MXPA96004634A - Compositions for controlled supply, liqui - Google Patents
Compositions for controlled supply, liquiInfo
- Publication number
- MXPA96004634A MXPA96004634A MXPA/A/1996/004634A MX9604634A MXPA96004634A MX PA96004634 A MXPA96004634 A MX PA96004634A MX 9604634 A MX9604634 A MX 9604634A MX PA96004634 A MXPA96004634 A MX PA96004634A
- Authority
- MX
- Mexico
- Prior art keywords
- agent
- composition
- implant
- liquid
- controlled release
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 224
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 164
- 239000007943 implant Substances 0.000 claims abstract description 114
- 229920000642 polymer Polymers 0.000 claims abstract description 105
- 239000007787 solid Substances 0.000 claims abstract description 59
- 239000011159 matrix material Substances 0.000 claims abstract description 52
- 239000003960 organic solvent Substances 0.000 claims abstract description 24
- 229920001169 thermoplastic Polymers 0.000 claims abstract description 23
- 238000006065 biodegradation reaction Methods 0.000 claims abstract description 21
- 239000007788 liquid Substances 0.000 claims description 139
- 239000003814 drug Substances 0.000 claims description 45
- 229920001577 copolymer Polymers 0.000 claims description 43
- 229920001244 Poly(D,L-lactide) Polymers 0.000 claims description 36
- 229920001730 Moisture cure polyurethane Polymers 0.000 claims description 35
- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- 239000003094 microcapsule Substances 0.000 claims description 24
- 239000011859 microparticle Substances 0.000 claims description 24
- -1 polyesteramides Polymers 0.000 claims description 23
- 239000011148 porous material Substances 0.000 claims description 18
- 239000011780 sodium chloride Substances 0.000 claims description 18
- 230000000975 bioactive Effects 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 17
- 239000000969 carrier Substances 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 13
- 239000006185 dispersion Substances 0.000 claims description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- 230000002459 sustained Effects 0.000 claims description 12
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 11
- 229920001610 polycaprolactone Polymers 0.000 claims description 10
- 239000007888 film coating Substances 0.000 claims description 9
- 238000009501 film coating Methods 0.000 claims description 9
- 239000002105 nanoparticle Substances 0.000 claims description 9
- 239000002344 surface layer Substances 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- JJTUDXZGHPGLLC-UHFFFAOYSA-N dilactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 238000005755 formation reaction Methods 0.000 claims description 8
- LZCLXQDLBQLTDK-UHFFFAOYSA-N Ethyl lactate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 claims description 7
- 229920000954 Polyglycolide Polymers 0.000 claims description 7
- 229920001710 Polyorthoester Polymers 0.000 claims description 7
- 239000000032 diagnostic agent Substances 0.000 claims description 7
- 229940116333 ethyl lactate Drugs 0.000 claims description 7
- 239000004744 fabric Substances 0.000 claims description 7
- 229920001281 polyalkylene Polymers 0.000 claims description 7
- 229920001897 terpolymer Polymers 0.000 claims description 7
- JBKVHLHDHHXQEQ-UHFFFAOYSA-N Caprolactam Chemical compound O=C1CCCCCN1 JBKVHLHDHHXQEQ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002502 liposome Substances 0.000 claims description 6
- 229920000747 poly(lactic acid) polymer Polymers 0.000 claims description 6
- 229920000515 polycarbonate Polymers 0.000 claims description 6
- 239000004417 polycarbonate Substances 0.000 claims description 6
- 239000004952 Polyamide Substances 0.000 claims description 5
- 229920000331 Polyhydroxybutyrate Polymers 0.000 claims description 5
- 229920002988 biodegradable polymer Polymers 0.000 claims description 5
- 239000004621 biodegradable polymer Substances 0.000 claims description 5
- 239000000835 fiber Substances 0.000 claims description 5
- 150000003891 oxalate salts Chemical class 0.000 claims description 5
- 239000005015 poly(hydroxybutyrate) Substances 0.000 claims description 5
- 229920000218 poly(hydroxyvalerate) Polymers 0.000 claims description 5
- 229920002627 poly(phosphazenes) Polymers 0.000 claims description 5
- 229920002647 polyamide Polymers 0.000 claims description 5
- 229920002635 polyurethane Polymers 0.000 claims description 5
- 239000004814 polyurethane Substances 0.000 claims description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N Oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 4
- 229920002732 Polyanhydride Polymers 0.000 claims description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-N glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 4
- 238000011065 in-situ storage Methods 0.000 claims description 4
- 230000004048 modification Effects 0.000 claims description 4
- 238000006011 modification reaction Methods 0.000 claims description 4
- 229920001308 poly(aminoacid) Polymers 0.000 claims description 4
- 238000005507 spraying Methods 0.000 claims description 4
- RUOJZAUFBMNUDX-UHFFFAOYSA-N Propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 claims description 3
- 239000003242 anti bacterial agent Substances 0.000 claims description 3
- 239000003096 antiparasitic agent Substances 0.000 claims description 3
- 239000003443 antiviral agent Substances 0.000 claims description 3
- 239000003102 growth factor Substances 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 238000010422 painting Methods 0.000 claims description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 3
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 claims description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N 2-Pyrrolidone Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 2
- 229920000858 Cyclodextrin Polymers 0.000 claims description 2
- MMOXZBCLCQITDF-UHFFFAOYSA-N DEET Chemical compound CCN(CC)C(=O)C1=CC=CC(C)=C1 MMOXZBCLCQITDF-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- GUVUOGQBMYCBQP-UHFFFAOYSA-N DMPU Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 claims description 2
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 claims description 2
- OBNCKNCVKJNDBV-UHFFFAOYSA-N Ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 claims description 2
- UYXTWWCETRIEDR-UHFFFAOYSA-N Glyceryl tributyrate Chemical compound CCCC(=O)OCC(OC(=O)CCC)COC(=O)CCC UYXTWWCETRIEDR-UHFFFAOYSA-N 0.000 claims description 2
- 229940088597 Hormone Drugs 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N Malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- HHVIBTZHLRERCL-UHFFFAOYSA-N Methylsulfonylmethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 claims description 2
- 210000004940 Nucleus Anatomy 0.000 claims description 2
- 239000005642 Oleic acid Substances 0.000 claims description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N Triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 claims description 2
- 229960002622 Triacetin Drugs 0.000 claims description 2
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 2
- 239000000730 antalgic agent Substances 0.000 claims description 2
- 230000001387 anti-histamine Effects 0.000 claims description 2
- 239000003429 antifungal agent Substances 0.000 claims description 2
- 239000000739 antihistaminic agent Substances 0.000 claims description 2
- 239000002220 antihypertensive agent Substances 0.000 claims description 2
- 239000000164 antipsychotic agent Substances 0.000 claims description 2
- 239000003699 antiulcer agent Substances 0.000 claims description 2
- 239000000168 bronchodilator agent Substances 0.000 claims description 2
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 2
- 239000002327 cardiovascular agent Substances 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims description 2
- 239000003576 central nervous system agent Substances 0.000 claims description 2
- 239000000812 cholinergic antagonist Substances 0.000 claims description 2
- NFKGQHYUYGYHIS-UHFFFAOYSA-N dibutyl propanedioate Chemical compound CCCCOC(=O)CC(=O)OCCCC NFKGQHYUYGYHIS-UHFFFAOYSA-N 0.000 claims description 2
- DKMROQRQHGEIOW-UHFFFAOYSA-N diethyl butanedioate Chemical compound CCOC(=O)CCC(=O)OCC DKMROQRQHGEIOW-UHFFFAOYSA-N 0.000 claims description 2
- OUWSNHWQZPEFEX-UHFFFAOYSA-N diethyl glutarate Chemical compound CCOC(=O)CCCC(=O)OCC OUWSNHWQZPEFEX-UHFFFAOYSA-N 0.000 claims description 2
- 239000001087 glyceryl triacetate Substances 0.000 claims description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 claims description 2
- 239000005556 hormone Substances 0.000 claims description 2
- 238000002513 implantation Methods 0.000 claims description 2
- 229940099690 malic acid Drugs 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 229920002866 paraformaldehyde Polymers 0.000 claims description 2
- 229920000141 poly(maleic anhydride) Polymers 0.000 claims description 2
- 229920002463 poly(p-dioxanone) polymer Polymers 0.000 claims description 2
- 229920002432 poly(vinyl methyl ether) polymer Polymers 0.000 claims description 2
- 239000000622 polydioxanone Substances 0.000 claims description 2
- 150000003900 succinic acid esters Chemical class 0.000 claims description 2
- UWHCKJMYHZGTIT-UHFFFAOYSA-N tetraethylene glycol Chemical compound OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 claims description 2
- ZFOZVQLOBQUTQQ-UHFFFAOYSA-N tributyl 2-hydroxypropane-1,2,3-tricarboxylate Chemical compound CCCCOC(=O)CC(O)(C(=O)OCCCC)CC(=O)OCCCC ZFOZVQLOBQUTQQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000001069 triethyl citrate Substances 0.000 claims description 2
- 235000013769 triethyl citrate Nutrition 0.000 claims description 2
- 229960005486 vaccines Drugs 0.000 claims description 2
- 239000003071 vasodilator agent Substances 0.000 claims description 2
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 claims description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 2
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims 1
- 230000003110 anti-inflammatory Effects 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 238000005266 casting Methods 0.000 claims 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 230000035558 fertility Effects 0.000 claims 1
- 239000003193 general anesthetic agent Substances 0.000 claims 1
- 229940074076 glycerol formal Drugs 0.000 claims 1
- 238000010952 in-situ formation Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000002138 osteoinductive Effects 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 229920003168 pharmaceutical polymer Polymers 0.000 claims 1
- 239000008196 pharmacological composition Substances 0.000 claims 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims 1
- 239000004416 thermosoftening plastic Substances 0.000 claims 1
- 238000005273 aeration Methods 0.000 abstract 1
- 229940079593 drugs Drugs 0.000 description 41
- 239000002904 solvent Substances 0.000 description 35
- 239000000243 solution Substances 0.000 description 33
- 238000009472 formulation Methods 0.000 description 27
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 27
- 239000000562 conjugate Substances 0.000 description 26
- 210000001519 tissues Anatomy 0.000 description 26
- AOJJSUZBOXZQNB-TZSSRYMLSA-N ADRIAMYCIN Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 21
- 229960004679 Doxorubicin Drugs 0.000 description 21
- 239000000460 chlorine Substances 0.000 description 16
- 229910052801 chlorine Inorganic materials 0.000 description 16
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 16
- DQCKKXVULJGBQN-XFWGSAIBSA-N Naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 13
- 229960003086 Naltrexone Drugs 0.000 description 13
- 239000000463 material Substances 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- GJNXBNATEDXMAK-PFLSVRRQSA-N (2S)-1-[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propanoyl]amino]-3-pyridin-3-ylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-6-[bi Chemical compound C([C@@H](C(=O)N[C@H](CCCCN=C(NCC)NCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN=C(NCC)NCC)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 GJNXBNATEDXMAK-PFLSVRRQSA-N 0.000 description 12
- 229920000249 biocompatible polymer Polymers 0.000 description 12
- WGSLWEXCQQBACX-UHFFFAOYSA-N Chlorin Chemical compound C=1C(C=C2)=NC2=CC(C=C2)=NC2=CC(C=C2)=NC2=CC2=NC=1CC2 WGSLWEXCQQBACX-UHFFFAOYSA-N 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 239000012530 fluid Substances 0.000 description 10
- 210000001124 Body Fluids Anatomy 0.000 description 9
- 239000010839 body fluid Substances 0.000 description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 9
- 229960000406 Ganirelix acetate Drugs 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- 239000002953 phosphate buffered saline Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000002585 base Substances 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 230000012010 growth Effects 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 239000000580 polymer-drug conjugate Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 230000036328 Free drug Effects 0.000 description 5
- 238000007792 addition Methods 0.000 description 5
- 239000003708 ampul Substances 0.000 description 5
- 239000011248 coating agent Substances 0.000 description 5
- 238000000576 coating method Methods 0.000 description 5
- 238000009792 diffusion process Methods 0.000 description 5
- 229960003794 ganirelix Drugs 0.000 description 5
- 201000001997 microphthalmia with limb anomalies Diseases 0.000 description 5
