GB2408510A - A biodegradable tri-block copolymer for drug delivery systems - Google Patents
A biodegradable tri-block copolymer for drug delivery systems Download PDFInfo
- Publication number
- GB2408510A GB2408510A GB0327750A GB0327750A GB2408510A GB 2408510 A GB2408510 A GB 2408510A GB 0327750 A GB0327750 A GB 0327750A GB 0327750 A GB0327750 A GB 0327750A GB 2408510 A GB2408510 A GB 2408510A
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- Prior art keywords
- polymer
- copolymer
- block copolymer
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- hydrogen
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- Granted
Links
- 229920001400 block copolymer Polymers 0.000 title claims description 25
- 238000012377 drug delivery Methods 0.000 title description 6
- 229920000642 polymer Polymers 0.000 claims abstract description 25
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 12
- 230000003073 embolic effect Effects 0.000 claims abstract description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 125000000524 functional group Chemical group 0.000 claims abstract description 5
- 230000002209 hydrophobic effect Effects 0.000 claims description 20
- 229940079593 drug Drugs 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 8
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 6
- 150000002431 hydrogen Chemical group 0.000 claims description 6
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 claims description 4
- 239000004380 Cholic acid Substances 0.000 claims description 4
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 4
- 229960002471 cholic acid Drugs 0.000 claims description 4
- 235000019416 cholic acid Nutrition 0.000 claims description 4
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 235000012000 cholesterol Nutrition 0.000 claims description 3
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 3
- 229930195729 fatty acid Natural products 0.000 claims description 3
- 239000000194 fatty acid Substances 0.000 claims description 3
- 150000004665 fatty acids Chemical class 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims 1
- 229920001577 copolymer Polymers 0.000 abstract description 39
- 239000002202 Polyethylene glycol Substances 0.000 abstract description 3
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 3
- 230000003013 cytotoxicity Effects 0.000 abstract description 3
- 238000002347 injection Methods 0.000 abstract description 3
- 239000007924 injection Substances 0.000 abstract description 3
- 229920001223 polyethylene glycol Polymers 0.000 abstract description 3
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 abstract description 2
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 abstract description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 238000013267 controlled drug release Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 29
- 239000000499 gel Substances 0.000 description 18
- 239000000017 hydrogel Substances 0.000 description 18
- 239000000178 monomer Substances 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 210000003734 kidney Anatomy 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 229920002988 biodegradable polymer Polymers 0.000 description 6
- 239000004621 biodegradable polymer Substances 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 241000283973 Oryctolagus cuniculus Species 0.000 description 5
- 210000001367 artery Anatomy 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 150000007942 carboxylates Chemical class 0.000 description 4
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 4
- 210000001105 femoral artery Anatomy 0.000 description 4
- 210000002254 renal artery Anatomy 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000002872 contrast media Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical group O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 description 2
- 208000005189 Embolism Diseases 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 239000005639 Lauric acid Substances 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 210000000709 aorta Anatomy 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 230000036760 body temperature Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000042032 Petrocephalus catostoma Species 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 206010063544 Renal embolism Diseases 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 238000002583 angiography Methods 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 230000009172 bursting Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229940107161 cholesterol Drugs 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 239000011557 critical solution Substances 0.000 description 1
- 125000005442 diisocyanate group Chemical group 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 210000002767 hepatic artery Anatomy 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- QNILTEGFHQSKFF-UHFFFAOYSA-N n-propan-2-ylprop-2-enamide Chemical compound CC(C)NC(=O)C=C QNILTEGFHQSKFF-UHFFFAOYSA-N 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- -1 polyethylene Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000012460 protein solution Substances 0.000 description 1
- 210000002796 renal vein Anatomy 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/66—Polyesters containing oxygen in the form of ether groups
- C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G2261/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
- C08G2261/10—Definition of the polymer structure
- C08G2261/12—Copolymers
- C08G2261/126—Copolymers block
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Polymers & Plastics (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
A thermo-sensitve copolymer of following formula; <EMI ID=3.1 HE=18 WI=99 LX=484 LY=603 TI=CF> <PC>is disclosed; wherein R1 is hydrogen, or -C(=O)-R2; R2 is C7-30 alkyl substituted or unsubstituted with functional groups; R3 is hydrogen, or C1-6 alkyl; and x, y or z individually is an integer greater than 0. The thermo-sensitive copolymers disclosed here are easy to be implanted into a human body through injection for controlled drug release systems or as embolic agents. The subunits in the polymer are chosen among blocks of PEG (polyethylene glycol) and PLGA (poly (lactide - co -glyceride)). The biodegradability is greatly improved and the cytotoxicity of the copolymers is low.
