CA2297025A1 - Polymer based pharmaceutical compositions for targeted delivery of biologically active agents - Google Patents
Polymer based pharmaceutical compositions for targeted delivery of biologically active agents Download PDFInfo
- Publication number
- CA2297025A1 CA2297025A1 CA002297025A CA2297025A CA2297025A1 CA 2297025 A1 CA2297025 A1 CA 2297025A1 CA 002297025 A CA002297025 A CA 002297025A CA 2297025 A CA2297025 A CA 2297025A CA 2297025 A1 CA2297025 A1 CA 2297025A1
- Authority
- CA
- Canada
- Prior art keywords
- acid
- polymeric
- serotonin
- construct
- polymer
- 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.)
- Abandoned
Links
- 229920000642 polymer Polymers 0.000 title claims abstract description 70
- 239000013543 active substance Substances 0.000 title claims abstract description 38
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 16
- 239000011159 matrix material Substances 0.000 claims abstract description 31
- 229920001577 copolymer Polymers 0.000 claims abstract description 23
- 241000124008 Mammalia Species 0.000 claims abstract description 15
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 177
- 229940076279 serotonin Drugs 0.000 claims description 83
- -1 poly(lactic acid) Polymers 0.000 claims description 74
- 150000001412 amines Chemical class 0.000 claims description 46
- 230000000035 biogenic effect Effects 0.000 claims description 42
- 229920001661 Chitosan Polymers 0.000 claims description 23
- SJBOEHIKNDEHHO-UHFFFAOYSA-N 2-[2-aminoethyl(carboxymethyl)amino]acetic acid Chemical class NCCN(CC(O)=O)CC(O)=O SJBOEHIKNDEHHO-UHFFFAOYSA-N 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 18
- 239000000952 serotonin receptor agonist Substances 0.000 claims description 17
- NBZBKCUXIYYUSX-UHFFFAOYSA-N iminodiacetic acid Chemical class OC(=O)CNCC(O)=O NBZBKCUXIYYUSX-UHFFFAOYSA-N 0.000 claims description 16
- 108010088751 Albumins Proteins 0.000 claims description 15
- 102000009027 Albumins Human genes 0.000 claims description 15
- 230000008685 targeting Effects 0.000 claims description 14
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- 235000001014 amino acid Nutrition 0.000 claims description 10
- 229940024606 amino acid Drugs 0.000 claims description 10
- 229930195712 glutamate Natural products 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 235000013922 glutamic acid Nutrition 0.000 claims description 9
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims description 8
- 150000001413 amino acids Chemical class 0.000 claims description 8
- 235000003704 aspartic acid Nutrition 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 8
- UDUSOMRJOPCWHT-UHFFFAOYSA-N disofenin Chemical group CC(C)C1=CC=CC(C(C)C)=C1NC(=O)CN(CC(O)=O)CC(O)=O UDUSOMRJOPCWHT-UHFFFAOYSA-N 0.000 claims description 7
- 210000004185 liver Anatomy 0.000 claims description 6
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 claims description 5
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 5
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 claims description 5
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 5
- 239000004472 Lysine Substances 0.000 claims description 5
- 239000004220 glutamic acid Substances 0.000 claims description 5
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 claims description 4
- 229920002305 Schizophyllan Polymers 0.000 claims description 4
- 150000001510 aspartic acids Chemical class 0.000 claims description 4
- 150000002307 glutamic acids Chemical class 0.000 claims description 4
- 210000003494 hepatocyte Anatomy 0.000 claims description 4
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 claims description 4
- SFLSHLFXELFNJZ-UHFFFAOYSA-N noradrenaline Chemical compound NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 claims description 4
- KJFMBFZCATUALV-UHFFFAOYSA-N phenolphthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2C(=O)O1 KJFMBFZCATUALV-UHFFFAOYSA-N 0.000 claims description 4
- 229920000768 polyamine Polymers 0.000 claims description 4
- 229920000515 polycarbonate Polymers 0.000 claims description 4
- 239000004417 polycarbonate Substances 0.000 claims description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 4
- 229920001285 xanthan gum Polymers 0.000 claims description 4
- 239000000230 xanthan gum Substances 0.000 claims description 4
- 235000010493 xanthan gum Nutrition 0.000 claims description 4
- 229940082509 xanthan gum Drugs 0.000 claims description 4
- 229930182837 (R)-adrenaline Natural products 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 229920002230 Pectic acid Polymers 0.000 claims description 3
- 229920001710 Polyorthoester Polymers 0.000 claims description 3
- 239000000150 Sympathomimetic Substances 0.000 claims description 3
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 claims description 3
- 229960004373 acetylcholine Drugs 0.000 claims description 3
- 239000003833 bile salt Substances 0.000 claims description 3
- 229940093761 bile salts Drugs 0.000 claims description 3
- 239000002872 contrast media Substances 0.000 claims description 3
- 239000000975 dye Substances 0.000 claims description 3
- 229960005139 epinephrine Drugs 0.000 claims description 3
- 229920001308 poly(aminoacid) Polymers 0.000 claims description 3
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 3
- 239000010318 polygalacturonic acid Substances 0.000 claims description 3
- 150000003573 thiols Chemical class 0.000 claims description 3
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 claims description 2
- LXUKTWZYHRVQQL-HNNXBMFYSA-N (2S)-2-[[3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl]methylideneamino]-3-phenylpropanoic acid Chemical compound Cc1ncc(CO)c(C=N[C@@H](Cc2ccccc2)C(O)=O)c1O LXUKTWZYHRVQQL-HNNXBMFYSA-N 0.000 claims description 2
- KDIGYCWRAAYWTQ-JTQLQIEISA-N (2S)-2-[[3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl]methylideneamino]pentanedioic acid Chemical compound C(C=1C(CO)=CN=C(C)C=1O)=N[C@@H](CCC(=O)O)C(=O)O KDIGYCWRAAYWTQ-JTQLQIEISA-N 0.000 claims description 2
- LJRDOKAZOAKLDU-UDXJMMFXSA-N (2s,3s,4r,5r,6r)-5-amino-2-(aminomethyl)-6-[(2r,3s,4r,5s)-5-[(1r,2r,3s,5r,6s)-3,5-diamino-2-[(2s,3r,4r,5s,6r)-3-amino-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-hydroxycyclohexyl]oxy-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]oxyoxane-3,4-diol;sulfuric ac Chemical compound OS(O)(=O)=O.N[C@@H]1[C@@H](O)[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[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO LJRDOKAZOAKLDU-UDXJMMFXSA-N 0.000 claims description 2
- XMENKXFLWCNNNV-UHFFFAOYSA-N 1h-benzimidazole;2-[carboxymethyl(methyl)amino]acetic acid Chemical compound C1=CC=C2NC=NC2=C1.OC(=O)CN(C)CC(O)=O XMENKXFLWCNNNV-UHFFFAOYSA-N 0.000 claims description 2
- DHPPAEHXIRAWPY-UHFFFAOYSA-N 2-[(2-acetylnaphthalen-1-yl)-(carboxymethyl)amino]acetic acid Chemical compound C1=CC=CC2=C(N(CC(O)=O)CC(O)=O)C(C(=O)C)=CC=C21 DHPPAEHXIRAWPY-UHFFFAOYSA-N 0.000 claims description 2
- GCBNPHYPETXYJJ-UHFFFAOYSA-N 2-[[2-(2-butylanilino)-2-oxoethyl]-(carboxymethyl)amino]acetic acid Chemical group CCCCC1=CC=CC=C1NC(=O)CN(CC(O)=O)CC(O)=O GCBNPHYPETXYJJ-UHFFFAOYSA-N 0.000 claims description 2
- XNORVCNKXNZYSE-UHFFFAOYSA-N 2-[[2-(3-butoxyanilino)-2-oxoethyl]-(carboxymethyl)amino]acetic acid Chemical group CCCCOC1=CC=CC(NC(=O)CN(CC(O)=O)CC(O)=O)=C1 XNORVCNKXNZYSE-UHFFFAOYSA-N 0.000 claims description 2
- XSYSSUAGVNOMCE-UHFFFAOYSA-N 2-[[2-(4-butylanilino)-2-oxoethyl]-(carboxymethyl)amino]acetic acid Chemical group CCCCC1=CC=C(NC(=O)CN(CC(O)=O)CC(O)=O)C=C1 XSYSSUAGVNOMCE-UHFFFAOYSA-N 0.000 claims description 2
- OVRQCZURNANBSK-UHFFFAOYSA-N 2-[[2-(4-tert-butylanilino)-2-oxoethyl]-(carboxymethyl)amino]acetic acid Chemical group CC(C)(C)C1=CC=C(NC(=O)CN(CC(O)=O)CC(O)=O)C=C1 OVRQCZURNANBSK-UHFFFAOYSA-N 0.000 claims description 2
- QHKMTHBQSIKVAC-UHFFFAOYSA-N 2-[[5-[1-[3-[[bis(carboxymethyl)amino]methyl]-4-hydroxyphenyl]-3-oxo-2-benzofuran-1-yl]-2-hydroxyphenyl]methyl-(carboxymethyl)amino]acetic acid Chemical compound C1=C(O)C(CN(CC(O)=O)CC(=O)O)=CC(C2(C3=CC=CC=C3C(=O)O2)C=2C=C(CN(CC(O)=O)CC(O)=O)C(O)=CC=2)=C1 QHKMTHBQSIKVAC-UHFFFAOYSA-N 0.000 claims description 2
- AIYRRERVRZFPKN-UHFFFAOYSA-N 2-[carboxymethyl-[2-(2,3-dimethylanilino)-2-oxoethyl]amino]acetic acid Chemical group CC1=CC=CC(NC(=O)CN(CC(O)=O)CC(O)=O)=C1C AIYRRERVRZFPKN-UHFFFAOYSA-N 0.000 claims description 2
- WNIDXAKKFOKNEF-UHFFFAOYSA-N 2-[carboxymethyl-[2-(2,6-diethylanilino)-2-oxoethyl]amino]acetic acid Chemical group CCC1=CC=CC(CC)=C1NC(=O)CN(CC(O)=O)CC(O)=O WNIDXAKKFOKNEF-UHFFFAOYSA-N 0.000 claims description 2
- OVMLLDXAYBWFBC-UHFFFAOYSA-N 2-[carboxymethyl-[2-(2-hexoxyanilino)-2-oxoethyl]amino]acetic acid Chemical group CCCCCCOC1=CC=CC=C1NC(=O)CN(CC(O)=O)CC(O)=O OVMLLDXAYBWFBC-UHFFFAOYSA-N 0.000 claims description 2
- BVXRFBZNNRXJGR-UHFFFAOYSA-N 2-[carboxymethyl-[2-[(3-cyano-4,5-dimethyl-1h-pyrrol-2-yl)amino]-2-oxoethyl]amino]acetic acid Chemical compound CC=1NC(NC(=O)CN(CC(O)=O)CC(O)=O)=C(C#N)C=1C BVXRFBZNNRXJGR-UHFFFAOYSA-N 0.000 claims description 2
- XFQYOFLFNKCHLG-UHFFFAOYSA-N 3-acetyl-6-bromochromen-2-one Chemical group BrC1=CC=C2OC(=O)C(C(=O)C)=CC2=C1 XFQYOFLFNKCHLG-UHFFFAOYSA-N 0.000 claims description 2
- FPTRWYHXARAFPO-UHFFFAOYSA-N Iprofenin Chemical group CC(C)C1=CC=C(NC(=O)CN(CC(O)=O)CC(O)=O)C=C1 FPTRWYHXARAFPO-UHFFFAOYSA-N 0.000 claims description 2
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims description 2
- SULVSHBBSDLJAM-UHFFFAOYSA-N N=C1C=C2C=CC=CC2=C(C(C(O)=O)C(O)=O)C1C(=O)C1C(=N)C=C2C=CC=CC2=C1C(C(O)=O)C(=O)O Chemical class N=C1C=C2C=CC=CC2=C(C(C(O)=O)C(O)=O)C1C(=O)C1C(=N)C=C2C=CC=CC2=C1C(C(O)=O)C(=O)O SULVSHBBSDLJAM-UHFFFAOYSA-N 0.000 claims description 2
- 229920000954 Polyglycolide Polymers 0.000 claims description 2
- 229940100389 Sulfonylurea Drugs 0.000 claims description 2
- 239000004098 Tetracycline Substances 0.000 claims description 2
- RGHRJBIKIYUHEV-SGPDEFQSSA-N Thyroxine glucuronide Chemical compound IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC(C=C1I)=CC(I)=C1OC1[C@H](O)[C@@H](O)[C@H](O)[C@@H](C(O)=O)O1 RGHRJBIKIYUHEV-SGPDEFQSSA-N 0.000 claims description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 2
- ARIFZLJIERKKEL-SNNHKCHZSA-N [(z)-[(1e)-1-(carbamothioylhydrazinylidene)-3-ethoxybutan-2-ylidene]amino]thiourea Chemical compound CCOC(C)\C(=N/NC(N)=S)\C=N\NC(N)=S ARIFZLJIERKKEL-SNNHKCHZSA-N 0.000 claims description 2
- FFINMCNLQNTKLU-UHFFFAOYSA-N adipiodone Chemical compound OC(=O)C1=C(I)C=C(I)C(NC(=O)CCCCC(=O)NC=2C(=C(C(O)=O)C(I)=CC=2I)I)=C1I FFINMCNLQNTKLU-UHFFFAOYSA-N 0.000 claims description 2
- UDSAIICHUKSCKT-UHFFFAOYSA-N bromophenol blue Chemical compound C1=C(Br)C(O)=C(Br)C=C1C1(C=2C=C(Br)C(O)=C(Br)C=2)C2=CC=CC=C2S(=O)(=O)O1 UDSAIICHUKSCKT-UHFFFAOYSA-N 0.000 claims description 2
- GHAFORRTMVIXHS-UHFFFAOYSA-L bromosulfophthalein sodium Chemical compound [Na+].[Na+].C1=C(S([O-])(=O)=O)C(O)=CC=C1C1(C=2C=C(C(O)=CC=2)S([O-])(=O)=O)C(C(Br)=C(Br)C(Br)=C2Br)=C2C(=O)O1 GHAFORRTMVIXHS-UHFFFAOYSA-L 0.000 claims description 2
- IQFVPQOLBLOTPF-HKXUKFGYSA-L congo red Chemical compound [Na+].[Na+].C1=CC=CC2=C(N)C(/N=N/C3=CC=C(C=C3)C3=CC=C(C=C3)/N=N/C3=C(C4=CC=CC=C4C(=C3)S([O-])(=O)=O)N)=CC(S([O-])(=O)=O)=C21 IQFVPQOLBLOTPF-HKXUKFGYSA-L 0.000 claims description 2
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 claims description 2
- 229960001340 histamine Drugs 0.000 claims description 2
- 229960002474 hydralazine Drugs 0.000 claims description 2
- 229960004657 indocyanine green Drugs 0.000 claims description 2
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 claims description 2
- 229940029355 iodipamide Drugs 0.000 claims description 2
- 229960004876 ioglycamic acid Drugs 0.000 claims description 2
- FZDZULUFHNDEDJ-UHFFFAOYSA-N ioglycamic acid Chemical compound OC(=O)C1=C(I)C=C(I)C(NC(=O)COCC(=O)NC=2C(=C(C(O)=O)C(I)=CC=2I)I)=C1I FZDZULUFHNDEDJ-UHFFFAOYSA-N 0.000 claims description 2
- 229960000310 isoleucine Drugs 0.000 claims description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims description 2
- MHPZZZZLAQGTHT-UHFFFAOYSA-N mebrofenin Chemical compound CC1=CC(C)=C(NC(=O)CN(CC(O)=O)CC(O)=O)C(C)=C1Br MHPZZZZLAQGTHT-UHFFFAOYSA-N 0.000 claims description 2
- 229960001428 mercaptopurine Drugs 0.000 claims description 2
- 229960002748 norepinephrine Drugs 0.000 claims description 2
- 229960001639 penicillamine Drugs 0.000 claims description 2
- 229960005382 phenolphthalein Drugs 0.000 claims description 2
- 229920006324 polyoxymethylene Polymers 0.000 claims description 2
- 229940081623 rose bengal Drugs 0.000 claims description 2
- 229930187593 rose bengal Natural products 0.000 claims description 2
- AZJPTIGZZTZIDR-UHFFFAOYSA-L rose bengal Chemical compound [K+].[K+].[O-]C(=O)C1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1C1=C2C=C(I)C(=O)C(I)=C2OC2=C(I)C([O-])=C(I)C=C21 AZJPTIGZZTZIDR-UHFFFAOYSA-L 0.000 claims description 2
- STRXNPAVPKGJQR-UHFFFAOYSA-N rose bengal A Natural products O1C(=O)C(C(=CC=C2Cl)Cl)=C2C21C1=CC(I)=C(O)C(I)=C1OC1=C(I)C(O)=C(I)C=C21 STRXNPAVPKGJQR-UHFFFAOYSA-N 0.000 claims description 2
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical compound OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 claims description 2
- 229960002180 tetracycline Drugs 0.000 claims description 2
- 229930101283 tetracycline Natural products 0.000 claims description 2
- 235000019364 tetracycline Nutrition 0.000 claims description 2
- 150000003522 tetracyclines Chemical class 0.000 claims description 2
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 claims description 2
- 229950003937 tolonium Drugs 0.000 claims description 2
- HNONEKILPDHFOL-UHFFFAOYSA-M tolonium chloride Chemical compound [Cl-].C1=C(C)C(N)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 HNONEKILPDHFOL-UHFFFAOYSA-M 0.000 claims description 2
- XBBDACCLCFWBSI-UHFFFAOYSA-N methyl 2-amino-3-(3,4-dihydroxyphenyl)propanoate Chemical compound COC(=O)C(N)CC1=CC=C(O)C(O)=C1 XBBDACCLCFWBSI-UHFFFAOYSA-N 0.000 claims 2
- 238000002560 therapeutic procedure Methods 0.000 claims 2
- PAYYOEIKGWDQKN-UHFFFAOYSA-N 2-[[2-(3-butylanilino)-2-oxoethyl]-(carboxymethyl)amino]acetic acid Chemical group CCCCC1=CC=CC(NC(=O)CN(CC(O)=O)CC(O)=O)=C1 PAYYOEIKGWDQKN-UHFFFAOYSA-N 0.000 claims 1
- IYPHTGWJAAENCL-UHFFFAOYSA-N 2-[carboxymethyl-[2-(4-hexoxyanilino)-2-oxoethyl]amino]acetic acid Chemical group CCCCCCOC1=CC=C(NC(=O)CN(CC(O)=O)CC(O)=O)C=C1 IYPHTGWJAAENCL-UHFFFAOYSA-N 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
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- 230000001975 sympathomimetic effect Effects 0.000 claims 1
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- BBBXWRGITSUJPB-YUMQZZPRSA-N Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](N)CCC(O)=O BBBXWRGITSUJPB-YUMQZZPRSA-N 0.000 description 28
- 239000000706 filtrate Substances 0.000 description 28
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- MDIGAZPGKJFIAH-UHFFFAOYSA-N Serotonin hydrochloride Chemical compound Cl.C1=C(O)C=C2C(CCN)=CNC2=C1 MDIGAZPGKJFIAH-UHFFFAOYSA-N 0.000 description 24
- 230000000717 retained effect Effects 0.000 description 19
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- 230000003993 interaction Effects 0.000 description 15
- 238000009472 formulation Methods 0.000 description 13
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000007995 HEPES buffer Substances 0.000 description 12
- 239000000725 suspension Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 9
- 239000011259 mixed solution Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
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- A—HUMAN NECESSITIES
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- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
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Abstract
This invention provides a polymeric construct for delivering a biologically active agent to a mammal comprising a first polymeric matrix, a biologically active agent contained within the polymeric matrix, and a second polymer chemically bound to the biologically active agent, said second polymer comprising an amino acid copolymer, said second polymer present in an amount effective to reduce leakage of the active agent from the polymeric construct prior to delivery to the desired situs.