- 239000002077 nanosphere Substances 0.000 description 5
- 230000001105 regulatory Effects 0.000 description 5
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-Nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 4
- 210000003567 Ascitic Fluid Anatomy 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Carbodicyclohexylimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- OKPYIWASQZGASP-UHFFFAOYSA-N N-(2-hydroxypropyl)-2-methylprop-2-enamide Chemical compound CC(O)CNC(=O)C(C)=C OKPYIWASQZGASP-UHFFFAOYSA-N 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- 241000048284 Potato virus P Species 0.000 description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 4
- 210000004027 cells Anatomy 0.000 description 4
- 238000005345 coagulation Methods 0.000 description 4
- 230000015271 coagulation Effects 0.000 description 4
- 230000001186 cumulative Effects 0.000 description 4
- 239000004632 polycaprolactone Substances 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 230000001737 promoting Effects 0.000 description 4
- 229920003176 water-insoluble polymer Polymers 0.000 description 4
- 210000000988 Bone and Bones Anatomy 0.000 description 3
- 229940039227 DIAGNOSTIC AGENTS Drugs 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N Hexamethylphosphoramide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- 102000002265 Human Growth Hormone Human genes 0.000 description 3
- 108010000521 Human Growth Hormone Proteins 0.000 description 3
- 239000000854 Human Growth Hormone Substances 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- 229940074730 OPHTHAMOLOGIC DIAGNOSTIC AGENTS Drugs 0.000 description 3
- 230000000561 anti-psychotic Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000003247 decreasing Effects 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229920000656 polylysine Polymers 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000001225 therapeutic Effects 0.000 description 3
- 231100000224 toxic side effect Toxicity 0.000 description 3
- 229920003169 water-soluble polymer Polymers 0.000 description 3
- BOURDYMMTZXVRY-UHFFFAOYSA-N 2-(2-methylprop-2-enoylamino)acetic acid Chemical compound CC(=C)C(=O)NCC(O)=O BOURDYMMTZXVRY-UHFFFAOYSA-N 0.000 description 2
- VHSHLMUCYSAUQU-UHFFFAOYSA-N 2-hydroxypropyl methacrylate Chemical compound CC(O)COC(=O)C(C)=C VHSHLMUCYSAUQU-UHFFFAOYSA-N 0.000 description 2
- 229940023040 Acyclovir Drugs 0.000 description 2
- WHTVZRBIWZFKQO-UHFFFAOYSA-N Chloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 2
- 229960003677 Chloroquine Drugs 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- 102000016359 Fibronectins Human genes 0.000 description 2
- 108010067306 Fibronectins Proteins 0.000 description 2
- 102000018997 Growth Hormone Human genes 0.000 description 2
- 108010051696 Growth Hormone Proteins 0.000 description 2
- 102000000589 Interleukin-1 Human genes 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- GPKJTRJOBQGKQK-UHFFFAOYSA-N Mepacrine Chemical compound C1=C(OC)C=C2C(NC(C)CCCN(CC)CC)=C(C=CC(Cl)=C3)C3=NC2=C1 GPKJTRJOBQGKQK-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 229940049954 Penicillin Drugs 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229940079923 Quinacrine Drugs 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- CXMXRPHRNRROMY-UHFFFAOYSA-N Sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 239000004809 Teflon Substances 0.000 description 2
- 229960000278 Theophylline Drugs 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N Theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 229960004150 aciclovir Drugs 0.000 description 2
- MKUXAQIIEYXACX-UHFFFAOYSA-N acyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 229960000626 benzylpenicillin Drugs 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000005354 coacervation Methods 0.000 description 2
- 230000001268 conjugating Effects 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 230000005670 electromagnetic radiation Effects 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000037320 fibronectin Effects 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000012216 imaging agent Substances 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 238000011068 load Methods 0.000 description 2
- 229960000901 mepacrine Drugs 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 230000003000 nontoxic Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N p-acetaminophenol Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 238000006068 polycondensation reaction Methods 0.000 description 2
- 229920002643 polyglutamic acid Polymers 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 210000004872 soft tissue Anatomy 0.000 description 2
- 239000011343 solid material Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 230000017423 tissue regeneration Effects 0.000 description 2
- 239000003021 water soluble solvent Substances 0.000 description 2
- VQOXZBDYSJBXMA-NQTDYLQESA-N (1S,3R,4E,6E,8E,10E,14E,16E,18S,19R,20R,21S,25R,27R,29R,32R,33R,35S,37S,38R)-3-[(2R,3S,4S,5S,6R)-4-amino-3,5-dihydroxy-6-methyloxan-2-yl]oxy-19,25,27,29,32,33,35,37-octahydroxy-18,20,21-trimethyl-23-oxo-22,39-dioxabicyclo[33.3.1]nonatriaconta-4,6,8,10,14, Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 1
- BFSMWENDZZIWPW-UHFFFAOYSA-N (4-amino-4-oxo-3,3-diphenylbutyl)-methyl-di(propan-2-yl)azanium;iodide Chemical compound [I-].C=1C=CC=CC=1C(C(N)=O)(CC[N+](C)(C(C)C)C(C)C)C1=CC=CC=C1 BFSMWENDZZIWPW-UHFFFAOYSA-N 0.000 description 1
- DQCKKXVULJGBQN-UWFFTQNDSA-N (4R,4aS,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one Chemical compound C([C@@]12[C@@]3(O)CCC(=O)C1OC=1C(O)=CC=C(C2=1)C[C@]31[H])CN1CC1CC1 DQCKKXVULJGBQN-UWFFTQNDSA-N 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N 1,2,3-propanetrioltrinitrate Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- NZJXADCEESMBPW-UHFFFAOYSA-N 1-methylsulfinyldecane Chemical compound CCCCCCCCCCS(C)=O NZJXADCEESMBPW-UHFFFAOYSA-N 0.000 description 1
- JDXQWYKOKYUQDN-UHFFFAOYSA-N 3-hydroxypyrrolidine-2,5-dione Chemical group OC1CC(=O)NC1=O JDXQWYKOKYUQDN-UHFFFAOYSA-N 0.000 description 1
- XRZWVSXEDRYQGC-UHFFFAOYSA-N 4-cyclohexylpyrrolidin-1-ium-2-carboxylate Chemical compound C1NC(C(=O)O)CC1C1CCCCC1 XRZWVSXEDRYQGC-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N 5-flurouricil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 1
- 229940116904 ANTIINFLAMMATORY THERAPEUTIC RADIOPHARMACEUTICALS Drugs 0.000 description 1
- 229940034982 ANTINEOPLASTIC AGENTS Drugs 0.000 description 1
- 229940022659 Acetaminophen Drugs 0.000 description 1
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N Acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 1
- 229940009456 Adriamycin Drugs 0.000 description 1
- PECIYKGSSMCNHN-UHFFFAOYSA-N Aminophylline Chemical compound NCCN.O=C1N(C)C(=O)N(C)C2=NC=N[C]21.O=C1N(C)C(=O)N(C)C2=NC=N[C]21 PECIYKGSSMCNHN-UHFFFAOYSA-N 0.000 description 1
- 229960003556 Aminophylline Drugs 0.000 description 1
- 229960003071 Bacitracin Drugs 0.000 description 1
- 108010001478 Bacitracin Proteins 0.000 description 1
- 229960005274 Benzocaine Drugs 0.000 description 1
- BLFLLBZGZJTVJG-UHFFFAOYSA-N Benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 1
- 102000007350 Bone Morphogenetic Proteins Human genes 0.000 description 1
- 108010007726 Bone Morphogenetic Proteins Proteins 0.000 description 1
- LEBVLXFERQHONN-UHFFFAOYSA-N Bupivacaine Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N Carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229960002908 Cimetidine Hydrochloride Drugs 0.000 description 1
- JYGXADMDTFJGBT-VWUMJDOOSA-N Cortisol Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 1
- 229940097362 Cyclodextrins Drugs 0.000 description 1
- 240000001879 Digitalis lutea Species 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N Diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- 102000018233 Fibroblast growth factor family Human genes 0.000 description 1
- 108050007372 Fibroblast growth factor family Proteins 0.000 description 1
- 229960002949 Fluorouracil Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N Flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 229940028334 Follicle Stimulating Hormone Drugs 0.000 description 1
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 1
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 208000006454 Hepatitis Diseases 0.000 description 1
- 208000006572 Human Influenza Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 206010022000 Influenza Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000014429 Insulin-like growth factor Human genes 0.000 description 1
- 108050003490 Insulin-like growth factor Proteins 0.000 description 1
- 229940047124 Interferons Drugs 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 229960001543 Isopropamide Iodide Drugs 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 229960005015 Local anesthetics Drugs 0.000 description 1
- 229940083877 Local anesthetics for treatment of hemorrhoids and anal fissures for topical use Drugs 0.000 description 1
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Loniten Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 description 1
- 210000002751 Lymph Anatomy 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229960003632 Minoxidil Drugs 0.000 description 1
- BQJCRHHNABKAKU-KBQPJGBKSA-N Morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 1
- 210000003205 Muscles Anatomy 0.000 description 1
- 210000003928 Nasal Cavity Anatomy 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 210000003666 Nerve Fibers, Myelinated Anatomy 0.000 description 1
- 229940053128 Nerve Growth Factor Drugs 0.000 description 1
- 102000015336 Nerve Growth Factor Human genes 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 229940053207 Niacin Drugs 0.000 description 1
- 229940014995 Nitroglycerin Drugs 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- 229940074726 OPHTHALMOLOGIC ANTIINFLAMMATORY AGENTS Drugs 0.000 description 1
- XQYZDYMELSJDRZ-UHFFFAOYSA-N Papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 1
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 1
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 1
- 208000000474 Poliomyelitis Diseases 0.000 description 1
- 229920000805 Polyaspartic acid Polymers 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N Prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- RJKFOVLPORLFTN-STHVQZNPSA-N Progesterone Natural products O=C(C)[C@@H]1[C@@]2(C)[C@H]([C@H]3[C@@H]([C@]4(C)C(=CC(=O)CC4)CC3)CC2)CC1 RJKFOVLPORLFTN-STHVQZNPSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 206010037742 Rabies Diseases 0.000 description 1
- 210000003296 Saliva Anatomy 0.000 description 1
- 210000002966 Serum Anatomy 0.000 description 1
- 229960005202 Streptokinase Drugs 0.000 description 1
- 108010023197 Streptokinase Proteins 0.000 description 1
- 208000002847 Surgical Wound Diseases 0.000 description 1
- RJKFOVLPORLFTN-LEKSSAKUSA-N Syngestrets Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 1
- 229940033123 Tannic Acid Drugs 0.000 description 1
- LRBQNJMCXXYXIU-NRMVVENXSA-N Tannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-NRMVVENXSA-N 0.000 description 1
- 206010043376 Tetanus Diseases 0.000 description 1
- OFVLGDICTFRJMM-WESIUVDSSA-N Tetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O OFVLGDICTFRJMM-WESIUVDSSA-N 0.000 description 1
- 229960002180 Tetracycline Drugs 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 231100000765 Toxin Toxicity 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H Tricalcium phosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 108010001801 Tumor Necrosis Factor-alpha Proteins 0.000 description 1
- 230000036462 Unbound Effects 0.000 description 1
- 229960003636 Vidarabine Drugs 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Xylocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive Effects 0.000 description 1
- 239000000464 adrenergic agent Substances 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000002429 anti-coagulation Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000002921 anti-spasmodic Effects 0.000 description 1
- 102000004965 antibodies Human genes 0.000 description 1
- 108090001123 antibodies Proteins 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940019336 antithrombotic Enzymes Drugs 0.000 description 1
- 150000008430 aromatic amides Chemical class 0.000 description 1
- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-N 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 230000000903 blocking Effects 0.000 description 1
- 230000003182 bronchodilatating Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229960003150 bupivacaine Drugs 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 230000002490 cerebral Effects 0.000 description 1
- QJHCNBWLPSXHBL-UHFFFAOYSA-N cimetidine hydrochloride Chemical compound [H+].[Cl-].N#C/N=C(/NC)NCCSCC=1N=CNC=1C QJHCNBWLPSXHBL-UHFFFAOYSA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000001112 coagulant Effects 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 150000001990 dicarboxylic acid derivatives Chemical class 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ZKBBUZRGPULIRN-UHFFFAOYSA-N diethyl 2,2-diethylpropanedioate Chemical compound CCOC(=O)C(CC)(CC)C(=O)OCC ZKBBUZRGPULIRN-UHFFFAOYSA-N 0.000 description 1
- 229960000520 diphenhydramine Drugs 0.000 description 1