Description
24085 1 0
THERMOSENSITIVE BIODEGRADABLE COPOLYMER
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a biodegradable:thermo-sensitive 5. polymer for medical use and,.more particularly.to a biodegradable thermo-sensitive polymer for a drug: delivery system or embolic agents. : :
2. Description of Related Art: . .
Several biodegradable polymers have been developed in the past: : - : decades for acting as drug release Systems for treating chronic diseases in hwnans. In 1988, Churchill. et al. suggested a dispersed polymer for; . improving the aqueous solubility and the stability of the biodegradable polymers for drug delivery. purposes (see U.S. patent No. 4,745,160).
However, owing to the requirement of dispersity, the application of these biodegradable polymers is.limted.. For improving the processibilit, and flexibility of biodegradable copolymers, Song et al. disclosed a multitiock biodegradable copolymer in U.S..patent No. 5,514,380. However, once . organic solvents are used in the complex manufacturing processes the application of these biodegradable copolymers continue to be investigated.
In 1997, thermosensitive biodegradable unblock copolyr.ners revere disclosed by Cha et al. (see U.S. patent No. 5,702,717). These tri-b'ock copolymers are suitable for drug delivery purposes because of their improved biodegradability and high thermo-sensitivity. However, since toxic monomers (e.g. diisocyanates) are used for manufacturing these thermo-sensitiYe biodegradable tri-block copolymers, the application of these tri-block copolymers in a human body is still limited. Moreover, these ermo-sensitive copolymers illustrated above cannot prevent the bursting 'I out of drugs from the polymeric Drug delivery system in a Short initial period of drug adnrnstration bme (burst effect). Therefore, these thermo-sensitive polymers for drug delivery purposes still camot be widely used. , ' On the other hand, in some cases, biodegradable polymers i, functioning as embolic agents forblocking the supply of nutrients to the disordered tissues or cancer cells through arteries are also in demand.
. . . However, suitable biodegradable polymers for functioning as embolic, agents Buyout toxicity are rare. In Addison, Me application of the polymeric embolic agents' is also limited by the methods for implanting. So : far, thermo-sensitive polymers Have been, suggested to be suitable candidates for embolic agents because of simple implantation (e.g. injection) methods and easy fomahon of gels. Nevertheless,, the toxicity and the biodegradability have become new Issues to be solved for these ermo-sensitive polymers. Moreover, thenno-sensitive polymers have also been proposed to be a carrier for- biological molecules. For example, copolymers of N-isopropylacrylamide and acrylic monomers were ' suggested to be used as implantable biohybnd pancreas in which pancreatic islets were encapsulated (see US 5,262,055). However, since poly(NIPAAm) is not a biodegradable polymer, its application in a human body is seriously limited.
In order to achieve the application of thermo-sensitive polymer ers for.
functioning as drug delivery systems and embolic agents, it is desirable to provide an improved method to mitigate the aforementioned problems.
: : I. ,
SUMMARY OF THE INVENTION
The object of the present invention is to provide a thenno-sensitive polymer having biodegradability and adequate LOST (lower critical solution temperature) to reduce hann to tissues, to simplify the implantation procedures or Me manufacturing process, and to reduce the burst effect for drug release.
To achieve the object, the biodegradable block copolymer of the present invention is of Me following formula (I): O - - - : CH, O Rl6O-Cat-Q-tCAd,-COR3 wherein Rl is hydrogen, or C(=O)-82; R2 isle C, 30 alkyl substituted or unsubstituted with functional groups; R3 ishydrogen, or Cl. 6 alkyl; and x, y or z individually is an integer greater than 0. :
Preferably, R of He polymer of the present invention is hydrogen, or is selected from the group consshngofcholic acid, fatty acid, folic acid, cholesterol, and vitamin E. More preferably, R' of the polymer of the present invention is hydrogen or cholic acid (i.e. 82 iS of following formula (II): ::
OH
it/, ,. . ' ' , '' '.' ' : . ,. . ..... : .......
