KR102099849B1 - Drug-polymer complex using electrostatic bonding between drug and polymer and preparation thereof - Google Patents
Drug-polymer complex using electrostatic bonding between drug and polymer and preparation thereof Download PDFInfo
- Publication number
- KR102099849B1 KR102099849B1 KR1020190034455A KR20190034455A KR102099849B1 KR 102099849 B1 KR102099849 B1 KR 102099849B1 KR 1020190034455 A KR1020190034455 A KR 1020190034455A KR 20190034455 A KR20190034455 A KR 20190034455A KR 102099849 B1 KR102099849 B1 KR 102099849B1
- Authority
- KR
- South Korea
- Prior art keywords
- drug
- comparative example
- complex
- complex formation
- polymer
- Prior art date
Links
- 239000003814 drug Substances 0.000 title claims abstract description 105
- 229940079593 drug Drugs 0.000 title claims abstract description 100
- 229920000642 polymer Polymers 0.000 title claims abstract description 71
- 238000002360 preparation method Methods 0.000 title description 2
- 238000004519 manufacturing process Methods 0.000 claims abstract description 14
- 239000007924 injection Substances 0.000 claims abstract description 7
- 238000002347 injection Methods 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 26
- 239000007864 aqueous solution Substances 0.000 claims description 19
- 229920001287 Chondroitin sulfate Polymers 0.000 claims description 17
- 229940059329 chondroitin sulfate Drugs 0.000 claims description 17
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 claims description 10
- 239000006184 cosolvent Substances 0.000 claims description 8
- 239000000725 suspension Substances 0.000 claims description 8
- 229960004205 carbidopa Drugs 0.000 claims description 7
- TZFNLOMSOLWIDK-JTQLQIEISA-N carbidopa (anhydrous) Chemical compound NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 TZFNLOMSOLWIDK-JTQLQIEISA-N 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- JBIMVDZLSHOPLA-LSCVHKIXSA-N olopatadine Chemical compound C1OC2=CC=C(CC(O)=O)C=C2C(=C/CCN(C)C)\C2=CC=CC=C21 JBIMVDZLSHOPLA-LSCVHKIXSA-N 0.000 claims description 7
- 229960004114 olopatadine Drugs 0.000 claims description 7
- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 claims description 7
- 229960002722 terbinafine Drugs 0.000 claims description 7
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims description 7
- 229960000303 topotecan Drugs 0.000 claims description 7
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 claims description 5
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 claims description 5
- 229960003405 ciprofloxacin Drugs 0.000 claims description 5
- 229960000908 idarubicin Drugs 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 claims description 5
- 229960003702 moxifloxacin Drugs 0.000 claims description 5
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 claims description 4
- PMXMIIMHBWHSKN-UHFFFAOYSA-N 3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCC(O)C4=NC=3C)=NOC2=C1 PMXMIIMHBWHSKN-UHFFFAOYSA-N 0.000 claims description 4
- YPELFRMCRYSPKZ-UHFFFAOYSA-N 4-amino-5-chloro-2-ethoxy-N-({4-[(4-fluorophenyl)methyl]morpholin-2-yl}methyl)benzamide Chemical compound CCOC1=CC(N)=C(Cl)C=C1C(=O)NCC1OCCN(CC=2C=CC(F)=CC=2)C1 YPELFRMCRYSPKZ-UHFFFAOYSA-N 0.000 claims description 4
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 claims description 4
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 claims description 4
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 claims description 4
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 claims description 4
- 229960004372 aripiprazole Drugs 0.000 claims description 4
- 238000009472 formulation Methods 0.000 claims description 4
- 229960003376 levofloxacin Drugs 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 229960004085 mosapride Drugs 0.000 claims description 4
- 229960001699 ofloxacin Drugs 0.000 claims description 4
- 229960005017 olanzapine Drugs 0.000 claims description 4
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 claims description 4
- 229960001057 paliperidone Drugs 0.000 claims description 4
- 229960002296 paroxetine Drugs 0.000 claims description 4
- 229960004431 quetiapine Drugs 0.000 claims description 4
- URKOMYMAXPYINW-UHFFFAOYSA-N quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 claims description 4
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 claims description 4
- 229960001534 risperidone Drugs 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 239000002674 ointment Substances 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 239000003826 tablet Substances 0.000 claims description 3
- -1 tamsrosine Chemical compound 0.000 claims description 3
- 239000007921 spray Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 21
- 238000005538 encapsulation Methods 0.000 abstract description 18
- 125000000524 functional group Chemical group 0.000 abstract description 17
- 230000009102 absorption Effects 0.000 abstract description 4
- 238000010521 absorption reaction Methods 0.000 abstract description 4
- 239000003889 eye drop Substances 0.000 abstract description 4
- 239000011859 microparticle Substances 0.000 abstract description 4
- 239000002105 nanoparticle Substances 0.000 abstract description 4
- 230000006641 stabilisation Effects 0.000 abstract description 3
- 238000011105 stabilization Methods 0.000 abstract description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 abstract description 3
- 238000013270 controlled release Methods 0.000 abstract description 2
- 230000008685 targeting Effects 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 230
- 230000009918 complex formation Effects 0.000 description 111
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 27
- ZNOZWUKQPJXOIG-XSBHQQIPSA-L [(2r,3s,4r,5r,6s)-6-[[(1r,3s,4r,5r,8s)-3,4-dihydroxy-2,6-dioxabicyclo[3.2.1]octan-8-yl]oxy]-4-[[(1r,3r,4r,5r,8s)-8-[(2s,3r,4r,5r,6r)-3,4-dihydroxy-6-(hydroxymethyl)-5-sulfonatooxyoxan-2-yl]oxy-4-hydroxy-2,6-dioxabicyclo[3.2.1]octan-3-yl]oxy]-5-hydroxy-2-( Chemical compound O[C@@H]1[C@@H](O)[C@@H](OS([O-])(=O)=O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H]2OC[C@H]1O[C@H](O[C@H]1[C@H]([C@@H](CO)O[C@@H](O[C@@H]3[C@@H]4OC[C@H]3O[C@H](O)[C@@H]4O)[C@@H]1O)OS([O-])(=O)=O)[C@@H]2O ZNOZWUKQPJXOIG-XSBHQQIPSA-L 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- 229920003045 dextran sodium sulfate Polymers 0.000 description 17
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- 229940006423 chondroitin sulfate sodium Drugs 0.000 description 14
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 12
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 11
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical group C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 10
- 239000002245 particle Substances 0.000 description 10
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- 239000000872 buffer Substances 0.000 description 7
- 229960000633 dextran sulfate Drugs 0.000 description 7
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- 239000002861 polymer material Substances 0.000 description 6
- DRHKJLXJIQTDTD-OAHLLOKOSA-N Tamsulosine Chemical compound CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 DRHKJLXJIQTDTD-OAHLLOKOSA-N 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 229960003722 doxycycline Drugs 0.000 description 5
- XQTWDDCIUJNLTR-CVHRZJFOSA-N doxycycline monohydrate Chemical compound O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O XQTWDDCIUJNLTR-CVHRZJFOSA-N 0.000 description 5
- 229960002613 tamsulosin Drugs 0.000 description 5
- 150000003527 tetrahydropyrans Chemical group 0.000 description 5
- 229960004679 doxorubicin Drugs 0.000 description 4
- 239000010419 fine particle Substances 0.000 description 4
- 125000004193 piperazinyl group Chemical group 0.000 description 4
- 125000003386 piperidinyl group Chemical group 0.000 description 4
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 4
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 4
- 229960000707 tobramycin Drugs 0.000 description 4