- 201000009910 diseases by infectious agent Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 201000009273 endometriosis Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002255 enzymatic Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 150000002270 gangliosides Chemical class 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 239000002474 gonadorelin antagonist Substances 0.000 description 1
- 229940121381 gonadotrophin releasing hormone (GnRH) antagonists Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 239000011796 hollow space material Substances 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing Effects 0.000 description 1
- 230000002209 hydrophobic Effects 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229940064003 local anesthetic throat preparations Drugs 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 201000005505 measles Diseases 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000002503 metabolic Effects 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 229930014694 morphine Natural products 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960000988 nystatin Drugs 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 210000000056 organs Anatomy 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 229960001789 papaverine Drugs 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 230000003239 periodontal Effects 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000004977 physiological function Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 230000001376 precipitating Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000000717 retained Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 230000004936 stimulating Effects 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000004083 survival Effects 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 229920001187 thermosetting polymer Polymers 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 108020003112 toxins Proteins 0.000 description 1
- 230000002936 tranquilizing Effects 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 150000003627 tricarboxylic acid derivatives Chemical class 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 230000000261 vasodilator Effects 0.000 description 1
- ZTHWFVSEMLMLKT-CAMOTBBTSA-N vidarabine monohydrate Chemical compound O.C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O ZTHWFVSEMLMLKT-CAMOTBBTSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Abstract
The present invention relates to a polymeric system suitable for use as a controlled release implant for the controlled release of an active agent, the system is characterized in that it comprises: a) a microporous solid matrix of biocompatible, biodegradable, thermoplastic polymer, the polymer is insoluble in an aqueous medium, and b) an active agent incorporated in a particulate, biodegradable, controlled release component, the particulate controlled release component is substantially insoluble in the aqueous medium, and the controlled release component is embedded within the microporous matrix; wherein the microporous matrix is prepared by contact between the aqueous medium and a delivery composition which includes a biocompatible organic solvent which has a solubility range of miscible to dispersible in an aqueous medium, the biocompatible thermoplastic polymer, and the active agent are incorporated into the lib component controlled particulate aeration, biodegradab
Description
COMPOSITIONS FOR SUPPLY, CXWT SWOT, LIQUIDS BACKGROUND OF THE INVENTION A variety of approaches have been developed to enable the sustained, sustained release of drugs to a subject. These controlled release systems are designed to protect the drug from the environment prior to delivery while allowing the controlled release of the drug to a target area. All currently available approaches, however, suffer from one or more disadvantages or limitations. A number of conventional controlled release systems are based on microstructures, such as lipospheres, liposomes, microcapsules, microparticles and nanoparticles. The microstructures are typically introduced into the body of a subject in the form of a dispersion. While microstructure dispersions are useful for many applications, these systems can not be used to form a continuous barrier film or a solid implant with the structural integrity required for prosthetic applications.
In addition, when inserted into a body cavity where there is considerable fluid flow, for example, the mouth or eyes, the microstructures may be poorly retained due to their small size and discontinuous nature. Another limitation of these systems based on microstructure is the lack of reversibility of introduction without extensive and complex surgical intervention. If complications arise after your
REF: 23206 introduction, systems based on microstructures are considerably more difficult to remove from the body of a subject than a solid implant. Conventional controlled supply systems can also be prepared as macrostructures. An active agent such as a drug can be mixed with a polymer. The mixture is then shaped into a specific form such as a cylinder, disc or fiber for implant. Alternatively, a solid porous implant, which is formed of a biodegradable polymer, can serve as a container for holding one of the controlled release microsystems described above on site in a subject. With any of these solid implant approaches, the drug delivery system is typically inserted into the body through an incision. These incisions are often larger than desired and may lead the subject to be reluctant to accept this treatment. Both microstructures and macrostructures of conventional controlled release systems can be prepared from polymer-drug conjugates. As such they have the same disadvantages as those previously described for similar structures of other conventional controlled release systems. In addition, polymer-drug conjugates can be prepared from water-soluble polymers, so that they can not be recovered if required. Because polymer-drug conjugates produce a variety of drug release mechanisms, such as hydrolysis, enzymatic cleavage, or photorelease and allow a greater degree of control over release rates, it would be convenient if they could be prepared without the above disadvantages. The disadvantages of the systems described above have been overcome to some extent by the development of drug delivery systems that can be administered as a liquid (for example by syringe) and subsequently transformed in a solid implant. For example, liquid polymeric compositions for use as biodegradable controlled release delivery systems are described in U.S. Pat. No. 4,938,763, 5,278,201 and 5,278,202. These compositions can be administered to the body in a liquid state. Once in the body, the compositions coagulate or cure to form a solid. Such a polymer composition includes a non-reactive thermoplastic polymer or copolymer, dissolved in a water-soluble solvent. This polymer solution is introduced to the body, for example by means of a syringe, where it "sets" or solidifies upon dissipating or diffusing the solvent in the surrounding body fluids. The other injectable polymer composition is based on a thermofix system of prepolymers that can be cured in itself. This polymer system includes reactive liquid oligomeric prepolymers, which cure by entanglement to form solids, usually with the aid of a curing agent. These injectable liquid polymer systems have a number of distinct advantages. While the requirement for an incision is avoided, liquid delivery systems allow for the formation of an implant with sufficient structural integrity to be used as prosthetic devices or as a continuous barrier film. Because a solid implant is formed, these liquid systems also avoid the dissipation problems observed with dispersions of microstructures in those portions of the body that experience considerable fluid flow. Despite these disadvantages, the liquid supply systems currently available to form
implants in itself, lack certain convenient features. When a liquid supply system includes a biodegradable polymer and an active agent dissolved in a water soluble solvent, it comes into contact with a medium
Water, such as a body fluid, the solvent dissipates or diffuses into the aqueous medium. As the polymer precipitates or coagulates to form a solid matrix, the active agent is treated or encapsulated through the polymer matrix. The release of the active agent then follows the general rules
for the dissolution or diffusion of a drug from inside a polymeric matrix. The formation of the solid matrix from the liquid supply system however is not instantaneous, but typically occurs over a period of several hours. During this initial period, the diffusion rate of the active agent can be much faster than the rate of release that occurs from the subsequently formed solid matrix. This initial discharge effect (i.e. the amount of active agent released in the first 24 hours) can result in the loss or release of a large amount of the active agent prior to the formation of the solid matrix. If the active agent is particularly toxic, this initial discharge or release will likely lead to these toxic side effects and may cause damage to adjacent tissues. The development of liquid delivery systems that would allow in-situ training of an implant while reducing or eliminating the initial discharge effect will represent a significant advance. These delivery systems will allow higher concentrations of an active agent to be safely incorporated into an implant. The efficiency of these systems will also be improved, since a much higher percentage of the active agent will remain in the implant for sustained release and will not be lost during the initial discharge. Optimally, the liquid delivery system will produce a number of ways to control the release of the active agent from the system. These advantages will extend the application of these treatments as well as reduce the possibility of toxic side effects. There is therefore a continuing need for controlled release systems that can be introduced in liquid form, to form a solid implant in itself and that will facilitate the sustained release of an active agent in the body of a subject, without creating an initial shock. of active agent. BRIEF DESCRIPTION OF THE INVENTION LT-5 The present invention provides liquid compositions that are useful for delivering active agents in vivo and allow the initial discharge of active agent to be controlled more effectively than previously possible. This can be done for example by incorporating the active agent in
a controlled release component and combine the controlled release component with the liquid polymer systems described in US Pat. Nos. 4,938,763, 5,278,201 and 5,278,202. The controlled release component may include a controlled release system of
microstructure (for example a microcapsule) or macrostructure (for example film or fiber), a molecular controlled release system (for example polymer / drug conjugate) or combinations thereof. The resulting liquid supply compositions may include either
liquid or solution formulations of a biocompatible prepolymer, polymer or copolymer in combination with the controlled release component. These liquid delivery compositions can be introduced in liquid form into the body of a subject. The liquid composition is then solidified or cured in situ to form a controlled release implant. The formulation employed to constitute the controlled release implant itself can be a liquid delivery composition that includes a biocompatible polymer that is substantially insoluble in aqueous medium., an organic solvent that is miscible or dispersible in aqueous medium, and the controlled release component. The biocompatible polymer dissolves substantially in the liquid solvent. The controlled release component can be dissolved, dispersed or entrapped in the polymer / solvent solution. In a preferred embodiment, the biocompatible polymer is biodegradable and / or bioerodible. The liquid supply composition can be used to form a solid controlled release implant in either the interior or the exterior of the body of the subject. In one embodiment of the invention, the composition for delivery of liquid is introduced to an implant site in the subject, wherein the composition solidifies to form the controlled release implant upon contact with a body fluid. In another embodiment of the invention, a solid implant can be formed outside the subject by contacting the liquid composition with an aqueous medium. The solid implant can then be inserted into an implant site in the subject. In yet another embodiment of the present invention, the composition for liquid delivery can be used to form a film coating on a tissue of a subject. An amount (effective to form a film coating) of the liquid composition is supplied to the fabric, such as by spraying, painting or jetting, and film coating is formed on the fabric by contacting the supply composition of the fabric. liquid with an aqueous medium. The invention also includes a method of treating a subject with an active agent by administering the liquid delivery composition to an implant site in a subject to form a solid controlled release implant in itself. The treatment of a subject with the active agent can also be carried out by inserting into the subject a solid sustained release implant that forms outside the subject upon contacting the liquid supply composition with an aqueous medium. The present invention also encompasses a method that includes treating the tissue of a subject (e.g., injured tissue) by administering an effective amount of the liquid delivery composition to form a liquid coating in the tissue.
