JPS6341416A - Production of microcapsule containing analgesic peptide - Google Patents
Production of microcapsule containing analgesic peptideInfo
- Publication number
- JPS6341416A JPS6341416A JP18746886A JP18746886A JPS6341416A JP S6341416 A JPS6341416 A JP S6341416A JP 18746886 A JP18746886 A JP 18746886A JP 18746886 A JP18746886 A JP 18746886A JP S6341416 A JPS6341416 A JP S6341416A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- microcapsules
- emulsion
- polymer
- drug
- 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
- 239000003094 microcapsule Substances 0.000 title claims abstract description 70
- 238000004519 manufacturing process Methods 0.000 title claims description 11
- 101500007657 Crotalus durissus terrificus Crotoxin chain gamma Proteins 0.000 title description 2
- 239000000839 emulsion Substances 0.000 claims abstract description 31
- 239000002253 acid Substances 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 239000002270 dispersing agent Substances 0.000 claims abstract description 5
- URLZCHNOLZSCCA-VABKMULXSA-N Leu-enkephalin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 URLZCHNOLZSCCA-VABKMULXSA-N 0.000 claims description 4
- 229920006158 high molecular weight polymer Polymers 0.000 claims 2
- 239000003814 drug Substances 0.000 abstract description 37
- 229940079593 drug Drugs 0.000 abstract description 36
- 229920000642 polymer Polymers 0.000 abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 21
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 abstract description 15
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 abstract description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 9
- 239000004310 lactic acid Substances 0.000 abstract description 7
- 235000014655 lactic acid Nutrition 0.000 abstract description 7
- 229920001577 copolymer Polymers 0.000 abstract description 6
- 239000007864 aqueous solution Substances 0.000 abstract description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 abstract description 4
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- 230000002378 acidificating effect Effects 0.000 abstract description 3
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- 238000002156 mixing Methods 0.000 abstract description 2
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 abstract description 2
- 238000000034 method Methods 0.000 description 25
- 239000010410 layer Substances 0.000 description 21
- -1 leunon Chemical compound 0.000 description 16
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 108090000765 processed proteins & peptides Proteins 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
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- 150000001875 compounds Chemical class 0.000 description 7
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- 108010092674 Enkephalins Proteins 0.000 description 3
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
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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 3
- 238000009835 boiling Methods 0.000 description 3
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- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
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- 125000001424 substituent group Chemical group 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- JVCXXLBLDDZMDG-SDHOMARFSA-N (2s)-2-[[(2s)-2-[[2-[[2-[[(2s)-2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]amino]acetyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoic acid Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C(=CC(O)=CC=1C)C)C1=CC=CC=C1 JVCXXLBLDDZMDG-SDHOMARFSA-N 0.000 description 2
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- 125000000539 amino acid group Chemical group 0.000 description 2
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- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- 238000005354 coacervation Methods 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 229960003750 ethyl chloride Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 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 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000000321 herbal drug Substances 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 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
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 description 1
- 229940037525 nasal preparations Drugs 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 150000002894 organic compounds Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001308 poly(aminoacid) Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 108010054442 polyalanine Proteins 0.000 description 1
- 229920001281 polyalkylene Polymers 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000002344 surface layer Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 239000006217 urethral suppository Substances 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
Description
【発明の詳細な説明】
檄1ユヱU引1
本発明は鎮痛性ペプチド含有マイクロカプセルの製造法
に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing analgesic peptide-containing microcapsules.
従来の技術
既に種々のマイクロカプセル剤が提唱されている。例え
ば、特開昭57−118512号公報には、鉱物油、植
物油などのコアセルベーション剤を用いた相分離法によ
るマイクロカプセル剤が記載されている。BACKGROUND OF THE INVENTION Various microcapsules have already been proposed. For example, JP-A-57-118512 describes microcapsules prepared by a phase separation method using a coacervation agent such as mineral oil or vegetable oil.
しかし、この方法で得られたマイクロカプセルは製造の
過程で粒子同志の粘着による合一、割断面の生成などが
起り易く、再分散性の低下、初期バーストの増大につな
がる恐れがある。また、用いる有機溶媒が複数であり、
調製したマイクロカプセル中の残留溶媒の問題がある。However, during the manufacturing process, the microcapsules obtained by this method tend to coalesce due to adhesion between particles and generate fractured surfaces, which may lead to a decrease in redispersibility and an increase in initial burst. In addition, multiple organic solvents are used,
There is a problem of residual solvent in the prepared microcapsules.
特開昭60−/O0516号公報には、水中乾燥法によ
るマイクロカプセルの調製法が開示されており、この方
法によると、マイクロカプセル中に薬物を効率よく取り
込ませることができ、その徐放性による薬物効果が期待
できる。JP-A-60-00516 discloses a method for preparing microcapsules by drying in water. According to this method, drugs can be efficiently incorporated into microcapsules, and their sustained release properties can be improved. drug effects can be expected.
売口が解決しようとする問題点
マイクロカプセル剤として薬物を生体に投与する場合に
おいて、生体本来の機能との相互作用に依存する要素が
高いマイクロカプセル剤に対する要望は多面的であり、
またこと医薬品に関するしのであるので、これら多面的
な要件をできるだけ満足しうろマイクロカプセルの提供
が求められている。Problems that sales outlets are trying to solve When administering drugs to living organisms as microcapsules, there are multifaceted demands for microcapsules that are highly dependent on interaction with the body's natural functions.
Furthermore, since this is a field related to pharmaceuticals, there is a need to provide Uro microcapsules that satisfy these multifaceted requirements as much as possible.
上記状況下、公知のマイクロカプセル剤によっては、満
足しろろ効果が技術的に達成されているとはいいがたい
。Under the above circumstances, it is difficult to say that a satisfactory gyroscope effect has been technically achieved using known microcapsules.
例えばいくつかの薬物において、マイクロカプセル壁膜
の構造が比較的線となる場合が生じ、初期に必要以上の
大きな薬物放出を見ることがあり、一定速変の放出から
大きく離れろことがある。For example, for some drugs, the structure of the microcapsule wall membrane may be relatively linear, which may result in an initial release of drug that is larger than necessary and may deviate significantly from a constant rate of release.
また薬物のマイクロカプセル中へのトラップ率(取込み
率)においてら、ある種の薬物においては通常用いろ濃
度範囲で、低下する事実が見られ、実用上困難を生じる
。In addition, the trapping rate (intake rate) of drugs into microcapsules has been observed to decrease in the concentration range for which certain drugs are normally used, which poses practical difficulties.
問題点を解決するための手段
このような事情に鑑み、本発明者らは、水溶性のペプチ
ドの徐放性製剤を開発するため、鋭、α研究を行ない、
マイクロカプセルの良好な性状と用いる薬物の物理化学
的性状および薬物の濃度との間に強い相関関係が存在す
ることを見い出し、さらに研究を重ね本発明を完成した
。Means to Solve the Problems In view of the above circumstances, the present inventors conducted intensive alpha research in order to develop a sustained release formulation of water-soluble peptides.
The inventors discovered that there is a strong correlation between the good properties of microcapsules, the physicochemical properties of the drug used, and the concentration of the drug, and completed the present invention after further research.