- 231100000111 LD50 Toxicity 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000679 carrageenan Substances 0.000 description 3
- 235000010418 carrageenan Nutrition 0.000 description 3
- 229920001525 carrageenan Polymers 0.000 description 3
- 229940113118 carrageenan Drugs 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 239000002131 composite material Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229920001661 Chitosan Polymers 0.000 description 2
- 229920002567 Chondroitin Polymers 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 229920006318 anionic polymer Polymers 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229920006317 cationic polymer Polymers 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- DLGJWSVWTWEWBJ-HGGSSLSASA-N chondroitin Chemical compound CC(O)=N[C@@H]1[C@H](O)O[C@H](CO)[C@H](O)[C@@H]1OC1[C@H](O)[C@H](O)C=C(C(O)=O)O1 DLGJWSVWTWEWBJ-HGGSSLSASA-N 0.000 description 2
- 230000009881 electrostatic interaction Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000004615 ingredient Substances 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
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 2
- 229960004768 irinotecan Drugs 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000006174 pH buffer Substances 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 150000003335 secondary amines Chemical group 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 150000003512 tertiary amines Chemical group 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- XYLJNLCSTIOKRM-UHFFFAOYSA-N Alphagan Chemical compound C1=CC2=NC=CN=C2C(Br)=C1NC1=NCCN1 XYLJNLCSTIOKRM-UHFFFAOYSA-N 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 1
- 206010013774 Dry eye Diseases 0.000 description 1
- 102100025101 GATA-type zinc finger protein 1 Human genes 0.000 description 1
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 1
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 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
- 238000004458 analytical method Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- VHYCDWMUTMEGQY-UHFFFAOYSA-N bisoprolol Chemical compound CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1 VHYCDWMUTMEGQY-UHFFFAOYSA-N 0.000 description 1
- 229960002781 bisoprolol Drugs 0.000 description 1
- 229960003679 brimonidine Drugs 0.000 description 1
- HCRKCZRJWPKOAR-JTQLQIEISA-N brinzolamide Chemical compound CCN[C@H]1CN(CCCOC)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 HCRKCZRJWPKOAR-JTQLQIEISA-N 0.000 description 1
- 229960000722 brinzolamide Drugs 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 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 1
- 229960004015 calcitonin Drugs 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 150000001721 carbon Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- NPAKNKYSJIDKMW-UHFFFAOYSA-N carvedilol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=NC3=CC=C[CH]C3=C12 NPAKNKYSJIDKMW-UHFFFAOYSA-N 0.000 description 1
- 229960004195 carvedilol Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- IAVUPMFITXYVAF-XPUUQOCRSA-N dorzolamide Chemical compound CCN[C@H]1C[C@H](C)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 IAVUPMFITXYVAF-XPUUQOCRSA-N 0.000 description 1
- 229960003933 dorzolamide Drugs 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 229960000980 entecavir Drugs 0.000 description 1
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 238000009775 high-speed stirring Methods 0.000 description 1
- OWGIPADQEWDBDL-UHFFFAOYSA-N hyalic acid Natural products C1CC2(OC(=O)C3=C)CC3CCC2C2(C)C1C(C)(C(O)=O)CCC2 OWGIPADQEWDBDL-UHFFFAOYSA-N 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine group Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960004502 levodopa Drugs 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 230000004677 mucosal permeability Effects 0.000 description 1
- 239000007908 nanoemulsion Substances 0.000 description 1
- 239000006070 nanosuspension Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 238000001139 pH measurement Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 description 1
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 1
- 229960003089 pramipexole Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- RUOKEQAAGRXIBM-GFCCVEGCSA-N rasagiline Chemical compound C1=CC=C2[C@H](NCC#C)CCC2=C1 RUOKEQAAGRXIBM-GFCCVEGCSA-N 0.000 description 1
- 229960000245 rasagiline Drugs 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- RPACBEVZENYWOL-XFULWGLBSA-M sodium;(2r)-2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate Chemical compound [Na+].C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)[O-])CO1 RPACBEVZENYWOL-XFULWGLBSA-M 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6905—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Dispersion Chemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
본 발명은 경구, 점안, 주사로 사용되는 다양한 치료 영역의 약물 가운데 질소 원자를 포함하는 염기성 작용기를 갖는 특정 약물과 설페이트기를 갖는 당구조의 고분자 물질 사이에 직접 정전기 결합으로 만들어지는 약물-고분자 복합체 및 이의 제조방법에 관한 것으로, 약물-고분자 복합체의 제조가 매우 용이하고, 나노입자 또는 마이크로입자를 나타낼 뿐 아니라 약물의 봉입률이 크게 향상될 수 있다. The present invention is a drug-polymer complex made of a direct electrostatic bond between a specific drug having a basic functional group containing a nitrogen atom and a polymer substance having a sulfate structure among the drugs of various therapeutic areas used for oral, eye drop, injection and the like. It relates to a manufacturing method, the production of the drug-polymer complex is very easy, as well as showing nanoparticles or microparticles, the encapsulation rate of the drug can be greatly improved.
약물수송체는 치료제 주성분 의약품의 가용화, 흡수개선, 방출제어, 안정화, 표적화 분포를 목적으로 하며 특히, 입자성 약물수송체의 봉입률과 입자크기의 조절은 그 기능을 발휘하기 위한 중요한 전제조건에 해당한다. The drug transporter aims at solubilization, absorption improvement, release control, stabilization, and targeted distribution of the drug substance, which is the main ingredient of the therapeutic agent. It corresponds.
입자성 약물수송체는 나노에멀젼, 나노현탁액, 리포좀, 미셀, 고분자성 나노입자 및 마이크로 입자, 분무건조 고체분산체, 복합체 등을 사용한 약물수송체가 개발되어 있다. 이들 약물수송체는 수송체 물질의 선정, 수송체 제조방법의 설정, 주성분 봉입률과 수율의 확보, 수송체 입자크기 조절 등의 전 과정이 복잡하여 효율성이 낮다는 공통적인 문제점을 안고 있다. Particle drug transporters have been developed as drug transporters using nanoemulsions, nanosuspensions, liposomes, micelles, polymeric nanoparticles and microparticles, spray-dried solid dispersions, complexes, and the like. These drug transporters have a common problem of low efficiency due to the complexities of the entire process of selecting transporter materials, setting transporter manufacturing methods, securing the encapsulation rate and yield of the main component, and controlling the particle size of the transporter.
복합체 기술 중에 정전기적 고분자 복합체 기술은 키토산과 같은 양이온성 고분자와 알긴산, 히알산, 카르복시메칠셀룰로오스, 카보머와 같은 음이온성 고분자의 정전기적 상호 작용에 의하여 복합체를 형성하는 기술로 주로 인슐린과 같은 단백질 약물이나, 칼시토닌, 헤파린, GLP-1과 같은 약물을 봉입하여 경구투여 시의 위장관 내에서의 안정성과 점막 투과성을 향상시키고자 활용되었다(대한민국 공개특허 제10-2017-0081129호). Among the complex technologies, the electrostatic polymer complex technology is a technology that forms a complex by electrostatic interaction between cationic polymers such as chitosan and anionic polymers such as alginic acid, hyalic acid, carboxymethylcellulose, and carbomer, mainly proteins such as insulin. A drug, or a drug such as calcitonin, heparin, or GLP-1, was encapsulated to improve stability and mucosal permeability in the gastrointestinal tract during oral administration (Republic of Korea Patent Publication No. 10-2017-0081129).
하지만, 대한민국 공개특허 제10-2017-0081129호에서는 반대 전하를 나타내는 고분자 물질 사이의 정전기 결합에 의존하여 주성분을 봉입하기 때문에 주성분의 봉입률이 낮고, 양이온과 음이온의 고분자를 모두 필요로 하기 때문에 가공방법을 최적화 하기 복잡하고, 크기 조절이 어려운 단점이 있다. However, in Korean Patent Application Publication No. 10-2017-0081129, since the main component is encapsulated depending on the electrostatic bonding between polymer materials exhibiting opposite charges, the encapsulation rate of the main component is low, and both the cation and the anion polymers are required. There are disadvantages in that it is complicated to optimize the method and difficult to adjust the size.
