 1
- 150000004667 medium chain fatty acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- -1 polyoxyethylene Polymers 0.000 description 1
- 229940048914 protamine Drugs 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
【発明の詳細な説明】
産業上ρ」更囲うし野−
零発・明は、ヒト癌壊死因子（Ｔｕｍｏｒ Ｎｅｃｒｏ
ｓｉｓＦａｃｔｏｒ；以下ｒヒトＴＮＦ Ｊという）又
はヒトインターロイキン１ （Ｉｎｔｅｒｌｅｕｋｉ
ｎ−１；以下「ヒ） ＩＬ−ＩＪという）の血中、リン
パ液中及び／又は病巣中濃度の持続を目的とする製剤に
関する。[Detailed Description of the Invention] Industrially ρ' Saraki Ushino - Reiha and Akira are human cancer necrosis factor (Tumor Necrosis factor).
sisFactor; hereinafter referred to as human TNF J) or human interleukin 1 (Interleuki
The present invention relates to a preparation aimed at sustaining the concentration of IL-IJ (hereinafter referred to as IL-IJ) in blood, lymph, and/or lesions.
更に詳しくは、少なくとも次の４成分からなる注射用持
続性製剤（以下「本発明の製剤」という）に関する。More specifically, the present invention relates to a long-acting preparation for injection (hereinafter referred to as "preparation of the present invention") comprising at least the following four components.
（ａ）ヒトＴＮＦ又はヒトＩＬ−１
（ロ）油性媒体
（ｃ）ステアリン酸アルミニウム
（ｄ）コレステロール
従来の技術
特開昭６０−９７９１８号、同６０−１２６１７号及び
同６２２３０７２９号には、生体内で分解し、生体内投
与が可能で低毒性の物質からなる担体に薬効成分が含有
されている持続性製剤を開示しているが、いずれも成分
（ｃ）及び（ｄ）を含んでいない点で、本発明の製剤と
は全く異なる。(a) Human TNF or human IL-1 (b) Oil-based medium (c) Aluminum stearate (d) Cholesterol The patent discloses a long-acting preparation in which a medicinal ingredient is contained in a carrier made of a low-toxic substance that is biodegradable and can be administered in vivo, but none of them contain ingredients (c) and (d). This is completely different from the formulation of the present invention.
Ｉｎｔ、 Ｊ、 Ｐｈａｒｍ、＋ ３２．２２３ （１
９８６）には、ポリオキシエチレン・ポリオキシプロピ
レン・フロック共重合体のゲル形成を利用した持続性製
剤を開示しているが、これには成分（ｂ）が含まれてお
らず、従ってそれに伴う作用も本発明の製剤とは全く異
なるものである。Int, J, Pharm, + 32.223 (1
No. 986) discloses a long-acting preparation that utilizes gel formation of polyoxyethylene-polyoxypropylene-floc copolymer, but this does not contain component (b) and therefore the accompanying The action is also completely different from that of the formulation of the present invention.
ＧＢ−１，４５４，１９５には、黄体形成ホルモン放出
因子の持続性製剤が開示されているが、生薬が異なる、
成分（ｄ）を含んでいない、投与経路が経鼻である等の
理由により、本発明の製剤とは全く異なるものである。GB-1,454,195 discloses a long-acting preparation of luteinizing hormone-releasing factor, but the herbal medicine is different.
This formulation is completely different from the formulation of the present invention because it does not contain component (d) and the route of administration is nasal.
が解° しようとする問題点
ヒトＴＮＦ及びヒ） ＩＬ−１は半減期が短いため、血
中、リンパ液中及び／又は病巣中濃度の持続が困難であ
る。Problems to be Solved Human TNF and Human IL-1) Since IL-1 has a short half-life, it is difficult to maintain its concentration in blood, lymph, and/or lesions.
本発明者等は、鋭意研究の結果、上記本発明の製剤がそ
こに含まれるヒトＴＮＦ又はヒトＩＬ−１の持続化を達
成できることを見出し、本発明を完成した。As a result of intensive research, the present inventors have found that the above-mentioned preparation of the present invention can maintain the human TNF or human IL-1 contained therein, and have completed the present invention.