すなわち本発明は、高分子重合物を含む油層と、該高分
子重合物に対して5〜20重…%に相当するエンケファ
リン、そのアナログまたはそれらのpKa4.0以上の
弱酸との塩を含む水、層とでW/O型乳化物を形成せし
め、これと分散剤水溶液とを混合してW/O/W型乳化
物を形成せしめ、ついで油層溶媒を留去することを特徴
とするマイクロカプセルの製造法を提供するものである
。That is, the present invention provides an oil layer containing a polymer and water containing a salt of enkephalin, an analog thereof, or a weak acid having a pKa of 4.0 or more, in an amount of 5 to 20% by weight based on the polymer. A microcapsule characterized in that a W/O emulsion is formed with the layers, a W/O/W emulsion is formed by mixing this with an aqueous dispersant solution, and then the oil layer solvent is distilled off. The present invention provides a method for manufacturing.
上9己エンケファリンおよびそのアナログとして鎮痛活
性を有する3−6のアミノ酸またはその誘導体からなる
ペプチドが挙げられ、例えば式%式%)
[式中、R1は水素または低級アルキルを、R2は水素
、置換基を存していてもよい低級アルキルらしくはアリ
ールを、R3は水素または低級アルキルを、Xは結合手
またはD−もしくはL−であってもよい中性アミノ酸残
基を、Yは水酸基または置換基を有していてもよいアミ
ンもしくはヒドラツノを示す]で表わされる化合物が挙
げられろ。Enkephalin and its analogues include peptides consisting of 3-6 amino acids or derivatives thereof that have analgesic activity, such as those with the formula (%) [wherein R1 is hydrogen or lower alkyl, and R2 is hydrogen or a substituted Lower alkyl which may have a group is aryl, R3 is hydrogen or lower alkyl, X is a bond or a neutral amino acid residue which may be D- or L-, and Y is a hydroxyl group or substituted Examples include compounds represented by:
なお化合物(1)中、不斉炭素を有する場合、特に注記
のないときはL−配置を示す。In addition, when compound (1) has an asymmetric carbon, the L-configuration is indicated unless otherwise noted.
上記II ’における低級アルキルをしてCl−ffア
ルキル(例、メチル、エチル、プロピル、イソプロピル
など)が挙げられる。The lower alkyl in II' above includes Cl-ff alkyl (eg, methyl, ethyl, propyl, isopropyl, etc.).
R2における置換基を有していてもよい低級アルキルら
しくはアリールとしては、水酸基、酸化されていてもよ
い低級(C,−3)アルキルチオ、エステル化らしくは
アミド化されていてもよいカルボキンル、ポルミル化さ
れていてもよいアミノ、グアニノノ、イミダゾールー3
−イルなどで置換されていてもよいC2−、アルキルら
しくはフェニルが挙げられる。Examples of aryl such as lower alkyl which may have a substituent in R2 include hydroxyl group, lower (C, -3) alkylthio which may be oxidized, carboquine which may be amidated as esterification, and polmyl. Amino, guanino, imidazole which may be
C2-, which may be substituted with -yl, etc., and phenyl as an example of alkyl.
R3における低級アルキルとしては、Cl−3アルキル
(メチル、エチル、プロピル、イソプロピル)が挙げら
れる。Examples of lower alkyl in R3 include Cl-3 alkyl (methyl, ethyl, propyl, isopropyl).
Xで孝わされる中性アミノ酸残基としては、酸化されて
いてもよいメチオニン、ロイノン、プロリンなどの残基
が挙げられる。Examples of neutral amino acid residues substituted by X include residues such as methionine, leunon, and proline, which may be oxidized.
Yで表わされる置換基を有していてもよいアミノらしく
はヒドラジノとしては、低級(C,−3)アルコキシ(
例、メトキシ、エトキン、プロポキシ)。Amino-like hydrazino which may have a substituent represented by Y is lower (C, -3) alkoxy (
e.g., methoxy, etquin, propoxy).
ハロゲン(例、フッ素、塩素、臭素、ヨウ素)、オキソ
。Halogens (e.g. fluorine, chlorine, bromine, iodine), oxo.
酸化されていてもよい低級(c 、−3)チオアルキル
。Lower (c, -3) thioalkyl which may be oxidized.
アミノカルボニル、アミノチオカルボニル、4.5−ジ
ヒドロ−2I−(−チオフェン−2オン−3−イルなど
を置換基として有していてもよい直鎖状らしくは分岐状
アルキル、低級アルケニルまたは低級脂肪族アシル置換
アミノもしくはヒドラジノおよび無置換アミノもしくは
ヒドラツノなどが挙げられる。Aminocarbonyl, aminothiocarbonyl, 4,5-dihydro-2I-(-thiophen-2one-3-yl, etc. as a substituent) Straight chain or branched alkyl, lower alkenyl or lower aliphatic Group acyl-substituted amino or hydrazino, unsubstituted amino or hydrazino, and the like.
化合物(1)に包含される化合物として、H−Tyr
−D −Met(0) −Gly −EtPhe −N
IINIICOCII、(E K−399)、H−Ty
r−D −Met(0)−Gly−MePhe−NH
NIICOCH3(E K −333)、 I−(−T
yr −D −Ala −Gly −!4ePhe −
Met −Nl12(metkephN112(、H−
Tyr −D −LysOレト
(CIip)−Giy−Phe−NH二(floe−8
25)、!−(−Tyr−D−Met −Gly −P
he −Pro−N11t、 H−Tyr −D −A
la −Gly −MePhe−Met(0) −of
(P K −33824)、 H−Tyr−D −Al
a−Gly−Phe −D −Lea−NHt、H−T
yr −D −Thr −Gly −Phe −L −
thiazolidine −4−carboxami
de、 H−Tyr −D −Ala −Gly −P
he −NHt、 0イシンエンケファリン、メチオニ
ンエンケファリンなどが挙げられる。As a compound included in compound (1), H-Tyr
-D -Met(0) -Gly -EtPhe -N
IINII COCII, (E K-399), H-Ty
r-D-Met(0)-Gly-MePhe-NH
NIICOCH3 (E K -333), I-(-T
yr-D-Ala-Gly-! 4ePhe −
Met-Nl12(metkephN112(,H-
Tyr-D-LysO(CIip)-Giy-Phe-NH2(floe-8
25),! -(-Tyr-D-Met-Gly-P
he -Pro-N11t, H-Tyr -D -A
la -Gly -MePhe-Met(0) -of
(PK-33824), H-Tyr-D-Al
a-Gly-Phe-D-Lea-NHt, H-T
yr −D −Thr −Gly −Phe −L −
thiazolidine-4-carboxami
de, H-Tyr-D-Ala-Gly-P
Examples include he-NHt, 0isine enkephalin, methionine enkephalin, and the like.
とりわけ本発明においては、E K −399,E K
−333などが有利に使用される。In particular, in the present invention, E K -399, E K
-333 etc. are advantageously used.
これらの化合物の物理、化学、生物学的性状および製造
法は、例えばケミカル・アンド・ファーマシュティカル
・ビュレチン(Chem、Pharm、 Bull、)
29.3630−3638(1981)、同誌、−影9
,3639〜3645 (1981)、同誌、■、36
46−3659 (1981)、ファルマシア(Pha
rmacia)、 13 、932−936 (197
7)、ライフ・サイエンス(LireSciences
)、 23 、2053−2056 (1978)、同
誌。The physical, chemical, biological properties and manufacturing methods of these compounds are described, for example, in the Chemical and Pharmaceutical Bulletin (Chem, Pharm, Bull).
29.3630-3638 (1981), same magazine, - Shadow 9
, 3639-3645 (1981), same magazine, ■, 36
46-3659 (1981), Pharmacia (Pha
rmacia), 13, 932-936 (197
7), Life Sciences
), 23, 2053-2056 (1978), same magazine.
