JPH0527608B2 - - Google Patents
Info
- Publication number
- JPH0527608B2 JPH0527608B2 JP59036127A JP3612784A JPH0527608B2 JP H0527608 B2 JPH0527608 B2 JP H0527608B2 JP 59036127 A JP59036127 A JP 59036127A JP 3612784 A JP3612784 A JP 3612784A JP H0527608 B2 JPH0527608 B2 JP H0527608B2
- Authority
- JP
- Japan
- Prior art keywords
- lactic acid
- copolymer
- molecular weight
- 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.)
- Expired - Lifetime
Links
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 62
- 229920000642 polymer Polymers 0.000 claims description 39
- 229920001577 copolymer Polymers 0.000 claims description 33
- 229960000448 lactic acid Drugs 0.000 claims description 32
- 229940079593 drug Drugs 0.000 claims description 31
- 239000003814 drug Substances 0.000 claims description 31
- 239000004310 lactic acid Substances 0.000 claims description 27
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 26
- 235000014655 lactic acid Nutrition 0.000 claims description 26
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical group C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 claims description 22
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 14
- 102000004169 proteins and genes Human genes 0.000 claims description 13
- 108090000623 proteins and genes Proteins 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000003405 delayed action preparation Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 229940088598 enzyme Drugs 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 238000009472 formulation Methods 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 238000013268 sustained release Methods 0.000 description 5
- 239000012730 sustained-release form Substances 0.000 description 5
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 4
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 4
- DDPFHDCZUJFNAT-PZPWKVFESA-N chembl2104402 Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CCCCCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 DDPFHDCZUJFNAT-PZPWKVFESA-N 0.000 description 4
- 108700032313 elcatonin Proteins 0.000 description 4
- 229960000756 elcatonin Drugs 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 229960005356 urokinase Drugs 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 108060001064 Calcitonin Proteins 0.000 description 2
- 102000055006 Calcitonin Human genes 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 229960004015 calcitonin Drugs 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000006866 deterioration Effects 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 102000009025 Endorphins Human genes 0.000 description 1
- 108010049140 Endorphins Proteins 0.000 description 1
- 208000005422 Foreign-Body reaction Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 108010003272 Hyaluronate lyase Proteins 0.000 description 1
- 102000001974 Hyaluronidases Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 108010056088 Somatostatin Proteins 0.000 description 1
- 102000005157 Somatostatin Human genes 0.000 description 1
- 239000004147 Sorbitan trioleate Substances 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 238000004847 absorption spectroscopy Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 229940116333 ethyl lactate Drugs 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 230000003480 fibrinolytic effect Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960002773 hyaluronidase Drugs 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 1
- 229960000553 somatostatin Drugs 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
【発明の詳細な説明】 本発明は徐放性剤の製法に関するものである。[Detailed description of the invention] The present invention relates to a method for producing sustained release agents.
従来、乳酸ポリマーとグリコール酸ポリマーと
は生体分解性高分子として、また生体吸収性であ
るうえ異物反応を殆んど起さない材料として徐放
性薬剤のための保持マトリツクス材として知られ
てきた。 Conventionally, lactic acid polymers and glycolic acid polymers have been known as biodegradable polymers and as retention matrix materials for sustained-release drugs as materials that are bioabsorbable and hardly cause foreign body reactions. .
また、乳酸ポリマーまたは乳酸とグリコール酸
とのコポリマーと薬物との複合体の従来の調整法
は(a)クロロホルムなどの該ポリマー可溶性の有機
溶媒を使用する方法(例えば製薬工場Vol3、No.
10、1983、P552−553;特時公昭55−44727:特
開昭56−46822)および(b)は200℃の高温で溶融す
る方法(特開昭58−216117)が採用されてきた。 In addition, conventional methods for preparing complexes of drugs and lactic acid polymers or copolymers of lactic acid and glycolic acid include (a) methods using organic solvents in which the polymer is soluble, such as chloroform (for example, Pharmaceutical Factory Vol. 3, No.