Description
WO ~/~ PCT/LTS98/15457 plyLy~ BpSgD pHARMACEUTICAL COMPOSITIONS FOR TARGETED DELIVERY OF BIOLOGICALLY
ACTIVE
AGENTS -BACKGROUND OF THE INVENTION
to FIELD OF THE INVENTION
This invention relates generally to polymeric constructs useful for the delivery of biologically active agents. In particular, it relates to polymeric constructs useful for delivery of biogenic amines, pharmaceutical compositions thereof, and methods for I5 treating disease states therewith.
RELATED ART
Various polymeric formulations of biologically active agents and methods for their preparation have been described.
2o U.S. Patent Nos. 3,773,919, 3,991,776, 4,076,779, 4,093,709, 4,118,470, 4,131,648, 4,138,344, 4,293,539 and 4,675,189, inter alia, disclose the preparation and use of biocompatible, biodegradable polymers, such as poly(lactic acid), poly(giycolic acid), copolymers of glycolic and lactic acids, poly(o-hydroxycarboxylic acid), polylactones, polyacetals, polyorthoesters and polyorthocarbonates, for the encapsulation 25 of drugs and medicaments. These polymers mechanically entrap the active constituents and later provide controlled release of the active ingredient via polymer dissolution or degradation. Certain condensation polymers formed from divinyl ethers and polyols are described in Polymer Letters, ~,$., 293 (1980). Polymers have proven to be successful controlled-release drug delivery devices; however, their performance would benefit from 3 o increased stability and integrity during storage and from increased target specificity, which should enhance the therapeutic index of an incorporated drug.
The disclosures of the foregoing patents and publications, as well as that of all other patents and publications referred to in this specification, are expressly incorporated herein by reference.
WO 99/04824 PCT/US98/15457 __ SUMMARY OF THE INVENTION
It is an object of this invention to provide means for improving the storage stability and delivery efficiency of biologically active agents, such as biogenic amines, incorporated in polymeric carriers.
This invention thus provides a polymeric construct for delivering a biologically active agent to a host comprising a first and primary polymeric matrix, a biologically active agent entrapped within the first polymeric matrix, and a second polymeric component chemically bound to the biologically active agent, which second polymer is present in an amount effective to minimize leakage of the active agent from the polymeric 1 o carrier. Optionally, the polymeric construct further comprises targeting moieties associated with its surface for directing the construct to the desired situs.
The second polymeric component may optionally be copolymerized or otherwise bound to the first polymeric matrix.
Also provided are pharmaceutical compositions of the polymeric constructs with pharmaceutically acceptable excipients and methods of treating mammalian conditions with the compositions. Treatment of conditions responsive to biogenic amines, particularly the treatment of Type II diabetes with serotonin or a serotonergic agonist is particularly preferred.
2 o DETAILED DESCRIPTION OF THE INVENTION
In its broadest embodiment, this invention provides a polymeric construct for delivering a biologically active agent to a host comprising a first and primary polymeric matrix, a biologically active agent entrapped within the first polymeric matrix, and a second polymeric component chemically bound to the biologically active agent, which 2 5 second polymer is present in an amount effective to minimize leakage of the active agent from the first polymeric matrix. Optionally, the polymeric construct further comprises targeting moieties associated with its surface for directing the construct to the desired situs: The second polymeric component may optionally be copolymerized or otherwise bound to the first polymeric matrix.
ACTIVE
AGENTS -BACKGROUND OF THE INVENTION
to FIELD OF THE INVENTION
This invention relates generally to polymeric constructs useful for the delivery of biologically active agents. In particular, it relates to polymeric constructs useful for delivery of biogenic amines, pharmaceutical compositions thereof, and methods for I5 treating disease states therewith.
RELATED ART
Various polymeric formulations of biologically active agents and methods for their preparation have been described.
2o U.S. Patent Nos. 3,773,919, 3,991,776, 4,076,779, 4,093,709, 4,118,470, 4,131,648, 4,138,344, 4,293,539 and 4,675,189, inter alia, disclose the preparation and use of biocompatible, biodegradable polymers, such as poly(lactic acid), poly(giycolic acid), copolymers of glycolic and lactic acids, poly(o-hydroxycarboxylic acid), polylactones, polyacetals, polyorthoesters and polyorthocarbonates, for the encapsulation 25 of drugs and medicaments. These polymers mechanically entrap the active constituents and later provide controlled release of the active ingredient via polymer dissolution or degradation. Certain condensation polymers formed from divinyl ethers and polyols are described in Polymer Letters, ~,$., 293 (1980). Polymers have proven to be successful controlled-release drug delivery devices; however, their performance would benefit from 3 o increased stability and integrity during storage and from increased target specificity, which should enhance the therapeutic index of an incorporated drug.
The disclosures of the foregoing patents and publications, as well as that of all other patents and publications referred to in this specification, are expressly incorporated herein by reference.
WO 99/04824 PCT/US98/15457 __ SUMMARY OF THE INVENTION
It is an object of this invention to provide means for improving the storage stability and delivery efficiency of biologically active agents, such as biogenic amines, incorporated in polymeric carriers.
This invention thus provides a polymeric construct for delivering a biologically active agent to a host comprising a first and primary polymeric matrix, a biologically active agent entrapped within the first polymeric matrix, and a second polymeric component chemically bound to the biologically active agent, which second polymer is present in an amount effective to minimize leakage of the active agent from the polymeric 1 o carrier. Optionally, the polymeric construct further comprises targeting moieties associated with its surface for directing the construct to the desired situs.
The second polymeric component may optionally be copolymerized or otherwise bound to the first polymeric matrix.
Also provided are pharmaceutical compositions of the polymeric constructs with pharmaceutically acceptable excipients and methods of treating mammalian conditions with the compositions. Treatment of conditions responsive to biogenic amines, particularly the treatment of Type II diabetes with serotonin or a serotonergic agonist is particularly preferred.
2 o DETAILED DESCRIPTION OF THE INVENTION
In its broadest embodiment, this invention provides a polymeric construct for delivering a biologically active agent to a host comprising a first and primary polymeric matrix, a biologically active agent entrapped within the first polymeric matrix, and a second polymeric component chemically bound to the biologically active agent, which 2 5 second polymer is present in an amount effective to minimize leakage of the active agent from the first polymeric matrix. Optionally, the polymeric construct further comprises targeting moieties associated with its surface for directing the construct to the desired situs: The second polymeric component may optionally be copolymerized or otherwise bound to the first polymeric matrix.
3 o The particular biologically active agent or agents employed does not impose any significant limitation upon the scope of the invention, provided that the agent may be 4 PCT/US98/15457 _ .
encapsulated or otherwise entrapped within a polymeric matrix without significant diminution of its inherent biological activity.
The first polymeric matrix may be, but is not limited to, poly(lactide/glycolide) copolymers (PLGA), poly(lactic acid), poly(glycolic acid), poly(o-hydroxycarboxylic acids), poly(lactones), poly(acetals), poly(orthoesters), poly(orthocarbonates), poly(amino acids), chitosan glutamate, poly(acrylic acid), poly(divinyl glycol), albumin, polycarbonates, polyamines, poly(hydroxybutyric acid), scleroglucans, polyoxypropylene-polyoxyethylenes, polygalacturonic acid (partially esterifled) and xanthan gum. In some embodiments of the invention, combinations of these primary polymers may be used 1 o together.
The second polymeric component comprises a polymer that carries negatively charged functional groups. In a preferred embodiment, the second polymeric component comprises a poly(amino acid) carrying a net negative charge. In another preferred embodiment, the second polymeric component comprises a copolymer of polylysine with other amino acids or compounds. Optionally, more than one anchoring secondary polymeric component may be used in the polymeric construct of the present invention.
In still another aspect, this invention comprises a method of making a polymeric construct comprising mixing a first biocompatible polymer, a second copolymer of polylysine-poly(glutamic acid/aspartic acid), a biogenic amine, and a targeting moiety, 2 o whereby said first and second polymers form a composite polymeric carrier containing the biogenic amine and the targeting moiety.
In one embodiment the biologically active agent comprises a biogenic amine, which includes the sympathomimetic amines, i.e. naturally occurring catecholamines and drugs that mimic their action, and autacoids that act at serotonin receptors to elicit an 2 5 hepatic glucose storage response. See Goodman and Gilman, The Pharmacological Basis of Therapeutics, 9th ed. Macmillan Publishing Co. {1995). Representative biogenic amines include, but are not limited to, L-~3-3,4-dihydroxyphenylalanine (L-DOPA), 3-(2-aminoethyl)-5-hydroxyindole (5-hydroxytryptamine or serotonin), 2-(4-imidazolyl)ethyl amine (histamine), 4-[1-hydroxy-2-(methylamino)ethyl]-1,2-benzenediol (epinephrine), 1-3 0 [3,4-dihydroxyphenyl]-2-aminoethanol (norepinephrine), y-amino-n-butyric acid, acetylcholine and amino acids. In a preferred embodiment, the biogenic amine is serotonin, a serotonin analog, or a serotonergic agonist. As used herein, the terms "serotonin analog" and "serotonergic agonist" refer to compounds which mimic the activity of serotonin, in particular compounds which act at 5-HT~,2c receptors of hepatocytes, which interaction is blocked by methysergide.
The targeting molecule attached to the surface of the polymeric construct directs the polymeric construct to an appropriate receptor, such as for example, a hepatobiliary receptor. Such target molecules for hepatobiliary receptors can be selected from substituted iminodiacetic acids, N'-substituted derivatives of ethylene diamine N,N-diacetic acid (EDDA), hepatobiliary dyes, hepatobiliary contrast agents, bile salts, hepatobiliary thiol complexes, and hepatobiiiary amine complexes.
1 o In preferred embodiments, the first polymeric matrix is selected from polymers such as polylysine, poly(lactide/glycolide), chitosan glutamate, poly(acrylic acid), poly(divinyl glycol), albumin, polycarbonates, polyamines, poly(hydroxybutyric acid), scleroglucans, polyoxypropylene-polyoxyethylene, polygalacturonic acid (partially esterified) and xanthan gum and the second polymeric component is a copolymer of polylysine and poly(giutamiclaspartic acid).
The polymeric constructs and pharmaceutical compositions of this invention are useful for the treatment of disease states responsive to biogenic amines, including sympathomimetic amines and autacoids. Such disease states may include, for example;
hypertension, shock, cardiac failure, arrhythmias, asthma, allergy, anaphylaxis and 2 o diabetes. Accordingly, the invention comprises a method of treating a disease state in a mammal by administering to the mammal a therapeutically effective amount of a biogenic amine in a pharmaceutical composition comprising a polymeric construct containing the biogenic amine and a second copolymer of polylysine and poly(glutamic/aspartic acid).
This invention is particularly useful for delivery of biogenic amines, which as 2 5 potent neurotransmitters, should be sequestered tightly within a polymeric construct in order to minimize or substantially eliminate interactions with receptors of organs or tissues other than those targeted by the construct. The biogenic amine neurotransmitters are water soluble and have polar chemical functionalities. The quaternary amines, such as epinephrine and acetylcholine, manifest a positive charge over a broad pH
range, while 3 o the other biogenic amine neurotransmitters are primary amines, positively charged at physiological pH and below.
WO 99!04824 PCT/US98/15457 Because the biogenic amines evince a pronounced polarity contributed by either a positively charged quaternary amine group or a positively charged primary amine group at physiological pH, they demonstrate unusual water-activity. They are thus difficult to retain within a polymeric construct, resulting in poor storage stability and undesirable, 5 and potentially toxic, leakage after administration. Biogenic amines interact with a wide variety of receptors on different cell.types, not necessarily associated with the condition to be treated. These cells include, inter alia, neurons, platelets, mast cells, and enterochromaffm cells.
This situation may be illustrated with the hormone and neurotransmitter serotonin.
to In earlier studies, such as described in U.S. Patent No. 4,761,287, it was shown that in order to adequately neat non-insulin dependent diabetes mellitus (Type II), it is necessary to deliver serotonin to the cellular hepatocytes in the liver using a targeted liposomal construct. The delivery of this hormone, in conjunction with the hormone insulin, signals the liver to store blood glucose as glycogen. This action results in the reduction of the high circulating levels of glucose and lessens exposure of other tissues and organs in the body to high glucose levels. If the hormone were to leak from its carrier, it would be difficult to deliver the correct dosage to the liver and the intended use of the targeted delivery system would be compromised.
Therefore, in a preferred embodiment, this invention is directed to the retention of 2 0 biogenic amines, such as serotonin or a serotonergic agonist, within a targeted polymeric construct. The sequestration of serotonin is required not only due to its hormonal function, but also because serotonin acts in vivo as a neurotransmitter in many different cell types not associated with the liver. Therefore if exogenous serotonin, which has been incorporated in a targeted polymer, is not strongly sequestered or retained by the polymer 2 5 structure, it may leak from the polymer and elicit undesirable pharmacological responses with other cell types that manifest serotonin receptors.
The novel polymeric constructs of this .invention provide a means to deliver a biologically active agent within a chemically stable carrier, due to strong ionic bonding and dipole-dipole interactions between the various carrier constituents. These chemical 3 o interactions effectively lower the water activity of the biologically active agent, e.g. the biogenic amine, within the polymeric construct and thus minimize diffusion of the agent from the polymeric carrier. Also the chemical and physical interactions among the active agents themselves (particularly when different agents are used together) are decreased. As a consequence of the overall lowering of water activity within the polymeric construct, there is less likelihood that individual constructs will fuse, coalesce, aggregate and/or precipitate. These interactions markedly increase shelf life stability and in addition protect the chemical integrity and stability of the biochemical cargo.