旦、1371−1376(197g)、FEBSレター
ズ(FEBS Letters)、76 9l−92
(1977)、米国特許第4277394号などに記載
されている。Dan, 1371-1376 (197g), FEBS Letters, 76 9l-92
(1977) and US Pat. No. 4,277,394.
上記化合物(ペプチド)と塩を形成しうるpKa(i離
指数)4,0以上の弱酸としては無機酸および有機酸の
いずれでもよく、例えば無機酸としては炭酸1重炭酸、
ホウ酸などが挙げられ、また有機酸としてはモノカルボ
ン酸、とりわけ低級(CI−3)アルカンモノカルボン
酸が好ましく、例えば酢酸。The weak acid with a pKa (i separation index) of 4.0 or more that can form a salt with the above compound (peptide) may be either an inorganic acid or an organic acid. Examples of the inorganic acid include carbonic acid, monobicarbonic acid,
Examples include boric acid, and the organic acid is preferably a monocarboxylic acid, especially a lower (CI-3) alkane monocarboxylic acid, such as acetic acid.
プロピオン酸などが挙げられる。Examples include propionic acid.
これらの弱酸は、とりわけpKa 4.5以上が好ま
しく、上限としてはpKa13以下とりわけpKa
9.5以下のものが好ましい。These weak acids preferably have a pKa of 4.5 or more, with an upper limit of pKa of 13 or less, especially a pKa of 4.5 or more.
It is preferably 9.5 or less.
本発明方法における油層に含有される高分子重合物とし
ては、水に難溶または不溶で、生体適合性のある高分子
重合物を示し、その例としては酸性残基を有するものが
好ましく、たとえば、生体内分解型としてポリ脂肪酸エ
ステル(例、ポリ乳酸、ポリグリコール酸、ポリ乳酸−
グリコール酸。The polymer contained in the oil layer in the method of the present invention is a polymer that is poorly soluble or insoluble in water and has biocompatibility, and preferably has acidic residues, such as , biodegradable polyfatty acid esters (e.g., polylactic acid, polyglycolic acid, polylactic acid-
Glycolic acid.
ポリ−ε−カプロラクトン、ポリクエン酸、ポリリンゴ
酸など)、ポリアルキル−α−シアノアクリル酸エステ
ル(例、ポリブチル−2−シアノアクリレート)、ポリ
ーβ−ヒドロキン酪酸′、ポリアルキレンオキサレート
(例、ポリトリメチレンオキサレート、ポリテトラメチ
レンオキサレートなど)。poly-ε-caprolactone, polycitric acid, polymalic acid, etc.), polyalkyl-α-cyanoacrylic acid esters (e.g., polybutyl-2-cyanoacrylate), poly-β-hydroquinebutyric acid’, polyalkylene oxalate (e.g., polytributyric acid), methylene oxalate, polytetramethylene oxalate, etc.).
ポリオルソエステル、ポリオルソカーボネートあるいは
その他のポリカーボネート(例、ポリエチレンカーボネ
ート、ポリエチレンプロピレンカーボネートなど)、ポ
リアミノ酸(例、ポリ−グーベンツルーし一グルタミン
酸、ポリーL−アラニン。Polyorthoesters, polyorthocarbonates or other polycarbonates (eg, polyethylene carbonate, polyethylene propylene carbonate, etc.), polyamino acids (eg, poly-gubentrue monoglutamic acid, poly L-alanine).
ポリーγ−メチルーL−グルタミン酸など)などが挙げ
られろ。さらに、生体適合性を有するその他の高分子重
合物として、ポリアクリル酸、ポリメタアクリル酸、ア
クリル酸とメタアクリル酸との共重合物、デキストラン
ステアレート、メチルセルロース、エチルセルロース、
アセチルセルロース。(poly γ-methyl-L-glutamic acid, etc.). Furthermore, other biocompatible polymers include polyacrylic acid, polymethacrylic acid, copolymers of acrylic acid and methacrylic acid, dextran stearate, methylcellulose, ethylcellulose,
Acetylcellulose.
ニトロセルロース、無水マレイン酸系共重合物などが挙
げられる。これらの重合物は一種でもよく、また二種以
上の共重合物、あるいは単なる混合物でもよい。Examples include nitrocellulose and maleic anhydride copolymers. These polymers may be used alone, or may be a copolymer of two or more types, or a mere mixture.
これらの重合物の中で、特に、注射剤として用いる場合
は生体内分解型高分子重合物が好ましく、最ら好ましい
ものとしては、ポリ乳酸、乳酸とグリコール酸との共重
合物、あるいはその混合物が挙げられる。この共重合物
中の乳酸とグリコール酸との比は乳酸が約40〜95モ
ル%、グリコール酸が約60〜5モル%がよく、好まし
くは乳酸が約50〜95モル%、グリコール酸が約50
〜5モル%がよく、さらに好ましくは乳酸が約60〜9
0モル%、グリコール酸が約40〜lOモル%がよい。Among these polymers, particularly when used as an injection, biodegradable polymers are preferred, and the most preferred are polylactic acid, a copolymer of lactic acid and glycolic acid, or a mixture thereof. can be mentioned. The ratio of lactic acid and glycolic acid in this copolymer is preferably about 40 to 95 mol% of lactic acid and about 60 to 5 mol% of glycolic acid, preferably about 50 to 95 mol% of lactic acid and about 60 to 5 mol% of glycolic acid. 50
-5 mol% is good, more preferably lactic acid is about 60-9
0 mol%, glycolic acid is preferably about 40 to 10 mol%.
本発明に使用されるこれらの高分子重合物の平均分子量
は約/O00ないし+00000のものが好ましく、よ
り好ましくは約2000ないし5ooooの範囲から選
択される。The average molecular weight of these polymers used in the present invention is preferably selected from the range of about /O00 to +00000, more preferably from about 2000 to 5000.
上記高分子重合物を含む溶液(油層)は、高分子重合物
を有機溶媒中に溶解したものが用いられる。The solution (oil layer) containing the above-mentioned high-molecular polymer is a solution in which the high-molecular polymer is dissolved in an organic solvent.
該有機溶媒としては、沸点が約120℃以下で、かつ水
と混和しにくい性質のもので、高分子重合物を溶解する
ものであればよく、たとえばハロゲン化アルカン(例、
ジクロロメタン、クロロホルム、クロロエタン、トリク
ロコニタン。四塩化炭素など)、酢酸エチル、エチルエ
ーテル、フクロヘキサン。ベンゼン、n−ヘキサン、ト
ルエンなどが挙げられ、これらは2種以上混合して用い
てもよい。The organic solvent may be one that has a boiling point of about 120° C. or less, is not easily miscible with water, and can dissolve the polymer, such as halogenated alkanes (e.g.
Dichloromethane, chloroform, chloroethane, tricloconitane. carbon tetrachloride, etc.), ethyl acetate, ethyl ether, fuclohexane. Examples include benzene, n-hexane, and toluene, and two or more of these may be used in combination.
極性を比較的有し、低沸点であるジクロロメタン、クロ
ロホルムが特に好ましい。Particularly preferred are dichloromethane and chloroform, which are relatively polar and have a low boiling point.