10, 1983, P552-553; Special Publication No. 55-44727: Japanese Unexamined Patent Publication No. 56-46822) and (b), a method of melting at a high temperature of 200°C (Japanese Unexamined Patent Publication No. 58-216117) has been adopted.
従つて、従来法による薬物の徐放性製剤では高
沸点の有機溶媒を用いる場合にはその有機溶媒の
除去に高い温度の加熱条件をともなう不適当な手
段であり、その他有機溶媒に不安定な薬物でも使
用できずまた溶媒が残存するおそれの欠点があつ
た。 Therefore, when using a high-boiling organic solvent in conventional sustained-release drug formulations, removal of the organic solvent requires high-temperature heating conditions, which is an inappropriate method, and other methods that are unstable to organic solvents are inappropriate. It also had the disadvantage that it could not be used even with drugs and there was a risk that solvents would remain.
また従来の溶融法では200℃近くに加熱する必
要があるので熱に不安定な薬物については使用で
きなかつた。また、マイクロカプセル化方法によ
る製剤においても疎水性の薬物にしか使用できな
い欠点があつた。 In addition, conventional melting methods require heating to nearly 200°C, so they cannot be used for drugs that are unstable to heat. Furthermore, formulations made by microencapsulation also have the disadvantage that they can only be used for hydrophobic drugs.
さらに、平均分子量約6000〜35000の乳酸とグ
リコール酸とのコポリマーを用い、90℃で寄生虫
感染治療および予防剤であるフエンベンダゾール
を乾熱溶融してなる製剤(特開昭56−46823)が
知られているが、しかしながら熱に不安定なペプ
チド系または蛋白質系薬物の良好な製剤を提供し
得るものではなかつた。 Furthermore, a preparation prepared by dry-heat-melting fuenbendazole, a parasitic infection treatment and prevention agent, at 90°C using a copolymer of lactic acid and glycolic acid with an average molecular weight of about 6,000 to 35,000 (Japanese Patent Laid-Open No. 56-46823) However, it has not been possible to provide a good formulation of heat-labile peptide or protein drugs.
本発明者らはペプチド系または蛋白質系薬物の
良好かつ簡便な徐放性製剤の研究について鋭意研
究の結果意外にも乳酸ポリマーおよび乳酸とグリ
コール酸とのコポリマーの分子量と軟化点との関
係から分子量20000以下の乳酸ポリマーまたは乳
酸とグリコール酸とのコポリマーは80℃以下の軟
化温度を示し、分子量20000以上のものでは軟化
温度が高くなる他に粘弾性が出て薬物の均一混合
が出来なくなることを見出して本発明に到達した
ものである。 The present inventors have conducted intensive research into a good and simple sustained-release formulation for peptide-based or protein-based drugs, and have unexpectedly found that the molecular weight Lactic acid polymers or copolymers of lactic acid and glycolic acid with a molecular weight of less than 20,000 have a softening temperature of less than 80°C, while those with a molecular weight of more than 20,000 have a high softening temperature and exhibit viscoelasticity, making it impossible to mix drugs uniformly. This discovery led to the present invention.
本発明方法では、80℃以下の温度で乳酸ポリマ
ーまたはコポリマーにペプチド系または蛋白質系
薬物を無溶媒下で均一に混合することができるの
で、従来使用できなかつた熱安定性の悪いペプチ
ド系または蛋白質系薬物でも使用できるし、形態
についても種々の形態が可能である。 In the method of the present invention, a peptide or protein drug can be uniformly mixed with a lactic acid polymer or copolymer without a solvent at a temperature below 80°C. It can also be used as a type drug, and various forms are possible.