본 발명의 목적은 약물과 고분자 간 직접 정전기적 결합을 이용하여 약물의 봉입률이 높고 제조방법이 간단하면서도 경제적인 약물-고분자 복합체 및 이의 제조방법을 제공하는 데에 있다.An object of the present invention is to provide a drug-polymer complex having a high encapsulation rate of a drug using a direct electrostatic bond between a drug and a polymer, a simple manufacturing method, and a manufacturing method thereof.
상기 목적을 달성하기 위하여, 본 발명은 (1) 질소(N)를 포함하는 6각 고리구조 화합물 중 피페라진기(piperazine structure), 피페리딘기(piperidine structure) 또는 몰폴린기(morpholine structure)를 포함하는 중량평균분자량 600 이하의 약물 또는 이들의 염; (2) 옥산구조와 직접 결합된 아민기를 포함하는 중량평균분자량 600 이하의 약물 또는 이들의 염; 또는 (3) 카비도파(carbidopa), 독시사이클린(doxycycline), 올로파타딘(olopatadine), 탐스로신(tamsulosin), 테르비나핀(terbinafine) 및 토포테칸(topotecan)으로 이루어진 군에서 선택된 염기성 작용기를 갖는 약물 또는 이들의 염; 중에서 선택된 하나 이상의 양전하를 띠는 약물 또는 이들의 염과, SO4 - 또는 SO3 - 작용기를 포함하며 음전하를 띠는 고분자 화합물 또는 이들의 염 간의 복합체를 형성하는 것을 특징으로 하는 약물-고분자 복합체를 제공한다.In order to achieve the above object, the present invention provides a piperazine structure, a piperidine structure or a morpholine structure among (1) a hexagonal ring structure compound containing nitrogen (N). Drugs having a weight average molecular weight of 600 or less, or salts thereof; (2) a drug having a weight average molecular weight of 600 or less containing an amine group directly bonded to the oxane structure or a salt thereof; Or (3) having a basic functional group selected from the group consisting of carbidopa, doxycycline, olopatadine, tamsulosin, terbinafine and topotecan Drugs or salts thereof; One or more positively charged drugs or salts thereof, and SO 4 - or SO 3 - provides a drug-polymer complex comprising a functional group and forming a complex between negatively charged polymer compounds or salts thereof.
또한, 본 발명은 (1) 질소(N)를 포함하는 6각 고리구조 화합물 중 피페라진기(piperazine structure), 피페리딘기(piperidine structure) 또는 몰폴린기(morpholine structure)를 포함하는 중량평균분자량 600 이하의 약물 또는 이들의 염; (2) 옥산구조와 직접 결합된 아민기를 포함하는 중량평균분자량 600 이하의 약물 또는 이들의 염; 또는 (3) 카비도파(carbidopa), 독시사이클린(doxycycline), 올로파타딘(olopatadine), 탐스로신(tamsulosin), 테르비나핀(terbinafine) 및 토포테칸(topotecan)으로 이루어진 군에서 선택된 염기성 작용기를 갖는 약물 또는 이들의 염; 중에서 선택된 하나 이상의 양전하를 띠는 약물 또는 이들의 염을 pH 0.1 내지 8.0의 조건 하 수용액 또는 에탄올 공용매에 용해시키는 제 1단계; SO4 - 또는 SO3 - 작용기를 포함하며 음전하를 띠는 고분자 화합물 또는 이들의 염을 pH 0.1 내지 8.0의 조건 하 수용액에 용해시키는 제 2단계; 및 상기 제 1단계의 용액에 제 2단계의 용액을 첨가하여 혼합시켜 약물-고분자 간의 복합체를 형성시키는 단계를 포함하며, 상기 음전하를 띠는 고분자 화합물 또는 이들의 염은 약물 또는 이들의 염의 총 중량에 대해 0.1배 내지는 5배의 중량 비율로 함유하는 것을 특징으로 하는 약물-고분자 복합체 제조방법을 제공한다.In addition, the present invention (1) weight average molecular weight comprising a piperazine group (piperazine structure), piperidine group (piperidine structure) or morpholine group (morpholine structure) of the hexagonal ring structure compound containing nitrogen (N) Up to 600 drugs or salts thereof; (2) a drug having a weight average molecular weight of 600 or less containing an amine group directly bonded to the oxane structure or a salt thereof; Or (3) having a basic functional group selected from the group consisting of carbidopa, doxycycline, olopatadine, tamsulosin, terbinafine and topotecan Drugs or salts thereof; A first step of dissolving at least one positively charged drug or a salt thereof in an aqueous solution or an ethanol co-solvent under conditions of pH 0.1 to 8.0; SO 4 - or SO 3 - a second step of dissolving a negatively charged polymer compound or a salt thereof containing a functional group in an aqueous solution under conditions of pH 0.1 to 8.0; And adding and mixing the solution of the second step to the solution of the first step to form a complex between the drug and the polymer, wherein the negatively charged polymer compound or salt thereof is the total weight of the drug or salt thereof It provides a method for producing a drug-polymer complex, characterized in that it contains at a weight ratio of 0.1 to 5 times.
본 발명은 다양한 치료제 중에 염기성 작용기를 가지며 pKa 값이 5 이상의 값을 가지는 주성분에 대해서 설페이트기(R-SO4 -, R-SO3 -)를 가지는 덱스트란 설페이트, 콘드로이틴 설페이트, 카라기난을 수용액 중에 반응시켜, 봉입률이 높고, 미립자 크기를 나타내는 약물-고분자 복합체를 제공할 수 있다. The present invention has a basic functional group in a variety of therapeutic agents sulfate group (R-SO respect to the main component having a pKa value of 5 or more values 4 -, R-SO 3 - is reacted in) with the dextran sulfate, chondroitin sulfate, carrageenan, an aqueous solution, a high encapsulation ratio, the drug indicating a particle size may provide a polymer composite.
본 발명에 따른 약물-고분자 복합체는 50% 이상의 우수한 약물 봉입률을 나타내고, 다양한 제어방출, 흡수개선, 약물의 안정화 및 표적화가 가능하며, 제조방법이 간단하고 경제적이며, 나노입자 내지는 마이크로 입자 크기로 조절이 가능한 복합체를 만들 수 있을 뿐 아니라, 경구, 주사, 경피, 경비, 점안, 흡입 등 다양한 투여경로에서 약물수송체로서 적용가능하다. The drug-polymer complex according to the present invention exhibits an excellent drug encapsulation rate of 50% or more, various controlled release, improved absorption, stabilization and targeting of the drug, simple and economical manufacturing method, and nano- or micro-particle size In addition to being able to make a controllable complex, it is applicable as a drug transporter in various routes of administration including oral, injection, transdermal, guard, eye drop, and inhalation.
이하, 본 발명을 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명의 발명자들은 저분자(중량평균분자량 800 미만, 바람직하게는 600 이하)이고, 염기성 작용기를 가지며 조절된 pH에서 양이온을 나타내는 약물을 대상으로 음이온성의 고분자 물질에 직접 정전기 결합을 형성시킴으로써 입자성 복합체 형성이 간단하게 가능하며, 이때 복합체 형성에 키토산과 같은 양이온성 고분자를 전혀 필요로 하지 않으며, 약물과 고분자간 직접 정전기 결합을 수반하기 때문에 봉입률이 높고, 제조방법이 간단하고 경제적이며, 미립자 상태로 수십나노미터에서 수십마이크로미터의 크기를 나타내는 약물수송체를 제공할 수 있다는 것을 밝혀내어 본 발명을 완성한 것이다.The inventors of the present invention are low molecular weight (less than 800 by weight average molecular weight, preferably 600 or less), and have a basic functional group and form a static electrostatic bond to an anionic polymer material directly on a drug that exhibits a cation at a controlled pH. Formation is simple, and does not require any cationic polymer, such as chitosan, to form a complex. Since it involves direct electrostatic bonding between the drug and the polymer, the encapsulation rate is high, the manufacturing method is simple and economical, and the particulate state The present invention was completed by finding out that a drug transporter having a size of tens of micrometers to tens of nanometers can be provided.