本発明のマイクロカプセルの製造法は、まずエンケファ
リンもしくはそのアナログの遊離体あるいは弱酸の塩を
高分子重合物に対して5〜20重量%に相当する量、好
ましくは5.0〜15.0%、に相当する量を水に溶解
し内水層とする。所望により薬物と高分子重合物の相互
作用を妨害しない範囲で薬物保持物質、あるいはpHf
l整剤l薬剤の安定化剤、保存剤を添加してもよい。In the method for producing microcapsules of the present invention, first, enkephalin or its analogue free form or salt of a weak acid is added in an amount corresponding to 5 to 20% by weight, preferably 5.0 to 15.0%, based on the polymer. An amount equivalent to , is dissolved in water to form an inner water layer. If desired, add a drug-retaining substance or pHf within a range that does not interfere with the interaction between the drug and the polymer.
A stabilizer and a preservative may be added to the drug.
上記薬物保持物質としては、水溶性で、油層の有機溶媒
に溶解し難いもので、水に溶解した状態で、すでに粘性
の高い半固体状となるか、あるいは、何かの外的因子、
たとえば温度、pH、金属イオン(例、Cu++ 、
p、 l+++、 z n++など)、化学縮合剤(例
、グルタルアルデヒド、アセトアルデヒドなど)などの
作用を与えろことによって、より著しく粘度か増大し、
半固体状ないし固体状のマトリックスとなる性質を有す
る物質が挙げられる。The above-mentioned drug-retaining substance is water-soluble and difficult to dissolve in the organic solvent of the oil layer, and when dissolved in water, it is already in a highly viscous semi-solid state, or due to some external factor,
For example, temperature, pH, metal ions (e.g. Cu++,
By applying the action of a chemical condensing agent (e.g., glutaraldehyde, acetaldehyde, etc.), the viscosity increases more significantly.
Examples include substances that have the property of forming a semi-solid or solid matrix.
該薬物保持物質の例としては、天然あるいは合成ガムあ
るいは高分子化合物があげ口r、る。[)H調整剤とし
ては、たとえば炭酸、酢酸、ノユウ酸。Examples of the drug-retaining substance include natural or synthetic gums and polymer compounds. [)H regulators include, for example, carbonic acid, acetic acid, and oxalic acid.
クエン酸、酒石酸、またはそれらのナトリウム塩あるい
はカリウム塩、塩酸、水酸化ナトリウムなどを添加して
もよい。安定化剤としてはたとえばアルブミン、ゼラチ
ン、クエン酸、エチレンノアミン四酢酸ナトリウム、デ
キストリン、ブドウ糖、ソルビトールなどの糖類、グリ
セリンなどのポリオール類、亜硫酸水素ナトリウムなど
を、あるいは保存剤として、たとえばパラオキシ安息香
酸エステル類(例、メヂルパラベン、プロピルパラベン
など)。Citric acid, tartaric acid, or their sodium or potassium salts, hydrochloric acid, sodium hydroxide, etc. may be added. Examples of stabilizers include albumin, gelatin, citric acid, sodium ethylenenoaminetetraacetate, dextrin, glucose, sugars such as sorbitol, polyols such as glycerin, sodium bisulfite, etc., and preservatives such as paraoxybenzoic acid. Esters (e.g. medylparaben, propylparaben, etc.).
ベンジルアルコール、クロロブタノール、チメロサール
などを添加してもよい。Benzyl alcohol, chlorobutanol, thimerosal, etc. may be added.
本発明においては、内水層中のペプチドの水に対する濃
度として約0.01〜90%(W/W)、好ましくは0
.1〜70%(W/W)とするのがよい。In the present invention, the concentration of peptide in the inner water layer relative to water is approximately 0.01 to 90% (W/W), preferably 0.
.. It is preferable to set it to 1 to 70% (W/W).
このようにして得られた内水層用水溶液を、高分子重合
物を含む溶液(油層)中に加え、ついで乳化操作を行い
、W/O型乳化物をつくる。The aqueous solution for the inner aqueous layer thus obtained is added to the solution (oil layer) containing the polymer, and then an emulsification operation is performed to produce a W/O emulsion.
該乳化操作は、公知の分散法が用いられる。該方法とし
ては、たとえば、断続振とう法、プロペラ型攪拌機ある
いはタービン型攪拌機などのミキサーによる方法、コロ
イドミル法、ホモジナイザー法、超音波照射法などが挙
げられる。A known dispersion method is used for the emulsification operation. Examples of the method include an intermittent shaking method, a method using a mixer such as a propeller type stirrer or a turbine type stirrer, a colloid mill method, a homogenizer method, and an ultrasonic irradiation method.
ついで、このようにして調製されたW/O型エマルジョ
ンをW/O/Wの三層に乳化し水中乾燥法に付す。すな
わち、該W/O型エマルジョンをさらに第3層目の水層
中に加え、W/O/W型乳化物を形成させた後、油層中
の溶媒を除去し、マイクロカプセルを、調製する。この
W/O/W型エマルジョンを、調製する際に、内水層お
よびW/O型エマルジョンの粘度が目的とするマイクロ
カプセルの形状、薬物のトラップ率などに影響し、適切
な粘度範囲内に設定することが好ましい。特にW/O型
エマルジョンの粘度は薬物のトラップ率に対する影響は
大きく、その粘度を150〜/O000cpとすること
が好ましい。Next, the W/O emulsion thus prepared is emulsified into three layers of W/O/W and subjected to an underwater drying method. That is, the W/O emulsion is further added to the third aqueous layer to form a W/O/W emulsion, and then the solvent in the oil layer is removed to prepare microcapsules. When preparing this W/O/W type emulsion, the viscosity of the inner aqueous layer and the W/O type emulsion affects the shape of the target microcapsules, the drug trapping rate, etc. It is preferable to set In particular, the viscosity of the W/O emulsion has a large effect on the drug trapping rate, and it is preferable that the viscosity is 150 to /O000 cp.
しかし、この過程、およびW/O/W型エマルノヨンと
して水中乾燥する際に、マイクロカプセルの形状、薬物
トラップ率、薬物の初期放出量に影響を与えるもう一つ
の重要な因子として、薬物と高分子重合物の相互作用が
あり、これを考慮した前記の条件内に設定することによ
って、さらに優れた薬物放出機能を持ったマイクロカプ
セルの調製が可能となった。However, during this process and when drying in water as a W/O/W type emulsion, another important factor that affects the shape of microcapsules, drug trapping rate, and initial release amount of drug is that the drug and polymer There is an interaction between polymers, and by setting the above conditions in consideration of this, it became possible to prepare microcapsules with even better drug release function.
すなわち、前記の条件で溶解したペプチド水溶液を上記
の薬物/高分子重合物の配合比率で、所定の容積比率の
W/O型エマルジョンとした後、一定の温度範囲に設定
し、これも一定の温度に保たれた外水層中に注入し、脱
有機溶媒してマイクロカプセルとする。この場合、薬物
と高分子重合物の相互作用にも、W / Oの容積比率
、W / O型エマルジョンの温度、さらには外水雇の
温度なども影響するので、薬物、高分子重合物の種類、
量によっである至適条件に設定する必要がめる。That is, the peptide aqueous solution dissolved under the above conditions is made into a W/O type emulsion with a predetermined volume ratio using the above drug/polymer compounding ratio, and then the temperature is set at a certain temperature range, which is also kept at a certain temperature range. It is injected into the outer aqueous layer kept at temperature, and the organic solvent is removed to form microcapsules. In this case, the interaction between the drug and the polymer is also affected by the W/O volume ratio, the temperature of the W/O type emulsion, and even the temperature of the outside water tank. kinds,
Depending on the amount, it may be necessary to set the optimum conditions.