従来、法では熱安定性の悪いペプチド系または
蛋白質薬物については有機溶媒を使用する方法が
採用されてきたが、これら有機溶媒は残存するお
それがあるし、また不安定なペプチド系または蛋
白質系薬物には使用できない欠点があつたが本発
明ではこれらのペプチド系または蛋白質系薬物に
も使用できる利点がある。 Conventionally, methods using organic solvents have been adopted for peptide or protein drugs that have poor thermal stability, but these organic solvents may remain, and also for unstable peptide or protein drugs. However, the present invention has the advantage that it can also be used with these peptide-based or protein-based drugs.
本発明は上記の知見に基づいて完成されたもの
で、分子量2000ないし20000でしかも80℃以下で
軟化する乳酸ポリマーまたはコポリマーに無溶媒
下ペプチド系または蛋白質系薬物を80℃以下の温
度で添加、混合、成形することを特徴とする徐放
性製剤の製法に関するものである。 The present invention was completed based on the above findings, and involves adding a peptide-based or protein-based drug without a solvent at a temperature of 80°C or lower to a lactic acid polymer or copolymer having a molecular weight of 2000 to 20000 and softening at 80°C or lower. The present invention relates to a method for producing a sustained release preparation, which is characterized by mixing and molding.
本発明では使用する乳酸ポリマーまたはコポリ
マーがL−乳酸ポリマー、DL−乳酸ポリマー、
L−乳酸とグリコール酸とのコポリマー、DL−
乳酸とグリコール酸とのコポリマーからなる群よ
り選ばれる1種または2種以上の混合物として使
用してもよく、また、分子量は2000なしい20000
でしかも80℃以下の軟化温度を有するものであ
る。 In the present invention, the lactic acid polymer or copolymer used is L-lactic acid polymer, DL-lactic acid polymer,
Copolymer of L-lactic acid and glycolic acid, DL-
It may be used as one kind or a mixture of two or more kinds selected from the group consisting of copolymers of lactic acid and glycolic acid, and the molecular weight is between 2000 and 20000.
Moreover, it has a softening temperature of 80°C or less.
本発明方法により乳酸ポリマーまたはコポリマ
ーとペプチド系または蛋白質系薬物との複合体を
製造するに際し、薬物の熱的安定性、および成形
性などを考慮して薬物を乳酸ポリマーまたはコポ
リマーと無溶媒下で混合、成形する温度は80℃以
下、好ましくは20℃なしい80℃である。 When producing a complex of a lactic acid polymer or copolymer and a peptide or protein drug by the method of the present invention, the drug is mixed with the lactic acid polymer or copolymer in the absence of a solvent, taking into consideration the thermal stability and moldability of the drug. The mixing and shaping temperature is 80°C or less, preferably 20°C to 80°C.
本発明では、上記の混合、成形温度に適合した
乳酸ポリマーおよびコポリマーが得られるように
その分子量、軟化温度および供重合する単量体に
もとづいて決定した。供重合する単量体に関して
は、例えば分子量約16000のL−乳酸ポリマーの
軟化点は約80℃、分子量約8000の同ポリマーの軟
化点は約50℃、分子量約4000の同ポリマーの軟化
点は約30℃、分子量約16000のDL−乳酸ポリマー
の軟化点は約70℃、分子量約8000の同ポリマーの
軟化点は約40℃、分子量約4000の同ポリマーの軟
化点は約25℃、さらに分子量約10000のL−乳酸
−グリコール酸コポリマーまたはDL−乳酸−グ
リコール酸コポリマー(コポリマーのモル比=75
〜50:25〜50)の軟化点は約65℃であり、同コポ
リマー(25:75)の軟化点は約70℃であり、さら
に同コポリマーの分子量約8000〜4000(コポリマ
ーのモル比=75〜25:25〜75)と軟化点は約40〜
20℃である。乳酸ポリマーおよびコポリマーの分
子量範囲は2000ないし20000である。 In the present invention, the lactic acid polymer and copolymer suitable for the above-mentioned mixing and molding temperatures were determined based on their molecular weight, softening temperature, and monomers to be copolymerized. Regarding monomers to be co-polymerized, for example, the softening point of an L-lactic acid polymer with a molecular weight of about 16,000 is about 80°C, the softening point of the same polymer with a molecular weight of about 8,000 is about 50°C, and the softening point of the same polymer with a molecular weight