照点を解 するための手
本発明の製剤の構成成分である成分（ａ）の使用量は成
分（ｂ） 、 （ｃ）及び（ｄ）の総量に対して、１５
讐ハ％以下であることが好ましい。The amount of component (a) used as a component of the formulation of the present invention is 15% relative to the total amount of components (b), (c) and (d).
It is preferable that the ratio is less than %.
成分（ｂ）は生体内で成分（ａ）を保持する作用を有し
、例えば、ゴマ油、落花生油、綿実油、大豆油、中鎖脂
肪酸トリグリセライド、ひまし油オリーブ油、とうもろ
こし油、ヨード化ケシ油脂肪酸エチルエステル、酢酸ト
コフェロール等が挙げられ、特に注射用として常用され
るゴマ油、大豆油、ヨード化ケシ油脂肪酸エチルエステ
ル又はこれらの混合物が好ましい。Component (b) has the effect of retaining component (a) in the body, and includes, for example, sesame oil, peanut oil, cottonseed oil, soybean oil, medium chain fatty acid triglyceride, castor oil, olive oil, corn oil, iodized poppy oil fatty acid ethyl ester. , tocopherol acetate, etc., and particularly preferred are sesame oil, soybean oil, iodized poppy oil fatty acid ethyl ester, or mixtures thereof, which are commonly used for injections.
成分（ｃ）は本発明の製剤中の成分（ａ）を含有する微
粒子の凝集を防止し、更に生体内で本発明の製剤を安定
化する作用を有する。Component (c) has the effect of preventing the aggregation of fine particles containing component (a) in the formulation of the present invention and further stabilizing the formulation of the present invention in vivo.
成分（ｃ）としては、モノ及び／又はジステアリン酸ア
ルミニウムが挙げられ、その使用量は成分（ｂ）に対し
て０．１〜刹ハχ、好ましくは０．５〜３ Ｗ／Ｖχで
ある。Component (c) includes aluminum mono- and/or distearate, and the amount used is 0.1 to 3 W/Vx, preferably 0.5 to 3 W/Vx, based on component (b).
成分（ｄ）の使用量は成分（ｂ）に対して０．１〜１０
Ｗ／Ｖ″Ａ、好ましくは１〜５ Ｗ／Ｖχである。The amount of component (d) used is 0.1 to 10% of component (b).
W/V″A, preferably 1 to 5 W/Vχ.
本発明の効果をより高めるには、成分（ａ）の安定化剤
を加えるのが好ましい。ヒトＴＮＦの安定化剤としては
、アルブミン、グロブリン、プロタミン、トレハロース
、Ｄ−グルコース、ゼラチン等が挙げられ、ヒ） ＩＬ
−１の安定化剤としては、アルブミン、デキストラン
トレハロース、ゼラチン等が挙げられる。In order to further enhance the effects of the present invention, it is preferable to add a stabilizer as component (a). Stabilizers for human TNF include albumin, globulin, protamine, trehalose, D-glucose, gelatin, etc.
-1 stabilizers include albumin, dextran
Examples include trehalose and gelatin.
成分（ａ）の放出を制御するには、成分（ｄ）の量を加
減するか、ポリオキシエチレン硬化ヒマシ油精製卵黄レ
シチン、大豆レシチン、水素添加レシチン、セスキオレ
イン酸ソルビタン等の放出制御剤を添加すればよい。To control the release of component (a), the amount of component (d) can be adjusted or a release controlling agent such as polyoxyethylene hydrogenated castor oil refined egg yolk lecithin, soybean lecithin, hydrogenated lecithin, or sorbitan sesquioleate can be used. Just add it.
成分（ａ）の安定化剤、成分（ａ）の放出制御剤、成分
（ｂ）及び成分（ｃ）はそれぞれ１種に限られず、複数
種のものを組み合わせて用いてもよい。The stabilizer of component (a), the release control agent of component (a), the component (b), and the component (c) are not limited to one type each, and a combination of multiple types may be used.