In another embodiment of the invention, the controlled release component incorporating the active agent can also be introduced into the body of a subject as part of a liquid delivery composition that includes a liquid, biocompatible prepolymer. The liquid prepolymer has at least one polymerizable ethylenically unsaturated group (for example a prepolymer terminated in acrylic ester). If a curing agent is employed, the curing agent is typically added to the composition just before use. The prepolymer remains, as a liquid for a short period of time after the introduction of the curing agent. During this period, the liquid supply composition can be introduced into a body, e.g. by syringe. The mixture then solidifies in itself to form a solid implant. Other
embodiments of the liquid delivery system may also include a pore-forming agent, or an organic solvent that is miscible or dispersible in an aqueous medium, in addition to the prepolymer and controlled release component. Alternately, the pore forming agent or the organic solvent
can be added to the liquid prepolymer composition together with or just after the addition of the curing agent. When a liquid supply composition including the pore forming agent or the organic solvent in combination with the prepolymer is employed, the implant that is formed includes a solid microporous polymer matrix having the controlled release component therein embedded. Another embodiment of the present invention is directed to a method of treating a subject with the active agent which includes introducing the liquid prepolymer composition to the subject. Yet another embodiment of the invention allows treating a damaged tissue of a subject that includes administering to the injured tissue an effective amount of the liquid prepolymer composition to form a film coating. Another method for providing liquid compositions that are useful for the delivery of active agents in vivo and allows the initial release of active agent to be controlled more effectively than previously possible consists in conjugating the active agent with a biocompatible polymer insoluble in water and dissolving the resulting active agent-polymer conjugated in a biocompatible solvent to form a liquid polymer system similar to that described in US Pat. Nos. 4,938,763, 5,278,201 and 5,278,202. The water-insoluble biocompatible polymers may be those described in the above patents or related copolymers. In addition, the liquid polymer system may also include a biocompatible water-insoluble polymer that is not conjugated to the active agent. In one embodiment of the invention, these liquid compositions can be introduced into the body of a subject in liquid form. The liquid composition is then solidified or coagulated in itself to form a controlled release implant, wherein the active agent is conjugated to the solid matrix polymer. In another embodiment of the invention, a solid implant can be formed outside the subject by contacting the liquid composition with an aqueous medium. The solid implant can then be inserted into an implant site in the subject. In yet another embodiment of the present invention, the liquid supply composition can be used to form a film coating in an lt fabric. of a subject. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the cumulative amount of naltresonone released from 75/25 poly (D, L-lactide-co-glycolide) (PLG) formulations dissolved in NMP. The formulations
include either free naltrexone or microparticles prepared by fusion of naltrexone and poly (D, L-lactide) (PLA). Each of the formulations contains 5.0% w / w of naltrexone (in a free drug base). Figure 2 shows the cumulative amount of a
antipsychotic drug (APD) released from formulations in 75/25 PLG dissolved in NMP. The formulations include either free APD or APD encapsulated with high molecular weight poly (vinyl pyrrolidinone) ("PVP"). Each of the formulations contains 5.0% w / w APD (in a free drug base).
Figure 3 shows the cumulative amount of chlorine
(chlorin) e6 released from formulations at 75/25 PLG dissolved in
DMSO. The formulations include either chlorine (free chlorine) and chlorine (chlorin) e6 covalently linked to a copolymer of (N-2-hydroxypropyl) -methacrylamide) / N-methacryloylglycine.
Each of the formulations contains 0.5% w / w chlorine (chlorin) e6 (in a free drug base). DETAILED DESCRIPTION OF THE INVENTION The present invention provides biocompatible liquid delivery compositions that can be employed to form solid structures that allow an active agent to be delivered in a controlled and sustained manner. The compositions are typically administered in liquid form.
After insertion, the compositions solidify or cure ("set") to form a solid or gelatinous matrix
("implant"), which is substantially insoluble in aqueous medium, such as body fluids. Based on the relative separation properties of the active agent in a given formulation, an initial release of a comparatively large amount of the active agent can be observed. In some cases, this initial release may not be problematic, for example the active agent may be a drug with a large therapeutic window. In other cases, however, the initial release may cause damage to adjacent tissues or lead to toxic side effects.
Liquid Polymer System with Controlled Release Component Initial discharge can be reduced or avoided by modifying the physical state of the active agent, for example incorporating the active agent in a controlled release component which is then dissolved, dispersed or entrapped in the delivery composition liquid For example, the controlled release component may include microstructures, ___ macrostructures, conjugates, complexes or salts of low l? ¯ solubility in water. In principle, the additional time required to release the active agent from the controlled release component will allow the formulation to solidify into a solid implant without the initial loss of a substantial amount of the active agent. In this way, the
The present compositions are useful for the delivery of active agents in vivo and allow the initial discharge of
• Active agent is controlled more selectively than previously possible. Examples of controlled release components
Suitable, include microstructures such as microparticles, nanoparticles, cyclodextrins, microcapsules, mycelia and liposomes. The controlled release component can also include macrostructures such as fibers, rods, films, discs or cylinders. Components of
Suitable controlled release also include salts of low water solubility of the active agent and complexes or conjugates wherein the active agent is operatively associated with a carrier molecule. In addition, combinations of the above approaches are included within the definition of the controlled release component. For example, the controlled release component can be a microstructure, such as a microcapsule, which includes the active agent as part of a complex, conjugate or salt of low water solubility. If the liquid supply composition is to be introduced to the subject by injection, the size of the microcapsules or microparticles is typically limited to no more than 500 microns and preferably no greater than 150 microns. Microeasures greater than 500 microns are difficult to supply by syringe or rubber tube and can be uncomfortable or irritating to the surrounding tissues. In other applications, the controlled release component may nevertheless include a macrostructure such as a fiber, a film or a larger polymer strip or beads. These may be dispersed, trapped or associated with the liquid portion of the liquid supply composition such that the composition solidifies to form a matrix with the macrostructure therein embedded. In alternate form, the liquid portion can act as an adhesive to hold the macrostructure in place, at an implant site in the subject's body. The macrostructures are larger than 500 microns. The upper limits in size of the macrostructures will depend on the particular application. Once a solid matrix is formed, the resulting implant provides at least dual modes to control the release of the active agent - a first mode based on the release rate of the active agent from the controlled release component and a second based mode in the release of the implant matrix. The second mode is regulated by the rate of biodegradation and / or bioerosion ll of the implant material and can also be governed by diffusion where the implant is a microporous matrix. The rate of release of the controlled release component can also be regulated by the rate of biodegradation and / or bioerosion of a polymer matrix, for example when the
The controlled release component is a microparticle or polymeric microcapsule. The rate of release may also depend on a variety of other processes, such as when the controlled release component includes a conjugate of a carrier molecule and the active agent. The
The rate of release of the active agent from the conjugate can also be regulated by the rate of breakdown or decomposition of the conjugate. The selection of the particular controlled release component will depend on the physical characteristics of the agent
Active (eg, solubility, stability, etc.) and the desired properties of the liquid composition and the resulting implant. The controlled release component may include one or more of a variety of materials. The controlled release component can include a polymer, for example as the matrix of a microparticle, as the coating of a microcapsule, or as the carrier molecule of an active agent conjugate. The controlled release component may also include a hydrophobic counter ion, such as when the active agent is present as a salt of low water solubility. The controlled release component can include combinations of the foregoing, such as when the controlled release component includes a conjugate-) active agent encapsulated within a polymeric coating. The controlled release component can include a plurality of microstructures such as microparticles, microcapsules or nanoparticles. Microparticles or microcapsules typically are between 1 and 500 microns in size, although smaller particles may be employed (for example nanoparticles that are in the range in size from 10 nanometers to 1000 nanometers). In this context, microcapsules are defined as deposit systems wherein a single deposit of material including the active agent is surrounded by a membrane cover. The reservoir may contain only the active agent or may include other materials such as a polymer or an agent for rate of release modification. Alternatively, the reservoir may include the active agent incorporated as part of a conjugate, a complex or a salt of low water solubility. Microparticles are small monolithic entities in which the active agent is distributed through the particle matrix, typically in a random fashion. However, many practical formulations fall between these two definitions. For example, microcapsules can agglomerate during the microencapsulation process. In other cases, the size of the active agent particles contained in a "microcapsule" system may be of the same order as the size of the microcapsules themselves. For purposes of this invention, the term "microstructure" is defined to include microparticles, nanoparticles, microcapsules or any related intermediate forms. Various physical and chemical methods to prepare these microstructures have been developed and the technology is well established and well documented. See for example Patrick V. Deasy, "Microencapsulation and Related Drug Processes"
(Microencapsulation and Related Drug Processes), Marcel
Dekker Inc., New York (1984). A variety of exemplary methods for preparing microcapsules and microparticles are known (see for example U.S. Patent Nos. 4,061,254, 4,818,542, 5,019,400 and 5,271,961; and Wakiyama et al., Chem. Pharm Bull .. 29, 3363-68 (1981 )). Depending on the desired physical and chemical properties, a number of these methods can be used to prepare microcapsules or microparticles. The microparticles may be in the form of lipospheres. In this case, the microparticles include a phospholipid and optionally an inert solid material, such as wax. Lipospheres are solid microparticles, insoluble in water, which has a layer of the phospholipid embedded in its surface. The nucleus of the lipospheres either contains a solid active agent, or an active agent that is dispersed in the inert solid material (see for example U.S. Patent No. 5, ..88, 837). Liposomes containing the active agent are typically formed in an aqueous solution by one of the well-known methods (see for example U.S. Patent No. 5,049,386). The aqueous solution containing the liposomes can be incorporated into the compositions of the present invention, for example by forming an oil-in-water emulsion of this solution in a liquid prepolymer. After curing, a polymer matrix is formed with the liposomes therein embedded. Nanoparticles are carriers for drugs or other active molecules that are prepared in the range of nanometer sizes (10 nm - 1000 nm). They may incorporate drugs into nanoparticles using colloidal coacervation of polymers, absorption on the surface of polymeric carriers colloidal solids, coating of the particles by polymerisation, polycondensation or coacervation, solidifying spherical micelles under nanocompartamentalización, by polymerization or polycondensation, and interfacial polymerization techniques using electrocapillary emulsification. For example, nanoparticles may include nanospheres as described by Gref et al., Science. 263. 