of about 4,000 is about 80°C. The softening point of the DL-lactic acid polymer with a molecular weight of about 16,000 at about 30℃ is about 70℃, the softening point of the same polymer with a molecular weight of about 8,000 is about 40℃, the softening point of the same polymer with a molecular weight of about 4,000 is about 25℃, and the softening point of the same polymer with a molecular weight of about 4,000 is about 25℃. Approximately 10,000 L-lactic acid-glycolic acid copolymers or DL-lactic acid-glycolic acid copolymers (molar ratio of copolymers = 75
~50:25~50) has a softening point of about 65°C, and that of the copolymer (25:75) has a softening point of about 70°C, and the molecular weight of the copolymer (25:75) is about 8000~4000 (mole ratio of copolymer = 75 ~25:25~75) and the softening point is approximately 40~
It is 20℃. The molecular weight range of lactic acid polymers and copolymers is 2000 to 20000.
分子量2000以下では、乳酸ポリマーまたはコポ
リマーの軟化点は低温(20℃)となり、保存調整
が困難になり、一方分子量20000以上では80℃よ
り高い温度て軟化するため用いる薬物の劣化を生
ずる可能性があり、また軟化後の粘弾性が高く薬
物のポリマーまたはコポリマーへの混合が難しく
なるので上記の分子量範囲に決定した。 If the molecular weight is less than 2,000, the softening point of the lactic acid polymer or copolymer will be low (20℃), making storage adjustment difficult. On the other hand, if the molecular weight is more than 20,000, it will soften at a temperature higher than 80℃, which may cause deterioration of the drug used. However, since the viscoelasticity after softening is high and it becomes difficult to mix the drug into the polymer or copolymer, the above molecular weight range was determined.
乳酸コポリマーにおいて乳酸とグリコール酸と
の配合割合は上記の記載より分子量、軟化温度
(点)を考慮してL−乳酸またはDL−乳酸99なし
い20モル対グリコール酸1ないし80モルの割合で
ある。 In the lactic acid copolymer, the blending ratio of lactic acid and glycolic acid is 99 to 20 moles of L-lactic acid or DL-lactic acid to 1 to 80 moles of glycolic acid, taking into account the molecular weight and softening temperature (point) from the above description. .
乳酸ポリマーまたはコポリマーと薬物との配合
割合は複合製剤が製造できれば特に制限がない
が、薬物0.01ないし70重量部当り乳酸ポリマーま
たはコポリマー99.99ないし30重量部である。好
ましくは0.5:99.5ないし50:50(重量比)であ
る。 The blending ratio of the lactic acid polymer or copolymer and the drug is not particularly limited as long as a composite preparation can be produced, but it is 99.99 to 30 parts by weight of the lactic acid polymer or copolymer per 0.01 to 70 parts by weight of the drug. Preferably the ratio is 0.5:99.5 to 50:50 (weight ratio).
本発明は薬物としてペプチド系または蛋白質系
薬物の医薬を含むもので熱に不安定な抗炎症製酵
素、繊維素溶解酵素等の酵素を含む徐放性製剤、
熱に不安定なポリペプチド系または蛋白系薬物を
含む徐放性製剤の製造に好適に使用できる。本発
明の製剤で使用される好ましい薬物の例として
は、ウロキナーゼ、ヒアルウロニダーゼ、その他
の酵素、カルシトニン、インシユリン、ソマトス
タチン、エンドルフインなどのポリペプチドなど
が挙げられる。 The present invention is a sustained-release preparation containing a peptide-based or protein-based drug as a drug, and containing enzymes such as heat-labile anti-inflammatory enzymes and fibrinolytic enzymes;
It can be suitably used for producing sustained release preparations containing heat-labile polypeptide or protein drugs. Examples of preferred drugs for use in the formulations of the invention include urokinase, hyaluronidase, other enzymes, calcitonin, insulin, somatostatin, polypeptides such as endorphin, and the like.