本発明の製剤の製造概略の一例を以下に説明する。成分
（ａ）のヒトＴＮＦ又はヒトＩＬ−１及びその安定化剤
を水に加えてよく撹拌し、必要に応じて加温又は冷却し
て、均一な水溶液とする。このとき、安定化剤のｐＨに
よっては、緩衝液を加えて成分（ａ）を最も安定化さ廿
るｐＨ付近にもってくる必要がある。An example of the outline of the production of the formulation of the present invention will be explained below. Component (a), human TNF or human IL-1, and its stabilizer are added to water, stirred well, and heated or cooled as necessary to form a uniform aqueous solution. At this time, depending on the pH of the stabilizer, it may be necessary to add a buffer solution to bring the component (a) to a pH that is most stable.
この水溶液に次の■、■を加え、撹拌機、ホモジナイザ
ー、超音波乳化機、フロージェットミキサー、マントン
ゴーリンホモジナイザー等を用いて乳化し、得られたエ
マルションを凍結乾燥することにより、成分（ａ）を微
粒子化する。Add the following (1) and (2) to this aqueous solution, emulsify using a stirrer, homogenizer, ultrasonic emulsifier, flow jet mixer, Manton-Gorlin homogenizer, etc., and freeze-dry the resulting emulsion to obtain component (a). into fine particles.
凍結乾燥前に成分（ａ）の放出制御剤を加えてもよい。A release controlling agent for component (a) may be added before lyophilization.
■水と混しらず、成分（ａ）を凍結乾燥するために用い
得る有機溶媒 （例えばシクロヘキサン）■親油性界面
活性剤 （例えばセスキオレイン酸ソルビタン）
この微粒子を、上記のホモジナイザー等を用い、成分（
ｃ）及び成分（ｄ）を添加溶解させた成分（ｂ）の油性
媒体中に懸濁させることにより、本発明の製剤を得るこ
とができる。又、この微粒子に上記媒体を添付した片時
懸濁型の製剤とすることもできる。■Organic solvent that can be used to freeze-dry component (a) without mixing with water (e.g. cyclohexane) ■Lipophilic surfactant (e.g. sorbitan sesquioleate) (
The formulation of the present invention can be obtained by suspending component (b) in an oily medium in which c) and component (d) are added and dissolved. Alternatively, a one-time suspension type preparation can be prepared in which the above-mentioned medium is attached to the fine particles.
光」レグ力」し
本発明の製剤は、投与前にはサスペンション状態である
が、投与後生体内で自然乳化して油滴内に成分（ａ）が
懸濁された０／ｗエマルションとなり、更に時間の経過
と共に、成分（ａ）が生体内の水分を吸収、溶解するこ
とにより、Ｗ１０／Ｗエマルションの形をとる。本発明
の製剤は、上記過程の進行を、成分（ｃ）及び成分（ｄ
）を組み合わせることにより遅延させ、成分（ａ）の徐
放化を達成する。The preparation of the present invention is in a suspension state before administration, but after administration, it spontaneously emulsifies in vivo to become an 0/w emulsion in which component (a) is suspended in oil droplets. With the passage of time, component (a) absorbs and dissolves moisture in the body, thereby taking the form of a W10/W emulsion. The preparation of the present invention can control the progress of the above process with component (c) and component (d).
) to achieve sustained release of component (a).
本発明の製剤は、ヒトＴＮＦ又はヒトＩＬ−１の血中、
リンパ液中及び／又は病巣白濃度が持続する。以下に実
験例を挙げて、本発明の製剤の効果を説明する。The preparation of the present invention contains human TNF or human IL-1 in blood,
Persistent white concentration in lymph fluid and/or lesions. The effects of the formulation of the present invention will be explained below by giving experimental examples.
実」（例」−
後記実施例１で作製した本製剤と、同力価のヒ） ＴＮ
Ｆを含有する対照製剤について、それぞれｉｎ ｖｉｔ
ｒｏで放出試験を行った。放出量の時間的推移をＥＩＡ
法によって測定した。(Example) - This preparation prepared in Example 1 below and H.
For control formulations containing F, each in vitro
Release tests were conducted on ro. EIA of temporal changes in release amount
It was measured by the method.