1600-1602 (1994). The nanospheres can be formed from diblock polymers having a lipophilic block and a hydrophilic block. The active agent is distributed through the nanosphere and is typically present as a molecular dispersion through the lipophilic core of the nanospheres. When nanospheres are present at a high charge, however, a phase separation of the active agent leading to the formation of agglomerates or crystals of active agent may occur. The liquid delivery compositions may also include a number of macrostructures such as fibers, rods, films, discs or cylinders. These macrostructures can consist of deposit systems in which the active agent is surrounded by a membrane that controls the rate of release, or monolithic systems in which the active agent is distributed through the macrostructure matrix. The present liquid delivery compositions offer the advantage of both safe and sustained release of an active agent without an initial discharge effect. In another embodiment of the invention, this can be achieved by incorporating the active agent (e.g., a drug) into a controlled release component that includes a conjugate. Conjugates in this context are defined as a controlled release component wherein the active agent is covalently linked to a carrier molecule. By covalent binding of the active agent to the carrier molecule, the solubility and transport properties of the active agent are altered. Preferably, the carrier molecule does not have its own biological activity and is easily biodegraded. The carrier molecule is typically a polymer, but it can also be a smaller organic molecule. For example, the active agent can be covalently linked to a small molecule such as stearic acid through an ester or amide bond, thereby decreasing the water solubility of the active agent. The polymers employed to prepare drug conjugates may be water-soluble, eg polyethylene glycol, poly-L-aspartic acid, poly (glutamic acid), polylysine, poly (malic acid), dextran and copolymers of N- (2-hydroxypropyl ) -methacrylamide (HPMA). The polymers employed to prepare drug conjugates may also include water-insoluble polymers such as polyglycolide, poly (lactide DL-) (PLA), polycaprolactone (PCL), polyorthoesters, polycarbonates, polyamides, polyanhydrides, polyurethanes, polyesteramides, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates and copolymers, terpolymers or combinations or mixtures thereof. Some polymers or copolymers can be soluble in water or, insoluble in water, depending on their molecular weight and proportion of monomers incorporated in the copolymer, for example poly (lactide-co-lysine) and poly (lactide-co-malolactonic acid). In order for the drug to be conjugated in these polymers, there must be active groups such as hydroxyl, carboxyl or amine groups. These reactive groups can either be at the terminal ends of the polymers or in side chains to the main polymer structure. If the reactive groups are terminal groups, the molecular weight of the polymer may need to be relatively low to have sufficient end groups to achieve the desired drug loading. There are a number of ways to connect a drug to polymers with reactive groups. These include the formation of activated ester groups such as p-nitrophenyl esters, hydroxysuccinimide esters, and the use of dicyclohexyl carbodiimide (DCC). The polymer-drug conjugates can be incorporated into the liquid polymer compositions either as microstructures or macrostructures. They can also be dissolved or dispersed simply in the liquid polymer compositions. A variety of polymers such as poly (amino acids), poly (amino acid esters), poly (carboxylic acids), poly (hydroxycarboxylic acids), polyoxy esters, polyphosphazenes, polyalkylene glycols and related copolymers, have been employed in the preparation of polymer / drug conjugates. For example, poly (amino acids) such as poly-L-aspartic acid, poly (lysine), and poly (glutamic acid) have been employed in the preparation of polymer / drug conjugates. Related copolymers such as poly (lactic acid-co-lysine) ^ (PLA / Lys) and a poly (ethylene glycol) -poly (aspartic acid) block copolymer have also been employed. Others
Polymers which are suitable for use in the preparation of polymer / drug conjugates, include dextran and copolymers of
- "N- (2-hydroxypropyl) -methacrylamide (HPMA copolymers) The polymers used to prepare drug conjugates can be soluble in water, for example polyethylene glycol, acid
poly-L-aspartic acid, and poly (lysine), or alternatively can be a water insoluble polymer such as poly (lactide-co-glycolide) (PLG). Some of the copolymers used, for example PLA / Lys, can be water-soluble or water-insoluble, depending on the proportion of monomers incorporated in them.
the copolymer. Other examples of thermoplastic polymers that can be employed as the carrier molecule include poly (glycolide), poly (D, L-lactide) (PLA), poly (caprolactone)
(PLC) and copolymers of malolactonic acid and D, L-lactide
(PLA / MLA). The liquid supply composition may consist only of an organic solvent and a conjugate having the active agent covalently linked to a thermoplastic polymer that is substantially insoluble in aqueous medium, for example a PLA or low molecular weight PLG. Alternatively, the composition may include the thermoplastic polymer in unbound form as well as linked to the active agent. In another embodiment of the present invention, the controlled release component can include a complex in which a carrier molecule is operatively associated with the active agent. The complex may also include a metal cation operatively associated with the active agent and the carrier molecule. For example, the complex may include a biodegradable polymer with carboxyl groups. The carboxyl groups in the polymer can form a coordination complex with a drug and a metal such as zinc, magnesium or calcium. These complexes can break in contact with water. However, the fact that the drug is part of a complex can prevent the drug from spreading out of the implant as quickly as the corresponding free drug.
The controlled release component can include a salt, such as a salt of low water solubility of the active agent. For purposes of this invention, the term "low water solubility salt" is defined as a salt having a solubility not greater than 25 mg / 1 (25 ppm). The solubility of the salt of low solubility in water, here is defined as the amount of salt that can be measured in solution when the salt is dispersed or stirred for 4 hours in distilled water at a temperature not higher than 40 ° C. The salt of low solubility (, < in water typically includes a non-toxic carboxylate anion, insoluble in water, as a counter ion to the active agent (eg the anionic form of pamico acid, tannic acid, or stearic acid). to reduce the initial discharge effect, it is particularly useful when the active agent is a water-soluble bioactive agent such as a peptide (see for example U.S. Patent No. 5,192,741.) The salt of low water solubility of the active agent In an alternating form, the salt of low or water solubility can be microencapsulated or dispersed in the polymer matrix of a microparticle before incorporation into the liquid supply composition. Present controlled release can be prepared from polymers or materials that are already soluble or insoluble in the feed composition. of liquid end, ie soluble and insoluble in the liquid prepolymer organic solvent. The polymer or materials used in the preparation is insoluble, the compositions can be prepared and stored as dispersions, for example of microparticles or microcapsules. When the polymer or material is soluble in the liquid bulk composition, the controlled release composition can be added and mixed in the composition, just before use. The exact time advantage during which these compositions can be employed will depend on the rate of dissolution of the polymer or material in the particular composition. For example, if the polymer or controlled release component material is only slightly soluble in the bulk composition, it may be possible to store the composition as a dispersion or mixture for a limited period of time. Alternatively, if the controlled release component is a conjugate of active agent that is soluble in the liquid bulk composition, all components of the composition can be mixed together to form the liquid composition well in advance of its use. In one embodiment of the invention, the controlled release component can be dissolved, dispersed or entrapped in a solution formulation of a polymer or copolymer to form the liquid delivery composition. The liquid supply composition typically includes a biodegradable and / or bioerodible biocompatible polymer or copolymer dissolved in a non-toxic organic solvent. The solvent is miscible or dispersible in aqueous medium, such as body fluids. This liquid composition can be injected or inserted into an implant site of the body of a subject. Upon contact with body fluids in adjacent tissues, the liquid composition solidifies in itself to form a controlled release implant. The controlled release implant is a solid polymer matrix that has the controlled release component embedded therein. Alternatively, the controlled release component can be dissolved or dispersed in a liquid formulation of a prepolymer to form the liquid delivery composition. After injection or insertion into an implant site, the prepolymer cures to form a solid polymer matrix having the controlled release component therein embedded. The curing step can be carried out with the aid of a curing agent or by other known methods, for example by exposing the prepolymer to electromagnetic radiation. If a curing agent is employed, a mixture is formed which includes the prepolymer and the controlled release component. The curing agent is typically added to this mixture to form a liquid prepolymer preparation just before injection.
In one embodiment of the present invention, the controlled release component including the active agent can be introduced into the body of a subject as part of a liquid composition. The liquid composition includes a biocompatible polymer that is substantially insoluble in aqueous medium, in combination with an organic solvent, and the controlled release component. The organic solvent is miscible or dispersible in aqueous medium. Preferably, the biocompatible polymer is biodegradable and / or bioerodible. The polymer is typically a thermoplastic polymer such as a polylactide, a polycaprolactone or a polyglycolide. The active agent can be a bioactive agent or a diagnostic agent. As used herein, the term "bioactive agent" means a drug, medicament or some other substance capable of producing an effect in a body. As used herein, the term "diagnostic agent" means a substance, such as an imaging agent, that allows the detection or verification of a physiological condition or function. The liquid supply composition can be injected or inserted into an implant site of the subject's body. Upon contact with the aqueous medium, such as body fluids in adjacent tissues, the liquid supply composition solidifies in itself to form a controlled release implant. The organic solvent of the liquid composition is dissipated in fluids from the surrounding tissues and the polymer coagulates to form a solid implant. The implant is a solid polymer matrix that has the controlled release component embedded there. The implant allows controlled delivery of active agents such as drugs, drugs, diagnostic agents and the like. The liquid composition can also be used to form an implant precursor outside the body. The structure of the implant precursor is composed of an outer bag and a liquid filling. After introduction of the implant precursor to the body of the subject, contact with the body fluid results in the in formation of the controlled release implant. The implant precursor includes a mixture of a biocompatible polymer that is substantially insoluble in aqueous medium, the controlled release component includes the active agent, and an organic solvent that is miscible or dispersible in an aqueous medium. As used herein, the term "implant site" is intended to include a site, in or on which the controlled release implant will be formed or applied, such as for example a soft tissue such as muscle or fat, or a hard tissue such as bone. Examples of implant sites include a tissue defect such as a tissue regeneration site; a hollow space such as a periodontal cavity, surgical incision or other cavity or receptacle formed, - a natural cavity such as the oral, vaginal, rectal or nasal cavities, the eye cavity and the like, - and other sites in which the composition for liquid delivery or implant precursor can be placed and formed in a solid implant. The present liquid delivery composition may include a biocompatible polymer or copolymer in combination with a controlled release component and an organic solvent. As described in U.S. Pat. No. 4,938,763, the description of which is incorporated / by reference herein, the organic solvent is biocompatible and miscible or dispersible in aqueous medium. The liquid composition may optionally include a pore forming agent and / or a physiologically acceptable rate modifying agent. The resulting liquid composition and implant precursor and / or solid implant are biocompatible in that neither the polymer, the solvent, the controlled release component nor the polymer matrix cause substantial tissue irritation or necrosis at the implant site. The polymers or copolymers are substantially insoluble in aqueous medium, for example body fluids and are biodegradable and bioerodible and / or bioabsorbable within the body of an animal. The term "biodegradable" means that the matrix of the polymer and / or polymer of the implant will be degraded over time by the action of enzymes, by hydrolytic action and / or by other similar mechanisms in the human body. By "bioerodible" is meant that the implant matrix erodes or degrades over time due at least in part to contact with substances found in the surrounding tissue fluids, cell action and the like. By "bioabsorbable" it is meant that the polymer matrix is broken and absorbed into the human body, for example by a cell, a tissue and the like. Thermoplastic polymers. Thermoplastic polymers useful in the liquid supply composition include biocompatible polymers that are biodegradable and / or bioerodible and / or bioabsorbable, and soften when exposed to heat, but return to their original state when cooled. Thermoplastic polymers are capable of dissolving substantially in an organic solvent. The thermoplastic polymers are also capable of coagulating or precipitating to form an outer membrane, and an inner core consisting of a solid microporous matrix upon dissipating the. solvent component of the polymer solution and the contact of the polymer with an aqueous medium. Thermoplastic polymers which are suitable for use in the polymer solution, generally include any having the following characteristics. Examples are polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polycarbonates, polycarbonates, polyorthoesters, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerate, polyalkylene oxalates, polyalkylene succinates, poly (amino acids), poly ( methyl vinyl ether), poly (maleic anhydride), citin, cytosan, and copolymers, terpolymers or combinations or mixtures thereof. Polylactides, polycaprolactones, polyglycolides and their copolymers are highly preferred thermoplastic polymers. The thermoplastic polymer is combined with a suitable organic solvent to form a solution. The solubility or miscibility of a polymer in a particular solvent will vary according to factors such as crystallinity, hydrophilicity, capacity for hydrogen bonding and molecular weight of the polymer. Consequently, the molecular weight and concentration of the polymer in the solvent are adjusted to achieve the desired solubility. Preferably, the thermoplastic polymers have a low degree of crystallization, a low degree of hydrogen bonding, low solubility in water and high solubility in organic solvents. Solvents Suitable solvents for use in the present liquid delivery composition are those that are biocompatible, pharmaceutically acceptable, miscible with the polymer ingredient and aqueous medium and capable of diffusing in an aqueous medium, such as, for example, tissue fluids surrounding the site. implant, such as blood serum, lymph, cerebral spinal fluid (CSF), saliva and the like.