WHO (II) ). As Rl is hydrogen, the copolymer of the present invention is a: all- block copolymer. The all-block copolymer is suitable for being applied for drug release system or embolic agents. R3 of the copolymer of the: : present invention can be hydrogen, or Cl 6 alkyl. Preferably, R3 is methyl.
The molecular weight of the. present invention is not limited. Basically, the:.. . ..
molecular weight of the present invention is the total sum of the: ! - ' hydrophobic block, the hydrophilic block and the acid part. Preferably, the molecular weight of the hydrophobic block: : O Ci l3 O - -C-Il -a-5t; ranging *om 1000 to 6000. The molecular weight of the hydrophilic block: : - 0-CH:-CHORD is preferred to be in a range from 200 to 5000. The ratio ofthree blocks (i.e. x: y z) of the present invention is not limited. Preferably, the ratio x: y: z is 3- l 8: 11-66: 4-114. The LCST of the copolymer is not limited. Preferably, the LOST of the copolymer ranges from 15 oC to 30 oC.
The method for preparing a thenno-sensitive polymer of the present.
invention, comprising the steps of co-polymerizing a mixture of at least a hydrophilic monomer, at least a hydrophobic monomer and optionally a compound having carboxylic functional group; wherein said hydrophilic monomer is methoxy polyethylene glycol or polyethylene gIycol; said hydrophobic monomer is glycolide endlactide, andsaid compound having a carboxylic functional group is carboxylate having 33.
The x, y, or z are.integers greater than 0. Preferably, the x of the present invention is an integer ranging from 3 to 18. The y is an integer : ,: ! ,: '.
1 0 greater Man 0. Preferably, y is an integer ranging Tom 11 to 66. The z is an integer greater than 0. Preferably, z.ls an integer ranging from 4 to 114. The i: content of said hydrophilic monomer used in the method of the present invention is not limited. Preferably,.the weight percentage of said: . : hydrophilic monomer in the mixture of hydrophilic monomer, hydrophobic monomers, and optionally carboxylates ranges from 30 wt% to 60 wt%.
The content of said hydrophobic monomer used in We method of the present invention is not limited. Preferably, the weight percentage of said hydrophobic monomer in the.:mixture o f hydrophilic monomer, hydrophobic monomers and optionally carboxylates:ranges Tom 70 wt% to 40 wt%. I: :
Other objects, advantages, and novel features of the invention will become more apparent from the following detailed description when taken in conjunction with the accompanying drawings.
P983 3GB 2 8. 11. 03
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is the graph of time vs. temperature in
example 8.
Figure 2 is the graph of gel viscosity vs. temperature
in example 8.
Figure 3 is a cross-section view of a Release Cell
used in example 5.
Figure 4 is a graph of cumulative release from the gel vs. time according to the data in example 5.
Figure 5 is a another graph of cumulative release from the gel vs. time according to the data in example 5.
Figure 6 is a graph of OD 570 absorption of various samples in example 6.
Figure 7 is another graph of weight percentage before degradation vs. time according to the date in example 6.
Figure 8 is a computer tomography picture obtained in
example 9.
DETAILS DESCRIPTION OF THE PREFERRED EMBODIMENT
The structure of the polymer of the present invention includes three major subunits: a hydrophobic unit, a hydro- philic unit and a hydrophobic carboxylic unit. The molecular weight of the hydrophilic monomer used for polymerising the copolymer of the present invention is not limited. Preferably, the molecular weight of the hydrophilic block ranges from 20 to 5000. Most preferably, the molecular weight of said hydrophilic block ranges from to 5000. In addition, the hydrophilic block helps to increase the solubility of the copolymer of the present invention. The hydrophilic unit also assists to increase the LOST of the whole copolymer. Therefore, the LCST of the copolymer of the present invention can be adjusted by adjusting the percentage of the hydrophilic unit. Furthermore, the hydrophobic block of the copolymer of the present invention can be eliminated by hydrolysis in the human body or in mammals after being implanted or injected into human body. In most cases, the LCST of the copolymer of the present invention Is below body temperature by adjusting the percentage of the hydrophilic u,nit.