본 발명은 (1) 질소(N)를 포함하는 6각 고리구조 화합물 중 피페라진기(piperazine structure), 피페리딘기(piperidine structure) 또는 몰폴린기(morpholine structure)를 포함하는 중량평균분자량 600 이하의 약물 또는 이들의 염; (2) 옥산구조와 직접 결합된 아민기를 포함하는 중량평균분자량 600 이하의 약물 또는 이들의 염; 또는 (3) 카비도파(carbidopa), 독시사이클린(doxycycline), 올로파타딘(olopatadine), 탐스로신(tamsulosin), 테르비나핀(terbinafine) 및 토포테칸(topotecan)으로 이루어진 군에서 선택된 염기성 작용기를 갖는 약물 또는 이들의 염; 중에서 선택된 하나 이상의 양전하를 띠는 약물 또는 이들의 염과, SO4 - 또는 SO3 - 작용기를 포함하며 음전하를 띠는 고분자 화합물 또는 이들의 염 간의 복합체를 형성하는 것을 특징으로 하는 약물-고분자 복합체를 제공한다.The present invention provides a weight average molecular weight of 600 or less including a piperazine structure, a piperidine structure, or a morpholine structure among (1) a hexagonal ring structure compound containing nitrogen (N). Drugs or salts thereof; (2) a drug having a weight average molecular weight of 600 or less containing an amine group directly bonded to the oxane structure or a salt thereof; Or (3) having a basic functional group selected from the group consisting of carbidopa, doxycycline, olopatadine, tamsulosin, terbinafine and topotecan Drugs or salts thereof; One or more positively charged drugs or salts thereof, and SO 4 - or SO 3 - provides a drug-polymer complex comprising a functional group and forming a complex between negatively charged polymer compounds or salts thereof.
상기 약물은 그 구조에서 염기성 작용기를 가지며, pKa가 5 이상인 것을 특징으로 하고, 중량평균분자량이 자유염기 기준으로 보통 600보다 작으며, 물에 녹거나 에탄올과 물의 공용매에 녹인 후 pH를 조절할 때에 보통 pH 0.1내지 pH 6.0 범위에서 양이온을 나타내는 특징이 있다. The drug has a basic functional group in its structure, is characterized in that the pKa is 5 or more, and the weight average molecular weight is usually less than 600 based on the free base, when dissolved in water or dissolved in a co-solvent of ethanol and water to adjust the pH. It is usually characterized by showing cations in the range of pH 0.1 to pH 6.0.
상기 (1)의 약물은 아리피프라졸(aripiprazole), 쿠에티아핀(quetiapine), 올란자핀(olanzapine), 시프로플록사신(ciprofloxacin), 레보플록사신(levofloxacin), 오플록사신(ofloxacin), 리스페리돈(risperidone), 이리노테칸(irinotecan), 팔리페리돈(paliperidone), 목시플록사신(moxifloxacin), 파록세틴(paroxetine) 및 모사프리드(mosapride)로 이루어진 군에서 선택되며, 중량평균분자량 600 이하의 치료성분 화합물이지만, 이에 한정되지는 않는다. 다만, 화합물 구조 중에 질소(N) 함유 6각 고리구조에서 해당 질소로부터 3번 위치 이내에 히드록실기(-OH)기를 갖거나, 해당 질소와 직접 결합된 탄소가 포화되지 않은 구조의 화합물은 제외하며, 이에 각각 해당하는 레보드로피진과 티몰롤은 상기 (1)의 약물에서 제외된다.The drugs of the above (1) are aripiprazole, quetiapine, olanzapine, ciprofloxacin, levofloxacin, ofloxacin, risperidone, iripercanone (iripercanone) ), Paliperidone, moxifloxacin, paroxetine and mosapride are selected from the group consisting of, but are not limited to, therapeutic ingredient compounds having a weight average molecular weight of 600 or less. However, in the compound structure, in the hexagonal ring structure containing nitrogen (N), a compound having a hydroxyl group (-OH) group within 3 positions from the corresponding nitrogen or carbon directly bonded to the nitrogen is not saturated is excluded. , Reboropizin and thymolol, respectively, corresponding to this, are excluded from the drug (1).
또한, 상기 (2)의 약물은 독소루비신(doxorubicin), 토브라마이신(tobramycin) 및 이다루비신(idarubicin)으로 이루어진 군에서 선택되며, 중량평균분자량 600 이하의 치료성분 화합물이지만, 이에 한정되지는 않는다. In addition, the drug (2) is selected from the group consisting of doxorubicin (doxorubicin), tobramycin (tobramycin) and idarubicin (idarubicin), but is not limited to a therapeutic ingredient compound having a weight average molecular weight of 600 or less. .
상기 음전하를 띠는 고분자 화합물은 구조 중에 R-SO4 -, R-SO3 - 작용기를 가지는 당구조의 화합물이며, 일례로서 콘드로이틴 설페이트(chondroitin sulfate), 덱스트란 설페이트(dextran sulfate), 카라기난(carrageenan) 및 이들의 염으로 이루어진 군에서 선택된 하나 이상일 수 있지만, 이에 한정되지는 않는다. 이러한 고분자 화합물은 알려진 pKa가 2보다 작아 pH 2 이상에서 음전하를 나타내는 공통적인 특징이 있다.Is a polymeric compound strip to the negative charge in the structure is R-SO 4 -, R-SO 3 - functional group The branch is a compound having a sugar structure, and may be one or more selected from the group consisting of chondroitin sulfate, dextran sulfate, carrageenan, and salts thereof, but is not limited thereto. These polymer compounds have a common characteristic that a known pKa is less than 2 and exhibits a negative charge at pH 2 or higher.
콘드로이틴 설페이트는 점안, 경구, 주사로 투여가 가능하며, 안전하고 일부 약리활성으로 안구건조나 안과의 수술보조제로 사용가능하다. 콘드로이틴 설페이트의 반수치사량(LD50)은 10g/kg 이상(Rat, 경구투여)으로 안전한 물질로 분류될 수 있다. 덱스트란 설페이트는 반수치사량(LD50)이 경구에서 2g/kg 이상(Rat, 경구투여)으로 안전한 고분자 물질이다. 카라기난은 식품이나 의약품의 첨가제로 폭넓게 사용되고 있으며 점도 조절이나 제제화의 개선을 위해 쓰이고 안전한 고분자 물질이다. 이들 고분자는 수용성을 증가시키기 위해 Na염과 같은 형태로도 사용가능하다. 하지만 이들 염 형태가 복합체 형성에는 영향을 미치지 않는다. 이들 고분자 물질의 사용에서 그 분자량이나 점도는 크게 영향이 없으나 다만, 혼합에서 자유로운 반응을 위해서는 1%의 기준으로 수용액에서 농도가 10만cp 이내이면 바람직하다.Chondroitin sulfate can be administered by instillation, oral, or injection. It is safe and can be used as a surgical aid for dry eye or ophthalmology with some pharmacological activity. Chondroitin sulfate can be classified as a safe substance with a half-lethal dose (LD50) of 10 g / kg or more (Rat, oral administration). Dextran sulfate is a safe polymer material with a semi-lethal dose (LD50) of 2 g / kg or more (Rat, oral administration) in the oral cavity. Carrageenan is widely used as an additive in food and pharmaceuticals, and is a safe and high-molecular substance used to improve viscosity control and formulation. These polymers can also be used in the form of Na salt to increase water solubility. However, these salt forms do not affect complex formation. In the use of these polymer materials, the molecular weight or viscosity is not significantly affected, but for a free reaction in mixing, it is preferable that the concentration in the aqueous solution is within 100,000 cp, based on 1%.
상기 양전하를 띠는 약물은 수용액 상에서 0.1 중량% 내지 10 중량%로 함유되며, pH 0.1 내지 pH 8의 범위, 바람직하게는 pH 0.1 내지 pH 6.0의 범위를 나타낼 수 있다.The positively charged drug is contained in an aqueous solution in an amount of 0.1% to 10% by weight, and may exhibit a range of pH 0.1 to pH 8, preferably a range of pH 0.1 to pH 6.0.