This invention provides a secondary polymeric anchor by which biologically active agents, including biogenic amines such as serotonin, can be effectively sequestered within a first polymeric matrix for an extended period of time to minimize their leakage to the external environment. In a preferred embodiment, the invention provides for the 1 o sequestration of biogenic amines such as serotonin within a hepatobiliary targeted polymeric construct. In one embodiment, serotonin and the hepatobiliary target molecule are retained within the first polymeric matrix using a secondary copolymeric anchor comprising polylysine-poly(glutamic-aspartic acid).
The use of the polymeric constructs of this invention facilitates the sequestering and delivery of biogenic amines by specific functional group interactions described in this disclosure. For example, the carbonyl and amino functional groups of the primary and secondary polymers can react with biogenic amines by engaging in hydrogen bond formation. Also, the negatively charged polymeric carboxyl groups can form ionic linkages with positively charged primary and quaternary biogenic amines. Thus the 2 o targeting and cargo molecules may be retained more securely, which effectively prevents drug leakage into the external aqueous phase.
Among the polymers useful as polymeric carriers are copolymers of lactic and glycolic acids (PLGA). These polymers are biocompatible, biodegradable and approved for human use. PLGA microspheres generally range in diameter from about 200 to about 2 5 1500 Angstroms depending upon the degree of polymerization.
This invention involves three interacting aspects. The first is the incorporation of a copolymer of lysine and glutamic and aspartic acids (or glutamate and aspartate) in the first polymeric matrix as an anchoring molecule for biogenic amines. The second aspect is the use of hepatobiliary target molecules bound either to the first polymeric matrix or, 3 0 optionally, to the anchoring polymer, for delivering the biogenic amine to the hepatocytes of the liver. Thus, the secondary copolymer may function both to chemically anchor hepatobiliary target molecules and also to retain the biogenic amine. The third aspect relates to the interaction between the primary and secondary polymers which contributes to construct stability among the primary polymeric matrix, the secondary polymeric anchor, the active agent, and other construct constituents.
Representative hepatobiliary targeting molecules include substituted iminodiacetic acids such as N-(2,6-diisopropylphenylcarbamoylmethyl)iminodiacetic acid, N-(2,6-diethylphenyl-carbamoyl methyl)iminodiacetic acid, N-(2,6-dimethylphenylcarbamoylmethyl)iminodiacetic acid, N-(4-isopropylphenylcarbamoylmethyl)iminodiacetic acid, N-(4-butylphenylcarbamoyl-methyl) iminodiacetic acid, N-(2,3-dimethylphenylcarbamoylmethyl)iminodiacetic acid, N-(3-1 o butylphenyl-carbamoylmethyl)iminodiacetic acid, N-(2-butylphenylcarbamoylmethyl) iminodiacetic acid, N-(4-t-butylphenylcarbamoylmethyl)iminodiacetic acid, N-(3-butoxyphenylcarbamoylmethyl)imino-diacetic acid, N-(2-hexyloxyphenylcarbamoylmethyl) iminodiacetic acid, N-(4-hexyloxyphenyl-carbamoylmethyl)iminodiacetic acid; azo substituted iminodiacetic acid, iminodicarboxymethyl-2-naphthyl ketone, phthalein complexone, N-(5-pregnene-3-~-0l-2-oylcarbamoylmethyl)imino-diacetic acid, 3a: '7a 12a: trihydroxy-24-norchol:
amyl-23-iminodiacetic acid, N-(3-bromo-2,4,6-trimethylphenylcarbamoylmethyl) iminodiacetic acid, benzimidazole-methyliminodiacetic acid, N-(3-cyano-4,5-dimethyl-2-pyrrylcarbamoylmethyl)iminodiacetic acid, other derivatives of N-(3-cyano-4-methyl-2-2 o pyrryl carbamoylmethyl)imninodiacetic acid, ethylenediamine-N,N-bis(-2-hydroxy-5-bromophenyl) acetate, N'-acyl and N'-sulfonylethylenediamine-N,N-diacetic acid; N'-substituted derivatives of ethylenediamine-N,N-diacetic acid (EDDA) such as N'-acetyl EDDA, N'-benzoyl EDDA, N'-(p-toluenesulfonyl) EDDA, N'-(p-t-butylbenzoyl) EDDA, N'-(benzenesulfonyl) EDDA, N'-(p-chlorobenzenesulfonyl) EDDA, N'-(p-ethylbenzenesulfonyl) EDDA, N'-(p-n-propylbenzenesulfonyl) EDDA, N'-(naphthalene-2-sulfonyl) EDDA, N'-(2,5-dimethylbenzenesulfonyl) EDDA; N-(2-acetylnaphthyl)iminodiacetic acid; N-(2-naphthylmethyl)-iminodiacetic acid;
hepatobiliary dyes such as rose bengal, Congo red, bromosulphthalein, bromophenol blue, phenolphthalein, toluidine blue, indocyanine green; hepatobiliary contrast agents such as 3 o iodipamide, ioglycamic acid; bile salts such as bilirubin, cholyglycyliodohistamine, thyroxineglucuronide; hepatobiliary thiol complexes such as penicillamine, ~i-mercaptoisobutyric acid, dihydroehioctic acid, 6-mercaptopurine, kethoxal-bis(thiosemicarbazone); hepatobiliary amine complexes such as 1-hydrazinophthalazine-(hydralazine)sulfonyl urea; hepatobiliary amino acid Schiff Base complexes such as pyridoxylidene glutamate, pyridoxylidene isoleucine, pyridoxylidene phenylalanine, pyridoxylidene tryptophan, pyridoxylidene 5-methyl tryptophan; additional pyridoxylidene aminates; 3-hydroxy-4-formyl-pyridene glutamic acid; and miscellaneous hepatobiliary complexes such as tetracycline, 7-carboxy-~i-hydroxyquinoline, phenolphthalexon, eosin, and verograffin.
The use of a primary polymeric matrix in conjunction with a secondary polylysine poly(glutamiclaspartic acid) copolymer provides a polymeric construct which anchors not l o only biogenic amines, but also hepatobiliary target molecules. This construct manifests a complex synergy of interaction that maintains the structural integrity of the entire targeted polymeric carrier system. Several polymers have been employed to illustrate the concept and benefits of the dual polymer construct and to delineate the specialized interactions that occur when different primary polymeric matrices are mixed with secondary copolymers.
One embodiment of a polymeric construct of this invention comprises a polylysine primary polymeric matrix and a secondary anchoring copolymer of polylysine-poly(glutamic-aspartic acids). Because a single s-amino functional group accompanies every amino acid residue of polylysine, amino groups occur far more frequently and are chemically more reactive than the amino functionalities generally found in naturally 2 0 occurring proteins. Therefore, chemical derivatization or subsequent chemical interaction may be manipulated with a high degree of precision. The rich cluster of amino groups of polylysine creates a favorable positively charged ionic environment that facilitates interaction between positively charged amino groups on the primary polymer matrix and the negatively charged carboxyl group functionalities on the polyglutamic-aspartic acid 2 5 portion of the secondary polymeric construct under physiological conditions. Thus the likelihood of developing significant polymer-to-polymer binding between the polylysine and the secondary copolymeric construct is markedly increased. The ionic interaction between the negatively charged y- and ~i-carboxyl groups of glutamic and aspartic acids, respectively, with the positively charged amine groups of biogenic amines enhances 3 0 retention of the active agent. Likewise, ionic bonding between the carboxyl groups of the hepatobiliary targeting molecule and the amino group of polylysine enhances retention of the targeting molecule on the surface of the polymeric carrier.
encapsulated or otherwise entrapped within a polymeric matrix without significant diminution of its inherent biological activity.
The first polymeric matrix may be, but is not limited to, poly(lactide/glycolide) copolymers (PLGA), poly(lactic acid), poly(glycolic acid), poly(o-hydroxycarboxylic acids), poly(lactones), poly(acetals), poly(orthoesters), poly(orthocarbonates), poly(amino acids), chitosan glutamate, poly(acrylic acid), poly(divinyl glycol), albumin, polycarbonates, polyamines, poly(hydroxybutyric acid), scleroglucans, polyoxypropylene-polyoxyethylenes, polygalacturonic acid (partially esterifled) and xanthan gum. In some embodiments of the invention, combinations of these primary polymers may be used 1 o together.
The second polymeric component comprises a polymer that carries negatively charged functional groups. In a preferred embodiment, the second polymeric component comprises a poly(amino acid) carrying a net negative charge. In another preferred embodiment, the second polymeric component comprises a copolymer of polylysine with other amino acids or compounds. Optionally, more than one anchoring secondary polymeric component may be used in the polymeric construct of the present invention.
In still another aspect, this invention comprises a method of making a polymeric construct comprising mixing a first biocompatible polymer, a second copolymer of polylysine-poly(glutamic acid/aspartic acid), a biogenic amine, and a targeting moiety, 2 o whereby said first and second polymers form a composite polymeric carrier containing the biogenic amine and the targeting moiety.
In one embodiment the biologically active agent comprises a biogenic amine, which includes the sympathomimetic amines, i.e. naturally occurring catecholamines and drugs that mimic their action, and autacoids that act at serotonin receptors to elicit an 2 5 hepatic glucose storage response. See Goodman and Gilman, The Pharmacological Basis of Therapeutics, 9th ed. Macmillan Publishing Co. {1995). Representative biogenic amines include, but are not limited to, L-~3-3,4-dihydroxyphenylalanine (L-DOPA), 3-(2-aminoethyl)-5-hydroxyindole (5-hydroxytryptamine or serotonin), 2-(4-imidazolyl)ethyl amine (histamine), 4-[1-hydroxy-2-(methylamino)ethyl]-1,2-benzenediol (epinephrine), 1-3 0 [3,4-dihydroxyphenyl]-2-aminoethanol (norepinephrine), y-amino-n-butyric acid, acetylcholine and amino acids. In a preferred embodiment, the biogenic amine is serotonin, a serotonin analog, or a serotonergic agonist. As used herein, the terms "serotonin analog" and "serotonergic agonist" refer to compounds which mimic the activity of serotonin, in particular compounds which act at 5-HT~,2c receptors of hepatocytes, which interaction is blocked by methysergide.
The targeting molecule attached to the surface of the polymeric construct directs the polymeric construct to an appropriate receptor, such as for example, a hepatobiliary receptor. Such target molecules for hepatobiliary receptors can be selected from substituted iminodiacetic acids, N'-substituted derivatives of ethylene diamine N,N-diacetic acid (EDDA), hepatobiliary dyes, hepatobiliary contrast agents, bile salts, hepatobiliary thiol complexes, and hepatobiiiary amine complexes.
1 o In preferred embodiments, the first polymeric matrix is selected from polymers such as polylysine, poly(lactide/glycolide), chitosan glutamate, poly(acrylic acid), poly(divinyl glycol), albumin, polycarbonates, polyamines, poly(hydroxybutyric acid), scleroglucans, polyoxypropylene-polyoxyethylene, polygalacturonic acid (partially esterified) and xanthan gum and the second polymeric component is a copolymer of polylysine and poly(giutamiclaspartic acid).
The polymeric constructs and pharmaceutical compositions of this invention are useful for the treatment of disease states responsive to biogenic amines, including sympathomimetic amines and autacoids. Such disease states may include, for example;
hypertension, shock, cardiac failure, arrhythmias, asthma, allergy, anaphylaxis and 2 o diabetes. Accordingly, the invention comprises a method of treating a disease state in a mammal by administering to the mammal a therapeutically effective amount of a biogenic amine in a pharmaceutical composition comprising a polymeric construct containing the biogenic amine and a second copolymer of polylysine and poly(glutamic/aspartic acid).
This invention is particularly useful for delivery of biogenic amines, which as 2 5 potent neurotransmitters, should be sequestered tightly within a polymeric construct in order to minimize or substantially eliminate interactions with receptors of organs or tissues other than those targeted by the construct. The biogenic amine neurotransmitters are water soluble and have polar chemical functionalities. The quaternary amines, such as epinephrine and acetylcholine, manifest a positive charge over a broad pH
range, while 3 o the other biogenic amine neurotransmitters are primary amines, positively charged at physiological pH and below.
WO 99!04824 PCT/US98/15457 Because the biogenic amines evince a pronounced polarity contributed by either a positively charged quaternary amine group or a positively charged primary amine group at physiological pH, they demonstrate unusual water-activity. They are thus difficult to retain within a polymeric construct, resulting in poor storage stability and undesirable, 5 and potentially toxic, leakage after administration. Biogenic amines interact with a wide variety of receptors on different cell.types, not necessarily associated with the condition to be treated. These cells include, inter alia, neurons, platelets, mast cells, and enterochromaffm cells.
This situation may be illustrated with the hormone and neurotransmitter serotonin.
to In earlier studies, such as described in U.S. Patent No. 4,761,287, it was shown that in order to adequately neat non-insulin dependent diabetes mellitus (Type II), it is necessary to deliver serotonin to the cellular hepatocytes in the liver using a targeted liposomal construct. The delivery of this hormone, in conjunction with the hormone insulin, signals the liver to store blood glucose as glycogen. This action results in the reduction of the high circulating levels of glucose and lessens exposure of other tissues and organs in the body to high glucose levels. If the hormone were to leak from its carrier, it would be difficult to deliver the correct dosage to the liver and the intended use of the targeted delivery system would be compromised.
Therefore, in a preferred embodiment, this invention is directed to the retention of 2 0 biogenic amines, such as serotonin or a serotonergic agonist, within a targeted polymeric construct. The sequestration of serotonin is required not only due to its hormonal function, but also because serotonin acts in vivo as a neurotransmitter in many different cell types not associated with the liver. Therefore if exogenous serotonin, which has been incorporated in a targeted polymer, is not strongly sequestered or retained by the polymer 2 5 structure, it may leak from the polymer and elicit undesirable pharmacological responses with other cell types that manifest serotonin receptors.
The novel polymeric constructs of this .invention provide a means to deliver a biologically active agent within a chemically stable carrier, due to strong ionic bonding and dipole-dipole interactions between the various carrier constituents. These chemical 3 o interactions effectively lower the water activity of the biologically active agent, e.g. the biogenic amine, within the polymeric construct and thus minimize diffusion of the agent from the polymeric carrier. Also the chemical and physical interactions among the active agents themselves (particularly when different agents are used together) are decreased. As a consequence of the overall lowering of water activity within the polymeric construct, there is less likelihood that individual constructs will fuse, coalesce, aggregate and/or precipitate. These interactions markedly increase shelf life stability and in addition protect the chemical integrity and stability of the biochemical cargo.
This invention provides a secondary polymeric anchor by which biologically active agents, including biogenic amines such as serotonin, can be effectively sequestered within a first polymeric matrix for an extended period of time to minimize their leakage to the external environment. In a preferred embodiment, the invention provides for the 1 o sequestration of biogenic amines such as serotonin within a hepatobiliary targeted polymeric construct. In one embodiment, serotonin and the hepatobiliary target molecule are retained within the first polymeric matrix using a secondary copolymeric anchor comprising polylysine-poly(glutamic-aspartic acid).
The use of the polymeric constructs of this invention facilitates the sequestering and delivery of biogenic amines by specific functional group interactions described in this disclosure. For example, the carbonyl and amino functional groups of the primary and secondary polymers can react with biogenic amines by engaging in hydrogen bond formation. Also, the negatively charged polymeric carboxyl groups can form ionic linkages with positively charged primary and quaternary biogenic amines. Thus the 2 o targeting and cargo molecules may be retained more securely, which effectively prevents drug leakage into the external aqueous phase.
Among the polymers useful as polymeric carriers are copolymers of lactic and glycolic acids (PLGA). These polymers are biocompatible, biodegradable and approved for human use. PLGA microspheres generally range in diameter from about 200 to about 2 5 1500 Angstroms depending upon the degree of polymerization.
This invention involves three interacting aspects. The first is the incorporation of a copolymer of lysine and glutamic and aspartic acids (or glutamate and aspartate) in the first polymeric matrix as an anchoring molecule for biogenic amines. The second aspect is the use of hepatobiliary target molecules bound either to the first polymeric matrix or, 3 0 optionally, to the anchoring polymer, for delivering the biogenic amine to the hepatocytes of the liver. Thus, the secondary copolymer may function both to chemically anchor hepatobiliary target molecules and also to retain the biogenic amine. The third aspect relates to the interaction between the primary and secondary polymers which contributes to construct stability among the primary polymeric matrix, the secondary polymeric anchor, the active agent, and other construct constituents.