The hydrophobic unit of the copolymer of the present nvenhon comes from the co-monomers having a polypa,ctide-co-glycolide? (PLGA3 block. The molecular weight of the hydrophobic block used for copolymerizing the polymer of,the present invention is under BOOO.
Preferably, the molecular weight of,the hydrophobic block ranges from 1000 to 6000. The hydrophobic block helps to increase the hydrophobility and the biodegradability,of the Copolymer of the present invention. ', Therefore, the biodegradabiljy 'of the copolymer of the present invention, ' ; can be greatly improved. In addition, the hydrophobic unit ofthe 'copolymer : of Me present invention also assists to lower the LCST of the copolymer.
The LCST of the copolymer of the present invention can be adjusted to " below or around body temperature by adjusting the percentage of the hydrophilic, unit and that of the hydrophobic unit. Furthermore, most of the, - ' hydrophobic unit will be degraded by hydrolysis in a human body, The carboxylic-based unit provides the hydrophobicity of the ','' : : : :: copolymer of the present invention and farther greatly improves the affinity Of the copolymer of the present invention' to hydrophobic drug. The carboxylic-based unit can be any conventional carboxylate having 7 to 33 carbons. Preferably, the carboxylicbased unit comes from compounds such.
as choIic acid, fatty acid, foiic acid and cholesterol.
More detailed examples are used to illustrate the present invention, and these examples are used to explain the present Invention. The examples below, which are given simply by way of illustration, must not be taken to limit the scope of the invention.
Example 1: Preparation of AB-type all-block copolymer (PEG-PLGA) . . - . . The reaction vessel is heated under nitrogen until the temperature reaches 110 oC. Then 50.0 g of lactide, 11.36 g of glycolide, 24.02g of m-PE4 are added into the reaction vessels together. The reaction vessel is kept heated for melting the added monomers. After all the monomers are : melted, O,OS % of catalytic Sn2+ is added to Me reaction vessel. The . , , : temperature of the reaction mixture in the reaction vessel is increased to around 160 oC slowly. Then the reaction mixture is stirred and heated at 160 oC for about 9 hours. The mixtureis then cooled to room temperature. 80 rnl of ClI2CI2 is added for dissolving the mixture. The CH2C12 solution is : it... : . ..
dropped into another solution of n-hexane/ether (9/1 j and stirred for 3 hours - , for precipitation. The solution is separated into two phases. The upper liquid is discarded Ad the bottom liquid Is rinsed and cleaned by a fresh solution of n-hexane/ether at least three thrones. The precipitates are heated at 4S oC for about 2 hours and vacuumed at 45 oC for another 24 hours.
500 MHz H-NMR, d-chloroform a 1.58 (d, J=6.5 Hz, Half), 3.39 (s, ÖCH3), 4.29 (m, H-1 2) 4.80 (m, FI 5) , 5.14(H-.
The route for synthesizing the all-block copolymer is shown in scheme 1 illustrated below.
Or OF. CotCH2CH2- r))p CH: o jO NO sn+2. 760 C C<CH2CH2C-CH-GCH2%OH
. . . . . . . ......DTD: O O. . ' - . .... . scheme I - .: - . Example 2: Preparation of: ABC-type tri- block copolymer (PEG-PLGA-FA(C12)) : Nitrogen is introduced to a flask (250 ml) for at least 30 men before: : reaction. A solution of lauric acid is prepared by adding 1.53 g of launc acid into 30 ml of CH2C12. Another solution is prepared by adding 1.58 g of DCC (dicyclohexyl carbodiirnide) into 20 ml of CH2C12. The CH2Ci2 : solution of DCC is added to the CH2CI2 solution of lawric acid and su: Ted for 30 rain. Another solution of AB-block copolymer is prepared by ! . : dissolving 1 g of all-block copolymer obtained from example I into SO rnl: of CHC13. Then 1.S g of triethylamne is added to He CHCI3 solution of AB-di-block copolymer and stirredfor 30 min. The CHC13 solution of AB-di-block copolymer prepared. through above procedure is added dropwise to He well-prepared mixture of:lauric acid and DCC and stirred j for 24 hours.