상기 음전하를 띠는 고분자 화합물 또는 이들의 염은 약물의 총 중량에 대해 0.1배 내지는 5배의 중량 비율로 함유하는 것이 바람직하며, 상기 함량 비율을 벗어나면 점도가 증가하여 혼합시 균질한 혼합상태에서의 복합체 형성이 어려운 문제가 야기될 수 있다.The negatively charged polymer compound or a salt thereof is preferably contained in a weight ratio of 0.1 to 5 times the total weight of the drug. Difficult formation of complexes may cause problems.
상기 약물과 음전하를 띠는 고분자 화합물 또는 이들의 염은 수용액 또는 에탄올과 물의 공용매에 녹일 수 있다. The drug and a negatively charged polymer compound or a salt thereof may be dissolved in an aqueous solution or a co-solvent of ethanol and water.
상기 음전하를 띠는 고분자 화합물 또는 이들의 염은 1 중량% 수용액의 점도가 1센티포아즈(cp)에서 5000센티포아즈(cp)의 범위를 나타낼 수 있다.The negatively charged polymer compound or a salt thereof may have a viscosity of 1 wt% aqueous solution ranging from 1 centipoise (cp) to 5000 centipoise (cp).
상기 음전하를 띠는 고분자 화합물 또는 이들의 염은 수용액 상에서 pH 0.1 내지 pH 8.0의 범위, 바람직하게는 pH 0.1 내지 pH 6.0의 범위를 나타낼 수 있다.The negatively charged polymer compound or a salt thereof may exhibit a range of pH 0.1 to pH 8.0 in an aqueous solution, preferably a range of pH 0.1 to pH 6.0.
에탄올과 물의 공용매는 에탄올이 0.1 중량% 내지 90 중량%의 함량으로 포함되며, 바람직하게는 에탄올이 10 내지 90 중량%의 함량으로 포함될 수 있다.The co-solvent of ethanol and water contains ethanol in an amount of 0.1% to 90% by weight, preferably ethanol in an amount of 10 to 90% by weight.
본 발명에 따른 약물-고분자 복합체는 현탁 상태이며, 이를 그대로 사용하거나 또는 추가로 물을 제거하여, 현탁제, 산제, 과립제, 캡슐제, 정제, 주사제, 연고제, 분무제 및 흡입제로 이루어진 군에서 선택된 제형으로 제조할 수 있다.The drug-polymer complex according to the present invention is in a suspended state, or it is used as it is or by removing water further, a formulation selected from the group consisting of suspensions, powders, granules, capsules, tablets, injections, ointments, sprays and inhalants Can be produced.
또한, 본 발명은 (1) 질소(N)를 포함하는 6각 고리구조 화합물 중 피페라진기(piperazine structure), 피페리딘기(piperidine structure) 또는 몰폴린기(morpholine structure)를 포함하는 중량평균분자량 600 이하의 약물 또는 이들의 염; (2) 옥산구조와 직접 결합된 아민기를 포함하는 중량평균분자량 600 이하의 약물 또는 이들의 염; 또는 (3) 카비도파(carbidopa), 독시사이클린(doxycycline), 올로파타딘(olopatadine), 탐스로신(tamsulosin), 테르비나핀(terbinafine) 및 토포테칸(topotecan)으로 이루어진 군에서 선택된 염기성 작용기를 갖는 약물 또는 이들의 염; 중에서 선택된 하나 이상의 양전하를 띠는 약물 또는 이들의 염을 pH 0.1 내지 8.0의 조건 하 수용액 또는 에탄올 공용매에 용해시키는 제 1단계; SO4 - 또는 SO3 - 작용기를 포함하며 음전하를 띠는 고분자 화합물 또는 이들의 염을 pH 0.1 내지 8.0의 조건 하 수용액에 용해시키는 제 2단계; 및 상기 제 1단계의 용액에 제 2단계의 용액을 첨가하여 혼합시켜 약물-고분자 간의 복합체를 형성시키는 단계를 포함하며, 상기 음전하를 띠는 고분자 화합물 또는 이들의 염은 약물 또는 이들의 염의 총 중량에 대해 0.1배 내지는 5배의 중량 비율로 함유하는 것을 특징으로 하는 약물-고분자 복합체 제조방법을 제공한다. In addition, the present invention (1) weight average molecular weight comprising a piperazine group (piperazine structure), piperidine group (piperidine structure) or morpholine group (morpholine structure) of the hexagonal ring structure compound containing nitrogen (N) Up to 600 drugs or salts thereof; (2) a drug having a weight average molecular weight of 600 or less containing an amine group directly bonded to the oxane structure or a salt thereof; Or (3) having a basic functional group selected from the group consisting of carbidopa, doxycycline, olopatadine, tamsulosin, terbinafine and topotecan Drugs or salts thereof; A first step of dissolving at least one positively charged drug or a salt thereof in an aqueous solution or an ethanol co-solvent under conditions of pH 0.1 to 8.0; SO 4 - or SO 3 - a second step of dissolving a negatively charged polymer compound or a salt thereof containing a functional group in an aqueous solution under conditions of pH 0.1 to 8.0; And adding and mixing the solution of the second step to the solution of the first step to form a complex between the drug and the polymer, wherein the negatively charged polymer compound or salt thereof is the total weight of the drug or salt thereof It provides a method for producing a drug-polymer complex, characterized in that it contains at a weight ratio of 0.1 to 5 times.
상기 수용액은 pH 조절제를 이용하여 pH 0.1 내지 8.0의 조건을 맞춘 수용액을 의미한다.The aqueous solution means an aqueous solution having a condition of pH 0.1 to 8.0 using a pH adjusting agent.
보다 상세하게는, 본 발명에 따른 약물-고분자 복합체 형성을 위해서는 약물과 고분자 각각의 용액을 pH 0.1 내지 8.0, 바람직하게는 pH 2.0 내지 pH 6.0의 범위에서 제조하고, 상호 혼합하며 교반하면 복합체 형성이 이루어진다. 이때 입자크기나 반응시간을 단축하기 위한 목적으로 고속교반력, 초음파력, 이외의 각종 혼합을 위한 물리적 에너지를 가하면 복합체 형성이 일어나 현탁된 상태를 얻을 수 있다. More specifically, in order to form a drug-polymer complex according to the present invention, a solution of each of the drug and the polymer is prepared in the range of pH 0.1 to 8.0, preferably pH 2.0 to pH 6.0, mixed with each other and stirred to form a complex. Is done. At this time, for the purpose of shortening the particle size or reaction time, when high-speed stirring force, ultrasonic force, and physical energy for various other mixing are applied, complex formation occurs and a suspended state can be obtained.
약물과 고분자 용액을 혼합하여 나타나는 pH의 범위는 pH 2 내지 pH 6의 범위이고, 바람직하게는 pH 3 내지 pH 5의 범위로 나타나게 된다. 반응을 위한 적절한 약물의 농도는 0.1%(w/v%) 이상에서 약물의 수용해도에 따라 높은 농도를 적용하는 것도 가능하다. 일반적으로 약물의 농도는 10%(w/v%) 이내의 농도에서 가능하다. 고분자 물질의 용해도는 약물 농도에 대비하여 낮거나 높게 설정하면 되며, 다만, 점도를 고려하여 고분자 물질을 녹인 점도가 20℃에서 10만cp 이내이면 바람직하다. The range of pH indicated by mixing the drug and the polymer solution is in the range of pH 2 to pH 6, and preferably in the range of pH 3 to pH 5. It is also possible to apply a high concentration depending on the water solubility of the drug at a concentration of 0.1% (w / v%) or more appropriate for the reaction. Generally, the concentration of the drug is possible at a concentration within 10% (w / v%). The solubility of the polymer material may be set to be low or high in comparison to the drug concentration. However, it is preferable if the viscosity of the polymer material dissolved in consideration of the viscosity is within 100,000 cp at 20 ° C.