本発明の製剤はポリマーマトリツクスおよびコ
ポリマーマトリツクスおよび活性成分のほかに医
薬製剤に通常使用される他と物質例えば固形希釈
剤、担体、結合剤、賦形剤および補助剤を含有さ
せることができる。例えば、トラガントゴム、ア
ラビアゴム、トウモロコシ澱粉、ゼラチン、アル
ギン酸、ステアリン酸マグネシウム、アルミニウ
ムモノステアレート、密ろう、蔗糖、乳糖、メチ
ルパラペン、プロピルパラベン、マンニツト、ブ
ロピレングリコール、結晶質セルローズ、珪酸カ
ルシウム、シリカ、ポリビニルピロリドン、セト
ステアリルアルコール、カカオ脂、ポリオキシエ
チレンソルビタンモノラウレート、乳酸エチル、
ソルビタントリオレエート、ステアリン酸カルシ
ウム、タルクなどがある。 In addition to the polymer matrix and copolymer matrix and the active ingredient, the formulations according to the invention can contain other substances commonly used in pharmaceutical preparations, such as solid diluents, carriers, binders, excipients and auxiliaries. . For example, gum tragacanth, gum arabic, corn starch, gelatin, alginic acid, magnesium stearate, aluminum monostearate, beeswax, sucrose, lactose, methylparapen, propylparaben, mannite, propylene glycol, crystalline cellulose, calcium silicate, silica, Polyvinylpyrrolidone, cetostearyl alcohol, cocoa butter, polyoxyethylene sorbitan monolaurate, ethyl lactate,
These include sorbitan trioleate, calcium stearate, and talc.
次いで本発明の徐放性製剤の製造例を示せば、
例えば分子量2000〜20000で80℃以下で軟化する
乳酸ポリマーまたはコポリマーを適宜選択し、こ
の一定量を容器、好ましくはステンレス製容器に
加え、直接または水浴もしくは恒温槽にて加温し
て軟化せしめる。次いで軟化後対象とするペプチ
ド系または蛋白質薬物の一定量をこれに添加し、
その軟化状態にて充分に混合せしめる。その後こ
の混合物をその軟化条件下にて直接目的の一定形
状に成形、加工してもよく、または一旦押出し成
形して固化成形後さらに加温して軟化条件目的の
形状、例えば球状形に造粒せしめてもよい。 Next, an example of manufacturing the sustained release preparation of the present invention will be shown.
For example, a lactic acid polymer or copolymer having a molecular weight of 2,000 to 20,000 and softening at 80° C. or lower is appropriately selected, a certain amount of the polymer is added to a container, preferably a stainless steel container, and the polymer is heated directly or in a water bath or a constant temperature bath to soften it. Then, after softening, a certain amount of the target peptide or protein drug is added thereto,
Mix thoroughly in the softened state. Thereafter, this mixture may be directly molded and processed into a desired shape under the softening conditions, or it may be extruded and solidified, then further heated and granulated into the desired shape, such as a spherical shape, under the softening conditions. You can force it.
このようにして得られた製剤は、対象とするペ
プチド系または蛋白質系薬物の劣化もなく、かつ
良好な徐放性効果を奏し、さらに簡便に製造し得
るものである。 The preparation thus obtained does not cause any deterioration of the target peptide-based or protein-based drug, exhibits a good sustained release effect, and can be manufactured easily.
次に実施例を掲げて本発明を説明するが、これ
に限定されるものではない。 Next, the present invention will be explained with reference to examples, but the present invention is not limited thereto.