In addition, the solvent is preferably biocompatible. Typically, the solvent has a Hildebrand solubility parameter from about 9 to about 13 (cal / cm 3) 1/2. The degree of polarity of the solvent should be effective to provide at least about 10% solubility in water, and to dissolve the polymer component. Solvent which are useful in the liquid supply composition, include for example N-methyl-2-pyrrolidone, -2-pyrrolidone; aliphatic alcohols having from two to eight carbon atoms, - propylene glycol; glycerol; tetraglycol; formal glycerol, - solcetal; alkyl esters such as ethyl acetate, ethyl lactate, ethyl butyrate, dibutyl malonate, tributyl citrate, tri-n-hexyl acetyl citrate, diethyl succinate, diethyl glutarate, diethyl malonate, and triethyl citrate; triacetin, tributyrin, diethyl carbonate, propylene carbonate; aliphatic ketones such as acetone and methyl ethyl ketone; dialkylamides such as dimethylacetamide and dimethyl formamide; cyclic alkyl amides such as caprolactam; dimethyl sulfoxide; dimethyl sulfone; decylmethylsulfoxide; oleic acid, aromatic amides such as N, N-diethyl-m-toluamide, 1-dodecylazacycloheptan-2-one, and 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidone and similar. Preferred solvents according to the present invention include N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone, ethyl lactate, dimethyl sulfoxide (DMSO) and propylene carbonate.
A mixture of solvents that provide varying degrees of safety for the polymeric components can be employed to implement the coagulation rate of polymers that exhibit a slow rate of sedimentation or coagulation. For example, the polymer can be combined with a mixture of solvents including a good solvent (ie, a solvent in which the polymer is highly soluble) and a deficient solvent (i.e. a solvent in which the polymer has a low degree of solubility) or a non-solvent (ie lv.7 one in which the polymer is insolvent). Preferably, the solvent mixture containing a deficient solvent or non-solvent and an effective amount of a good solvent, in a mixture such that the polymer remains soluble while in solution but coagulates or precipitates upon dissipating the solvents
in a neighbor aqueous medium, for example tissue fluids at the implant site. The concentration of polymer in the liquid composition will generally allow rapid and effective dissipation of the solvent and coagulation or precipitation of the polymer. This
The concentration may be in the range of about 0.01 gram of polymer / ml of solvent at an approximate saturated concentration, preferably of about 0.1 gram / ml at an approximate saturated concentration and more preferably about 0.2 gram / ml at
approximately 0.7 gram / ml.
Thermofix Polymers. A biodegradable forming implant itself can also be constructed by interweaving properly functionalized biodegradable prepolymers. The liquid thermoset systems of the present invention include the controlled release component and reactive liquid prepolymers. The liquid prepolymers will cure in the form of a solid matrix, usually with the aid of a curing catalyst. In general, any biocompatible oligomer that can be linked to a polymerizable functional group to form a biocompatible prepolymer can be employed. Although any of the biodegradable thermoplastic polymers described herein can be employed, the limiting criterion is that low molecular weight oligomers of these polymers must be liquid and must have at least one functional group that can be reacted with a derivatizing agent containing a polymerizable functional group. Suitable liquid prepolymers include oligomers having pendant or secondary hydroxyl groups, which have been reacted with a derivatizing agent to form a prepolymer having at least one polymerizable ethylenically unsaturated group. For example, a low molecular weight polylactide terminated in hydroxy can be reacted with acryloyl chloride, to produce polylactide oligomer end-terminated with an acrylic ester. The ethylenically unsaturated groups in the prepolymers can then be polymerized by the addition of a curing catalyst, such as a free radical initiator or by exposure to electromagnetic radiation. Because the prepolymer will remain liquid for a short period of time after the addition of a curing agent, a mixture of the liquid prepolymer with a controlled release component of a curing agent can be handled, for example, placed in a syringe and injected into the syringe. the body of a subject. The mixture then forms a solid implant in itself avoiding the need for an incision. As with systems based on the thermoplastic polymers, the rate of release of the active agent will be affected by the diffusion rates of the agent outside the implant. In some cases, the rate of release will be regulated by the biodegradation and / or bioerosion of the polymer matrix implant. In others, the rate of release will be regulated by the rate of release of the active agent from the controlled release component. Active Agent The liquid delivery compositions of the present invention include an active agent, such as a bioactive agent or a diagnostic agent, either alone or in combination, such that the implant or the film coating will provide a delivery system for the active agent to tissues and organs adjacent or distant in the subject. Bioactive agents that can be used alone or in combination in the implant precursor and implant, include for example a medicament, drug or other substance biologically-, physiologically- or pharmaceutically active-, which is capable of providing local or systemic effects biological, physiological or Therapeutic in the body of an animal including a mammal, and released from the solid implant matrix in adjacent or surrounding tissue fluids. Diagnostic agents that can be employed include imaging agents such as radiodiagnosis agents. The active agent can be soluble in the polymer solution to form a homogeneous mixture, or insoluble in the polymer solution to form a suspension or dispersion. Before implantation, the active agent is preferably embedded within the implant matrix. As the matrix degrades with time, the active agent is released from the matrix in adjacent tissue fluids, preferably at a controlled rate. The release of the active agent from the matrix can be varied, for example by the solubility of the active agent in an aqueous medium, the distribution of the agent within the matrix, the size, shape, porosity, solubility and biodegradability of the implant matrix and the like. . The liquid supply composition includes the bioactive agent in an amount effective to provide the desired level of biological, physiological, pharmacological and / or therapeutic effect in the animal. In general there is no critical upper limit on the amount of the bioactive agent included in the liquid delivery composition other than that dictated by the pharmacological properties of the particular bioactive agent. The lower limit of the amount of the bioactive agent incorporated in the polymer solution will depend on the activity of the bioactive agent and the desired period of time for treatment. The bioactive agent can stimulate a biological or physiological activity with the animal. For example, the agent can act to improve cell growth and tissue regeneration, function in birth control, stimulate nerves or growth of bones and the like. Examples of useful bioactive agents include a substance, or metabolic precursor, which is capable of promoting the growth and survival of cells and tissues, or increase the functioning of cells, such as for example a nerve growth promoting substance such as ganglioside, a nerve growth factor and the like; a hard or soft tissue growth promoting agent such as fibronectin (FN), human growth hormone (HGH), interleukin-1 protein growth factor (IL-1) and the like, - a bone growth promoting substance such as hydroxyapatite, tricalcium phosphate and the like; and a substance useful for preventing infection at the implant site, such as for example an antiviral agent such as vidarabine or acyclovir, an antibacterial agent such as penicillin or tetracycline, an antiparasitic agent such as quinacrine or chloroquine. Suitable bioactive agents for use in the invention also include anti-inflammatory agents such as hydrocortisone, prednisone and the like; antibacterial agents such as penicillin, cephalosporins, bacitracin and the like; antiparasitic agents such as quinacrine, chloroquine and the like; antifungal agents such as nystatin, gentamicin and the like; antiviral agents such as acyclovir, ribarivin, interferons and the like, antineoplastic agents such as methotrexate, 5-fluorouracil, adriamycin, tumor-specific antibodies, conjugates in toxins, tumor necrosis factor and the like; analgesic agents such as salicylic acid, acetaminophen, ibuprofen, flurbiprofen, morphine and the like, - local anesthetics such as lidocaine, bupivacaine, benzocaine and the like; vaccines such as hepatitis, influenza, measles, rubrola, tetanus, polio, rabies and the like, - central nervous system agents such as tranquilizers, blocking / S-adrenergic agents, dopamine and the like, - growth factors, such as stimulating factor colony, platelet-derived growth factor, fibroblast growth factor, factor for growth transformation B, human growth hormone, bone morphogenetic protein, insulin-like growth factor and the like; hormones such as progesterone, follicle-stimulating hormone, insulin, somatotropins and the like; antihistamines such as diphenhydramine, chlorfencramine and the like; cardiovascular agents such as digitalis, nitroglycerin, papaverine, streptokinase and the like, anti-ulcer agents such as cimetidine hydrochloride, isopropamide iodide and the like; bronchodilators such as metaproternal sulfate, aminophylline and the like; vasodilators such as theophylline, niacin, minoxidil and the like, - and other similar substances. The bioactive agent can also be an antihypertensive agent, an anticoagulant, an agent? antispasmodic or an antipsychotic agent. For additional examples of bioactive agents that may be employed in the present invention, see U.S. Patent application. corresponding to Applicant Serial No. 07 / 783,512, filed on October 28, 1991, the description of which is incorporated herein by reference. Accordingly, the implant formed can function as a system for delivery of drugs, medicaments, other biologically active agents and diagnostic agents, to tissues adjacent to or distant from the implant site. The active agent is incorporated into the controlled release component. In another embodiment of the invention, the active agent can also be incorporated directly into the polymer matrix surrounding the released release component. Polymer-Drug Conjugates Liquids. The initial drug discharge from the liquid polymer systems described in US Pat. Nos. 4,938,763, 5,278,201 and 5,278,202 can also be decreased or avoided by conjugating the active agent directly to a biodegradable water insoluble polymer and dissolving the resulting polymer-drug conjugate in a biocompatible solvent to form a liquid polymer system similar to those described in the previous patents. Water-insoluble biocompatible polymers can be those described in these patents or related copolymers. In this way, polyglycolide, poly (D, L-lactide), polycaprolactone, polyorthoesters, polycarbonates, polyamides, polyanhydrides, polyurethanes, polyesteramides, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerate, polyalkylene oxalates and copolymers, terpolymers or combinations or mixtures thereof with sufficiently low molecular weight to achieve the desired drug load can be used. Also copolymers or related terpolymers such as poly (lactide-co-malolactonic acid), or combinations or blends of the polymers listed above with other polymers, can be employed to form a solid implant, wherein the active agent is conjugated directly to the matrix of polymer.