이렇게 얻어진 약물-고분자 복합체는 수용액에 현탁된 상태이며 보통 수십 내지 수백 나노미터 크기의 콜로이드 상태를 나타내거나 수십 마이크로미터 이내의 미세 현탁상을 나타낸다. 이들은 이 상태 그대로 혹은 물을 제거하여, 산제, 과립제, 정제, 캡슐제, 연고제, 좌제, 패취제, 흡입제로 적용가능하고, 혹은 무균제제로 pH와 삼투성, 무균성을 조절하여 점안제, 주사제로도 적용가능하다. The drug-polymer complex thus obtained is suspended in an aqueous solution and usually exhibits a colloidal state of several tens to hundreds of nanometers in size or a fine suspension within a few tens of micrometers. They can be applied as it is or by removing water, and can be applied as powders, granules, tablets, capsules, ointments, suppositories, patches, inhalants, or even as eye drops and injections by adjusting pH, osmolarity, and sterility as a disinfectant. It is applicable.
본 발명에 따른 약물-고분자 복합체는 그 구성이 약물과 고분자의 특수한 반응성에 의존함으로 기존에 동일한 발명의 제시가 없으며, 신규하고 진보한 발명으로서, 매우 간단하고 효율적인 제조방법으로 나노미터 또는 마이크로미터의 미립자를 경제성 있게 제조할 수 있고, 봉입효율이 50% 이상으로 우수하고, 다양한 제제로의 적용이 가능한 장점을 가진다.The drug-polymer composite according to the present invention does not have the present invention of the same invention because its composition depends on the specific reactivity of the drug and the polymer. As a new and advanced invention, it is a very simple and efficient manufacturing method of nanometer or micrometer. Fine particles can be produced economically, and the encapsulation efficiency is excellent at 50% or more, and it has the advantage of being applicable to various formulations.
이하, 본 발명을 실시예 및 시험예를 통하여 더욱 상세히 설명한다. 그러나, 하기 실시예 및 시험예는 본 발명을 예시하기 위한 것으로, 본 발명의 범위가 이들에만 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples and test examples. However, the following examples and test examples are intended to illustrate the present invention, and the scope of the present invention is not limited thereto.
<비교예 1 내지 비교예 18> 약물과 고분자간 복합체를 형성하지 않는 염기성 약물 이용<Comparative Example 1 to Comparative Example 18> Use of a basic drug that does not form a complex between the drug and the polymer
다음 표 1을 근거로 약물-고분자 복합체를 형성하고자 하였다.Based on the following Table 1, it was intended to form a drug-polymer complex.
각 비교예에 해당하는 pH 조건의 아세트산 완충액(45 mM)과 에탄올을 3 : 7 비율로 혼합한 용액 500 μL에 각 비교예에 해당하는 농도의 약물을 진탕하여 녹였다. 각 비교예에 해당하는 pH 조건의 아세트산 완충액(45 mM) 500 μL에 각 비교예에 해당하는 농도의 고분자를 녹였다.Acetic acid buffer (45 mM) in pH condition corresponding to each comparative example and ethanol in a ratio of 3: 7 were dissolved in 500 μL of the solution corresponding to each comparative example by shaking. Polymers having a concentration corresponding to each comparative example were dissolved in 500 μL of acetic acid buffer (45 mM) at pH conditions corresponding to each comparative example.
상기 약물 용액에 probe형 초음파파쇄기(ultrasonicator)를 담그고 작동하며 상기 고분자 용액을 적가하여 2분간 초음파진동을 가하면서 혼합하였다. The probe solution was immersed in a probe type ultrasonicator, and the polymer solution was added dropwise and mixed while applying ultrasonic vibration for 2 minutes.
농도(%) drug
density(%)
농도(%)Polymer
density(%)
염기성 작용기Drug
Basic functional group
설페이트 나트륨Dextran
Sodium sulfate
설페이트 나트륨Chondroitin
Sodium sulfate
설페이트 나트륨Dextran
Sodium sulfate
설페이트 나트륨Chondroitin
Sodium sulfate
<비교예 19 내지 비교예 108> 약물과 고분자간 복합체를 형성하지 않는 염기성 약물 이용<Comparative Example 19 to Comparative Example 108> Use of a basic drug that does not form a complex between the drug and the polymer
다음 표 2를 근거로 약물-고분자 복합체를 형성하고자 하였다.Based on the following Table 2, it was intended to form a drug-polymer complex.
각 비교예에 해당하는 pH 조건의 아세트산 완충액(45 mM) 500 μL에 각 비교예에 해당하는 농도의 약물을 진탕하여 녹였다. 각 비교예에 해당하는 pH 조건의 아세트산 완충액(45 mM) 500 μL에 각 비교예에 해당하는 농도의 고분자를 진탕하여 녹였다. 500 μL of acetic acid buffer (45 mM) in pH condition corresponding to each comparative example was shaken to dissolve the drug at a concentration corresponding to each comparative example. 500 μL of acetic acid buffer solution (45 mM) under pH conditions corresponding to each comparative example was shaken and dissolved by shaking a polymer having a concentration corresponding to each comparative example.
상기 약물 용액에 probe형 초음파파쇄기(ultrasonicator)를 담그고 작동하며 상기 고분자 용액을 적가하여 2분간 초음파진동을 가하면서 혼합하였다. The probe solution was immersed in a probe type ultrasonicator, and the polymer solution was added dropwise and mixed while applying ultrasonic vibration for 2 minutes.
농도(%) drug
density(%)
농도(%)Polymer
density(%)
염기성 작용기Drug
Basic functional group
설페이트
나트륨Dextran
Sulfate
salt
6각형 고리구조
(피페라진 구조)이면서 해당
질소로부터 3번 위치 이내에
히드록실기(-OH)와 결합된 탄소를 갖는 구조 Nitrogen (N) content
Hexagonal ring structure
(Piperazine structure)
Within 3 positions from nitrogen
Structure with carbon bonded to hydroxyl group (-OH)
설페이트
나트륨Chondroitin
Sulfate
salt
설페이트
나트륨Dextran
Sulfate
salt
설페이트
나트륨Chondroitin
Sulfate
salt
Thymolol
6각형 고리구조
(몰폴린구조)이면서 해당 질소로부터 직접
결합하는 원소가 포화 탄소가
아닌 구조Nitrogen (N) content
Hexagonal ring structure
(Morpholine structure) and directly from the nitrogen
The element to be bound is saturated carbon
Not structure
<실시예 1 및 실시예 2><Example 1 and Example 2>
다음 표 3을 근거로 약물-고분자 복합체를 형성하고자 하였다.Based on the following Table 3, it was intended to form a drug-polymer complex.
각 실시예에 해당하는 pH 조건의 아세트산 완충액(45 mM)과 에탄올을 3 : 7 비율로 혼합한 용액 500 μL에 각 실시예에 해당하는 농도의 약물을 진탕하여 녹였다. 각 실시예에 해당하는 pH 조건의 아세트산 완충액(45 mM) 500 μL에 각 실시예에 해당하는 농도의 고분자를 녹였다.Acetic acid buffer (45 mM) in pH condition corresponding to each example and ethanol in a 3: 7 ratio of the solution were dissolved by shaking the drug of the concentration corresponding to each example in 500 μL. Polymers having a concentration corresponding to each example were dissolved in 500 μL of acetic acid buffer (45 mM) at pH conditions corresponding to each example.
상기 약물 용액에 probe형 초음파진동기(ultrasonicator)를 담그고 작동하며 상기 고분자 용액을 적가하여 2분간 초음파진동을 가하면서 혼합하였다. The probe solution was immersed in a probe type ultrasonic vibrator, and the polymer solution was added dropwise and mixed while applying ultrasonic vibration for 2 minutes.