Representative hepatobiliary targeting molecules include substituted iminodiacetic acids such as N-(2,6-diisopropylphenylcarbamoylmethyl)iminodiacetic acid, N-(2,6-diethylphenyl-carbamoyl methyl)iminodiacetic acid, N-(2,6-dimethylphenylcarbamoylmethyl)iminodiacetic acid, N-(4-isopropylphenylcarbamoylmethyl)iminodiacetic acid, N-(4-butylphenylcarbamoyl-methyl) iminodiacetic acid, N-(2,3-dimethylphenylcarbamoylmethyl)iminodiacetic acid, N-(3-1 o butylphenyl-carbamoylmethyl)iminodiacetic acid, N-(2-butylphenylcarbamoylmethyl) iminodiacetic acid, N-(4-t-butylphenylcarbamoylmethyl)iminodiacetic acid, N-(3-butoxyphenylcarbamoylmethyl)imino-diacetic acid, N-(2-hexyloxyphenylcarbamoylmethyl) iminodiacetic acid, N-(4-hexyloxyphenyl-carbamoylmethyl)iminodiacetic acid; azo substituted iminodiacetic acid, iminodicarboxymethyl-2-naphthyl ketone, phthalein complexone, N-(5-pregnene-3-~-0l-2-oylcarbamoylmethyl)imino-diacetic acid, 3a: '7a 12a: trihydroxy-24-norchol:
amyl-23-iminodiacetic acid, N-(3-bromo-2,4,6-trimethylphenylcarbamoylmethyl) iminodiacetic acid, benzimidazole-methyliminodiacetic acid, N-(3-cyano-4,5-dimethyl-2-pyrrylcarbamoylmethyl)iminodiacetic acid, other derivatives of N-(3-cyano-4-methyl-2-2 o pyrryl carbamoylmethyl)imninodiacetic acid, ethylenediamine-N,N-bis(-2-hydroxy-5-bromophenyl) acetate, N'-acyl and N'-sulfonylethylenediamine-N,N-diacetic acid; N'-substituted derivatives of ethylenediamine-N,N-diacetic acid (EDDA) such as N'-acetyl EDDA, N'-benzoyl EDDA, N'-(p-toluenesulfonyl) EDDA, N'-(p-t-butylbenzoyl) EDDA, N'-(benzenesulfonyl) EDDA, N'-(p-chlorobenzenesulfonyl) EDDA, N'-(p-ethylbenzenesulfonyl) EDDA, N'-(p-n-propylbenzenesulfonyl) EDDA, N'-(naphthalene-2-sulfonyl) EDDA, N'-(2,5-dimethylbenzenesulfonyl) EDDA; N-(2-acetylnaphthyl)iminodiacetic acid; N-(2-naphthylmethyl)-iminodiacetic acid;
hepatobiliary dyes such as rose bengal, Congo red, bromosulphthalein, bromophenol blue, phenolphthalein, toluidine blue, indocyanine green; hepatobiliary contrast agents such as 3 o iodipamide, ioglycamic acid; bile salts such as bilirubin, cholyglycyliodohistamine, thyroxineglucuronide; hepatobiliary thiol complexes such as penicillamine, ~i-mercaptoisobutyric acid, dihydroehioctic acid, 6-mercaptopurine, kethoxal-bis(thiosemicarbazone); hepatobiliary amine complexes such as 1-hydrazinophthalazine-(hydralazine)sulfonyl urea; hepatobiliary amino acid Schiff Base complexes such as pyridoxylidene glutamate, pyridoxylidene isoleucine, pyridoxylidene phenylalanine, pyridoxylidene tryptophan, pyridoxylidene 5-methyl tryptophan; additional pyridoxylidene aminates; 3-hydroxy-4-formyl-pyridene glutamic acid; and miscellaneous hepatobiliary complexes such as tetracycline, 7-carboxy-~i-hydroxyquinoline, phenolphthalexon, eosin, and verograffin.
The use of a primary polymeric matrix in conjunction with a secondary polylysine poly(glutamiclaspartic acid) copolymer provides a polymeric construct which anchors not l o only biogenic amines, but also hepatobiliary target molecules. This construct manifests a complex synergy of interaction that maintains the structural integrity of the entire targeted polymeric carrier system. Several polymers have been employed to illustrate the concept and benefits of the dual polymer construct and to delineate the specialized interactions that occur when different primary polymeric matrices are mixed with secondary copolymers.
One embodiment of a polymeric construct of this invention comprises a polylysine primary polymeric matrix and a secondary anchoring copolymer of polylysine-poly(glutamic-aspartic acids). Because a single s-amino functional group accompanies every amino acid residue of polylysine, amino groups occur far more frequently and are chemically more reactive than the amino functionalities generally found in naturally 2 0 occurring proteins. Therefore, chemical derivatization or subsequent chemical interaction may be manipulated with a high degree of precision. The rich cluster of amino groups of polylysine creates a favorable positively charged ionic environment that facilitates interaction between positively charged amino groups on the primary polymer matrix and the negatively charged carboxyl group functionalities on the polyglutamic-aspartic acid 2 5 portion of the secondary polymeric construct under physiological conditions. Thus the likelihood of developing significant polymer-to-polymer binding between the polylysine and the secondary copolymeric construct is markedly increased. The ionic interaction between the negatively charged y- and ~i-carboxyl groups of glutamic and aspartic acids, respectively, with the positively charged amine groups of biogenic amines enhances 3 0 retention of the active agent. Likewise, ionic bonding between the carboxyl groups of the hepatobiliary targeting molecule and the amino group of polylysine enhances retention of the targeting molecule on the surface of the polymeric carrier.
Another embodiment of the invention uses PLGA as the primary polymeric matrix.
By varying the molar ratio of glycolide-to-lactide the hydrophilicity of the copolymeric construct may be regulated. The primary polymeric matrix thus provides numerous carbonyl functional groups that can participate in hydrogen bond formation.
The polylysine-poly(glutamic/aspartic) acid secondary copolymeric anchor provides multiple binding sites for all constituents of the carrier. Furthermore, ionic interaction Between the positively charged nitrogen atoms of the biogenic amines and the ~i-carboxyl groups of aspartic acid and the y-carboxyl groups of glutamic acid enhances stability.
A third embodiment of a polymeric construct of this invention employs chitosan 1 o glutamate as the primary polymeric matrix. Chitosan glutamate is a deacylated derivative of chitin and may be prepared by mixing chitosan and giutamic acid together. A
key distinction between chitosan glutamate and native chitosan is that chitosan glutamate is water soluble, whereas native chitosan is generally only soluble in dilute organic acids.
Chitosan glutamate is a polymeric amino sugar with a free amino functional group on carbon #2 of every glucosamine residue which is glycosidically linked ~i-(1-->
4) in linear sequence to every other glucosamine residue in the polymer. Chitosan glutamate has strong hydrogen bonding functional groups such as hydroxyl and amino groups.
The molecule manifests an array of positive charges at physiological pH and below, a high molecular weight, good polymer chain flexibility and surface energy properties which 2 o favor molecular interaction with other kinds of polymers, including the secondary copolymer of polylysine-poly(glutamic/aspartic acid). This construct has a polysaccharide primary polymer backbone.
The three aforementioned polymer constructs are representative members of distinct polymer classes and illustrate the diversity of polymer carriers.
Other 2 5 representative first and primary polymers include, but are not limited to, polycarbophil, a high molecular weight copolymer of acrylic acid cross-linked with divinyl glycol, albumin, polycarbonates, polyamines and polyhydroxybutyric acid. Nonionic polymers include polysaccharides such as scleroglucans, homopolysaccharides having glucose subunits, e.g. dextran, starch and hydroxyethyl starch. Also, polyoxyethylene polymers 3 o and copolymers may be used as the primary polymers in this invention.
Anionic polymers suitable as primary polymers include some polymeric sugars and are represented by pectin and xanthan gum.
WO X9/04824 PCT/US98/15457 __ The polymeric constructs of this invention are useful for administering an active agent to a host. Accordingly, the constructs of this invention are useful as pharmaceutical compositions in combination with pharmaceutically acceptable carriers.
Administration of the constructs described herein can be via any of the accepted modes of administration for 5 the biologically active substances drat are desired to be administered.
These methods include oral, topical, parenteral, ocular, transdermal, nasal and other systemic or aerosol forms.
Depending on the intended mode of administration, the compositions used may be in the form of solid, semi-solid or liquid dosage forms, such, as for example, tablets, 1 o suppositories, pills, capsules, powders, liquids, suspensions, or the like, preferably in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical compositions will include the polymeric construct as described and a pharmaceutically acceptable excipient, and, optionally, may include other active agents, carriers, adjuvants, etc.
Topical formulations composed of the polymeric constructs hereof, penetration enhancers, and other ingredients may be applied in various ways. The solution can be applied dropwise, from a suitable delivery device, to the appropriate area of skin or mucous membranes and rubbed in by hand or simply allowed to air dry. A
suitable gelling agent can be added to the solution and the preparation can be applied to the 2 o appropriate area and rubbed in. Alternatively, the solution formulation can be placed into a spray device and be delivered as a spray. This type of drug delivery device is particularly well suited for application to large areas of skin, to highly sensitive skin, or to the nasal or oral cavities.
Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the. like. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor 3 0 amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH
buffering agents and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolaine oleate, etc.
The amount of active compound administered will of course, be dependent on the subject being treated, the type and severity of the affliction, the manner of administration-and the judgment of the prescribing physician. In addition, if the dosage form is intended for sustained release, the total dose will be integrated over the total time period of the sustained release device in order to compute the appropriate dose required.
Although effective dosage ranges for specific biologically active substances of interest are dependent upon a variety of factors, and are generally known to one of ordinary skill in the art, some dosage guidelines can be generally defined. For most forms of administration, the polymeric component will be suspended in an aqueous solution and generally not exceed 30% (w/v) of the total formulation. The drug component of the formulation will most likely be less than 20 % (w/v) of the formulation and generally greater than 0.01 % (w/v) In general, topical formulations are prepared in gels, creams or solutions having an active ingredient in the range of from 0.001 % to 10% (w/v), preferably 0.01 to 5%, and most preferably about 1 % to about 5 % . (Of course, these ranges are subject to variation depending upon the potency of the biogenic amine, and could in appropriate circumstances fall within a range as broad as from 0.001 % to 20 % . ) In all of these exemplary formulations, as will other topical formulations, the total dose given will depend upon the size of the affected area of the skin and the number of doses per day.
For oral administration, a pharmaceutically acceptable, non-toxic composition is 2 o formed by the incorporation of any of the normally employed excipients, such as, for example, manrlitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like. Such compositions include solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations and the like.
2 5 Preferably the compositions will take the form of a pill or tablet. Thus the composition will contain along with the active ingredient: a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, gelatin, polyvinylpyrolidine, cellulose and derivatives thereof, and the like.
3 o Liquid pharmaceutically administrable compositions can, for example, be prepared by dispersing or suspending the polymeric construct as described above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington:
The Science and Practice of Pharmacy, 19th ed., 1995 (Mack Publishing Co., Easton, PA).
The composition or formulation to be administered will, in any event, contain a quantity of the 1 o active biogenic amine in an amount sufficient to effectively treat the disorder or disease of the subject being treated.
Dosage forms or compositions containing active ingredient in the range of 0.005 to 95 % with the balance made up from non-toxic carrier may be prepared. The exact composition of these formulations may vary widely depending on the particular properties of the biogenic amine in question. However, they will generally comprise from 0.01 % to 95 % , and preferably from 0.05 % to 10 % active ingredient for highly potent agents, and from 40-85 % for moderately active agents.
For a solid dosage form, the suspension, in for example propylene carbonate, vegetable oils or triglycerides, is preferably encapsulated in a gelatin capsule. Such 2 o suspensions and the preparation and encapsulation thereof, can be prepared by methods that are disclosed in U.S. Patents Nos. 4,328,245; 4,409,239; and 4,410,545.
For a liquid dosage form, the suspension may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g. water, to be easily measured for administration.
2 5 Alternatively, liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the polymeric construct in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g. propylene carbonate) and the like, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells.
Other useful formulations include those set forth in U.S. Patents Nos. Re.
28,819 3 o and 4,358,603.
Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH
buffering agents, solubility enhancers, and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, cyclodextrins, etc.
A more recently devised approach for parenteral administration employs the implantation of a slow-release or sustained-release system, such that a constant level of to dosage is maintained. See, e.g., U.S. Patent No. 3,710,795.
The percentage of active agent contained in parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject. However, percentages of active ingredient of 0.01 ~ to 10 l in solution are employable, and will be higher if the composition is a solid which will be subsequently diluted to the above percentages. Preferably the composition will comprise 0.2 - 2 % of the active agent in solution.
Nasal suspensions of the polymeric construct alone or in combination with pharmaceutically acceptable excipients can also be administered.
Formulations of the polymeric construct may also be administered to the 2 o respiratory tract as an aerosol for a nebulizer. In such a case, the particles of the formulation have diameters of less than 50 microns, preferably less than 10 microns.
EXAMPLES
The following specific Examples are intended to illustrate the invention and should 2 5 not be construed as limiting the scope of the claims.
All of the following binding studies were performed in solutions buffered with HEPES at pH 7Ø
Example 1. Association of serotonin HCl with bovine serum albumin.
3 o Experiment A. A bovine serum albumin solution was prepared by dissolving 40 mg of albumin in 10 ml of 10 mM HEPES buffer, pH 7Ø A serotonin solution was prepared by adding 10 mg of serotonin HCl (5-hydroxytryptamine HCl) to 10 ml of 10 mM
HEPES
*rB
buffer, pH 7.0, and then adding a minute quantity (50 izl) of radiolabeled 5-hydroxytryptamine creatinine sulfate to the solution. 1.0 ml of the albumin solution was mixed with 1.0 ml of the serotonin solution and vortexed for 20 seconds. A 25 p.l aliquot and a 50 ~,1 aliquot were taken of this mixture for use as standards. The final concentration of albumin in the mixed solution was 2 mg/ml (0.03 mM). The final concentration of serotonin in the mixed solution was 0.5 mg/ml (2.4 mM).
The remaining 1.925 ml solution was placed in a clear Centricon tube having a filter with a molecular weight cut-off of 30,000. The tube was spun for 30 minutes at 6500 rpm. Three 192.5 ~l aliquots of the filtrate were counted on a scintillation counter.
1 o The scintillation counter results indicated that 924 wg serotonin HCl was in the filtrate (95.9% of 963 p.g/1.925 ml). Therefore, 4.1 % of the serotonin appeared to have been retained on the filter, presumably due to binding with the albumin.
Experiment B. One ml of the albumin solution (4 mg/ml) from Experiment A was mixed with 20 ~1 of the serotonin solution (1 mg/ml) from Experiment A and vortexed for 20 seconds. A 20 pl aliquot was taken of this mixture for use as standards.
The final concentration of albumin in the mixed solution was 4 mg/ml (0.06 mM). The final concentration of serotonin HCl in the mixed solution was 0.020 mg/ml (0.094 mM).
The 1.0 mi of the solution was placed in a green Centricon tube having a filter with a molecular weight cut-off of 10,000. The sample was then spun for 30 minutes at 2 0 6500 rpm. Two 100 p,l aliquots of the filtrate were counted on the scintillation counter.
The results indicated that 16.3 p.g of the serotonin HCl remained in the filtrate (81.5 % of 20 p.g/1 ml) while 18.5 % of the serotonin was retained on the Centricon filter.
Experiment C. In this experiment, an albumin solution (40 mg/ml) was prepared 2 5 by dissolving 120 mg of albumin in 3.0 ml of 10 mM HEPES buffer, pH 7Ø
The serotonin solution (1 mg/ml) from Experiment A was used. 1.0 ml of this albumin solution was mixed with 20 ~1 of the serotonin solution and vortexed for 20 seconds. A
~,1 aliquot was taken of this mixture for use as a standard. This mixture was allowed to stand for 20 minutes. The final concentrations of albumin and serotonin HCl in the 3 o mixture were 40 mg/ml (0.61 mM) and 0.02 mg/ml (0.094 mM), respectively.
WO 99/04824 PCT/US98I1S457 _.
1.0 ml was placed in a clear Centricon tube having a filter with a molecular weight cut-off of 30,000. The sample was then spun for 30 minutes at 6500 rpm. Two 100 pl aliquots of the filtrate were counted on the scintillation counter.
The results indicated that 9.3 p,g of serotonin HCl was in the filtrate (47.5 % of 20 5 ~,g/m 1), whereas 52.5 % of the serotonin was retained by the Centricon filter.
The results of Experiments A, B, and C are summarized in the following table:
Molar Ratios Serotonin Retained Sero nin Albumin 10 Experiment A: 80 moles 1 mole 4.1 Experiment B: 3 moles 1 mole 18.5 %
Experiment C: 1 mole 6.5 moles52.5 Example 2. Association of serotonin with phytic acid, poly-lysine, poly-lysine-succinyl, 15 and N-2,6-(diisopropylphenylcarbamoylmethyl)iminodiacetic acid (DIDA).