油溜の高分子重合物の濃度は、その種類によって異なる
が、およそ5%ないし80%(W/W)が好ましい。The concentration of the polymer in the oil sump varies depending on its type, but is preferably about 5% to 80% (W/W).
W / O型エマルジョンの容積比は用いる薬物、重合
物、溶媒の種類、量によって異なるが、水層lに対して
!ないし200、より好ましくは1ないし/O0の範囲
内に入るようにする。The volume ratio of the W/O type emulsion varies depending on the type and amount of the drug, polymer, and solvent used, but the volume ratio is 1 to the aqueous layer! The value should be within the range of 1 to 200, more preferably 1 to /O0.
W/O型エマルジョン、お上び外水層の温度は約−/O
℃から用いる有機溶媒の沸点までで行うことが出来るが
、通常、約θ℃から35℃の範囲内で乳化するのが好ま
しい。W/O type emulsion, the temperature of the upper and outer water layers is approximately -/O
Although emulsification can be carried out at a temperature of from 0.degree. C. to the boiling point of the organic solvent used, it is usually preferable to carry out emulsification at a temperature within the range of about .theta..degree. C. to 35.degree.
外層の水層中には乳化剤を加えてもよく、その例として
は、一般に安定なO/W型エマルジョンを形成するもの
であればいずれでもよいが、たとえば、アニオン界面活
性剤(例、オレイン酸ナトリウム、ステアリン酸ナトリ
ウム、ラウリル硫酸ナトリウムなど)、非イオン性界面
活性剤[ポリオキシエチレンソルビタン脂肪酸エステル
(Tween8G、 tween 60.アトラスパウ
ダー社製、米国)、ポリオキシエチレンヒマシ油誘導体
(HCO−60゜HCO−30,日光ケミカルズ社製)
など]、あるいはポリビニールピロリドン、ポリビニー
ルアルコール、カルボキシメチルセルロース。レシチン
。An emulsifier may be added to the outer aqueous layer, and any emulsifier that generally forms a stable O/W type emulsion may be added. For example, anionic surfactants (e.g., oleic acid (sodium, sodium stearate, sodium lauryl sulfate, etc.), nonionic surfactants [polyoxyethylene sorbitan fatty acid ester (Tween 8G, tween 60. manufactured by Atlas Powder Co., USA), polyoxyethylene castor oil derivative (HCO-60゜HCO-30, manufactured by Nikko Chemicals)
], or polyvinyl pyrrolidone, polyvinyl alcohol, carboxymethylcellulose. lecithin.
ゼラチンなどが挙げられ、これらの中の一種類か、いく
つかを組み合せて使用してもよい。とりわけポリビニー
ルアルコール、カルボキシメチルセルロース、ゼラチン
の一種類または二〜三種類を組合せて使用するのが好ま
しい。使用の際の濃度は約0.0!%から20%の範囲
から適宜、選定でき、より好ましくは約0.05%から
/O%の範囲で用いられる。Examples include gelatin, and one or a combination of these may be used. In particular, it is preferable to use one type or a combination of two or three types of polyvinyl alcohol, carboxymethyl cellulose, and gelatin. The concentration during use is approximately 0.0! It can be appropriately selected from the range of % to 20%, more preferably from about 0.05% to /O%.
水中乾燥法における油層の溶媒の除去は、通常用いられ
る方法が採用される。該方法としては、たとえば単にW
/O/W型乳化物をプロペラ型攪拌機、あるいはマグネ
チックスクーラーなどで攪拌しながら放置するか、加温
するか、窒素ガスなどを吹きつけるかすることなどによ
る。また、徐々に減圧して行なうか、ロータリーエバポ
レーターなどを用いて、真空度を調節しながら除去して
もよい。溶媒の除去工程において、高分子重合物の固化
がある程度進行した時点で、溶媒の除去をより完全にす
る目的で、W/O/W型乳化物を徐々に加温して行うと
所要時間を短縮することができる。In the underwater drying method, a commonly used method is employed to remove the solvent from the oil layer. As the method, for example, simply W
The /O/W type emulsion may be left to stand while being stirred with a propeller type stirrer or a magnetic cooler, heated, or blown with nitrogen gas or the like. Alternatively, the removal may be carried out by gradually reducing the pressure, or by using a rotary evaporator or the like, while adjusting the degree of vacuum. In the solvent removal process, once the solidification of the polymer has progressed to a certain extent, the W/O/W type emulsion is gradually heated in order to remove the solvent more completely. Can be shortened.
このようにして得られたマイクロカプセルは遠心分離あ
るいはろ過して分取した後、マイクロカプセルの表面に
付着している遊離の水溶性薬物などを、蒸留水で数回繰
り返し洗浄し、必要に応じ、凍結乾燥、あるいは加温し
減圧下でマイクロカプセル中の水分の除去およびマイク
ロカプセル膜中の溶媒の除去をより完全に行なう。After the microcapsules obtained in this way are separated by centrifugation or filtration, free water-soluble drugs adhering to the surface of the microcapsules are washed several times with distilled water, and as needed. The water in the microcapsules and the solvent in the microcapsule membrane are more completely removed by lyophilization, lyophilization, or heating under reduced pressure.
上記で得られたマイクロカプセルは、必要であれば篩過
などによって、大きすぎるマイクロカプセル部分の除去
など、必要とする粒子径部分の分取を行なう。マイクロ
カプセルの粒子径は、徐放性の程度により、懸濁剤とし
て使用する場合には、その分散性、運針性を満足させる
範囲であればよく、たとえば、平均径として約0.5〜
400μmの範囲が挙げられ、より好ましくは約2〜/
O0μmの範囲にあることが望まれる。The microcapsules obtained above are subjected to sieving, if necessary, to remove excessively large microcapsules and separate the necessary particle size. The particle size of the microcapsules depends on the degree of sustained release, and when used as a suspension agent, the particle size of the microcapsules may be within a range that satisfies the dispersibility and transportability.For example, the average size is about 0.5 to
A range of 400 μm is mentioned, and more preferably about 2 to 400 μm.
It is desirable that the thickness be in the range of 00 μm.
このように、本発明の方法によれば、生薬であるペプチ
ドのマイクロカプセルへのトラップ率を高めることがで
き、初期過剰放出の少ない強固な壁膜を有するマイクロ
カプセルを製造することができる。As described above, according to the method of the present invention, it is possible to increase the trapping rate of peptides, which are herbal medicines, in microcapsules, and it is possible to produce microcapsules having strong wall membranes with little initial excessive release.
また、本発明方法によって製造されたマイクロカプセル
は、製造工程中でマイクロカプセル同志の凝集が少なく
、球形状のよく整ったマイクロカプセルを得ることがで
きろこと、また、油層中の溶媒の除去工程の制御が容易
で、それによって、薬物放出速度を左右するマイクロカ
プセルの表面構造(たとえば薬物の主な放出経路となる
細孔の敗および大きさなど)を調節することが出来ろこ
となど多くの長所を有している。In addition, the microcapsules produced by the method of the present invention have little aggregation of microcapsules during the production process, and it is possible to obtain well-defined spherical microcapsules. It is easy to control the surface structure of the microcapsules that affects the drug release rate (e.g., the size and size of the pores that are the main drug release route). It has its advantages.