After the reaction is finished, the precipitate is removed by DCU (dicyclohexylurea). The remaining filtrate is dropped into a solution of n-hexane/ether and stirred. The precipitated Is then washed and reprecipitated 3 times. Then the precipitates are heated at 45 C for about 2 hours and vacuumed at 45 C for another 24 hoursto remove the residual organic solvent.
500 MHz 'H-NMR, d-chloroform: 0.86 (t, J=6.8:Hz,H-O? 1.23(m, H-7), 1.58 (d, 1=6.5 Hz, H-, : ; 2.38 (m, H-), 3.39 (s, -OCH3), 4.29 (m, H-1, O. 4.80 (m, lI-5), 5.14 (m, : H 3\ _} . . : The route for synthesizing the tri-block copolymer is shown in scheme 2 illustrated below.
CH3O(CH2CH2OCH-ACHE jOH: - . . . . . . . : . . . . :. . : CH3(CH2)40COOH:: : CHG13: : : :.
: DCC I TEA: : O CH3 O. O CH3O(CH2CH2OC-CH-OC H,iO-C-(CH2),0CH3 : scheme 2 Example 3: Preparation of ABC-type tri-block copolymer (PEG-PLGA-CA) Nitrogen is introduced to a flask (250 ml) for at least 30 man before to reaction. A solution of cholic acid is prepared by adding 6. 27 g of Catholic acid into 30 ml of 1,4-doxane. Another solution is prepared by adding 3.16 g of DCC into 20 rnl of 1,4-dioxane. The 1,4- dioxane solution of DCC is added to the 1,4-dioxane solution of cholic acid and stirred for 30 min. Another solution of AB-block copolymer is prepared by dissolving 10 g of all-block copolymer obtained Dom example I into 100 ml of 1,4-dioxane.
Then 2.0 rot of triethylamine is added to the 1,4-dioxane solution of ABdi-block copolymer and stirred for 30 ruin.
After the reaction is finished, the precipitate is removed by DCU.
The remaining filtrate is droppedinto a solution of n-hexane/ether and - . . . . . ...
stirred. The precipitate is then washed and reprecipitated 3 times. Then the precipitates are heated at 45 oc for about 2 liours and vacuumed at 45 oc for another 24 hours to remove residual organic solvent. ; 500 MHz H-NMR, d-chloroform - 0.67 (s, H-O, 0.87 (s, H-2), 0.97 (d, J=6.8, H-7), 1.58 (d, J=6.5 Hz, : H- O, 2.38 (m,H-6), 3.39 (s,-OCH3), 4.29 (m,H-1,O, 4.80 (m,H-O,5.l4 (m, H-3). I.
Example 4 Preparation of hydrogel/protein solution The block copolymers synthesized above were dissolved in D.. ..
water. 100 mg/mL bovine serum albumin conjugated with FITC (BSA-FITC) solution was added in to the hydrogel solution and the mixture was gently shaken to assure homogeneous mixing of protein throughout the hydrogel solution. The final concentration of the copolymer was in the li. . ..
range of 10-50 % (w/w) and the protein concentration was in the range of 0-50 mg/mL. All the materials used in this example were pre-cooled at 4 C before use. All the Steps mentioned' above were performed at low temperature, thereby avoiding undesired gel formation during preparation. s
Example S Dru,g release test ', ,
. : . . : 0.2 rnL of the hydrogeVBSA solutionmade Coin example was loaded on the bottom of the Release Cell, as shown in Fig 3. The Release Cell lO was placed on a Thennstate Module at 37.0 i1.0 C for 10 min Upon "elation oftbe hydrogeVBSA solution 50,'Srnl of pre-warmed (37 C) release medium 20 (phosphate buffer solution) was added into the Release Cell, directly above arid In contact with the gel. A galvanized iron net 30 and a stir bar 40 were then mounted in 'tine Release Cell.' The releasing test was cawed out at 37 C and the speed was set at lOO rpm. The release medium 20 was replaced with flesh release medium at a predetermined time penod. The BSA concentration:n the medium was determined by fluorescent spectrophotometer. ' , ' , According to the results In FIG 4 and FIG. 5 obtained *om the duplicated or triplicated separated experiments, the burst release of BSA was observed in the ABA-type tn-block copolymer hydrogel system...DTD: However, the burst release was significantly Improved by using the AB- type all-block copolymer and the ABC-type tri-block copolymer hydrogels prepared in examples 1-3.