A solution of phytic acid was prepared by mixing 5.6 mg with 10 ml of 10 mM
HEPES buffer, pH 7Ø The poly-lysine solution contained 5.6 mg in 10 ml of HEPES
buffer, pH 7Ø A poly-lysine-succinyl solution also was prepared with 5.6 mg in 10 ml of HEPES buffer, pH 7Ø The DIDA solution contained 8.4 mg in 10 mI HEPES
buffer, 2 o pH 7Ø 20 pl of the serotonin solution from Example 1, Experiment A, (1 mg/ml) was added to 1.0 ml of the phytic acid solution (0.56 mg/ml) and vortexed. 1.0 ml of the poly-lysine solution (0.56 mg/ml} was then added and vortexed. 1.0 ml of the poly-lysine-succinyl solution (0.56 mg/ml) was added and the mixture again vortexed. Finally, wl of the DIDA solution (0.84 mg/ml) was added to the mixture.
2 5 Final concentrations of the components of the mixture were as follows:
serotonin HCI: 0.007 mglml (0.033 mM) phytic acid: 0.18 mg/ml (0.20 mM) poly-lysine: 0.18 mg/ml (1.4 mM) poly-lysine-succinyl: 0.18 mg/ml (0.80 mM) 3 o DIDA: 0.006 mg/ml (0.02 mM) 1.0 ml of this mixture was placed in a yellow Centricon tube having a filter with a molecular weight cut-off of 3,000. The sample was then centrifuged for two hours at *rB
6500 rpm. A 100 pl aliquot of the original mixture and two 100 p.l aliquots of the filtrate-were counted on the scintillation counter.
The amount of serotonin HCl in the filtrate was 5.0 ~g (75.8 % of 20 wg/3.040 ml). This indicates that 24.2 % of the serotonin was retained by the Centricon filter in this experiment, presumably due to ionic and/or hydrogen bonding interactions between the serotonin and the polymeric components of the solution mixture.
Example 3. Association of serotonin .with chitosan (Mr=70kD), poly-Glu-Lys, and N-(2,6-diisopropylphenylcarbamoylmetbyl) iminodiacetic acid (DIDA).
10 mg of the chitosan polymer was dispersed in 10 ml of distilled water and titrated with 0.6 ml of glacial acetic acid to facilitate dissolution. A poly-GIu-Lys solution was prepared by dissolving 10 mg into 10 ml of 10 mM HEPES buffer, pH 7.0 and sonicating for 30 seconds. 20 p.l of the serotonin HCl solution from Example 1, Experiment 3, (1 mg/ml) was added to 1.0 ml of the poly-Glu-Lys solution (1.0 mg/ml) and vortexed. Next, 10 p.l of the DIDA solution (0.84 mg/ml) was added and vortexed.
500 ~1 of the chitosan solution (0.94 mg/ml) was also added to the mixture, followed by vortexmg.
The final concentrations in the mixed solution were as follows:
chitosan: 0. 31 mg/ml ( 1. 9 mM) 2 0 poly-Glu-Lys: 0.65 mg/ml (2.7 mM) DIDA: 0.006 mg/ml (0.002 mM) serotonin HCI: 0.013 mg/ml (0.061 mM) A 1.0 m1 aliquot was placed in a Centricon tube having a filter with a molecular weight cut-off of 30,000. The sample was then centrifuged for 30 minutes. 100 ~1 2 5 aliquots were taken from the original sample and from the filtrate to be counted on the scintillation counter.
By varying the molar ratio of glycolide-to-lactide the hydrophilicity of the copolymeric construct may be regulated. The primary polymeric matrix thus provides numerous carbonyl functional groups that can participate in hydrogen bond formation.
The polylysine-poly(glutamic/aspartic) acid secondary copolymeric anchor provides multiple binding sites for all constituents of the carrier. Furthermore, ionic interaction Between the positively charged nitrogen atoms of the biogenic amines and the ~i-carboxyl groups of aspartic acid and the y-carboxyl groups of glutamic acid enhances stability.
A third embodiment of a polymeric construct of this invention employs chitosan 1 o glutamate as the primary polymeric matrix. Chitosan glutamate is a deacylated derivative of chitin and may be prepared by mixing chitosan and giutamic acid together. A
key distinction between chitosan glutamate and native chitosan is that chitosan glutamate is water soluble, whereas native chitosan is generally only soluble in dilute organic acids.
Chitosan glutamate is a polymeric amino sugar with a free amino functional group on carbon #2 of every glucosamine residue which is glycosidically linked ~i-(1-->
4) in linear sequence to every other glucosamine residue in the polymer. Chitosan glutamate has strong hydrogen bonding functional groups such as hydroxyl and amino groups.
The molecule manifests an array of positive charges at physiological pH and below, a high molecular weight, good polymer chain flexibility and surface energy properties which 2 o favor molecular interaction with other kinds of polymers, including the secondary copolymer of polylysine-poly(glutamic/aspartic acid). This construct has a polysaccharide primary polymer backbone.
The three aforementioned polymer constructs are representative members of distinct polymer classes and illustrate the diversity of polymer carriers.
Other 2 5 representative first and primary polymers include, but are not limited to, polycarbophil, a high molecular weight copolymer of acrylic acid cross-linked with divinyl glycol, albumin, polycarbonates, polyamines and polyhydroxybutyric acid. Nonionic polymers include polysaccharides such as scleroglucans, homopolysaccharides having glucose subunits, e.g. dextran, starch and hydroxyethyl starch. Also, polyoxyethylene polymers 3 o and copolymers may be used as the primary polymers in this invention.
Anionic polymers suitable as primary polymers include some polymeric sugars and are represented by pectin and xanthan gum.
WO X9/04824 PCT/US98/15457 __ The polymeric constructs of this invention are useful for administering an active agent to a host. Accordingly, the constructs of this invention are useful as pharmaceutical compositions in combination with pharmaceutically acceptable carriers.
Administration of the constructs described herein can be via any of the accepted modes of administration for 5 the biologically active substances drat are desired to be administered.
These methods include oral, topical, parenteral, ocular, transdermal, nasal and other systemic or aerosol forms.
Depending on the intended mode of administration, the compositions used may be in the form of solid, semi-solid or liquid dosage forms, such, as for example, tablets, 1 o suppositories, pills, capsules, powders, liquids, suspensions, or the like, preferably in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical compositions will include the polymeric construct as described and a pharmaceutically acceptable excipient, and, optionally, may include other active agents, carriers, adjuvants, etc.
Topical formulations composed of the polymeric constructs hereof, penetration enhancers, and other ingredients may be applied in various ways. The solution can be applied dropwise, from a suitable delivery device, to the appropriate area of skin or mucous membranes and rubbed in by hand or simply allowed to air dry. A
suitable gelling agent can be added to the solution and the preparation can be applied to the 2 o appropriate area and rubbed in. Alternatively, the solution formulation can be placed into a spray device and be delivered as a spray. This type of drug delivery device is particularly well suited for application to large areas of skin, to highly sensitive skin, or to the nasal or oral cavities.
Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the. like. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor 3 0 amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH
buffering agents and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolaine oleate, etc.
The amount of active compound administered will of course, be dependent on the subject being treated, the type and severity of the affliction, the manner of administration-and the judgment of the prescribing physician. In addition, if the dosage form is intended for sustained release, the total dose will be integrated over the total time period of the sustained release device in order to compute the appropriate dose required.
Although effective dosage ranges for specific biologically active substances of interest are dependent upon a variety of factors, and are generally known to one of ordinary skill in the art, some dosage guidelines can be generally defined. For most forms of administration, the polymeric component will be suspended in an aqueous solution and generally not exceed 30% (w/v) of the total formulation. The drug component of the formulation will most likely be less than 20 % (w/v) of the formulation and generally greater than 0.01 % (w/v) In general, topical formulations are prepared in gels, creams or solutions having an active ingredient in the range of from 0.001 % to 10% (w/v), preferably 0.01 to 5%, and most preferably about 1 % to about 5 % . (Of course, these ranges are subject to variation depending upon the potency of the biogenic amine, and could in appropriate circumstances fall within a range as broad as from 0.001 % to 20 % . ) In all of these exemplary formulations, as will other topical formulations, the total dose given will depend upon the size of the affected area of the skin and the number of doses per day.
For oral administration, a pharmaceutically acceptable, non-toxic composition is 2 o formed by the incorporation of any of the normally employed excipients, such as, for example, manrlitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like. Such compositions include solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations and the like.
2 5 Preferably the compositions will take the form of a pill or tablet. Thus the composition will contain along with the active ingredient: a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, gelatin, polyvinylpyrolidine, cellulose and derivatives thereof, and the like.
3 o Liquid pharmaceutically administrable compositions can, for example, be prepared by dispersing or suspending the polymeric construct as described above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington:
The Science and Practice of Pharmacy, 19th ed., 1995 (Mack Publishing Co., Easton, PA).
The composition or formulation to be administered will, in any event, contain a quantity of the 1 o active biogenic amine in an amount sufficient to effectively treat the disorder or disease of the subject being treated.
Dosage forms or compositions containing active ingredient in the range of 0.005 to 95 % with the balance made up from non-toxic carrier may be prepared. The exact composition of these formulations may vary widely depending on the particular properties of the biogenic amine in question. However, they will generally comprise from 0.01 % to 95 % , and preferably from 0.05 % to 10 % active ingredient for highly potent agents, and from 40-85 % for moderately active agents.
For a solid dosage form, the suspension, in for example propylene carbonate, vegetable oils or triglycerides, is preferably encapsulated in a gelatin capsule. Such 2 o suspensions and the preparation and encapsulation thereof, can be prepared by methods that are disclosed in U.S. Patents Nos. 4,328,245; 4,409,239; and 4,410,545.
For a liquid dosage form, the suspension may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g. water, to be easily measured for administration.
2 5 Alternatively, liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the polymeric construct in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g. propylene carbonate) and the like, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells.
Other useful formulations include those set forth in U.S. Patents Nos. Re.
28,819 3 o and 4,358,603.
Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH
buffering agents, solubility enhancers, and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, cyclodextrins, etc.
A more recently devised approach for parenteral administration employs the implantation of a slow-release or sustained-release system, such that a constant level of to dosage is maintained. See, e.g., U.S. Patent No. 3,710,795.
The percentage of active agent contained in parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject. However, percentages of active ingredient of 0.01 ~ to 10 l in solution are employable, and will be higher if the composition is a solid which will be subsequently diluted to the above percentages. Preferably the composition will comprise 0.2 - 2 % of the active agent in solution.
Nasal suspensions of the polymeric construct alone or in combination with pharmaceutically acceptable excipients can also be administered.
Formulations of the polymeric construct may also be administered to the 2 o respiratory tract as an aerosol for a nebulizer. In such a case, the particles of the formulation have diameters of less than 50 microns, preferably less than 10 microns.
EXAMPLES
The following specific Examples are intended to illustrate the invention and should 2 5 not be construed as limiting the scope of the claims.
All of the following binding studies were performed in solutions buffered with HEPES at pH 7Ø
Example 1. Association of serotonin HCl with bovine serum albumin.
3 o Experiment A. A bovine serum albumin solution was prepared by dissolving 40 mg of albumin in 10 ml of 10 mM HEPES buffer, pH 7Ø A serotonin solution was prepared by adding 10 mg of serotonin HCl (5-hydroxytryptamine HCl) to 10 ml of 10 mM
HEPES
*rB
buffer, pH 7.0, and then adding a minute quantity (50 izl) of radiolabeled 5-hydroxytryptamine creatinine sulfate to the solution. 1.0 ml of the albumin solution was mixed with 1.0 ml of the serotonin solution and vortexed for 20 seconds. A 25 p.l aliquot and a 50 ~,1 aliquot were taken of this mixture for use as standards. The final concentration of albumin in the mixed solution was 2 mg/ml (0.03 mM). The final concentration of serotonin in the mixed solution was 0.5 mg/ml (2.4 mM).
The remaining 1.925 ml solution was placed in a clear Centricon tube having a filter with a molecular weight cut-off of 30,000. The tube was spun for 30 minutes at 6500 rpm. Three 192.5 ~l aliquots of the filtrate were counted on a scintillation counter.
1 o The scintillation counter results indicated that 924 wg serotonin HCl was in the filtrate (95.9% of 963 p.g/1.925 ml). Therefore, 4.1 % of the serotonin appeared to have been retained on the filter, presumably due to binding with the albumin.
Experiment B. One ml of the albumin solution (4 mg/ml) from Experiment A was mixed with 20 ~1 of the serotonin solution (1 mg/ml) from Experiment A and vortexed for 20 seconds. A 20 pl aliquot was taken of this mixture for use as standards.
The final concentration of albumin in the mixed solution was 4 mg/ml (0.06 mM). The final concentration of serotonin HCl in the mixed solution was 0.020 mg/ml (0.094 mM).
The 1.0 mi of the solution was placed in a green Centricon tube having a filter with a molecular weight cut-off of 10,000. The sample was then spun for 30 minutes at 2 0 6500 rpm. Two 100 p,l aliquots of the filtrate were counted on the scintillation counter.
The results indicated that 16.3 p.g of the serotonin HCl remained in the filtrate (81.5 % of 20 p.g/1 ml) while 18.5 % of the serotonin was retained on the Centricon filter.
Experiment C. In this experiment, an albumin solution (40 mg/ml) was prepared 2 5 by dissolving 120 mg of albumin in 3.0 ml of 10 mM HEPES buffer, pH 7Ø
The serotonin solution (1 mg/ml) from Experiment A was used. 1.0 ml of this albumin solution was mixed with 20 ~1 of the serotonin solution and vortexed for 20 seconds. A
~,1 aliquot was taken of this mixture for use as a standard. This mixture was allowed to stand for 20 minutes. The final concentrations of albumin and serotonin HCl in the 3 o mixture were 40 mg/ml (0.61 mM) and 0.02 mg/ml (0.094 mM), respectively.
WO 99/04824 PCT/US98I1S457 _.
1.0 ml was placed in a clear Centricon tube having a filter with a molecular weight cut-off of 30,000. The sample was then spun for 30 minutes at 6500 rpm. Two 100 pl aliquots of the filtrate were counted on the scintillation counter.
The results indicated that 9.3 p,g of serotonin HCl was in the filtrate (47.5 % of 20 5 ~,g/m 1), whereas 52.5 % of the serotonin was retained by the Centricon filter.
The results of Experiments A, B, and C are summarized in the following table:
Molar Ratios Serotonin Retained Sero nin Albumin 10 Experiment A: 80 moles 1 mole 4.1 Experiment B: 3 moles 1 mole 18.5 %
Experiment C: 1 mole 6.5 moles52.5 Example 2. Association of serotonin with phytic acid, poly-lysine, poly-lysine-succinyl, 15 and N-2,6-(diisopropylphenylcarbamoylmethyl)iminodiacetic acid (DIDA).
A solution of phytic acid was prepared by mixing 5.6 mg with 10 ml of 10 mM
HEPES buffer, pH 7Ø The poly-lysine solution contained 5.6 mg in 10 ml of HEPES
buffer, pH 7Ø A poly-lysine-succinyl solution also was prepared with 5.6 mg in 10 ml of HEPES buffer, pH 7Ø The DIDA solution contained 8.4 mg in 10 mI HEPES
buffer, 2 o pH 7Ø 20 pl of the serotonin solution from Example 1, Experiment A, (1 mg/ml) was added to 1.0 ml of the phytic acid solution (0.56 mg/ml) and vortexed. 1.0 ml of the poly-lysine solution (0.56 mg/ml} was then added and vortexed. 1.0 ml of the poly-lysine-succinyl solution (0.56 mg/ml) was added and the mixture again vortexed. Finally, wl of the DIDA solution (0.84 mg/ml) was added to the mixture.
2 5 Final concentrations of the components of the mixture were as follows:
serotonin HCI: 0.007 mglml (0.033 mM) phytic acid: 0.18 mg/ml (0.20 mM) poly-lysine: 0.18 mg/ml (1.4 mM) poly-lysine-succinyl: 0.18 mg/ml (0.80 mM) 3 o DIDA: 0.006 mg/ml (0.02 mM) 1.0 ml of this mixture was placed in a yellow Centricon tube having a filter with a molecular weight cut-off of 3,000. The sample was then centrifuged for two hours at *rB
6500 rpm. A 100 pl aliquot of the original mixture and two 100 p.l aliquots of the filtrate-were counted on the scintillation counter.
The amount of serotonin HCl in the filtrate was 5.0 ~g (75.8 % of 20 wg/3.040 ml). This indicates that 24.2 % of the serotonin was retained by the Centricon filter in this experiment, presumably due to ionic and/or hydrogen bonding interactions between the serotonin and the polymeric components of the solution mixture.
Example 3. Association of serotonin .with chitosan (Mr=70kD), poly-Glu-Lys, and N-(2,6-diisopropylphenylcarbamoylmetbyl) iminodiacetic acid (DIDA).