本発明方法によって製造されたマイクロカプセルは、そ
のまま埋込剤として生体に投与することができる。また
、種々の製剤に成形して投与することもでき、そのよう
な製剤を製造する際の原料物質としても使用され得る。The microcapsules produced by the method of the present invention can be administered to a living body as is as an implant. It can also be administered by forming into various preparations, and can also be used as a raw material when manufacturing such preparations.
上記製剤としては、注射剤、経口投与剤、経鼻投与剤、
直、陽、尿道、膣坐剤などが挙げられる。The above preparations include injections, oral preparations, nasal preparations,
Examples include direct, positive, urethral, and vaginal suppositories.
たとえば、本発明のマイクロカプセルを注射剤とするに
は、本発明のマイクロカプセルを分散剤(例、Twee
n 80. HCO−60,カルボキシメチルセル
ロース、アルギン酸ナトリウムなど)、保存剤(例、メ
ヂルパラベン、プロピルパラベンなど)。For example, in order to make the microcapsules of the present invention into an injection, the microcapsules of the present invention may be mixed with a dispersing agent (e.g., Twee).
n 80. HCO-60, carboxymethyl cellulose, sodium alginate, etc.), preservatives (e.g., medylparaben, propylparaben, etc.).
等張化剤(例、塩化ナトリウム、マンニトール、ソルビ
トール、ブドウ糖など)などと共に水性懸濁剤とするか
ゴマ油、コーン浦などの植物油と共に分散して油性懸濁
剤として実際に使用できる徐放性注射剤とする。Sustained-release injection that can actually be used as an aqueous suspension with isotonic agents (e.g., sodium chloride, mannitol, sorbitol, glucose, etc.) or as an oil-based suspension by dispersing it with vegetable oils such as sesame oil and corn ura. as a drug.
さらに、上記のマイクロカプセルの徐放性注射剤は、!
8濁剤として、上記の組成以外に、賦形剤(たとえば、
マンニトール、ソルビトール、ラクトース、ブドウ糖な
ど)を加えて、再分散した後、凍結乾燥もしくは噴霧乾
燥して固型化し、同時に、注射用蒸留水あるいは適当な
分散媒を加えると、より安定した徐放性注射剤が得られ
る。Furthermore, the above-mentioned microcapsule sustained-release injection is!
8. As a clouding agent, in addition to the above composition, excipients (for example,
Adding mannitol, sorbitol, lactose, glucose, etc.), redispersing it, solidifying it by freeze-drying or spray-drying, and adding distilled water for injection or a suitable dispersion medium at the same time will result in more stable sustained release. An injection is obtained.
本発明の徐放性製剤の投与量は、生薬であるペプチドの
種類と含量、剤形、薬物放出の持続期間。The dosage of the sustained release preparation of the present invention depends on the type and content of the peptide, which is a crude drug, the dosage form, and the duration of drug release.
投与対象動物[例11.1に血捕乳動物(例、マウス、
ラット、ウマ、979人)j、投与目的により種々異な
るが、該主薬の有効量であればよい。にとえば、上記温
血吐乳動物に1回あfこり投与量として、マイクロカプ
セルの重量が好ましくは約0.Img?、fいし/O0
mg/ kg体重、より好ましくは約0 、2 mg
ないし50 mg/ kg体重の範囲から、適宜1択す
ることができる。なお、上記注射剤として投与する場合
の懸濁溶液の容量は、約0.1ないし5滅、好ましくは
約02ないし3滅の範囲から適宜選ぶことができる。Animals to be administered [Example 11.1 blood-fed mammals (e.g. mice,
(rats, horses, 979 people)j, although it varies depending on the purpose of administration, it may be an effective amount of the main drug. For example, the weight of the microcapsules is preferably about 0.05 kg as a single administration dose to the above-mentioned warm-blooded mammals. Img? ,fish/O0
mg/kg body weight, more preferably about 0,2 mg
One can be selected as appropriate from the range of 50 to 50 mg/kg body weight. The volume of the suspension solution to be administered as the above-mentioned injection can be appropriately selected from the range of about 0.1 to 5 ml, preferably about 0.2 to 3 ml.
このようにして、通常の一回投与量より多い有効量の水
溶性薬物、および生体適合性のある高分子重合物よりな
り、長期間にわfこって薬物を持続的に放出させること
ができるマイクロカプセルとして調製された医薬組成物
が得られる。In this way, the drug can be continuously released over a long period of time by containing an effective amount of a water-soluble drug and a biocompatible polymer, which is larger than the usual single dose. A pharmaceutical composition prepared as microcapsules is obtained.
本発明においては、酸性残基を有する高分子が上記の塩
基性残基を得するペプチドとその残基同志の相互作用に
よって、強固なマイクロカプセル壁の形成、およびマイ
クロカプセルの比較的表層に近い部における拡散速度の
低下による、トラップ率の向上、不必要な初期放出の抑
制が得られると考えられる。従って、塩基性残基を有す
るペプチドのうち、その残基の塩基性が高い程、また残
基の数が多い程過剰な初期放出を防げるし、トラップ率
も高くなる。すなわち、既存のペプチドにリジン、アル
ギニン、ヒスデシン残基などを化学的に付加してもよく
、さらにはペプチド以外の生理活性を有する有機化合物
に、この塩基性残基を有するベプヂド鎖を化学結合させ
ることによって、同様の優れたマイクロカプセルを製造
することができる。In the present invention, a polymer having acidic residues forms a strong microcapsule wall and a portion relatively close to the surface layer of the microcapsule is formed by the interaction between the peptide and the residues that obtain the above-mentioned basic residue. It is thought that by reducing the diffusion rate in , the trapping rate can be improved and unnecessary initial release can be suppressed. Therefore, among peptides having basic residues, the higher the basicity of the residues and the greater the number of residues, the more excessive initial release can be prevented and the trapping rate will be higher. That is, lysine, arginine, hisdecine residues, etc. may be chemically added to existing peptides, and furthermore, peptide chains containing these basic residues may be chemically bonded to organic compounds with physiological activity other than peptides. Similar excellent microcapsules can be produced by this method.
本発明により製造された徐放性製剤は、たとえば次の特
徴を有する。The sustained release preparation produced according to the present invention has, for example, the following characteristics.
(1) 種々の投与剤形でペプチドの良好な徐放性が
得られ、特に注射剤においては期待される治療を行なう
のに、長期間投与が必要な場合、毎日投与するかわりに
、−週間に一回、−月間に一回、あるいは一年間に一回
の注射で、所望の薬理効果が安定して得られ、従来の徐
放性製剤に比較して、より長期にわたる徐放性が得られ
る。(1) Good sustained release properties of peptides can be obtained in various dosage forms, and especially in injections, when long-term administration is required to perform the expected treatment, instead of daily administration, peptides can be administered for -weeks. The desired pharmacological effect can be stably obtained with injections once every month, once a month, or once a year, and it provides sustained release over a longer period of time compared to conventional sustained release formulations. It will be done.
(2)生体内分解型高分子重合物を用い注射剤として投
与する場合、埋込みなどの外科手術が一切不用で、一般
の懸濁注射剤とまったく同様に容易に皮下および筋肉内
に投与でき、再び取り出す必要がない。(2) When administering a biodegradable polymer as an injection, no surgical procedures such as implantation are required, and it can be easily administered subcutaneously and intramuscularly in the same way as general suspension injections. There is no need to take it out again.