対照製剤は、後記実施例１で調製したヒｌ−ＴＮＦを含
有する粉末Ｃ０，２ｇにＩ Ｗ／Ｗχのモノステアリン
酸アルミニウムを含むゴマ油５ｍｌを加え、ホモジナイ
ザーを用いて粉末粒子を均一に懸濁させることにより製
造した。For the control formulation, 5 ml of sesame oil containing aluminum monostearate of I W/W χ was added to 0.2 g of the powder C containing Hill-TNF prepared in Example 1 below, and the powder particles were uniformly suspended using a homogenizer. It was manufactured by
結果を図１に示す。図１かられかるように、ゴマ油にモ
ノステアリン酸アルミニウムのみを溶解した対照製剤は
２４時間で約７０χのヒ） ＴＮＦを放出するのに対し
、モノステアリン酸アルミニウム及びコレステロールを
溶解した本製剤では約１７χであった。The results are shown in Figure 1. As can be seen from Figure 1, the control formulation in which only aluminum monostearate was dissolved in sesame oil released approximately 70x of TNF in 24 hours, whereas the present formulation in which aluminum monostearate and cholesterol were dissolved released approximately 70% of TNF. It was 17χ.
東」１燃」−
後記実施例１で作製した木製剤と、実験例１で述べた対
照製剤のそれぞれを、担癌マウスに腫瘍内投与し、１１
！！瘍内残存量をＥＩＡ法により測定し、投与量に対す
る残存率の時間的推移を調べた。The wooden preparation prepared in Example 1 described later and the control preparation described in Experimental Example 1 were each intratumorally administered to tumor-bearing mice.
! ! The amount remaining in the tumor was measured by the EIA method, and the time course of the residual rate relative to the dose was investigated.
結果を図２に示す。図２かられかるように、対照製剤に
おけるヒトＴＮＦの腫瘍内残存率は、投与３時間後で約
２５χ、９時間後で約１２χであるのに対して、本製剤
では、投与３時間後で約７５χ、９時間後でも約３２χ
の高い残存率を示した。The results are shown in Figure 2. As can be seen from Figure 2, the intratumoral residual rate of human TNF in the control formulation was approximately 25χ at 3 hours after administration and approximately 12χ at 9 hours, whereas in the present formulation, the residual rate was approximately 25χ at 3 hours after administration. Approximately 75χ, approximately 32χ even after 9 hours
showed a high survival rate.
１１九り
特開昭６０−２３２０９７の実施例３で調製したヒトＴ
ＮＦ （力価 ２Ｘ １０７ＪＲＵ／ｍｌ ） １
ｍｌと２０Ｗ／Ｖ％ゼラチン水溶液（０，０５Ｍ、 ｐ
Ｈ７リン酸緩衝液含有）５ｍ１を均一に混合撹拌し、水
ｍ ￥＆、 Ａを得た。Human T prepared in Example 3 of JP-A No. 60-232097
NF (Titer 2X 107JRU/ml) 1
ml and 20W/V% gelatin aqueous solution (0.05M, p
5ml of H7 phosphate buffer solution was mixed and stirred uniformly to obtain water m\&A.
別に、セスキオレイン酸ソルビタン０．５ｇをシクロヘ
キサン５０ｍ１に溶解し、シクロヘキサン溶液Ｂを得た
。次に水溶液Ａ及びシクロヘキサン溶液Ｂを混合撹拌し
、超音波ホモジナイザーにより乳化してエマルションを
得た。このエマルションを凍結乾燥し、粉末Ｃを得た。Separately, 0.5 g of sorbitan sesquioleate was dissolved in 50 ml of cyclohexane to obtain a cyclohexane solution B. Next, aqueous solution A and cyclohexane solution B were mixed and stirred, and emulsified using an ultrasonic homogenizer to obtain an emulsion. This emulsion was freeze-dried to obtain powder C.
この粉末０．２ｇにｌ Ｗ／Ｖχのモノステアリン酸ア
ルミニウム及び３ Ｗ／ＶＸのコレステロールを含むゴ
マ油５ｍｌを加え、上記ホモジナイザーを用いて粉末粒
子を均一に懸濁させることにより、ヒ） ＴＮＦを含む
油性の懸濁型持続性製剤を得た。5 ml of sesame oil containing 1 W/Vx of aluminum monostearate and 3 W/Vx of cholesterol was added to 0.2 g of this powder, and the powder particles were uniformly suspended using the homogenizer described above. An oily suspension type long-acting preparation was obtained.