10 mg of the chitosan polymer was dispersed in 10 ml of distilled water and titrated with 0.6 ml of glacial acetic acid to facilitate dissolution. A poly-GIu-Lys solution was prepared by dissolving 10 mg into 10 ml of 10 mM HEPES buffer, pH 7.0 and sonicating for 30 seconds. 20 p.l of the serotonin HCl solution from Example 1, Experiment 3, (1 mg/ml) was added to 1.0 ml of the poly-Glu-Lys solution (1.0 mg/ml) and vortexed. Next, 10 p.l of the DIDA solution (0.84 mg/ml) was added and vortexed.
500 ~1 of the chitosan solution (0.94 mg/ml) was also added to the mixture, followed by vortexmg.
The final concentrations in the mixed solution were as follows:
chitosan: 0. 31 mg/ml ( 1. 9 mM) 2 0 poly-Glu-Lys: 0.65 mg/ml (2.7 mM) DIDA: 0.006 mg/ml (0.002 mM) serotonin HCI: 0.013 mg/ml (0.061 mM) A 1.0 m1 aliquot was placed in a Centricon tube having a filter with a molecular weight cut-off of 30,000. The sample was then centrifuged for 30 minutes. 100 ~1 2 5 aliquots were taken from the original sample and from the filtrate to be counted on the scintillation counter.
11.4 pg of the serotonin HCl was found in the filtrate (85.1 % of 20 p.g/1.53 ml).
Therefore, 14.9 % of the serotonin HCl was retained on the filter in this experiment, presumably due to association with the polymers present in the mixture.
Example 4. Association of serotonin with poly(L-Iactide acid-co-glycolide);
poly-Glu-Lys, and N-(2,6-diisopropylphenylcarbamoylmethyl)iminodiacetic acid (DIDA).
WO 99/04824 PCTIUS98/15457 , The poly(L-lactide acid-co-glycolide) polymer (PLGA) does not dissolve with acetic acid, ethanol or NaOH, but does dissolve in dimethyl sulfoxide (DMSO).
10 mg of PLGA -was dissolved in 0.5 ml of DMSO at 60°C for 30 seconds. Then 9.5 ml of 10 mM
HEPES, pH 7.0 was added to the polymer/DMSO and the mixture vortexed. In a clean test tube, one ml of the Poly-Glu-Lys solution (1 mg/ml) from Example 3 was mixed with 20 pl of the serotonin HCl solution (1 mg/ml) from Example 1, Experiment A, and warmed to 60°C and vortexed. A 10 wl aliquot a DIDA solution (0.84 mg/ml) was added and the mixture again vortexed. Finally, 0.5 ml of a poly(L-lactide acid-co-glycolide) solution (1 mg/ml) was added. The entire mixture was warmed and vortexed.
1 o The final concentrations of the mixture were as follows:
poly (L-lactide acid-co-glycolide): 0.33 mg/ml (1.0 mM) poly-Glu-Lys: 0.65 mg/ml (2.7 mM) serotonin HCI: 0.013 mg/ml (0.061 mM) DIDA: 0.005 mg/ml (0.0014 mM) 1.0 ml of the solution mixture was placed in a green Centricon tube having a filter with a molecular weight cut-off of 10,000. The sample was then centrifuged at 6500 rpm for 1 hour. 100 ~,1 aliquots were taken of the original sample and of the filtrate and counted on the scintillation counter.
11.5 lzg of serotonin HCl was detected in the filtrate (87.8 % of 20 pg/1.530 ml), 2 o indicating that 12.2 % of the serotonin HCl in the mixed solution was retained on the filter.
Example 5. Association of serotonin with polyoxypropylene-polyoxyethylene (Pluronic~ F-127), poly-Glu-Lys, poly(Tyr-Glu)Ala-Lys, and N-(2,6-2 5 diisopropylphenylcarbamoylmethyl) iminodiacetic acid (DIDA) .
1.0 ml of a poly-Glu-Lys solution (1 mg/ml) was heated to 100°C for two minutes, and then 20 pl of the 1 mg/ml serotonin HCl solution from Example 1, Experiment A, was added. In a separate test tube, 1.0 ml of a poly(Tyr-Glu)Ala-Lys solution (1 mglml) was heated to 100°C and then added to the above-mentioned solution.
Next, 10 ~1 of a 3 o DIDA solution (0.84 mg/ml) was mixed into the solution mixture. The entire mixture was vortexed and allowed to cool to room temperature and then chilled to 4°C. 0.5 ml of a cold lmg/ml solution of polyoxypropylene-polyoxyethylene (Pluronic~ F-27) was then added to the solution mixture. The solution mixture was vortexed and stored at 4°C for 64 hours.
The final concentrations of the components of the solution mixture were as follows:
poly-Glu-Lys: 0.40 mg/ml (1.7 mM) poly(Tyr-Glu)Ala-Lys: 0.40 mg/ml (0.94 ~nM) serotonin HCI: 0.008 mg/ml (0.04 mM) DIDA: 0.003 mg/ml (0.001 mM) Pluronic~ F-127: 0.20 mg/ml (1.7 mM) 1.0 ml of the solution mixture was placed in a green Centricon tube having a filter with a molecular weight cut-off of 30,000. The sample was centrifuged for 1 hour. 100 wl aliquots were taken from the filtrate for counting in the scintillation counter.
The concentration of serotonin HCl in the filtrate was found to be 7.4 wg/ml (92.5 % of 20 pg/2.530 ml). This result indicates that approximately 7.5 % of the serotonin HCI in the original solution mixture was retained on the filter, presumably as part of a complex with the polymers of the solution.
Example 6. Association of serotonin with ATP, poly-Glu-Lys, poly-lysine, and N-(2,6-diisopropylphenylcarbamoylmethyl)iminodiacetic acid (DIDA).
2 o The ATP solution was prepared by weighing 10 mg in 10 ml of 10 mM HEPES
buffer, pH 7Ø In a separate test tube, 20 ~1 of the 1 mg/ml serotonin HCl solution from Example 1, Experiment A, was added to 1.13 ml of a poly-Glu-Lys solution (1 mg/ml) and vortexed. Then, 26 pl of a solution of ATP (1 mg/ml) was added and vortexed. 1.07 ml of a poly-Lys solution (0.56 mg/ml) was added next. 10 pl of a DIDA
solution (0.84 2 5 mg/ml) was then added to the mixture and vortexed.
The final concentrations of the components in the solution mixture were as follows:
serotonin HCI: 0.009 mg/ml (0.04 mM) poly-Glu-Lys: 0.50 mg/ml (2.0 mM) 3 o poly-Lys: 0.27 mg/ml (2.0 mM) ATP-Na2 : 0.012 mg/ml (0.022 mM) DIDA: 0.0037 mg/ml (0.01 mM) 1.0 ml of the mixed solution was placed into a green Centricon tube having a filter with a molecular weight cut-off of 30,000. The sample was centrifuged for 1 hour. 100 pl aliquots of the filtrate were taken to be counted on the scintillation counter.
The results indicated that serotonin HCl was present in the filtrate at a concentration of 7.4 p.g/ml (82 % of 0. 02 mg/2.256 ml) . Therefore, approximately 18 of the serotonin had been retained at the filter, presumably as part of an ionic and/or hydrogen bonding complex with the polymers of the solution mixture.
Example 7. Association of serotonin with poly(acrylic acid), poly-Glu-Lys, and N-(2,6-to diisopropylphenyicarbamoylmethyl)iminodiacetic acid (DIDA).
1.3 ml of poly(acrylic acid) solution (25 % aqueous) was added to 20 pl of the 1.0 mg/ml solution of serotonin HCl from Example 1, Experiment A, and vortexed for seconds. In a separate vial, 1.13 ml of a 1.0 mg/ml solution of poly-Glu-Lys was added to 10 p,l of an 0.84 mg/ml solution of DIDA and vortexed for 20 seconds. The two vials were vortexed together and two 200 ~1 aliquots were taken for use as standards in the scintillation counter.
The final concentrations of the reaction mixture components were as follows:
poly(acrylic acid): 0.13 mg/ml (1.9 mM) poly-Glu-Lys: 0.46 mg/ml (1.9 mM) 2 0 serotonin -HCI: 0.01 mg/ml (0.04 mM) DIDA: < 0.01 mg/ml ( < 0.01 mM) 0.5 ml of this solution mixture was placed in a Centricon tube having a filter with a molecular weight cut-off of 10,000. The tube was centrifuged for 30 minutes.
One 200 p,l aliquot was taken from the filtrate and counted on the scintillation counter.
The results indicated that 74% of the serotonin was present in the filtrate.
Therefore, approximately 26 % of the serotonin appeared to have been retained by the Centricon filter, presumably due to ionic association and/or hydrogen bonding with the polymeric components of the solution mixture.
3 o Example 8. Association of serotonin with polyvinyl sulfonic acid), poly-Glu-Lys, and N-(2,6-diisopropylphenylcarbamoylmethyl) iminodiacetic acid (DIDA).
3.3 ml of a polyvinyl sulfonic acid) solution (15% aqueous) was added to 20 ~1 of the 1.0 mglml serotonin HCl solution from Example 1, Experiment A, and vortexed for 20 seconds. In a separate vial, 1:13 ml of a 1.0 mg/ml solution of poly-Glu-Lys was added to 10 ~.1 of 0.84 mg/ml solution of DIDA and vortexed for 20 seconds.
The two 5 vials were then vortexed together and three 200 pl aliquots were taken for use as standards in the scintillation counter.
The final concentrations of the components of the solution mixture were as follows:
polyvinyl sulfonic acid): 0.10 mg/ml (1.0 mM) to poly-Glu-Lys: 0.25 mg/ml (1.0 mM) serotonin HCI; 0.0004 mg/ml (0.02 mM) DIDA: < 0.01 mg/ml ( < 0.01 mM) 0.5 ml of this mixture was placed in a Centricon tube having a filter with a molecular weight cut-off of 10,000. The sample was centrifuged for 30 minutes.
One 15 200 ~,1 aliquot was taken from the filtrate and counted on the scintillation counter.
The results from the scintillation counter indicated that approximately 88 %
of the original serotonin was present in the filtrate. It is assumed that 12% of the serotonin was retained on the filter of the Centricon tube due to association of the serotonin with a polymeric complex in the solution mixture.
Example 9. Association of serotonin with poly(aspartic acid), poly-Glu-Lys, and N-(2,6-diisopropylphenylcarbamoylmethyl}iminodiacetic acid (DIDA).
0.62 ml of a poly(aspartic acid) solution (1.0 mg/ml} was added to 20 p,l of 1.0 mg/ml serotonin HCI from Example 1, Experiment A, and vortexed for 20 seconds.
In a 2 5 separate vial, 1.13 ml of a 1.0 mg/ml solution of poly-Glu-Lys was added to 10 p,l of a 0.84 mg/ml solution of DIDA and vortexed for 20 seconds. The two vials were vortexed together and two 200 ~,1 aliquots were taken for use as standards.
The final concentrations of the individual components of the vortexed solution mixture were as follows:
poly(aspartic acid) 0.35 mg/ml (2.6 mM) poly-Glu-Lys 0.63 mg/ml (2.6 mM) serotonin HCl 0.01 mg/ml (0.05 mM) DIDA < 0.01 mg/ml ( < 0.01 mM) 0.5 ml of this mixture was placed in a Centricon tube having a filter with a molecular weight cut-off of 10,000. The sample was centrifuged for 30 minutes.
Two 200 ~1 aliquots were taken from the filtrate and counted on the scintillation counter.
1 o Approximately 92 % of the original serotonin was found in the filtrate.
Approximately 8 % was assumed to have been retained on the filter of the Centricon tube due to ionic interactions and/or hydrogen bonding with the polymers in the solution mixture.
15 Example 10. Association of serotonin with poly(lysine), phytic acid, poly-Glu-Lys, and N-(2,6-diisopropylphenylcarbamoylmethy)iminodiacetic acid (DIDA).
In this experiment, 1.05 ml of poly(lysine) solution (0.56 mg/ml) was added to p,l of a 0.84 mg/inl solution of DIDA and vortexed for 20 seconds. In a separate vial, 1.28 ml of a 0.56 mg/ml solution of phytic acid added to 20 ~1 of the 1.0 mg/ml serotonin 2 o HCl solution from Example 1, Experiment A. 1.13 ml of a 1.0 mg/ml solution of poly-Glu-Lys was also added to the second vial. The contents of the second vial were vortexed for 20 seconds. The two vials were then vortexed together and two 200 ~1 aliquots were taken for use as standards.
The final concentrations of the various components of the mixed solution were as 2 5 follows:
poly(lysine): 0.17 mg/ml (1.3 mM) phytic Acid: 0.21 mglml (0.2 mM) poly-Glu-Lys: 0.32 mglml (1.3 mM) serotonin HCI: < 0.01 mglml ( < 0.01 mM) 3 o DIDA: < 0.01 mg/ml ( < 0.01 mM) 0.5 ml of this mixture was placed in a Centricon tube having a filter with a molecular weight cut-off of 10,000. The tube was centrifuged for 30 minutes.
Two 200 p,l aliquots were then taken from the filtrate and counted on the scintillation counter.
The data from the scintillation counter indicated that 86 % of the original serotonin was in the filtrate. This result suggests that approximately 14 % of the original serotonin was bound to the polymers of the solution mixture and was therefore retained on the filter.
Example 11. Association of serotonin with poly(glutamic acid), chitosan, and N-(2,6-diisopropylphenylcarbamoylmethy)iminodiacetic acid (DIDA).
1 o In this experiment, 1.06 ml of 0.5 mg/ml poly(glutamic acid) was added to 20 ~.1 of the 1.0 mg/ml solution of serotonin HCI from Example l, Experiment A, and vortexed for 20 seconds. Then 0.76 of a 1.0 mg/ml solution of low molecular weight (MW) chitosan was added to 10 ~l of a 0.84 mg/ml solution of DIDA and vortexed for seconds. The two vials were vortexed together, and two 200 pl aliquots were taken for use as standards in the scintillation counter.
Final concentrations of the individual components in the solution mixture were as follows:
poly(glutamic acid): 0.29 mg/ml (2.5 mM) chitosan (low MW): 0.41 mg/ml {2.5 mM) 2 o serotonin -HCI: 0.01 mg/ml (0.05 mM) DIDA: < 0.01 mglml ( < 0.01 mM) 0.5 ml of this mixture was placed in a Centricon tube having a filter with a molecular weight cut-off of 10,000, and the tube was then centrifuged for 30 minutes.
Two 200 ~1 aliquots were taken from the filtrate and counted on the scintillation counter.
2 5 The results indicated that the filtrate contained 95 % of the original serotonin. 5 %
of the original serotonin was retained by the filter.
Example 12. Association of serotonin with poly(galacturonic acid), poly-Glu-Lys, and N-(2,6-diisopropylphenylcarbamoylmethy)iminodiacetic acid ~(DIDA).
30 20 pl of the serotonin HCl solution from Example 1, Experiment A, (lmglml) was added to 0.370 ml of poly{galacturonic acid) solution (2mg/ml) and heated for a few seconds at 60°C and vortexed. Then 1.0 ml of the poly-Glu-Lys solution (1 mg/ml) was added to the above mixture and vortexed. 10 ~1 of DIDA (0.84 mg/ml) was then added.
The solutions were mixed by again vortexing.
Concentrations in the final solution mixture were as follows:
poly(galacturonic acid): 0.53 mg/ml (3 mM) poly-Glu-Lys: 0.71 mg/ml (3 mM) serotonin HCI: 0.014 mg/ml (0.07 mM) DIDA: 0.0006 mg/ml (0.02 mM) 1 ml of this mixture was placed into a green Centricon tube having a filter with a molecular weight cut-off of 10,000. The sample was centrifuged for 1 hour at 6,500 rpm on a Sorvall refrigerated centrifuge at 10°C. 100 ~l aliquots of the sample, before and after filtration, were counted on the scintillation counter.
The data from the scintillation counter indicated that the filtrate contained 90 % of the serotonin that was in the mixed solution. Approximately 10 % of the original serotonin appeared to have been retained on the Centricon filter, presumably due to binding of serotonin to the polymeric components of the solution mixture.
Example 13. Failure of serotonin to bind with poly (L-lactide acid-co-glycolide), chitosan (Mr=70kD), and N-(2,6-diisopropylphenylcarbamoylmethyl) iminodiacetic acid (DIDA) in the absence of an anchoring secondary polymer.