The proportions of monomer (D, L-lactide against malolactonic acid) can be varied to obtain the balance of insolubility in water and desired carboxyl group content for a particular application. In some cases, in order to obtain a copolymer with the desired properties, it may be advantageous to use other monomer combinations. For example, MLABE can also be polymerized with glycolide or caprolactone to give, after removal of the benzyl protecting groups by hydrogenation, poly (glycolide-co-malolactonic acid) or poly (caprolactone-co-malolactonic acid), respectively. Terpolymers such as poly (D, L-lactide / glycolide / malolatonic acid) can also be prepared by the same method. Poro structure. The implants formed using the present liquid delivery compositions, preferably include a microporous inner core and a microporous outer surface layer. Typically, the pores of the inner core are substantially uniform and the surface layer of the solid implant is generally non-porous as compared to the porous nature of the core. Preferably, the outer surface layer of the implant has pores with diameters significantly smaller in size than these pores in the inner core, for example the average pore size ratio in the core of average pore size in the surface layer, is about 2/1 to about 100/1, and preferably about 2/1 to about 10 / l. Pores can be formed within the implant matrix by various means. The dissipation, dispersion or diffusion of the solvent outside the solidifying polymer matrix in the adjacent tissue fluids can generate pores, including pore channels in the polymer matrix. The dissipation of the solvent from the coagulation mass creates pores within the solid implant. The pore size of the solid implant is in the range of about 1-1000 microns, preferably the pore size of the surface layer is approximately 3-500 microns. The solid microporous implant has a porosity in the range of about 5-95%. Preferably, the surface layer has a porosity of 5% to about 10% and the core has a porosity of about 40% to about 60%. Optionally, a pore-forming agent can be included in the polymer solution, to generate additional pores in the polymer matrix. This approach is described more fully in U.S. Pat. Serial No. 07 / 283,512, the description of which is incorporated herein by reference. Convenient pore forming agents include a sugar, a salt, a water soluble polymer, and a water insoluble substance that degrades rapidly in a water soluble substance. Release Rate Modification Agents. The polymer solution may include a modifying agent of
release rate to provide a sustained and controlled release of a bioactive agent from the solid implant matrix. Suitable rate-of-release modifying agents include an acid ester
* - monocarboxylic acid, an ester of dicarboxylic acid, an ester of tricarboxylic acid, a polyhydroxy alcohol, a fatty acid, a triester of glycerol, a sterol, an alcohol and their combinations. ? The present invention can be further described by reference to the following examples. Example 1 Naltrexone / PLA microparticles in PLG / NMP. A 1: 1 melt / melt mixture is prepared on a Teflon film by melting poly (D, L-lactide) (PLA, approximately 2,000 Molecular Weight, - Boehringer-Ingleheim, - Resomer L104) and adding an equal amount 0 of base naltrexone. The melt is then allowed to cool to a fused solid. The fused solid separates from the Teflon film and grinds to a fine powder. A five percent w / w formulation in naltrexone is prepared by adding 30 mg of the PLA / naltrexone powder fused / melted to 300 mg of the poly (D) solution, L-lactide-co-glycolide) (PLG) in N-methylpyrrolidone (NMP). A 5% w / w control formulation of naltrexone is prepared by adding 15 mg of crude naltrexone base to 300 mg of PLG / NMP solution. The in-vitro release of naltrexone from each of the formulations is evaluated by adding a drop of formulation to a 5 ml aliquot of phosphate-buffered saline (PBS) in a 10-ml ampule. The amount of naltrexone released is determined by storing the ampule at 37 ° C and verifying the absorbance at 280 nm as a function of time. The results (illustrated in Figure 1) indicate that the formulation including the fused / naltrexone / PLA fused microparticles dispersed in the PLG / NMP solution significantly reduces the initial release of naltrexone (as compared to the naltrexone control solution in PLG / NMP). Example 2 Ganirelix microparticles in PLG / NMP. Ganirelix acetate
(a GnRH antagonist suitable for treating endometriosis and prostate carcinoma) is incorporated into microparticles of a polymer of rapid biodegradation insoluble in solvent. This was done by decreasing the solubility of ganirelix in polymer / solvent formulation and to improve the dispersion characteristics of ganirelix acetate in this same formulation. Ganirelix acetate (6 gm) and poly (sebacic acid) (4 gm; "PSA") are mixed to form a homogenous powder mixture. The powder mixture was melted on a hot plate at 80 ° C and mixed until the ganirelix acetate was dispersed homogeneously in the PSA fusion. The fusion of ganirelix acetate / PSA is allowed to cool to room temperature to form a solid which is then ground in a cryo-mill for one minute to form a fine powder. The powder is sieved to connect the particles of less than 60 micras. A 50:50 solution of PLA in ethyl lactate is formed by dissolving an equal amount of PLA in ethyl lactate using an '< sonicator at 45 ° C. The final formulation is prepared by adding 1.14 gm of ganirelix acetate / PSA microparticles to 4 ml of the PLA / ethyl lactate solution. The resulting mixture that was mixed well by agitation could be administered through a 20 gauge needle. Due to the solubility of PSA in ethyl lactate, this formulation is employed within one hour of mixing. A relatively large discharge effect is observed with formulations in which ganirelix is simply dissolved in the PLA / NMP solution (> 10% during the first day after administration). This initial release of ganirelix may cause local tissue irritation and is clinically unacceptable. In vitro and in vivo experiments demonstrated that the liquid composition with the PSA / ganirelix acetate microparticles eliminated the high initial release of ganirelix (<3% during the first day after administration).
Example 3 Porcine Somatotropin Microcapsules in PLA / NMP.
A solution of PLA / NMP material is prepared by dissolving PLA
(2000 PM) in an equal amount of N-methylpyrrolidone (50:50 PLA / NMP). A liquid composition containing porcine somatotropin (PST) microcapsules is prepared by adding 0.2 g of microcapsules containing 41% by weight of PST in a carboxymethyl cellulose matrix to 2.0 g of the PLA / NMP solution. A similar formulation is prepared by adding microcapsules containing PST in a gelatin matrix to the 50:50 solution
PLA / NMP. The in vitro release of PST from these formulations is examined by filling the formulation (150-300 microliters) through a 20 gauge needle directly into 10 ml of phosphate buffered saline. The release rate of the microcapsule formulations is significantly lower than the PST release rate of the microcapsules alone.
Example 4 Antipsychotic Drug Microencapsulated in PLG / NMP. Seventeen
(17.0) grams of an antipsychotic drug benzisoazolpiri-midinone (APD) can be added to an aqueous solution (17.0 g of polymer in 300 ml of water) of a water-soluble, biodegradable polymer, poly (vinyl pyrrolidinone) ("PVP" PM 100,000).
The resulting preparation is a well dispersed suspension.
This suspension is spray-dried using a Büchi 190 mini-spray dryer, with the following parameters: heating speed of 11, suction speed of 20, compressed air pressure of 5.62 kg / cm2 (80 psi), air flow of 800 NL / hour, nozzle opening of 0.7 mm, inlet temperature of 167 ° C and an outlet temperature of 103 ° C. After 75 minutes of processing using the above conditions, 3.2 g of APD fine powder encapsulated in PVP are obtained. A 5% w / w formulation of APD dispersed in polymer solution can be prepared by adding 27 mg of PVP encapsulated particles to a solution of poly (D, L-lactide-co-glycolide) (60% 75/25 PLG) (0.11)) NMP. A control formulation is prepared by adding untreated APD (13.5 mg) to the same 60% PLG / NMP solution. The in vitro release of APD from these formulations can be evaluated by adding a drop of the respective formulations to aliquots of 5.0 ml of buffer solution (in 10 ml ampules) and stored at 37 ° C. The absorbance is verified at 280 nm as a function of time. The results indicate that coating the solid APD particles with a water soluble polymer of high molecular weight, reduces the initial release of APD (see Figure 2). Example 5 Chlorine (? Hlprjn) e6 L? Gado «c_on Polymer in PLG / DMSO. A chlorine conjugate is covalently linked to a copolymer of N- (2-hydroxypropyl) -methacrylamide / N-methacryloylglycine (copolymer HPMA) containing glycyl side chains is prepared according to the procedures described by Krinick, Ph.D. . Dissertation: Combination Polymeric Drugs as Anticancer Agents (PhD Dissertation: Combination of Polymeric Drugs as Anticancer Agents), University of Utah (1992). The conjugate contains 11% by weight of chlorine (chlorin) e6 and 89% by weight of HMPA copolymer. Chlorine (chlorin) is linked to the HPMA copolymer through the carboxyl groups of the secondary glycine residues. Two formulations were prepared, each containing 0.5% by weight of chlorine (chlorin) is (in a free drug base). One of the formulations contains 53% by weight of PLG (iv = 0.11 dl / g), 46.5% by weight of DMSO and 0.5% by weight of chlorine (chlorin) is free. The second formulation, 51% by weight of PLG, 44.75% by weight of DMSO and 4.25% by weight of the HMPA / chlorine (chlorin) e6 copolymer conjugate. Drops of the two formulations were precipitated in 5 ml of saline buffered with phosphate and the samples were placed in an environmental stirrer at 37 ° C. The concentration of chlorine in the solution is verified as a function of time using visible / UV spectroscopy (lambdamax = 650 nm). The cumulative percentage of drug released is illustrated in Figure 3. The results indicate that chlorine (chlorin) e6 is released much more slowly from the formulation containing the HMPA / chlorine (chlorin) e6 copolymer conjugate. In addition, no discharge effect of the HMPA / chlorine (chlorin) e6 copolymer conjugate formulation is observed.
Example 6 PLA / MLA-p-doxorubicin in PLG / NMP. A water soluble copolymer of D, L-lactide with malolactonic acid (PLA / MLA) is prepared by initially copolymerizing D, L-lactide with monolazyl ester of malolactonic acid (MLABE). The benzyl protecting groups can be removed from the resulting copolymer by hydrogenation, to give a copolymer (PLA / MLA) with free carboxyl secondary chain groups. The free carboxyl groups can be reacted with dicyclohexylcarbodiimide and p-nitrophenol to give a PLA / MLA copolymer with secondary p-nitrophenol ester groups. Doxorubicin can be connected to the PLA / MLA copolymer by an aminolysis reaction to give a PLA / MLA-p-doxorubicin copolymer. Sufficient PLA / MLA-p-doxorubicin can be added to a 60:40 PLG / NMP material solution, to form a liquid composition having 2.0 wt% doxorubicin (in a doxorubicin free base). A control formulation of free doxorubicin can be prepared by adding 20 mg of doxorubicin to 980 mg of the 60:40 PLG / NMP material solution. The in vitro release of doxorubicin from each of the formulations can be evaluated by adding one drop of the formulation to an aliquot of five ml of phosphate buffered saline solution (PBS) in a 10 ml ampule. The formulation of free doxorubicin may show a substantial initial discharge of the drug. Essentially, doxorubicin can not be released over a 3-day period from a sample that includes PLA / MLA-p-doxorubicin. The in vitro determination can be repeated by adding a drop of formulation to a 5 ml aliquot of rabbit peritoneal fluid in a 10 ml ampule. The free doxorubicin formulation can show a substantial initial release of doxorubicin. The composition containing PLA / MLA-p-doxorubicin may not show discharge and the rate of release of doxorubicin may be much slower than the rate observed for the formulation of free doxorubicin. Example 7 PLG / t-Doxorubicin in PLG / NMP. Poly (D, L-lactide-co-glycolide) of low molecular weight (PLG) with terminal carboxyl groups can be driven with dicyclohexylcarbodiimide and p-nitrophenol, to give a PLG copolymer with terminal p-nitrophenol ester groups. Then doxorubicin can be reacted with the p-nitrophenol ester groups to give a PLG copolymer with doxorubicin connected to the terminal carboxyl groups of the copolymer (PLG-t-doxorubicin). The PLG-t-doxorubicin conjugate can then be added to a 60:40 PLG / NMP material solution to form a liquid composition having 2.0 wt% doxorubicin (in a free doxorubicin base). The rate of release of doxorubicin in PBS and rabbit peritoneal fluid can be determined using standard methods. As seen with the composition of PLA / MA-p-doxorubicin, essentially doxorubicin can not be released for a period of 3 days from the addition of the sample including PLG-t-doxorubicin to PBS. No discharge effect can be observed with the addition of one drop of the PLG-t-doxorubicin composition to rabbit peritoneal fluid. Again, the rate of release of doxorubicin in rabbit peritoneal fluid from the composition of PLG-t-doxorubicin may be much slower than the rate observed for the formulation of free doxorubicin. All publications and patent applications in this specification are indicative of the level of ordinary skill in the art to which this invention relates. All publications and patent applications cited herein are incorporated by reference in the same proportion as if each publication or individual patent application was specifically and individually incorporated by reference. The invention has been described with reference to various specific and preferred modalities and techniques. However, it will be understood that many variations and modifications may be practiced while remaining within the spirit and scope of the invention. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:
Claims (34)
1. A pharmacological composition for an insoluble, liquid, suitable for the formation of an implant for controlled release, characterized by comprising effective amounts of: a) a biodegradable, biocompatible thermoplastic polymer that is insoluble in an aqueous medium; b) a biocompatible organic solvent for the polymer that is raiscible to dispersible in an aqueous medium; and c) a controlled release component comprising a pharmaceutically active agent; where when contacting the aqueous medium, the composition V forms a solid implant by dissipation or dispersion of the organic solvent in the aqueous medium, with the controlled release component incorporated therein.