농도(%)Polymer
density(%)
염기성 작용기Drug
Basic functional group
6각형 고리구조
(피페라진 구조)Nitrogen (N) content
Hexagonal ring structure
(Piperazine structure)
<실시예 3 내지 실시예 85> < Examples 3 to 85>
다음 표 4를 근거로 약물-고분자 복합체를 형성하고자 하였다.Based on the following Table 4, it was intended to form a drug-polymer complex.
각 실시예에 해당하는 pH 조건의 아세트산 완충액(45 mM) 500 μL에 각 실시예에 해당하는 농도의 약물을 진탕하여 녹였다. 각 실시예에 해당하는 pH 조건의 아세트산 완충액(45 mM) 500 μL에 각 실시예에 해당하는 농도의 고분자를 진탕하여 녹였다. 500 μL of acetic acid buffer (45 mM) under pH conditions corresponding to each example was shaken to dissolve the drug at a concentration corresponding to each example. 500 μL of acetic acid buffer (45 mM) under pH conditions corresponding to each example was shaken to melt the polymer of the concentration corresponding to each example.
상기 약물 용액에 probe형 초음파파쇄기(ultrasonicator)를 담그고 작동하며 상기 고분자 용액을 적가하여 2분간 초음파진동을 가하면서 혼합하였다. The probe solution was immersed in a probe type ultrasonicator, and the polymer solution was added dropwise and mixed while applying ultrasonic vibration for 2 minutes.
농도(%) drug
density(%)
농도(%)Polymer
density(%)
조건pH
Condition
염기성 작용기Drug
Basic functional group
6각형 고리구조
(피페라진 구조)Nitrogen (N) content
Hexagonal ring structure
(Piperazine structure)
설페이트 나트륨Dextran
Sodium sulfate
설페이트 나트륨Dextran
Sodium sulfate
설페이트 나트륨Dextran
Sodium sulfate
설페이트 나트륨Dextran
Sodium sulfate
6각형 고리구조
(피페리딘 구조)Nitrogen (N) content
Hexagonal ring structure
(Piperidine structure)
설페이트 나트륨Dextran
Sodium sulfate
설페이트 나트륨 Dextran
Sodium sulfate
설페이트 나트륨Dextran
Sodium sulfate
설페이트 나트륨Dextran
Sodium sulfate
설페이트 나트륨Dextran
Sodium sulfate
6각형 고리구조
(몰폴린 구조)Nitrogen (N) content
Hexagonal ring structure
(Morpholine structure)
설페이트
나트륨Dextran
Sulfate
salt
설페이트
나트륨Chondroitin
Sulfate
salt
카라기난kappa
Carrageenan
설페이트 나트륨Dextran
Sodium sulfate
설페이트 나트륨Dextran
Sodium sulfate
설페이트 나트륨Dextran
Sodium sulfate
설페이트 나트륨Dextran
Sodium sulfate
설페이트 나트륨Dextran
Sodium sulfate
설페이트 나트륨Dextran
Sodium sulfate
설페이트
나트륨Dextran
Sulfate
salt
설페이트
나트륨Chondroitin
Sulfate
salt
카라기난kappa
Carrageenan
<실험예 1> 복합체의 pH, 입자크기, 봉입률 평가<Experimental Example 1> Evaluation of the complex pH, particle size, and encapsulation rate
본 발명의 약물과 고분자간 복합체가 실제로 형성되는지를 확인하기 위하여, 제조된 비교예와 실시예에 대한 성상을 관찰하여 확인하였다. In order to confirm whether the drug-polymer complex of the present invention is actually formed, it was confirmed by observing the properties of the prepared comparative examples and examples.
1) pH 측정1) pH measurement
본 발명의 약물복합체 제조에 있어서, 약물 용액과 고분자 용액의 pH 조건을 달리하여 약물복합체를 제조하는 경우 제조된 현탁액의 pH를 확인하기 위하여, pH 측정기(S220 SevenCompact™ ph/Ion, Mettler Toledo)를 이용한 pH 측정을 통하여 확인하였다.In preparing the drug complex of the present invention, in order to confirm the pH of the prepared suspension when preparing the drug complex by varying the pH conditions of the drug solution and the polymer solution, a pH meter (S220 SevenCompact ™ ph / Ion, Mettler Toledo) It was confirmed by measuring the pH used.
2) 평균입자크기 측정2) Average particle size measurement
본 발명의 약물복합체 제조에 있어서, 약물 용액과 고분자 용액의 pH 조건을 달리하여 약물 복합체를 제조하는 경우 제조된 현탁액의 특성 변화를 살펴보기 위하여, 입도분석기(NanoBrook 90Plus, Brookhaven instruments Corporation)를 이용한 평균입자크기를 측정하였다. In the preparation of the drug complex of the present invention, in order to examine the change in properties of the prepared suspension when preparing the drug complex by varying the pH conditions of the drug solution and the polymer solution, the average using a particle size analyzer (NanoBrook 90Plus, Brookhaven instruments Corporation) The particle size was measured.
3) 봉입률 평가3) Evaluation of sealing rate
본 발명에 따른 약물을 포함하는 약물복합체 내부에 약물이 봉입된 정도를 확인하기 위하여 봉입률을 분석하였다.The encapsulation rate was analyzed to confirm the degree of encapsulation of the drug in the drug complex containing the drug according to the present invention.
약물복합체 내부에 포함된 약물의 양을 분석하기 위하여 UV 분석을 이용하여 정량 분석하였다. 구체적으로 제조된 현탁액을 15,000 rpm에서 15분간 원심분리하여 약물을 포함한 상층액을 각 pH 완충액으로 희석하여 검액으로 사용하였다. 약물 종류에 따라서 정량하기 위한 표준액을 각 pH 완충액으로 제조하였다. 준비된 표준액과 검액을 각각의 흡수극대를 나타내는 파장을 적용하여 흡광도를 측정하여 검액의 농도를 구하였다. 약물과 고분자간 복합체의 약물 봉입률은 아래와 같은 식에 의하여 산출하였다.Quantitative analysis was performed using UV analysis to analyze the amount of drug contained in the drug complex. The specifically prepared suspension was centrifuged at 15,000 rpm for 15 minutes, and the supernatant containing the drug was diluted with each pH buffer and used as a test solution. Standard solutions for quantification according to drug types were prepared with each pH buffer. The absorbance was measured by applying the wavelengths representing the absorption maxima to the prepared standard solution and the sample solution to obtain the concentration of the sample solution. The drug encapsulation rate of the drug-polymer complex was calculated by the following equation.
[계산식 1][Calculation formula 1]
약물 봉입률 (%) = 〔(처음의 약물농도(mg/mL)×0.5 - 검액의 약물농도(mg/mL)×희석배수〕 × 100 / (처음의 약물농도(mg/mL)×0.5Drug encapsulation rate (%) = 〔(Initial drug concentration (mg / mL) × 0.5-Test drug concentration (mg / mL) × Dilution multiple) × 100 / (Initial drug concentration (mg / mL) × 0.5
그 결과, 상기 비교예에 해당하는 약물과 고분자 간의 제조조건에서는 복합체 형성이 전혀 이루어지지 않았고, 봉입률이 측정될 수 없었다. 하지만, 실시예에 해당하는 약물과 고분자간의 미립자 복합체 형성이 이루어 졌으며, 성상이나 입자크기 측정에서 모두 10 ㎛ 크기보다 작은 미립자 상태를 나타내었다. 실시예의 경우 봉입률은 모두 예외 없이 50% 이상의 높은 값을 나타내었다. 이로써, 본 발명을 통해 약물과 고분자간의 특징적 정전기 상호작용을 통해 약물수송체로 기능이 가능하고, 미립자 상태이며, 봉입률이 우수한 복합체를 제조할 수 있었다. As a result, complex formation was not achieved at all under the manufacturing conditions between the drug and the polymer corresponding to the comparative example, and the encapsulation rate could not be measured. However, the formation of a fine particle complex between the drug and the polymer corresponding to the example was performed, and both the properties and particle size measurements showed a fine particle state smaller than 10 μm. In the case of the examples, all of the encapsulation rates showed a high value of 50% or more without exception. Thus, through the present invention, a composite capable of functioning as a drug transporter through a characteristic electrostatic interaction between a drug and a polymer, having a fine particle state, and having an excellent encapsulation rate could be manufactured.