(3)従来のW/O/W型の三層エマルジョンをつくり
、これを水中乾燥に付す製造法よりし、内水層に特に薬
物保持物質を添加することなくマイクロカプセル中に生
薬であるペプチドを効率よく取込ませることができ、し
かも微細な、球状の整ったマイクロカプセルを得ろこと
ができる。(3) A traditional W/O/W type three-layer emulsion is made and then dried in water. The herbal drug peptide is placed in microcapsules without adding any particular drug-retaining substance to the inner aqueous layer. It is possible to efficiently incorporate microcapsules into fine, spherical, well-formed microcapsules.
(4)従来のW/O/W型エマルジョンを調製しこれを
水中乾燥に付す製造法よりも必要以上な初期放出を減少
させたマイクロカプセルが得られ、より一定速度の安全
な優れた徐放性製剤となり得る。(4) Compared to the conventional manufacturing method of preparing a W/O/W type emulsion and drying it in water, microcapsules with less unnecessary initial release can be obtained, resulting in a safer and superior sustained release at a more constant rate. It can be a sex preparation.
作用および実施例
以下に実施例を挙げて、本発明をさらに具体的に説明す
る。Effects and Examples The present invention will be explained in more detail with reference to Examples below.
実施例1
エンケファリン誘導体H−Tyr−D−Met(0)−
Gly −EtPhe −NH−N1(COCH,−A
cO■(E K −399,米国特許第4277394
号参照)の40.80,200.300および400m
g(PLGAに対して1〜/O重量%)をそれぞれ蒸留
水0.5顧に溶解し、これにPLGA4gをジクロロメ
タン5gに溶解したものを加え、ポリトロン(キネマチ
カ社製、スイス)を用い、30〜60秒間混合し、W/
O型エマルジョンを調製した。これを3〜12℃に冷却
した後、あら刀)じめ11〜」5℃に冷却した0゜25
%ポリビニルアルコール(PVA)水溶液1g中に注入
し、タービン式ホモミキサーを使用してW/O/w型エ
マルジョンとした。この後、W/O/W型エマルジョン
液を攪拌しつつジクロロメタンの揮故によって内部のW
/O型エマルジョンを固化させた後、遠心分離器で捕集
した。これを再び蒸留水に分散しさらに遠心分離を行な
い遊離薬物等を洗滌した。Example 1 Enkephalin derivative H-Tyr-D-Met(0)-
Gly-EtPhe-NH-N1(COCH,-A
cO■(E K-399, U.S. Patent No. 4277394
40.80, 200.300 and 400m
g (1 to 0% by weight based on PLGA) was dissolved in 0.5 g of distilled water, and 4 g of PLGA dissolved in 5 g of dichloromethane was added thereto. Mix for ~60 seconds, W/
A type O emulsion was prepared. After cooling this to 3 to 12℃, it was cooled to 11 to 5℃.
% polyvinyl alcohol (PVA) aqueous solution, and a W/O/w type emulsion was prepared using a turbine homomixer. After that, while stirring the W/O/W type emulsion liquid, the internal W is removed by volatilization of dichloromethane.
After the /O type emulsion was solidified, it was collected using a centrifuge. This was dispersed again in distilled water and further centrifuged to wash away free drugs and the like.
捕集されたマイ、クロカプセルは凍結乾燥によりて脱溶
媒および脱水をより完全とした後、粉末として得られた
。The collected microcapsules were freeze-dried to remove solvent and dehydrate more completely, and then were obtained as a powder.
上記の方法で、P L GAに対して1〜lO%のEK
−399を仕込んだマイクロカプセルの薬物トラップ
率(仕込み量に対して実際に取込まれた量の%)、およ
び37℃でpH7,0リン酸緩衝液中で行なったin
vitro溶出試験の中で、1日後のマイクロカブ・
ピル中に残存する量を測定し表−1に示す。In the above method, 1-10% EK for P L GA
-399-loaded microcapsules (% of the amount actually taken up with respect to the loaded amount) and the in-
In the in vitro dissolution test, microcubs after 1 day
The amount remaining in the pill was measured and shown in Table 1.
表−I E、に−399マイクロカプセルElll
I 71.721.7E112.
2 69.9 ・47,
7E113.、、 5 78,6
73.0E114 7.5 97,3
82.63> PLGAに対する% b
)(n=3の平均値)E K −399の場合、弱酸で
ある酢酸塩であるが1%、2%の低仕込み量のロットで
はトラップ率の低下傾向と、大きな初期放出が見られ、
PLGAに対するEK −399の濃度が5〜/O%の
範囲で良好なマイクロカプセルが得られている。Table-I E-399 Microcapsule Ell
I 71.721.7E112.
2 69.9 ・47,
7E113. ,, 5 78,6
73.0E114 7.5 97,3
82.63>% b for PLGA
) (Average value of n = 3) In the case of E K -399, acetate is a weak acid, but in lots with low loadings of 1% and 2%, a tendency for the trapping rate to decrease and a large initial release were observed.
Good microcapsules were obtained when the concentration of EK-399 relative to PLGA was in the range of 5 to 0%.
実施例2
エンケファリン誘導体H−Tyr −D −Met(0
)−Gly −MePhe −NH−NHCOCH3−
Ac0H(E K −333)の40〜800mg(P
LGAに対して1〜20%)を、それぞれ蒸留水0.5
−に溶解し、以下、実施例1と同様にしてE K −3
33の8種類のマイクロカプセルを得た。Example 2 Enkephalin derivative H-Tyr-D-Met(0
)-Gly-MePhe-NH-NHCOCH3-
40-800 mg (P
1-20% of LGA) and 0.5% of distilled water, respectively.
- and the following procedure was carried out in the same manner as in Example 1 to prepare E K
33 8 types of microcapsules were obtained.
表−2にこれらのマイクロカプセルのトラップ率、in
vitro溶出試験における初期放出を示す。Table 2 shows the trapping rate of these microcapsules, in
Initial release in vitro dissolution test is shown.
表−2E K −333マイクロカプセルE3111
1 69.7 16.5E3
112 2 60.2 29
.9E 3113 5 80.0
72.2E3114 7.5 83
.4 82□4E3115 /O
87.6 91.1E3116 12
90.4 90.5E3117
15 90.7 87.0a
) PLGAに対する% b)、n73の平均値E
K −399と同様に1%、2%の低い仕込み量の場
合、トラップ率は低く、初期放出が顕著に大きかった。Table-2E K-333 Microcapsule E3111
1 69.7 16.5E3
112 2 60.2 29
.. 9E 3113 5 80.0
72.2E3114 7.5 83
.. 4 82□4E3115 /O
87.6 91.1E3116 12
90.4 90.5E3117
15 90.7 87.0a
)% relative to PLGA b), average value E of n73
Similar to K-399, at low loadings of 1% and 2%, the trapping rate was low and the initial release was significantly large.
20%仕込み時はトラップ率に少し低下、り(見られた
が、初期放出はそれほど大きくなかった二PLGAに対
するE K −333の濃度が5〜20%で良好なマイ
クロカプセルが得られた。At 20% loading, a slight decrease in trapping rate was observed, but the initial release was not so large. Good microcapsules were obtained at a concentration of E K-333 relative to PLGA of 5 to 20%.
実施例3
実施例!および2の方法で得られたマイクロカプセルの
in vitroおよびラット皮下に投与された後の
in vivo薬物放出性(投与部位マイクロカプセ
ル中の薬物残存量を測定)を検討し、その結果を表−3
および表−4に示す。Example 3 Example! The in vitro and in vivo drug release properties of the microcapsules obtained by method 2 and subcutaneous administration to rats (measurement of the amount of drug remaining in the microcapsules at the administration site) were investigated, and the results are shown in Table 3.
and shown in Table 4.