Example 6
: ..
Various synthesized hydrogel suspensions of 0.01 g/ml and traditional (ABtype all-block copolymer) hydrogel: suspensions of same concentration are provided. These hydrogel suspensions are then diluted to a concentration of 500 fig / ml by adding ceil culture medium. The-pH of:.
these hydrogel suspensions is adjusted to around 1.4 by adding IN NaOH Each hydrogel suspension is laid to a well of a 24-well dish a volume of 1 : : ml and farther incubated for 1 day. Each hydrogel mixture is taken out. . - .. .:.
through pipettes, Each well is added With MTT (5 mg/ml) and incubated for an additional 2-4 hours. Each well with MTT is taken out through pipettes.
DMSO is added to each well until the.blue grains.are dissolved. After all the: blue grains are completely dissolved, the: ceil viability of each well is: analyzed by the absorption of OD 570 nm. The result is listed in FIG. 6.
In FIG. 6, the medium represents the. cell:culhre medium without. : any hydrogel solution. Sample 1 represents PEG-PL.GA hydrogel and cell. : medium mixture. Sample 2 represents PEG-PLGA-EA(C12) hydrogel and cellmedium mixture solutions. . i.
Example 7: : :
Hydrogel samples (AB-type copolymers prepared from example) Of various concentrations (25wt%(di-911227) 33wt%(di-911227) 20wt% (di-FA)) are prepared in vials. Each hydrogel sample is stored for a predetermined time (O day, 1 days 3 days 5 days 7 days 9days 13 days 16 days 20 days 25 days 31 days 38 days 46 days). 0.2 rnl of each hydrogeI sample of each vial is taken out after the predetermined period and is loaded into a bigger vial (4 ml). Solid gel accord panted with hydrogel liquid may appear after predetermined penods. The weight of each solid gel or hydrogel liquid (not solid gel) can be obtained 'through weighing and calculation. Then 3 ml of'water is added into each bigger vial (4 rail). Each, bigger vial is shaken in a water bath at 37 C and at a rotation speed of 50 : run The upper part of liquid in the shaker vial is decantedand the solid gel remaining in the shaken vial is carefia, llywashed with, DI water, collected and frozen-dried. The *ozen-dried gel is weghedfor calculating the reducing weight from degradation. The result, is shown in FIG. 7.
- - :.
Example 8 measurement of the gelfonnation time in vitro and the : evaluation of temperature on gel forTnation The gel formation time is measured by Brookfield DVIII+ cone and plate rheometer. The rheometer is calibrated by various standard solutions (100, 5000 and lOOOOcP) first before each measurement. The measurement : is perfonned by placing a tested gel sample (a.s ml) in the center of a plate ' at a temperature below 1 0 C. A thermocouple sensor is mounted under the 'I bottom of the center of the plate for measuring the temperature of the center.
A cone #CPDS2 is used as the probe in the rheometer. ..
Wann water at a temperature of 38 C (or higher than 38 C but lower Man 50 C) is first introduced into the ironer part of Me plate at the beginning of measurement. Then the temperature of the plate is heated rapidly to 36-38 C. The related: data of viscosity time temperature of thermo couple the rotating speed and the torque of Ale rheometer are recorded by Rheocalc (the software specific to the rheometer) Tom the begirming of and during the measurement. The rotation speed of the rheometer is adjusted so that torque value falls in between 80-100% during the measurement for obtaining reliable-experimental data. The gel Connation time is defined as the time that a sample needs for increasing the viscosity up to lOOOOcP from the starting viscosity.
The vanation ofthe viscosity of gel samples of 15wt % 20 wt % 25 At % arid 33 wt % is shown in Fig. I. The LEST can be obtained Tom the graph of gel viscosity vs. temperature. Lee gelling time can be estimated or obtained by the graph of AB gel viscosity vs. gelling time. As shown in Fig. 1 the gelling time ranges from 10-to 20 seconds. As shown in Fig. 2 the LCST ranges Tom 15 C to 30 C.