이상으로 본 발명의 특정한 부분을 상세히 기술한 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현 예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.The specific parts of the present invention have been described in detail above, and it is obvious that for those skilled in the art, these specific techniques are only preferred embodiments, and the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
본 발명의 범위는 후술하는 특허청구범위에 의하여 나타내어지며, 특허청구범위의 의미 및 범위 그리고 그 균등 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.The scope of the present invention is indicated by the following claims, and all changes or modifications derived from the meaning and scope of the claims and equivalent concepts should be interpreted to be included in the scope of the present invention.
Claims (10)
콘드로이틴 설페이트(chondroitin sulfate)를 pH 3 내지 5의 조건 하 수용액에 용해시킨 제2용액의 혼합을 통해 현탁 상태의 복합체를 형성하는 것을 특징으로 하는 약물-콘드로이틴 설페이트 복합체.Aripiprazole, quetiapine, olanzapine, ciprofloxacin, levofloxacin, ofloxacin, risperidone, paliperidone, moxifloxacin, paroxetine, mosapride, idarubicin, carbidopa, tamsrosine, terbinafine, olopatadine and A first solution in which a drug selected from the group consisting of topotecan or a salt thereof is dissolved in an aqueous solution or a co-solvent of ethanol and water under conditions of pH 3 to 5,
A drug-chondroitin sulfate complex characterized by forming a complex in suspension by mixing a second solution in which chondroitin sulfate is dissolved in an aqueous solution under conditions of pH 3 to 5.
콘드로이틴 설페이트(chondroitin sulfate)를 pH 3 내지 5의 조건 하 수용액에 용해시킨 용액을 준비하는 제 2단계; 및
상기 제 1단계의 용액에 제 2단계의 용액을 첨가하여 혼합시켜 약물-콘드로이틴 설페이트 간의 현탁 상태의 복합체를 형성시키는 단계를 포함하며,
상기 콘드로이틴 설페이트는 약물 또는 이들의 염의 총 중량에 대해 0.1배 내지는 5배의 중량 비율로 함유하는 것을 특징으로 하는 약물-콘드로이틴 설페이트 복합체 제조방법.
Aripiprazole, quetiapine, olanzapine, ciprofloxacin, levofloxacin, ofloxacin, risperidone, paliperidone, moxifloxacin, paroxetine, mosapride, idarubicin, carbidopa, tamsrosine, terbinafine, olopatadine and A first step of preparing a solution of a drug selected from the group consisting of topotecan or a salt thereof dissolved in an aqueous solution or a co-solvent of ethanol and water under conditions of pH 3 to 5;
A second step of preparing a solution of chondroitin sulfate dissolved in an aqueous solution under conditions of pH 3 to 5; And
And adding and mixing the solution of the second step to the solution of the first step to form a complex in a suspension state between the drug and chondroitin sulfate.
The chondroitin sulfate is a drug or chondroitin sulfate complex manufacturing method characterized in that it contains in a weight ratio of 0.1 to 5 times the total weight of the salt.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020190034455A KR102099849B1 (en) | 2019-03-26 | 2019-03-26 | Drug-polymer complex using electrostatic bonding between drug and polymer and preparation thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020190034455A KR102099849B1 (en) | 2019-03-26 | 2019-03-26 | Drug-polymer complex using electrostatic bonding between drug and polymer and preparation thereof |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020180120543A Division KR102097401B1 (en) | 2018-10-10 | 2018-10-10 | Drug-polymer complex using electrostatic bonding between drug and polymer and preparation thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
KR102099849B1 true KR102099849B1 (en) | 2020-04-10 |
Family
ID=70291822
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020190034455A KR102099849B1 (en) | 2019-03-26 | 2019-03-26 | Drug-polymer complex using electrostatic bonding between drug and polymer and preparation thereof |
Country Status (1)
Country | Link |
---|---|
KR (1) | KR102099849B1 (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20120106412A (en) * | 2011-03-18 | 2012-09-26 | 한남대학교 산학협력단 | Water-soluble positive-charged drug delivery system with sustained release behavior |
KR20170081129A (en) | 2015-12-31 | 2017-07-11 | 인터올리고 주식회사 | Complex For Stabilizing And Delivery Of Drugs And Processes For Preparing The Same |
-
2019
- 2019-03-26 KR KR1020190034455A patent/KR102099849B1/en active IP Right Grant
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20120106412A (en) * | 2011-03-18 | 2012-09-26 | 한남대학교 산학협력단 | Water-soluble positive-charged drug delivery system with sustained release behavior |
KR20170081129A (en) | 2015-12-31 | 2017-07-11 | 인터올리고 주식회사 | Complex For Stabilizing And Delivery Of Drugs And Processes For Preparing The Same |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6101332B2 (en) | Pharmaceutical composition for treatment of oral diseases containing rebamipide | |
KR101555293B1 (en) | Low viscosity, highly flocculated triamcinolone acetonide suspensions for intravitreal injection | |
WO2007025767A2 (en) | Nanoparticulate inclusion and charge complex for pharmaceutical formulations | |
Bartos et al. | Study of sodium hyaluronate-based intranasal formulations containing micro-or nanosized meloxicam particles | |
KR20100017714A (en) | Low-molecule drug-containing nanoparticle having sustained release negatively charged group | |
US8617606B2 (en) | Hydrogel suspension and manufacturing process thereof | |
Liu et al. | Preparation and characterization of glutaraldehyde cross-linked O-carboxymethylchitosan microspheres for controlled delivery of pazufloxacin mesilate | |
WO2020034989A1 (en) | Injectable pharmaceutical composition and preparation method therefor | |
Uppuluri et al. | Design and evaluation of thermo-responsive nasal in situ gelling system dispersed with piribedil loaded lecithin-chitosan hybrid nanoparticles for improved brain availability | |
CN102100663B (en) | Method for preparing pH sensitive in-situ gel nano slow-release eye drop | |
KR102099849B1 (en) | Drug-polymer complex using electrostatic bonding between drug and polymer and preparation thereof | |
KR102099848B1 (en) | Drug-polymer complex using electrostatic bonding between drug and polymer and preparation thereof | |
KR102097401B1 (en) | Drug-polymer complex using electrostatic bonding between drug and polymer and preparation thereof | |
WO2010052896A1 (en) | Preparation for local administration containing fluticasone propionate | |
EP3616726B1 (en) | Protein particle wrapped with medicine insoluble in water and preparation method therefor | |
CN103222962B (en) | Injection esomeprazole composition and preparation method thereof | |
CN110693830A (en) | Veterinary oxfendazole nano suspension and preparation method thereof | |
US20110152212A1 (en) | Aqueous Formulations | |
TWI778069B (en) | Poorly water-soluble component solubilized micelle and liquid agent containing same | |
Elmowafy et al. | Stable colloidal chitosan/alginate nanocomplexes: fabrication, formulation optimization and repaglinide loading | |
CN115429773B (en) | Method for preparing drug nano-crystalline preparation | |
WO2023221774A1 (en) | Turmeric self-dispersing particle system, method for preparing same, preparation device, and use thereof | |
US11110064B2 (en) | Gel formulation for treating diabetic foot ulcer infections | |
Vieira et al. | Supramolecular as‐semblies of cisplatin and polyelectrolytes: preparation, characterization and activity against cancer cells | |
KR20230126068A (en) | A pharmaceutical composition for the controlled release of drug using cationic-exchange resin |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
E902 | Notification of reason for refusal | ||
E701 | Decision to grant or registration of patent right | ||
GRNT | Written decision to grant |