実施例 1
L−乳酸ポリマー(分子量約16000)50gをス
チレン製容器に入れ、恒温槽にて80℃に加温して
軟化させた後同温度条件下にてウロキナーゼ
600000単位(東洋醸造製)を添加して均一に混合
するまで混捏し、次いで直径3mmを有する棒状体
に押出成型した。得られた成形品を約3mmの長さ
に切断後コーテイングパンに入れた後約70℃にて
加温しつつ球状にし常温まで冷却した。酵素活性
はフイブリプレート法により測定した結果酵素活
性の低下は認められなかつた。Example 1 50 g of L-lactic acid polymer (molecular weight approximately 16,000) was placed in a styrene container, heated to 80°C in a constant temperature bath to soften it, and then treated with urokinase under the same temperature conditions.
600,000 units (manufactured by Toyo Jojo Co., Ltd.) were added and kneaded until uniformly mixed, and then extruded into a rod-shaped body having a diameter of 3 mm. The obtained molded product was cut into a length of about 3 mm, placed in a coating pan, heated at about 70° C., shaped into a sphere, and cooled to room temperature. Enzyme activity was measured by the fibriplate method, and no decrease in enzyme activity was observed.
溶出試験は37℃の振とう機付恒温槽を用いて生
理食塩水中に球状成形品を浸漬し、280nmにお
ける紫外線吸収スペクトル法(UV法)により外
液中のウロキナーゼ濃度を定量して行なつた。定
量の結果、薬剤は1日目で約10%溶出し、その後
徐々に溶出量が減少し、約1ケ月で全量が溶出し
た。 The dissolution test was performed by immersing the spherical molded product in physiological saline using a constant temperature bath with a shaker at 37°C, and quantifying the urokinase concentration in the external solution using ultraviolet absorption spectroscopy (UV method) at 280 nm. . As a result of quantitative analysis, about 10% of the drug was eluted on the first day, and the amount eluted gradually decreased after that, and the entire amount was eluted in about one month.
同様に、分子量約16000のL−乳酸ポリマーの
代りに分子量約7800のL−乳酸ポリマーを使用
し、50℃で加温軟化した場合、1日目でウロキナ
ーゼの約20%が溶出し、2週間で全量が溶出し
た。分子量3200のL−乳酸ポリマーを使用し25℃
で加温軟化した場合には1日目で約30%が溶出
し、約1週間後全量が溶出した。 Similarly, when an L-lactic acid polymer with a molecular weight of about 7,800 is used instead of an L-lactic acid polymer with a molecular weight of about 16,000 and softened by heating at 50°C, about 20% of urokinase is eluted on the first day, and it takes about 2 weeks. The entire amount was eluted. Using L-lactic acid polymer with a molecular weight of 3200 at 25℃
When softened by heating, about 30% was eluted on the first day, and the entire amount was eluted after about one week.
実施例 2
L−乳酸とグリコール酸とのコポリマー(75:
25)(分子量約7600)50gをステンレス製容器に
入れ、水浴上40℃に加温し軟化させた後エルカト
ニン(合成カルシトニン誘導体、東洋醸造製)
10000単位を加え均一に混合するまで混捏し、直
径3mmの大きさの棒状体に押出成形した。この成
形品を約3mmを長さに切断後、コーテイングパン
に入れ、約50℃に加温下球状にして製品を得た。
エルカトニンのカルシトニン活性は血清カルシウ
ムの低下作用により測定した結果活性の低下は認
められなかつた。Example 2 Copolymer of L-lactic acid and glycolic acid (75:
25) Place 50g (molecular weight approximately 7600) in a stainless steel container, heat it to 40℃ on a water bath to soften it, and then add elcatonin (synthetic calcitonin derivative, manufactured by Toyo Jojo Co., Ltd.)
10,000 units were added, kneaded until uniformly mixed, and extruded into a rod-shaped body with a diameter of 3 mm. This molded product was cut into a length of about 3 mm, placed in a coating pan, and heated to about 50° C. to form a sphere to obtain a product.