: . : ' : Example 9 experimental model of renal artery embolism In a rabbit : ' ' ! ' ' , ' . ' Since the diameter of catheter for a human is:larger than the diameter of the hepatic artery of a rabbit; therefore embolism in rabbit renal artery model is used for evaluating the embolism of the theTmo-sensitive copolymers of the present invention.
The flow model of the kidney artery is built and recognized Tough the following method illustrated below. A G22 intravenous catheter is introduced right into the femoral artery of a rabbit. After the needle of Is: intravenous catheter is removed, a guide wire is forced to pass along Me.
femoral artery Into the kidney artery. An angiograph catheter is then introduced via the aid of guide wire. MA contrast medurn, Lipiodol() . . solution (2 mlfkg dosage), is added through the angiogTaph catheter after: the catheter reaches the renal artery. The distribution and the flow of the contrast medium in femoral artery, aorta and the renal artery can be clearly observed through the assistance of the X-ray photography. According to the. i.
observation. of the X-ray photography, the developer flowed from the femoral artery to the aorta and further to the renal artery in subsequence.
Then the contrast medium stayed in the kidney for a while, after which it backflowed to the heart through the renal vein. Thecontrast medium then flowed to all the body aher the contrast medium was output from the heart.
Then the distribution of: blood vessels is indicated through angiography under the assistance: of X-ray. The aqueous: solution of thTno-sensitive copolymer of thepresent invention is prepared in 25% with PBS. The copolymer solution is injected at a predetenTuned position of. . : - . We kidney artery for. blocking t he flowing of blood. After the: ermosensitive copolymer of the present invention is injected and the: I. cmbolic surgery is finished, the kidney artery of the rabbit is observed by: : : CT. Once the themosensitlve copolymer solution is injected through the catheter it become gelatinous immediately and blocks blood flow. Fig 8 : : : : : demonstrates a dark area in the led kidney in CT photograph which reveals : Bat no blood flow is observed within the. kidney. In other words, the injected theo-sensitive copolymer of the present invention acts as an 16: ombolic agent successfully in animal blood vessels. :
The thermo-sensitive copolymers of the present invention, both the ABtype and the ABC-type block copolymers, are easy to be implanted into a human body through injection since they contain adequate LEST. In addition, the high biodegradability and the low cytotoxicity of the copolymers of the present invention also make them good candidates for embolic agents or for a delivery system for drugs. Therefore, the copolymer Of the present invention is improved greatly in biodegradability and cytotoxicity and is adequate for drug-releasing or embolicing.
Although the present invention has been explained in relation to its preferred embodiment, it: is. to be understood that many other possible: modifications and variations can be made:without departing from the spins and scope of the invention as hereinafter claimed. : : . . :
Claims (10)
- WHAT IS CLAIMED IS: 1. A biodegradable block copolymer of the followingformula (I): R. jO- Cal-Cat-C-CH2-CtORJ (lo : wherein Rl is hydrogen, or-C(=O)-R2; R2 is C730 allyl substituted or unsubstituted with functional groups; R3 is hydrogen, or.CI alkyl, and x, y or z individually is an integer greater than 0. : : : :
- 2. The polymer of claim 1, wherein said R1 is selected from the: : group consisting of cholic acid, fatty-acid, Policy acid and cholesterol. -:: : : - : :
- 3. Thepolymerofclalml,:wherelnsaidR2 is: : . -. ::: . . ) ' ;_OH/ .: .. ,, , ,,, , J. I:: : . . . / ' . ... . HO (II); :
- 4. The polymer as claimed in claim 1, wherein said R3 is methyl.
- 5. The poller as claimed in claim 1, wherein said R2 is.hydrogen, and said polymer is apphed for drug releasing or embolic agents.
- 6. The polymer as claimed in claim 1, wherein the molecular weight of the hydrophobic block: : Ho-c--: i' ' - - : . ranges from 1000 to 6000. .. : - . I'. : : . -
- 7. The polymer as claimed In claim 1,.wherein the.rnolecular: : weight of said hydrophilic: block: H2-COR3 - . . : ranges from 200 to 5000. : :
- 8. The polymer as claimed in claim 2, wherein x: :y: z is. . :. . .3-18:11-66:4-114. : : : I: :I: . . . : . : : .: . .