In a first vial, 1.49 ml of the poly (L-lactide acid-co-glycolide) solution (1.0 mg/ml) from Example 4 was added to 20 ~1 of the 1.0 mg/ml serotonin HCl solution from Example l, Experiment A, and vortexed for 20 seconds. A solution of DIDA was prepared by weighing out 8.4 mg of DIDA and dissolving it in 10 ml of 10 mM
HEPES
buffer, pH 7Ø In a second vial, 0.85 ml of the low molecular weight chitosan solution 2 5 (1.0 mg/ml) from Example 3 was added to 10 ~1 of the DIDA solution, and the mixture was vortexed for 20 seconds. The two vials were mixed together and two 100 ~1 aliquots were taken for use as standards The final concentrations of the various components of the solution mixture were as follows:
3 o Poly (L-lactide acid-co-glycolide): 0.68 mg/ml {2.1 mM) chitosan (Mr=70kD): 0.39 mg/ml (2.4 mM) serotonin HCI: 0.01 mg/ml (0.04 mM) WO 99/04824 PCT/ITS98/15457 _.
DIDA: < 0.01 mg/ml ( < 0.01 mM) 1.0 ml of this mixture was placed in a yellow Centricon tube having a filter with a molecular weight cut-off of 3,000. The tube and contents were centrifuged for one hour.
Two 100 pl aliquots were taken from the filtrate and counted on the scintillation counter.
The data from the scintillation counter indicated that the filtrate contained 100 % of the serotonin originally in the solution mixture. None of the serotonin appeared to have been retained on the Centricon filter. This result suggests that without the anchoring presence of a suitable secondary polymer such as poly-Glu-Lys, serotonin may be unable to form a stable association with primary polymeric matrices such as poly(L-lactide acid-1 o co-glycolide) and chitosan.
While the invention has been described with respect to the specific embodiments described herein, it is understood that modifications thereto and equivalents and variations thereof will be apparent to one skilled in the art and are intended to be and are included within the scope of the claims appended hereto.
Therefore, 14.9 % of the serotonin HCl was retained on the filter in this experiment, presumably due to association with the polymers present in the mixture.
Example 4. Association of serotonin with poly(L-Iactide acid-co-glycolide);
poly-Glu-Lys, and N-(2,6-diisopropylphenylcarbamoylmethyl)iminodiacetic acid (DIDA).
WO 99/04824 PCTIUS98/15457 , The poly(L-lactide acid-co-glycolide) polymer (PLGA) does not dissolve with acetic acid, ethanol or NaOH, but does dissolve in dimethyl sulfoxide (DMSO).
10 mg of PLGA -was dissolved in 0.5 ml of DMSO at 60°C for 30 seconds. Then 9.5 ml of 10 mM
HEPES, pH 7.0 was added to the polymer/DMSO and the mixture vortexed. In a clean test tube, one ml of the Poly-Glu-Lys solution (1 mg/ml) from Example 3 was mixed with 20 pl of the serotonin HCl solution (1 mg/ml) from Example 1, Experiment A, and warmed to 60°C and vortexed. A 10 wl aliquot a DIDA solution (0.84 mg/ml) was added and the mixture again vortexed. Finally, 0.5 ml of a poly(L-lactide acid-co-glycolide) solution (1 mg/ml) was added. The entire mixture was warmed and vortexed.
1 o The final concentrations of the mixture were as follows:
poly (L-lactide acid-co-glycolide): 0.33 mg/ml (1.0 mM) poly-Glu-Lys: 0.65 mg/ml (2.7 mM) serotonin HCI: 0.013 mg/ml (0.061 mM) DIDA: 0.005 mg/ml (0.0014 mM) 1.0 ml of the solution mixture was placed in a green Centricon tube having a filter with a molecular weight cut-off of 10,000. The sample was then centrifuged at 6500 rpm for 1 hour. 100 ~,1 aliquots were taken of the original sample and of the filtrate and counted on the scintillation counter.
11.5 lzg of serotonin HCl was detected in the filtrate (87.8 % of 20 pg/1.530 ml), 2 o indicating that 12.2 % of the serotonin HCl in the mixed solution was retained on the filter.
Example 5. Association of serotonin with polyoxypropylene-polyoxyethylene (Pluronic~ F-127), poly-Glu-Lys, poly(Tyr-Glu)Ala-Lys, and N-(2,6-2 5 diisopropylphenylcarbamoylmethyl) iminodiacetic acid (DIDA) .
1.0 ml of a poly-Glu-Lys solution (1 mg/ml) was heated to 100°C for two minutes, and then 20 pl of the 1 mg/ml serotonin HCl solution from Example 1, Experiment A, was added. In a separate test tube, 1.0 ml of a poly(Tyr-Glu)Ala-Lys solution (1 mglml) was heated to 100°C and then added to the above-mentioned solution.
Next, 10 ~1 of a 3 o DIDA solution (0.84 mg/ml) was mixed into the solution mixture. The entire mixture was vortexed and allowed to cool to room temperature and then chilled to 4°C. 0.5 ml of a cold lmg/ml solution of polyoxypropylene-polyoxyethylene (Pluronic~ F-27) was then added to the solution mixture. The solution mixture was vortexed and stored at 4°C for 64 hours.
The final concentrations of the components of the solution mixture were as follows:
poly-Glu-Lys: 0.40 mg/ml (1.7 mM) poly(Tyr-Glu)Ala-Lys: 0.40 mg/ml (0.94 ~nM) serotonin HCI: 0.008 mg/ml (0.04 mM) DIDA: 0.003 mg/ml (0.001 mM) Pluronic~ F-127: 0.20 mg/ml (1.7 mM) 1.0 ml of the solution mixture was placed in a green Centricon tube having a filter with a molecular weight cut-off of 30,000. The sample was centrifuged for 1 hour. 100 wl aliquots were taken from the filtrate for counting in the scintillation counter.
The concentration of serotonin HCl in the filtrate was found to be 7.4 wg/ml (92.5 % of 20 pg/2.530 ml). This result indicates that approximately 7.5 % of the serotonin HCI in the original solution mixture was retained on the filter, presumably as part of a complex with the polymers of the solution.
Example 6. Association of serotonin with ATP, poly-Glu-Lys, poly-lysine, and N-(2,6-diisopropylphenylcarbamoylmethyl)iminodiacetic acid (DIDA).
2 o The ATP solution was prepared by weighing 10 mg in 10 ml of 10 mM HEPES
buffer, pH 7Ø In a separate test tube, 20 ~1 of the 1 mg/ml serotonin HCl solution from Example 1, Experiment A, was added to 1.13 ml of a poly-Glu-Lys solution (1 mg/ml) and vortexed. Then, 26 pl of a solution of ATP (1 mg/ml) was added and vortexed. 1.07 ml of a poly-Lys solution (0.56 mg/ml) was added next. 10 pl of a DIDA
solution (0.84 2 5 mg/ml) was then added to the mixture and vortexed.
The final concentrations of the components in the solution mixture were as follows:
serotonin HCI: 0.009 mg/ml (0.04 mM) poly-Glu-Lys: 0.50 mg/ml (2.0 mM) 3 o poly-Lys: 0.27 mg/ml (2.0 mM) ATP-Na2 : 0.012 mg/ml (0.022 mM) DIDA: 0.0037 mg/ml (0.01 mM) 1.0 ml of the mixed solution was placed into a green Centricon tube having a filter with a molecular weight cut-off of 30,000. The sample was centrifuged for 1 hour. 100 pl aliquots of the filtrate were taken to be counted on the scintillation counter.
The results indicated that serotonin HCl was present in the filtrate at a concentration of 7.4 p.g/ml (82 % of 0. 02 mg/2.256 ml) . Therefore, approximately 18 of the serotonin had been retained at the filter, presumably as part of an ionic and/or hydrogen bonding complex with the polymers of the solution mixture.
Example 7. Association of serotonin with poly(acrylic acid), poly-Glu-Lys, and N-(2,6-to diisopropylphenyicarbamoylmethyl)iminodiacetic acid (DIDA).
1.3 ml of poly(acrylic acid) solution (25 % aqueous) was added to 20 pl of the 1.0 mg/ml solution of serotonin HCl from Example 1, Experiment A, and vortexed for seconds. In a separate vial, 1.13 ml of a 1.0 mg/ml solution of poly-Glu-Lys was added to 10 p,l of an 0.84 mg/ml solution of DIDA and vortexed for 20 seconds. The two vials were vortexed together and two 200 ~1 aliquots were taken for use as standards in the scintillation counter.
The final concentrations of the reaction mixture components were as follows:
poly(acrylic acid): 0.13 mg/ml (1.9 mM) poly-Glu-Lys: 0.46 mg/ml (1.9 mM) 2 0 serotonin -HCI: 0.01 mg/ml (0.04 mM) DIDA: < 0.01 mg/ml ( < 0.01 mM) 0.5 ml of this solution mixture was placed in a Centricon tube having a filter with a molecular weight cut-off of 10,000. The tube was centrifuged for 30 minutes.
One 200 p,l aliquot was taken from the filtrate and counted on the scintillation counter.
The results indicated that 74% of the serotonin was present in the filtrate.
Therefore, approximately 26 % of the serotonin appeared to have been retained by the Centricon filter, presumably due to ionic association and/or hydrogen bonding with the polymeric components of the solution mixture.
3 o Example 8. Association of serotonin with polyvinyl sulfonic acid), poly-Glu-Lys, and N-(2,6-diisopropylphenylcarbamoylmethyl) iminodiacetic acid (DIDA).
3.3 ml of a polyvinyl sulfonic acid) solution (15% aqueous) was added to 20 ~1 of the 1.0 mglml serotonin HCl solution from Example 1, Experiment A, and vortexed for 20 seconds. In a separate vial, 1:13 ml of a 1.0 mg/ml solution of poly-Glu-Lys was added to 10 ~.1 of 0.84 mg/ml solution of DIDA and vortexed for 20 seconds.
The two 5 vials were then vortexed together and three 200 pl aliquots were taken for use as standards in the scintillation counter.
The final concentrations of the components of the solution mixture were as follows:
polyvinyl sulfonic acid): 0.10 mg/ml (1.0 mM) to poly-Glu-Lys: 0.25 mg/ml (1.0 mM) serotonin HCI; 0.0004 mg/ml (0.02 mM) DIDA: < 0.01 mg/ml ( < 0.01 mM) 0.5 ml of this mixture was placed in a Centricon tube having a filter with a molecular weight cut-off of 10,000. The sample was centrifuged for 30 minutes.
One 15 200 ~,1 aliquot was taken from the filtrate and counted on the scintillation counter.
The results from the scintillation counter indicated that approximately 88 %
of the original serotonin was present in the filtrate. It is assumed that 12% of the serotonin was retained on the filter of the Centricon tube due to association of the serotonin with a polymeric complex in the solution mixture.
Example 9. Association of serotonin with poly(aspartic acid), poly-Glu-Lys, and N-(2,6-diisopropylphenylcarbamoylmethyl}iminodiacetic acid (DIDA).
0.62 ml of a poly(aspartic acid) solution (1.0 mg/ml} was added to 20 p,l of 1.0 mg/ml serotonin HCI from Example 1, Experiment A, and vortexed for 20 seconds.
In a 2 5 separate vial, 1.13 ml of a 1.0 mg/ml solution of poly-Glu-Lys was added to 10 p,l of a 0.84 mg/ml solution of DIDA and vortexed for 20 seconds. The two vials were vortexed together and two 200 ~,1 aliquots were taken for use as standards.
The final concentrations of the individual components of the vortexed solution mixture were as follows:
poly(aspartic acid) 0.35 mg/ml (2.6 mM) poly-Glu-Lys 0.63 mg/ml (2.6 mM) serotonin HCl 0.01 mg/ml (0.05 mM) DIDA < 0.01 mg/ml ( < 0.01 mM) 0.5 ml of this mixture was placed in a Centricon tube having a filter with a molecular weight cut-off of 10,000. The sample was centrifuged for 30 minutes.
Two 200 ~1 aliquots were taken from the filtrate and counted on the scintillation counter.
1 o Approximately 92 % of the original serotonin was found in the filtrate.
Approximately 8 % was assumed to have been retained on the filter of the Centricon tube due to ionic interactions and/or hydrogen bonding with the polymers in the solution mixture.
15 Example 10. Association of serotonin with poly(lysine), phytic acid, poly-Glu-Lys, and N-(2,6-diisopropylphenylcarbamoylmethy)iminodiacetic acid (DIDA).
In this experiment, 1.05 ml of poly(lysine) solution (0.56 mg/ml) was added to p,l of a 0.84 mg/inl solution of DIDA and vortexed for 20 seconds. In a separate vial, 1.28 ml of a 0.56 mg/ml solution of phytic acid added to 20 ~1 of the 1.0 mg/ml serotonin 2 o HCl solution from Example 1, Experiment A. 1.13 ml of a 1.0 mg/ml solution of poly-Glu-Lys was also added to the second vial. The contents of the second vial were vortexed for 20 seconds. The two vials were then vortexed together and two 200 ~1 aliquots were taken for use as standards.
The final concentrations of the various components of the mixed solution were as 2 5 follows:
poly(lysine): 0.17 mg/ml (1.3 mM) phytic Acid: 0.21 mglml (0.2 mM) poly-Glu-Lys: 0.32 mglml (1.3 mM) serotonin HCI: < 0.01 mglml ( < 0.01 mM) 3 o DIDA: < 0.01 mg/ml ( < 0.01 mM) 0.5 ml of this mixture was placed in a Centricon tube having a filter with a molecular weight cut-off of 10,000. The tube was centrifuged for 30 minutes.
Two 200 p,l aliquots were then taken from the filtrate and counted on the scintillation counter.
The data from the scintillation counter indicated that 86 % of the original serotonin was in the filtrate. This result suggests that approximately 14 % of the original serotonin was bound to the polymers of the solution mixture and was therefore retained on the filter.
Example 11. Association of serotonin with poly(glutamic acid), chitosan, and N-(2,6-diisopropylphenylcarbamoylmethy)iminodiacetic acid (DIDA).
1 o In this experiment, 1.06 ml of 0.5 mg/ml poly(glutamic acid) was added to 20 ~.1 of the 1.0 mg/ml solution of serotonin HCI from Example l, Experiment A, and vortexed for 20 seconds. Then 0.76 of a 1.0 mg/ml solution of low molecular weight (MW) chitosan was added to 10 ~l of a 0.84 mg/ml solution of DIDA and vortexed for seconds. The two vials were vortexed together, and two 200 pl aliquots were taken for use as standards in the scintillation counter.
Final concentrations of the individual components in the solution mixture were as follows:
poly(glutamic acid): 0.29 mg/ml (2.5 mM) chitosan (low MW): 0.41 mg/ml {2.5 mM) 2 o serotonin -HCI: 0.01 mg/ml (0.05 mM) DIDA: < 0.01 mglml ( < 0.01 mM) 0.5 ml of this mixture was placed in a Centricon tube having a filter with a molecular weight cut-off of 10,000, and the tube was then centrifuged for 30 minutes.
Two 200 ~1 aliquots were taken from the filtrate and counted on the scintillation counter.
2 5 The results indicated that the filtrate contained 95 % of the original serotonin. 5 %
of the original serotonin was retained by the filter.
Example 12. Association of serotonin with poly(galacturonic acid), poly-Glu-Lys, and N-(2,6-diisopropylphenylcarbamoylmethy)iminodiacetic acid ~(DIDA).
30 20 pl of the serotonin HCl solution from Example 1, Experiment A, (lmglml) was added to 0.370 ml of poly{galacturonic acid) solution (2mg/ml) and heated for a few seconds at 60°C and vortexed. Then 1.0 ml of the poly-Glu-Lys solution (1 mg/ml) was added to the above mixture and vortexed. 10 ~1 of DIDA (0.84 mg/ml) was then added.
The solutions were mixed by again vortexing.
Concentrations in the final solution mixture were as follows:
poly(galacturonic acid): 0.53 mg/ml (3 mM) poly-Glu-Lys: 0.71 mg/ml (3 mM) serotonin HCI: 0.014 mg/ml (0.07 mM) DIDA: 0.0006 mg/ml (0.02 mM) 1 ml of this mixture was placed into a green Centricon tube having a filter with a molecular weight cut-off of 10,000. The sample was centrifuged for 1 hour at 6,500 rpm on a Sorvall refrigerated centrifuge at 10°C. 100 ~l aliquots of the sample, before and after filtration, were counted on the scintillation counter.
The data from the scintillation counter indicated that the filtrate contained 90 % of the serotonin that was in the mixed solution. Approximately 10 % of the original serotonin appeared to have been retained on the Centricon filter, presumably due to binding of serotonin to the polymeric components of the solution mixture.
Example 13. Failure of serotonin to bind with poly (L-lactide acid-co-glycolide), chitosan (Mr=70kD), and N-(2,6-diisopropylphenylcarbamoylmethyl) iminodiacetic acid (DIDA) in the absence of an anchoring secondary polymer.