表−3
EK−333E3115 91.1 77.2 58,
3 25.3 1.48表−4
いずれもPLGA(乳酸/グリコール酸比ニア5/25
、平均分子ffi 14000)を用いたマイクロカプ
セルで、重合物に対して/O%の薬物を仕込み調製した
ものであるが、in vitroにおいて低い初期放出
性と4週間にわたる0次放出に近い良好な放出制御を有
するマイクロカプセルが得られていることを示している
。これらのマイクロカプセルは走査型電子顕微鏡による
観察の結果、平均粒子径が20〜30ミクロンのよく整
ったきれいな球形をしていた。また、適当な分散媒を用
いて23〜22ゲージの注射針によってスムースに容易
に注射可能であった。Table-3 EK-333E3115 91.1 77.2 58,
3 25.3 1.48 Table-4 Both are PLGA (lactic acid/glycolic acid ratio near 5/25
The microcapsules were prepared using microcapsules with an average molecular weight of 14,000) containing /0% of the drug based on the polymer, but in vitro they showed low initial release and good near zero-order release over 4 weeks. This shows that microcapsules with controlled release have been obtained. As a result of observation using a scanning electron microscope, these microcapsules had a well-ordered, clean spherical shape with an average particle diameter of 20 to 30 microns. Moreover, it could be smoothly and easily injected with a 23-22 gauge needle using an appropriate dispersion medium.
実施例4
実施例2の方法で、PLGAに対して5%の仕込み量の
E K −333を含有する内水相にクエン酸を薬物に
対して0,01〜4Mに相当する量を添加し、pKa4
.0未満の酸添加塩のマイクロカプセル調製に及ぼす影
響を検討した。その結果を表−5に示す。Example 4 Using the method of Example 2, citric acid was added in an amount equivalent to 0.01 to 4 M based on the drug to the internal aqueous phase containing EK-333 at a charge amount of 5% based on PLGA. , pKa4
.. The effect of less than 0 acid addition salts on microcapsule preparation was investigated. The results are shown in Table-5.
表−5E K −333マイクロカプセルクエン酸°)
トラ・プ 1日後の
E3172 0.1 57.7
42.5E3173 1
61.0 27.9E3174
2 81.0 11.3
a) E K −333に対するモル比用いたE K
−333は酢酸塩であるが、さらにクエン酸を添加し
た場合0.1M比以上で添加濃度に依存した初期放出の
増加が見られ、1M相当では72.1%が1日で放出さ
れた。Table-5E K-333 Microcapsule Citric Acid °)
Tora Pu E3172 after 1 day 0.1 57.7
42.5E3173 1
61.0 27.9E3174
2 81.0 11.3
a) E K using molar ratio to E K -333
-333 is an acetate salt, but when citric acid was further added, an increase in initial release depending on the added concentration was observed at a ratio of 0.1M or higher, and at a ratio of 1M, 72.1% was released in one day.
発明の効果
本発明の製造法によれば、生薬のマイクロカプセルへの
取込率が高く、初期過剰放出か少なく、長期にわたり安
定に主薬を放出する徐放性マイクロカプセルが得られる
。Effects of the Invention According to the production method of the present invention, sustained-release microcapsules can be obtained that have a high rate of incorporation of crude drugs into microcapsules, have little initial excessive release, and stably release the active drug over a long period of time.
Claims (1)
〜20重量%に相当するエンケファリン、そのアナログ
またはそれらのpKa4.0以上の弱酸との塩を含む水
層とでW/O型乳化物を形成せしめ、これと分散剤水溶
液とで混合してW/O/W型乳化物を形成せしめ、つい
で油層溶媒を留去することを特徴とするマイクロカプセ
ルの製造法。An oil layer containing a high molecular weight polymer, and 5% for the high molecular weight polymer.
A W/O emulsion is formed with an aqueous layer containing ~20% by weight of enkephalin, its analog, or their salt with a weak acid with a pKa of 4.0 or more, and this is mixed with an aqueous dispersant solution to form a W/O emulsion. 1. A method for producing microcapsules, which comprises forming a /O/W type emulsion and then distilling off an oil layer solvent.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP18746886A JPS6341416A (en) | 1986-08-08 | 1986-08-08 | Production of microcapsule containing analgesic peptide |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP18746886A JPS6341416A (en) | 1986-08-08 | 1986-08-08 | Production of microcapsule containing analgesic peptide |
Publications (1)
Publication Number | Publication Date |
---|---|
JPS6341416A true JPS6341416A (en) | 1988-02-22 |
Family
ID=16206608
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP18746886A Pending JPS6341416A (en) | 1986-08-08 | 1986-08-08 | Production of microcapsule containing analgesic peptide |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS6341416A (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0461630A2 (en) * | 1990-06-13 | 1991-12-18 | Eisai Co., Ltd. | Production process of microspheres |
JPH04321622A (en) * | 1990-02-13 | 1992-11-11 | Takeda Chem Ind Ltd | Long period sustained release type micro capsule |
US5395916A (en) * | 1991-09-06 | 1995-03-07 | Teijin Limited | Biodegradable copolymer from hydroxy proline |
US5643607A (en) * | 1990-02-13 | 1997-07-01 | Takeda Chemical Industries, Ltd. | Prolonged release microcapsules |
KR100537952B1 (en) * | 2001-04-13 | 2005-12-21 | 주식회사 태평양 | Hollow type microcapsule made of hydrophobic polymer and preparation method thereof, and cosmetic compositions containing the microcapsule |
JP2021534155A (en) * | 2018-12-17 | 2021-12-09 | ジー2ジーバイオ インコーポレイテッドG2Gbio, Inc. | Sustained release injection containing deslorerin and its manufacturing method |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS60100516A (en) * | 1983-11-04 | 1985-06-04 | Takeda Chem Ind Ltd | Preparation of sustained release microcapsule |
-
1986
- 1986-08-08 JP JP18746886A patent/JPS6341416A/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS60100516A (en) * | 1983-11-04 | 1985-06-04 | Takeda Chem Ind Ltd | Preparation of sustained release microcapsule |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH04321622A (en) * | 1990-02-13 | 1992-11-11 | Takeda Chem Ind Ltd | Long period sustained release type micro capsule |
LT3278B (en) | 1990-02-13 | 1995-05-25 | Takeda Chemical Industries Ltd | Microcapsules and process for preparing thereof |
US5643607A (en) * | 1990-02-13 | 1997-07-01 | Takeda Chemical Industries, Ltd. | Prolonged release microcapsules |
US5814342A (en) * | 1990-02-13 | 1998-09-29 | Takeda Chemical Industries, Ltd. | Prolonged release microcapsules |
EP0461630A2 (en) * | 1990-06-13 | 1991-12-18 | Eisai Co., Ltd. | Production process of microspheres |
US5395916A (en) * | 1991-09-06 | 1995-03-07 | Teijin Limited | Biodegradable copolymer from hydroxy proline |
KR100537952B1 (en) * | 2001-04-13 | 2005-12-21 | 주식회사 태평양 | Hollow type microcapsule made of hydrophobic polymer and preparation method thereof, and cosmetic compositions containing the microcapsule |
JP2021534155A (en) * | 2018-12-17 | 2021-12-09 | ジー2ジーバイオ インコーポレイテッドG2Gbio, Inc. | Sustained release injection containing deslorerin and its manufacturing method |
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