- 9. The polymer as claimed in claim 1, wherein said polymer is themo- sensitive polrer:having an LOST ranging Dom 15 on to 30 oC. . :
- 10. The polymer as claimed in claim: 1, wherein said polymer is.-finctioned as an embolic agent. :
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| GB0327750A GB2408510B (en) | 2003-11-28 | 2003-11-28 | Thermosensitive biodegradable copolymer |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2111877A1 (en) * | 2008-04-23 | 2009-10-28 | Tyco Healthcare Group LP | Bioabsorbable surgical composition |
| EP2135525A2 (en) | 2008-06-10 | 2009-12-23 | L'Oréal | Eyelash make-up and/or care kit |
| WO2010079305A1 (en) | 2009-01-07 | 2010-07-15 | Polymerexpert Sa | Anti-snoring composition containing a thermogelling polymer |
| US9408785B2 (en) | 2012-10-15 | 2016-08-09 | L'oreal | Hair styling compositions containing aqueous wax dispersions |
| US10413496B2 (en) | 2012-10-15 | 2019-09-17 | L'oreal | Aqueous wax dispersions |
| US10561596B2 (en) | 2014-04-11 | 2020-02-18 | L'oreal | Compositions and dispersions containing particles comprising a polymer |
| US10626294B2 (en) | 2012-10-15 | 2020-04-21 | L'oreal | Aqueous wax dispersions containing volatile solvents |
| FR3091996A1 (en) | 2019-01-24 | 2020-07-31 | Les Laboratoires Brothier | HEALING COMPOSITION |
| WO2023064210A1 (en) * | 2021-10-15 | 2023-04-20 | Croda, Inc. | Polylactic acid and polyether compounds |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102391498B (en) * | 2011-08-17 | 2014-01-01 | 沈阳药科大学 | Polyethylene glycol di-fatty acid glyceride derivatives and application thereof to medicine delivery |
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| US6117949A (en) * | 1998-10-01 | 2000-09-12 | Macromed, Inc. | Biodegradable low molecular weight triblock poly (lactide-co-glycolide) polyethylene glycol copolymers having reverse thermal gelation properties |
| US6451346B1 (en) * | 1998-12-23 | 2002-09-17 | Amgen Inc | Biodegradable pH/thermosensitive hydrogels for sustained delivery of biologically active agents |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
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| EP2111877A1 (en) * | 2008-04-23 | 2009-10-28 | Tyco Healthcare Group LP | Bioabsorbable surgical composition |
| US8263704B2 (en) | 2008-04-23 | 2012-09-11 | Tyco Healthcare Group Lp | Bioabsorbable surgical composition |
| EP2135525A2 (en) | 2008-06-10 | 2009-12-23 | L'Oréal | Eyelash make-up and/or care kit |
| WO2010079305A1 (en) | 2009-01-07 | 2010-07-15 | Polymerexpert Sa | Anti-snoring composition containing a thermogelling polymer |
| US9408785B2 (en) | 2012-10-15 | 2016-08-09 | L'oreal | Hair styling compositions containing aqueous wax dispersions |
| US10413496B2 (en) | 2012-10-15 | 2019-09-17 | L'oreal | Aqueous wax dispersions |
| US10626294B2 (en) | 2012-10-15 | 2020-04-21 | L'oreal | Aqueous wax dispersions containing volatile solvents |
| US10888504B2 (en) | 2012-10-15 | 2021-01-12 | L'oreal | Hair styling compositions containing aqueous wax dispersions |
| US10561596B2 (en) | 2014-04-11 | 2020-02-18 | L'oreal | Compositions and dispersions containing particles comprising a polymer |
| FR3091996A1 (en) | 2019-01-24 | 2020-07-31 | Les Laboratoires Brothier | HEALING COMPOSITION |
| EP3698768A1 (en) | 2019-01-24 | 2020-08-26 | Les Laboratoires Brothier | Healing composition |
| WO2023064210A1 (en) * | 2021-10-15 | 2023-04-20 | Croda, Inc. | Polylactic acid and polyether compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| GB0327750D0 (en) | 2003-12-31 |
| GB2408510B (en) | 2008-05-14 |
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