2. A pharmaceutical composition for delivery. liquid, suitable for the formation of a controlled release implant, characterized in that it comprises effective amounts of: a) a conjugate of pharmaceutically active agent, covalently bound to a biocompatible, biodegradable, thermoplastic first polymer that is insoluble in an aqueous medium; and b) a biocompatible organic solvent for the polymer that is miscible to dispersible in an aqueous medium; wherein upon contacting the aqueous medium, the composition forms a solid implant by dissipation or dispersion of the organic solvent in the aqueous medium, with the controlled release component incorporated therein.
3. The liquid supply composition according to claim 2, characterized in that it also comprises a second biocompatible thermoplastic polymer that is substantially insoluble in an aqueous medium.
4. The liquid supply composition according to any of claims 1 or 2, characterized in that the composition on contact with the aqueous medium forms a solid microporous matrix having a core surrounded by a surface layer, the surface layer it has pores with a diameter substantially smaller than the pores of the nucleus.
5. The liquid supply composition according to claim 4, characterized in that the surface layer has a porosity of about 5% to about 10%, and the core has a porosity of about 40% to about 60%.
6. The liquid supply composition according to any of claims 1 or 2, characterized in that the liquid composition has a viscosity that effectively allows aerosolization of the composition.
7. A pharmaceutical polymer system suitable for use as a controlled release implant, characterized in that it comprises: a) a solid microporous matrix of a biocompatible, biodegradable polymer, the polymer is substantially insoluble in an aqueous medium; and b) a controlled release component comprising a pharmaceutically active agent, incorporated within the microporous matrix; wherein the matrix is prepared by contact between an aqueous medium with the liquid supply composition of claims 1 or 2.
8. A biodegradable microporous film coating, characterized in that it is formed from the liquid supply composition of the claim 1 or 2.
9. A controlled release implant precursor for implant in a subject, formed from the liquid delivery composition of claims 1 or 2; placed in contact with an aqueous medium; wherein the structure of the implant precursor is an outer bag and a liquid pad; and upon further contact with an aqueous medium, the implant precursor forms a solid implant by dissipation or dispersion of the organic solvent within the aqueous medium.
10. The supply composition of claim 1 or 2, characterized in that the thermoplastic polymer is selected from the group consisting of polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals,, polycarbonates, polyorthoesters, polyphosphobenzenes, polyhydroxybutyrates, polyhydroxyvalerate, polyalkylene oxalates, polyalkylene succinates, poly (malic acid), poly (amino acid), poly (methyl vinyl ether), poly (maleic anhydride), citin, cytosan and copolymers, terpolymers and mixtures thereof.
The supply composition of claim 1 or 2, characterized in that the thermoplastic polymer is selected from the group consisting of polyglycolides, poly (D, L-lactide), polycaprolactones, polyorthoesters, polycarbonates, polyamides, polyhydrides, polyurethanes, polyesteramides, polyphosphazenes, polyhydroxybutyrates , polyhydroxyvalerates, polyalkylene oxalates and copolymers, terpolymers and their mixtures.
12. The delivery composition of claim 1 or 2, characterized in that the thermoplastic polymer is a copolymer of glycolide, caprolactone or lactide, or a copolymer of D, L-lactide and malolactonic acid.
The supply composition of claim 1 or 2, characterized in that the organic solvent is selected from the group consisting of N-methyl-2-pyrrolidone, 2-pyrrolidone, aliphatic alcohols having from two to eight carbon atoms, propylene glycol, glycerol, tetraglycol, glycerol formal, solcetal, ethyl acetate, ethyl lactate, ethyl butyrate, dibutyl malonate, tributyl citrate, tri-n-hexyl acetyl citrate, diethyl succinate, diethyl glutarate, diethyl malonate, triethyl citrate, triacetin, tributyrin, diethyl carbonate, propylene carbonate, acetone, methyl ethyl ketone, dimethylacetamide, dimethyl ormamide, caprolactam, dimethyl sulfoxide, dimethyl sulfone, tetrahydrofuran, caprolactam, decyl et i sulphide, oleic acid, N, N-diethyl-m-toluamide, and 1-dodecylazacycloheptan-2-one, 1,3-dimethyl-3, 4,5,6-tetrahydro-2 (lH) -pyrimidinone and mixtures thereof.
14. A liquid, supply composition suitable for the in situ formation of a biodegradable controlled release implant, characterized in that it comprises: a liquid biocompatible prepolymer having at least one polymerizable ethylenically unsaturated group and a controlled release component including an active agent? wherein when placing in a patient, the composition forms a solid implant with the controlled release component therein embedded.
15. The liquid prepolymer composition according to claim 14, characterized in that it also comprises a curing agent.
16. A liquid prepolymer composition according to claim 14, characterized in that the ethylenically unsaturated polymerizable group is an α, β-unsaturated carbonyl group.
17. A liquid prepolymer composition according to claim 14, in which the biocompatible liquid polypolymer is a prepolymer terminated in acrylic ester.
18. A liquid prepolymer composition according to claim 14, which is a biocompatible organic solvent for the prepolymer that is miscible or dispersible in an aqueous medium.
19. The delivery composition according to claim 1 or 14, characterized in that the controlled release component is a microstructure, macrostructure, salt of low water solubility of the active agent, conjugate of the active agent covalently linked to a carrier molecule, active agent complex and a carrier molecule, or active agent complex, a carrier molecule and a metal cation.
The delivery composition according to claim 1 or 14, characterized in that the controlled release component is selected from the group consisting of a microcapsule, microparticle, nanoparticle, cyclodextrin, liposome, mycelium, fiber, film, rod, disc and a cylinder.
21. The supply composition according to claim 1, 2 or 14, characterized in that the active agent is a * Bioactive 'agent' or a diagnostic agent.
22. The delivery composition according to claim 1, 2 or 14, characterized in that the active component is selected from the group consisting of antibacterial agent, antifungal agent, antiviral agent, anti-inflamatory agent, antiparasitic agent, anti-neoplastic agent, analgesic agent, anesthetic agent, antipsychotic agent, vaccine, central nervous system agent, growth factor, hormone, antihistamine, osteo-inductive agent, cardiovascular agent, anti-ulcer agent, bronchodilator agent, vasodilator agent, birth control agent, antihypertensive agent, anticoagul It is an antispasmodic agent and an agent that improves fertility.
23. The supply composition according to claim 1, 2 or 14, characterized in that the supply composition, liquid further comprises an agent for physiologically acceptable release rate modification, a pore-forming agent or both.
24. Use of the liquid delivery composition of claim 1, 2 or 14, to form a microporous sustained release implant with the controlled release component therein embedded, in situ in or on a site of a subject's implant.
25. Use of the liquid supply composition of any of claims 1, 2 or 14, for delivering an active agent to a subject.
26. Use according to claim 24 or 25, for forming a film coating in a fabric.
27. Use according to any of claims 24, 25 or 26, wherein the delivery composition, liquid / is in the form to be supplied by spraying, painting or casting or jetting on the implant site.
28. Use of the delivery composition will liquidate any of claims 1, 2 or 14 to make a medicament for forming a controlled release implant to deliver an active agent to a subject.
29. Use of the liquid delivery composition of any of claims 1 or 2, for the manufacture of a microporous sustained release implant, for delivering an active agent to a subject, the implant is formed by contacting the composition with a aqueous medium.
30. A method for forming a microporous sustained release implant in situ at or on an implant site in a subject, characterized in that it comprises: administering the liquid supply composition of claim 1, 2 or 14, to the implant site, and allowing the The composition forms a solid implant with the controlled release component embedded therein.
31. A method for delivering a pharmaceutically active agent to a subject, whether or not to administer the composition for liquid delivery of any of claim 1, 2 or 14 to an implant site of the subject; wherein a solid microporous controlled release implant is formed with the controlled release component therein embedded.
32. The method according to claim 30 or 31, characterized in that the liquid delivery composition is filled onto a fabric to form a film, and the composition solidifies to form a film coating on the fabric.
33. The method according to claim 30, 31 or 32, characterized in that the delivery composition is liquidated by spraying, painting or spraying the composition onto the implant site.
34. A method for delivering a pharmaceutically active agent to a subject, cararteriza or perqué caipspfe: inserting a microporous sustained release implant at an implantation site of the subject, which forms outside the subject upon contact with the liquid supply composition of the subject. Claim 1 or 2 with an aqueous medium.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US22514094A | 1994-04-08 | 1994-04-08 | |
US225140 | 1994-04-08 | ||
US225,140 | 1994-04-08 |
Publications (2)
Publication Number | Publication Date |
---|---|
MX9604634A MX9604634A (en) | 1997-11-29 |
MXPA96004634A true MXPA96004634A (en) | 1998-07-03 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1125577B1 (en) | Liquid drug delivery compositions | |
CA2235919C (en) | Non-polymeric sustained release delivery system | |
CA2079831C (en) | Biodegradable polymer composition | |
Sayed et al. | Porous inorganic drug delivery systems—a review | |
ES2240236T3 (en) | COMPOSITION OF BIODEGRADABLE POLYMER. | |
JP2001508431A (en) | Injectable implant | |
Sinha et al. | Formulation, characterization, and evaluation of ketorolac tromethamine-loaded biodegradable microspheres | |
AU684931C (en) | Liquid delivery compositions | |
MXPA96004634A (en) | Compositions for controlled supply, liqui | |
NZ286487A (en) | Method of forming an in situ implant using a thermoplastic polymer |