本発明の製剤はそのまま投与できる形のものも片時懸濁
型のもののいずれも、５°Ｃで３か月間安定である。The formulations of the present invention, both in ready-to-administer form and in temporary suspension form, are stable for 3 months at 5°C.
支順はＬ
特開昭６０−２３２０９７の実施例３で調製したヒトＴ
ＮＦ１ｍｌの代わりに、特開昭６１−２７１２２２の実
施例２で調製したヒトＩＬ−１α（力価８．５ ｍｇ／
ｍｌ）５ｍｌを用いる他は、実施例１と同様にしてヒト
ＩＬ−１αを含む油性の懸濁型持続性製剤を得た。Human T prepared in Example 3 of JP-A No. 60-232097
Instead of 1 ml of NF, human IL-1α prepared in Example 2 of JP-A-61-271222 (potency 8.5 mg/
An oil-based suspension-type long-acting preparation containing human IL-1α was obtained in the same manner as in Example 1, except that 5 ml of the suspension was used.
本製剤も、そのまま投与できる形のもの、片時懸濁型の
もののいずれも、５°Ｃで３か月間安定である。Both the ready-to-administer form and the temporary suspension form of this preparation are stable at 5°C for 3 months.
実」［伝」一
実施例１で得たヒ） ＴＮＦを含有する粉末ＣＯ，２ｇ
にＩ Ｗ／ＶＸのモノステアリン酸アルミニウム及び３
Ｗ／Ｖχのコレステロールを含むヨード化ケシ油脂肪
酸エチルエステル５ｍｌを加え、ホモジナイザーを用い
て粉末粒子を油相中に均一に懸濁させることにより、ヒ
トτＮＦを含む油性の懸濁型持続性製剤を得た。Powder CO containing TNF obtained in Example 1, 2 g
I W/VX aluminum monostearate and 3
By adding 5 ml of iodized poppy oil fatty acid ethyl ester containing cholesterol of W/Vχ and uniformly suspending the powder particles in the oil phase using a homogenizer, an oil-based suspended long-acting preparation containing human τNF was prepared. Obtained.
支２
実施例２で得たヒ） ＩＬ−１αを含有する粉末Ｃ０１
２ｇにＩ Ｗ／Ｖχのモノステアリン酸アルミニウム及
び３ Ｗ／Ｖχのコレステロールを含むヨード化ケシ油
脂肪酸エチルエステル５ｍｌを加え、ホモジナイザーを
用いて粉末粒子を油相中に均一に懸濁させることにより
、ヒトＩＬ−１αを含む油性の懸濁型持続性製剤を得た
。Support 2 Powder C01 containing IL-1α obtained in Example 2
By adding 5 ml of iodized poppy oil fatty acid ethyl ester containing aluminum monostearate of I W/Vχ and cholesterol of 3 W/Vχ to 2 g and uniformly suspending the powder particles in the oil phase using a homogenizer, An oil-based suspension type long-acting preparation containing human IL-1α was obtained.
図１はｉｎ ｖｉｔｒｏにおけるｐＨ７のリン酸緩衝生
理食塩液中でのヒトＴＮＦの放出曲線であり、図２は
ｉｎ ｖｉｖｏにおける担癌マウス腫瘍内投与時の、ヒ
トＴＮＦの腫瘍内残存率の時間的推移であり、いずれも
丸印が本発明の製剤、四角印が対照ヒトＴＮＦ製剤であ
る。
図１
経過時間（ｈｒ）Figure 1 shows the release curve of human TNF in phosphate buffered saline at pH 7 in vitro, and Figure 2 shows the release curve of human TNF in phosphate buffered saline at pH 7 in vitro.