The calcitonin activity of elcatonin was measured by its serum calcium lowering effect, and no decrease in activity was observed.
溶出試験は生理食塩水中で実施例1と同様の条
件下で行ない、外液中のエルカトニン濃度はEIA
法により定量した。 The dissolution test was conducted in physiological saline under the same conditions as in Example 1, and the elcatonin concentration in the external solution was determined by EIA.
Quantitated by method.
定量の結果、1日目で約7%のエルカトニンが
溶出し、その後徐々に溶出量が減少し、約2ケ月
で全量が溶出した。 As a result of quantitative determination, about 7% of elcatonin was eluted on the first day, and the amount eluted gradually decreased thereafter, and the entire amount was eluted in about 2 months.
Claims (1)
軟化する乳酸ポリマーまたはコポリマーに無溶媒
下、ペプチド系または蛋白質系薬物を80℃以下の
温度で添加、混合、成形することを特徴とする徐
放性製剤の製法。 2 乳酸ポリマーまたはコポリマーがL−乳酸ポ
リマー、DL−乳酸ポリマー、L−乳酸またはDL
−乳酸とグリコール酸とのコポリマーまたはこれ
らの混合体である特許請求の範囲第1項記載の製
法。 3 L−乳酸とグリコール酸とのコポリマーまた
はDL−乳酸とグリコール酸とのコポリマーがL
−乳酸またはDL−乳酸99ないし20モル当りグル
コール酸1ないし80モルである特許請求の範囲第
1項または第2項記載の製法。 4 薬物と乳酸ポリマーまたはコポリマーとの使
用比率が薬物0.01ないし70重量部対乳酸ポリマー
またはコポリマー99.99ないし30重量部である特
許請求の範囲第1項記載の製法。 5 上記80℃以下の温度が20℃ないし80℃である
特許請求の範囲第1項記載の製法。[Claims] 1. A peptide-based or protein-based drug is added, mixed, and molded without a solvent to a lactic acid polymer or copolymer having a molecular weight of 2,000 to 20,000 and softening at a temperature of 80°C or below at a temperature of 80°C or below. A method for producing a sustained-release preparation. 2 Lactic acid polymer or copolymer is L-lactic acid polymer, DL-lactic acid polymer, L-lactic acid or DL
- The manufacturing method according to claim 1, which is a copolymer of lactic acid and glycolic acid or a mixture thereof. 3 A copolymer of L-lactic acid and glycolic acid or a copolymer of DL-lactic acid and glycolic acid is
-Lactic acid or DL-Lactic acid - 1 to 80 moles of glycolic acid per 99 to 20 moles of lactic acid. 4. The method according to claim 1, wherein the ratio of the drug to the lactic acid polymer or copolymer is 0.01 to 70 parts by weight of the drug to 99.99 to 30 parts by weight of the lactic acid polymer or copolymer. 5. The manufacturing method according to claim 1, wherein the temperature below 80°C is 20°C to 80°C.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP59036127A JPS60181029A (en) | 1984-02-29 | 1984-02-29 | Preparation of sustained release preparation |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP59036127A JPS60181029A (en) | 1984-02-29 | 1984-02-29 | Preparation of sustained release preparation |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS60181029A JPS60181029A (en) | 1985-09-14 |
JPH0527608B2 true JPH0527608B2 (en) | 1993-04-21 |
Family
ID=12461113
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP59036127A Granted JPS60181029A (en) | 1984-02-29 | 1984-02-29 | Preparation of sustained release preparation |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS60181029A (en) |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS60181029A (en) * | 1984-02-29 | 1985-09-14 | Toyo Jozo Co Ltd | Preparation of sustained release preparation |
JPS61172813A (en) * | 1985-01-28 | 1986-08-04 | Japan Atom Energy Res Inst | Sustained release composite containing polylactic acid as carrier and production thereof |
JP2539789B2 (en) * | 1986-03-06 | 1996-10-02 | 日本原子力研究所 | Process for producing sustained-release drug complex composed of polylactone |