In a first vial, 1.49 ml of the poly (L-lactide acid-co-glycolide) solution (1.0 mg/ml) from Example 4 was added to 20 ~1 of the 1.0 mg/ml serotonin HCl solution from Example l, Experiment A, and vortexed for 20 seconds. A solution of DIDA was prepared by weighing out 8.4 mg of DIDA and dissolving it in 10 ml of 10 mM
HEPES
buffer, pH 7Ø In a second vial, 0.85 ml of the low molecular weight chitosan solution 2 5 (1.0 mg/ml) from Example 3 was added to 10 ~1 of the DIDA solution, and the mixture was vortexed for 20 seconds. The two vials were mixed together and two 100 ~1 aliquots were taken for use as standards The final concentrations of the various components of the solution mixture were as follows:
3 o Poly (L-lactide acid-co-glycolide): 0.68 mg/ml {2.1 mM) chitosan (Mr=70kD): 0.39 mg/ml (2.4 mM) serotonin HCI: 0.01 mg/ml (0.04 mM) WO 99/04824 PCT/ITS98/15457 _.
DIDA: < 0.01 mg/ml ( < 0.01 mM) 1.0 ml of this mixture was placed in a yellow Centricon tube having a filter with a molecular weight cut-off of 3,000. The tube and contents were centrifuged for one hour.
Two 100 pl aliquots were taken from the filtrate and counted on the scintillation counter.
The data from the scintillation counter indicated that the filtrate contained 100 % of the serotonin originally in the solution mixture. None of the serotonin appeared to have been retained on the Centricon filter. This result suggests that without the anchoring presence of a suitable secondary polymer such as poly-Glu-Lys, serotonin may be unable to form a stable association with primary polymeric matrices such as poly(L-lactide acid-1 o co-glycolide) and chitosan.
While the invention has been described with respect to the specific embodiments described herein, it is understood that modifications thereto and equivalents and variations thereof will be apparent to one skilled in the art and are intended to be and are included within the scope of the claims appended hereto.
Claims (25)
1. A polymeric construct for delivering a biologically active agent to a mammal comprising:
a) a first polymeric matrix;
b) a biologically active agent contained within the polymeric matrix; and c) a second polymer chemically bound to the biologically active agent, said second polymer being an amino acid copolymer, said second polymer present in an amount effective to reduce leakage of the active agent from the polymeric construct prior to delivery to the desired situs.
a) a first polymeric matrix;
b) a biologically active agent contained within the polymeric matrix; and c) a second polymer chemically bound to the biologically active agent, said second polymer being an amino acid copolymer, said second polymer present in an amount effective to reduce leakage of the active agent from the polymeric construct prior to delivery to the desired situs.
2. A polymeric construct of claim 1 further comprising a targeting moiety bound to at least one of the first or second polymers.
3. A polymeric construct of claim 1 wherein the first polymeric component is selected from .the group consisting of copoly(lactidelglycolide), poly(lactic acid), poly(glycolic acid), poly(hydroxycarboxylic acids), polylactones, polyacetals, polyorthoesters polycarbonates, poly(amino acids), chitosan glutamate, polyacrylates, poly(divinyl glycol), albumin, polyamines, poly(hydroxybutyric acid), scleroglucans, polyoxyalkylenes, polygalacturonic acid (partially esterified) and xanthan gum.
4. A polymeric construct of claim 1 wherein the second polymer is a copolymer of lysine with other amino acids.
5. A polymeric construct of claim 1 wherein the biologically active agent comprises a biogenic amine.
6. A polymeric construct of claim 5 wherein the biogenic amine comprises an sympathomimetic amine or an autacoid.
7. A polymeric construct of claim 6 wherein the biogenic amine is selected from the group consisting of L-.beta.-3,4-dihydroxyphenylalanine (L-DOPA), 3-(2-aminoethyl)-5-hydroxyindole (5-hydroxytryptamine or serotonin), 2-(4-imidazolyl)ethylamine (histamine), 4-[1-hydroxy-2-(methylamino)ethyl]-1,2-benzenediol (epinephrine), 1-[3,4-dihydroxyphenyl]-2-aminoethanol (norepinephrine), .gamma.-amino-n-butyric acid, acetylcholine, serotonergic agonists and amino acids.
8. A polymeric construct of claim 7 wherein the biogenic amine is serotonin or a serotonergic agonist.
9. A polymeric construct of claim 2 wherein the targeting molecule comprises a biliary-attracted molecule.
10. A polymeric construct of claim 9 in which the biliary-attracted molecule is selected from the group consisting of substituted iminodiacetic acids, N'-substituted derivatives of ethylene diamine-N,N-diacetic acid (EDDA), hepatobiliary dyes, hepatobiliary contrast agents, bile salts, hepatobiliary thiol complexes, and hepatobiliary amine complexes.
11. A polymeric construct of claim 10 wherein the biliary-attracted molecule is N-(2,6-diisopropylphenylcarbamoylmethyl)iminodiacetic acid, N-(2,6-diethylphenyl carbamoylmethyl)iminodiacetic acid, N-(2,6-dimethylphenylcarbamoylmethyl) iminodiacetic acid, N-(4-isopropylphenylcarbamoylmethyl)iminodiacetic acid, N-(4-butylphenylcarbamoylmethyl)iminodiacetic acid, N-(2,3-dimethylphenylcarbamoyl methyl)iminodiacetic acid, N-(3-butylphenylcarbamoylmethyl)iminodiacetic acid, N-(2-butylphenylcarbamoylmethyl)iminodiacetic acid, N-(4-tertiary-butylphenyl carbamoylmethyl)iminodiacetic acid, N-(3-butoxyphenylcarbamoylmethyl) iminodiacetic acid, N-(2-hexyloxyphenylcarbamoylmethyl)iminodiacetic acid, N-(4-hexyloxyphenylcarbamoylmethyl)iminodiacetic acid; azo substituted iminodiacetic acid, iminodicarboxymethyl-2-naphthyl ketone, phthalein complexone, N-(5,pregnene-3-.beta.-ol-2-oylcarbamoylmethyl)iminodiacetic acid, 3a: 7a: 12a: trihydroxy-24-norchol anyl-23-iminodiacetic acid, N-(3-bromo-2,4,6-trimethylphenylcarbamoylmethyl) iminodiacetic acid, benzimidazole methyliminodiacetic acid, N-(3-cyano-4,5-dimethyl-2-pyrrylcarbamoyl-methyl)iminodiacetic acid, ethylenediamine-N,N-bis(-2-hydroxy-bromophenyl) acetate, N'acyl and N'-sulfonyl ethylene diamine-N,N diacetic acid;
N'-acetyl EDDA, N'-benzoyl EDDA, N'-(p-toluenesulfonyl) EDDA, N'-(P-t-butylbenzoyl) EDDA, N'-(benzenesulfonyl) EDDA, N'-(p-chlorobenzenesulfonyl) EDDA, N'(p-ethylbenzenesulfonyl) EDDA, N'-(p-n-propylbenzenesulfonyl) EDDA, N'-(naphthalene-2-sulfonyl) EDDA, N'-(2,5-dimethylbenzenesulfonyl) EDDA; N-(2-acetylnaphthyl) iminodiacetic acid; N-(2-naphthyl)methyl)iminodiacetic acid; rose bengal, congo red, bromosulphthalein, bromophenol blue, phenolphthalein, toluidine blue, indocyanine green, iodipamide, ioglycamic acid, bilirubin, cholyglycyliodohistamine, thyroxineglucuronide, penicillamine, .beta.-mercaptoisobutyric acid, dihydroehioctic acid, 6-mercaptopurine, kethoxal-bis(thiosemicarbazone);
1-hydrazinophthalazine(hydralazine)sulfonyl urea; pyridoxylidene glutamate, pyridoxylidene isoleucine, pyridoxylidene phenylalanine, pyridoxylidene tryptophan, pyridoxylidene 5-methyl tryptophan; 3-hydroxy-4-formyl-pyridene glutamic acid; tetracycline, 7-carboxy-.beta.-hydroxyquinoline, phenolphthalexon, eosin or verograffin.
N'-acetyl EDDA, N'-benzoyl EDDA, N'-(p-toluenesulfonyl) EDDA, N'-(P-t-butylbenzoyl) EDDA, N'-(benzenesulfonyl) EDDA, N'-(p-chlorobenzenesulfonyl) EDDA, N'(p-ethylbenzenesulfonyl) EDDA, N'-(p-n-propylbenzenesulfonyl) EDDA, N'-(naphthalene-2-sulfonyl) EDDA, N'-(2,5-dimethylbenzenesulfonyl) EDDA; N-(2-acetylnaphthyl) iminodiacetic acid; N-(2-naphthyl)methyl)iminodiacetic acid; rose bengal, congo red, bromosulphthalein, bromophenol blue, phenolphthalein, toluidine blue, indocyanine green, iodipamide, ioglycamic acid, bilirubin, cholyglycyliodohistamine, thyroxineglucuronide, penicillamine, .beta.-mercaptoisobutyric acid, dihydroehioctic acid, 6-mercaptopurine, kethoxal-bis(thiosemicarbazone);
1-hydrazinophthalazine(hydralazine)sulfonyl urea; pyridoxylidene glutamate, pyridoxylidene isoleucine, pyridoxylidene phenylalanine, pyridoxylidene tryptophan, pyridoxylidene 5-methyl tryptophan; 3-hydroxy-4-formyl-pyridene glutamic acid; tetracycline, 7-carboxy-.beta.-hydroxyquinoline, phenolphthalexon, eosin or verograffin.
12. A polymeric construct for delivering a biogenic amine to a mammal comprising:
a) a first polymeric matrix;
b) a biogenic amine contained within the polymeric matrix; and c) a second polymer chemically bound to the biogenic amine, said second polymer comprising an amino acid coploymer, said second polymer present in an amount effective to reduce leakage of the biogenic amine from the polymeric construct prior to delivery to the desired situs.
a) a first polymeric matrix;
b) a biogenic amine contained within the polymeric matrix; and c) a second polymer chemically bound to the biogenic amine, said second polymer comprising an amino acid coploymer, said second polymer present in an amount effective to reduce leakage of the biogenic amine from the polymeric construct prior to delivery to the desired situs.
13. A polymeric construct of claim 12 further comprising a targeting moiety bound to at least one of the first or second polymers
14. A polymeric construct of claim 12 wherein the biogenic amine comprises serotonin or a serotonergic agonist.
15. A polymeric construct of claim 12 wherein the second polymer is a copolymer of lysine with other amino acids.
16. A polymeric construct for delivering serotonin or a serotonergic agonist to the hepatocytes of the liver of a mammal comprising:
a) a first polymeric matrix;
b) serotonin or a serotonergic agonist contained within the polymeric matrix;
c) a second polymer chemically bound to serotonin or the serotonergic agonist, said second polymer comprising an amino acid coploymer of lysine and at least one of aspartic and glutamic acids, said second polymer present in an amount effective to reduce leakage of the serotonin or serotonergic agonist from the polymeric construct prior to delivery to the desired situs; and d) an hepatobiliary targeting moiety bound to at least one of the first or second polymers.
a) a first polymeric matrix;
b) serotonin or a serotonergic agonist contained within the polymeric matrix;
c) a second polymer chemically bound to serotonin or the serotonergic agonist, said second polymer comprising an amino acid coploymer of lysine and at least one of aspartic and glutamic acids, said second polymer present in an amount effective to reduce leakage of the serotonin or serotonergic agonist from the polymeric construct prior to delivery to the desired situs; and d) an hepatobiliary targeting moiety bound to at least one of the first or second polymers.
17. A pharmaceutical composition comprising a polymer construct of claim 1 and a pharmaceutically acceptable excipient.
18. A pharmaceutical composition comprising a polymer construct of claim 12 and a pharmaceutically acceptable excipient.
19. A pharmaceutical composition comprising a polymer construct of claim 16 and a pharmaceutically acceptable excipient.
20. A method of treating a disease state in a mammal which method comprises administering a therapeutically effective amount of a polymeric construct of claim 1 to the mammal.
21. A method of treating a disease state in a mammal responsive to therapy with biogenic amines which method comprises administering a therapeutically effective amount of a polymeric construct of claim 12 to the mammal.
22. A method of treating a disease state in a mammal responsive to therapy with serotonin or a serotonergic agonist which method comprises administering a therapeutically effective amount of a polymeric construct of claim 16 to the mammal.
23. A method of treating Type II diabetes in a mammal which method comprises administering a therapeutically effective amount of a pharmaceutical composition of claim 19 to the mammal.
24. A method of treating Type II diabetes in a mammal which method comprises administering a therapeutically effective amount of a pharmaceutical composition comprising:
a) a first polymeric matrix;
b) serotonin or a serotonergic agonist contained within the polymeric matrix;
c) a second polymer chemically bound to serotonin or the serotonergic agonist, said second polymer comprising an amino acid coploymer of lysine and at least one of aspartic and glutamic acids, said second polymer present in an amount effective to reduce leakage of the serotonin or serotonergic agonist from the polymeric construct prior to delivery to the desired situs;
d) an hepatobiliary targeting moiety bound to at least one of the first or second polymers;
and e) a pharmaceutically acceptable excipient.
a) a first polymeric matrix;
b) serotonin or a serotonergic agonist contained within the polymeric matrix;
c) a second polymer chemically bound to serotonin or the serotonergic agonist, said second polymer comprising an amino acid coploymer of lysine and at least one of aspartic and glutamic acids, said second polymer present in an amount effective to reduce leakage of the serotonin or serotonergic agonist from the polymeric construct prior to delivery to the desired situs;
d) an hepatobiliary targeting moiety bound to at least one of the first or second polymers;
and e) a pharmaceutically acceptable excipient.
25. A method of claim 24 in which the amount of serotonin is from about 100 µg to about 200 µg.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US5372997P | 1997-07-25 | 1997-07-25 | |
US60/053,729 | 1997-07-25 | ||
PCT/US1998/015457 WO1999004824A1 (en) | 1997-07-25 | 1998-07-24 | Polymer based pharmaceutical compositions for targeted delivery of biologically active agents |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2297025A1 true CA2297025A1 (en) | 1999-02-04 |
Family
ID=21986168
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002297025A Abandoned CA2297025A1 (en) | 1997-07-25 | 1998-07-24 | Polymer based pharmaceutical compositions for targeted delivery of biologically active agents |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0999855A1 (en) |
JP (1) | JP2001510811A (en) |
CN (1) | CN1264310A (en) |
AU (1) | AU8591298A (en) |
CA (1) | CA2297025A1 (en) |
WO (1) | WO1999004824A1 (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP4586022B2 (en) | 2003-09-29 | 2010-11-24 | 日東電工株式会社 | Biodegradable polyacetals for in vivo polynucleotide delivery |
US7674452B2 (en) | 2005-03-16 | 2010-03-09 | Nitto Denko Corporation | Polymer coating of cells |
US7588754B2 (en) | 2005-05-10 | 2009-09-15 | Nitto Denko Corporation | Biodegradable polyacetals and methods |
BR112019015141A2 (en) | 2017-01-27 | 2020-03-24 | Cornell University | POLYMERS AND HYDROGELS MODIFIED WITH ZWITTERION |
US10611857B2 (en) | 2017-08-02 | 2020-04-07 | Exxonmobil Chemical Patents Inc. | Bisphenolate transition metal complexes, production and use thereof |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3360633D1 (en) * | 1982-02-12 | 1985-10-03 | Unitika Ltd | Anti-cancer device |
SE8804164A0 (en) * | 1988-11-17 | 1990-05-18 | Per Prisell | Pharmaceutical preparation |
CA2046830C (en) * | 1990-07-19 | 1999-12-14 | Patrick P. Deluca | Drug delivery system involving inter-action between protein or polypeptide and hydrophobic biodegradable polymer |
AU5605894A (en) * | 1992-11-12 | 1994-06-08 | Molecular Dynamics, Inc. | Lipophilic peptide-based carriers for targeted drug delivery using rational drug-binding design |
US5847047A (en) * | 1993-06-22 | 1998-12-08 | E. I. Du Pont De Nemours And Company | Antimicrobial composition of a polymer and a peptide forming amphiphilic helices of the magainin-type |
WO1996004001A1 (en) * | 1994-08-05 | 1996-02-15 | Molecular/Structural Biotechnologies, Inc. | Site-specific biomolecular complexes |
-
1998
- 1998-07-24 CN CN 98807413 patent/CN1264310A/en active Pending
- 1998-07-24 CA CA002297025A patent/CA2297025A1/en not_active Abandoned
- 1998-07-24 JP JP2000503875A patent/JP2001510811A/en active Pending
- 1998-07-24 AU AU85912/98A patent/AU8591298A/en not_active Abandoned
- 1998-07-24 WO PCT/US1998/015457 patent/WO1999004824A1/en not_active Application Discontinuation
- 1998-07-24 EP EP98937127A patent/EP0999855A1/en not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
CN1264310A (en) | 2000-08-23 |
EP0999855A1 (en) | 2000-05-17 |
WO1999004824A1 (en) | 1999-02-04 |
AU8591298A (en) | 1999-02-16 |
JP2001510811A (en) | 2001-08-07 |
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EEER | Examination request | ||
FZDE | Discontinued |