This is a time course of the intratumoral residual rate of human TNF when administered intratumorally to tumor-bearing mice in vivo, and in both cases, circles indicate the formulation of the present invention, and squares indicate the control human TNF formulation. Figure 1 Elapsed time (hr)
Claims (5)
はヒトインターロイキン１の注射用持続性製剤。 （ａ）ヒト癌壊死因子又はヒトインターロイキン１（ｂ
）油性媒体 （ｃ）ステアリン酸アルミニウム （ｄ）コレステロール(1) An injectable long-acting preparation of human cancer necrosis factor or human interleukin-1 consisting of at least the following four components. (a) Human cancer necrosis factor or human interleukin 1 (b)
) Oily medium (c) Aluminum stearate (d) Cholesterol
項記載の注射用持続性製剤。(2) Claim 1 containing a stabilizer as component (a)
Injectable long-acting preparations as described in Section 1.
ス又はゼラチンである特許請求の範囲第２項記載の持続
性製剤。(3) The long-acting preparation according to claim 2, wherein the stabilizer of component (a) is albumin, trehalose, or gelatin.
化ケシ油脂肪酸エチルエステル又は酢酸トコフェロール
である特許請求の範囲第１項記載の持続性製剤。(4) The long-acting preparation according to claim 1, wherein component (b) is soybean oil, sesame oil, castor oil, iodized poppy oil fatty acid ethyl ester, or tocopherol acetate.
粒子化し、ステアリン酸アルミニウム及びコレステロー
ルを溶解させた油性媒体に、これを懸濁させることを特
徴とする注射用持続性製剤の製造方法。(5) A method for producing a long-acting preparation for injection, which comprises micronizing human cancer necrosis factor or human interleukin 1 and suspending the microparticles in an oily medium in which aluminum stearate and cholesterol are dissolved.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1109691A JPH02286625A (en) | 1989-04-27 | 1989-04-27 | Sustained release pharmaceutical for injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1109691A JPH02286625A (en) | 1989-04-27 | 1989-04-27 | Sustained release pharmaceutical for injection |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH02286625A true JPH02286625A (en) | 1990-11-26 |
Family
ID=14516751
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1109691A Pending JPH02286625A (en) | 1989-04-27 | 1989-04-27 | Sustained release pharmaceutical for injection |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02286625A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002066006A1 (en) * | 2001-02-19 | 2002-08-29 | Lg Life Sciences Ltd. | Sustained-release suspension of ceftiofur hydrochloride |
| JP2013517269A (en) * | 2010-01-14 | 2013-05-16 | ウメクライン ムード エービー | Pharmaceutical composition containing 3-beta-hydroxy-5-alpha-pregnan-20-one having improved shelf life and solubility characteristics |
| JP2020514250A (en) * | 2017-01-09 | 2020-05-21 | アサリナ ファーマ アーベー | Injectable suspension |
-
1989
- 1989-04-27 JP JP1109691A patent/JPH02286625A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002066006A1 (en) * | 2001-02-19 | 2002-08-29 | Lg Life Sciences Ltd. | Sustained-release suspension of ceftiofur hydrochloride |
| AU2002232263B2 (en) * | 2001-02-19 | 2006-05-25 | Ctcbio Inc. | Suspension of Ceftiofur Hydrochloride |
| AU2002232263B8 (en) * | 2001-02-19 | 2006-11-23 | Ctcbio Inc. | Suspension of Ceftiofur Hydrochloride |
| JP2013517269A (en) * | 2010-01-14 | 2013-05-16 | ウメクライン ムード エービー | Pharmaceutical composition containing 3-beta-hydroxy-5-alpha-pregnan-20-one having improved shelf life and solubility characteristics |
| US9687496B2 (en) | 2010-01-14 | 2017-06-27 | Asarina Pharma Ab | Pharmaceutical composition comprising 3-beta-hydroxy-5-alpha-pregnan-20-one with improved storage and solubility properties |
| US11534446B2 (en) | 2010-01-14 | 2022-12-27 | Asarina Pharma Ab | Pharmaceutical composition comprising 3-beta-hydroxy-5-alpha-pregnan-20-one with improved storage and solubility properties |
| JP2020514250A (en) * | 2017-01-09 | 2020-05-21 | アサリナ ファーマ アーベー | Injectable suspension |
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