JPS63218632A (en) * | 1987-03-06 | 1988-09-12 | Japan Atom Energy Res Inst | Production of biodegradable copoly(glycolic/l-lactic acid) complex which can gradually release hormons |
HU221294B1 (en) * | 1989-07-07 | 2002-09-28 | Novartis Ag | Process for producing retarde compositions containing the active ingredient in a polymeric carrier |
CH679207A5 (en) * | 1989-07-28 | 1992-01-15 | Debiopharm Sa | |
US5439688A (en) * | 1989-07-28 | 1995-08-08 | Debio Recherche Pharmaceutique S.A. | Process for preparing a pharmaceutical composition |
US5225205A (en) * | 1989-07-28 | 1993-07-06 | Debiopharm S.A. | Pharmaceutical composition in the form of microparticles |
US5075115A (en) * | 1990-04-02 | 1991-12-24 | Fmc Corporation | Process for polymerizing poly(lactic acid) |
US5456917A (en) * | 1993-04-12 | 1995-10-10 | Cambridge Scientific, Inc. | Method for making a bioerodible material for the sustained release of a medicament and the material made from the method |
US5855915A (en) | 1995-06-30 | 1999-01-05 | Baylor University | Tablets or biologically acceptable implants for long-term antiinflammatory drug release |
US6071982A (en) * | 1997-04-18 | 2000-06-06 | Cambridge Scientific, Inc. | Bioerodible polymeric semi-interpenetrating network alloys for surgical plates and bone cements, and method for making same |
ATE382337T1 (en) | 2005-04-28 | 2008-01-15 | Nipro Corp | BIOABSORBABLE PHARMACEUTICAL COMPOSITION CONTAINING A PLGA COPOLYMER |
CN104968338B (en) * | 2012-10-19 | 2018-09-28 | 胡幼圃 | The double Nabufulin ester-PLGA controlled release forms of long-acting anodyne decanedioyl |
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---|---|---|---|---|
US4011312A (en) * | 1975-06-25 | 1977-03-08 | American Home Products Corporation | Prolonged release drug form for the treatment of bovine mastitis |
JPS5646823A (en) * | 1979-09-12 | 1981-04-28 | Lilly Co Eli | Releaseecontrolled parasiticide |
JPS57150609A (en) * | 1981-02-16 | 1982-09-17 | Ici Ltd | Pharmaceutical composition, heterogeneous copolymer comprising lactic acid and glycolic acid units and manufacture |
JPS60181029A (en) * | 1984-02-29 | 1985-09-14 | Toyo Jozo Co Ltd | Preparation of sustained release preparation |
JPH0527608A (en) * | 1991-07-24 | 1993-02-05 | Fuji Xerox Co Ltd | Form feeder for image transfer device |
-
1984
- 1984-02-29 JP JP59036127A patent/JPS60181029A/en active Granted
Patent Citations (5)
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---|---|---|---|---|
US4011312A (en) * | 1975-06-25 | 1977-03-08 | American Home Products Corporation | Prolonged release drug form for the treatment of bovine mastitis |
JPS5646823A (en) * | 1979-09-12 | 1981-04-28 | Lilly Co Eli | Releaseecontrolled parasiticide |
JPS57150609A (en) * | 1981-02-16 | 1982-09-17 | Ici Ltd | Pharmaceutical composition, heterogeneous copolymer comprising lactic acid and glycolic acid units and manufacture |
JPS60181029A (en) * | 1984-02-29 | 1985-09-14 | Toyo Jozo Co Ltd | Preparation of sustained release preparation |
JPH0527608A (en) * | 1991-07-24 | 1993-02-05 | Fuji Xerox Co Ltd | Form feeder for image transfer device |
Also Published As
Publication number | Publication date |
---|---|
JPS60181029A (en) | 1985-09-14 |
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