WO2014041486A1 - Biodegradable elastomer and a production method thereof - Google Patents
Biodegradable elastomer and a production method thereof Download PDFInfo
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- WO2014041486A1 WO2014041486A1 PCT/IB2013/058454 IB2013058454W WO2014041486A1 WO 2014041486 A1 WO2014041486 A1 WO 2014041486A1 IB 2013058454 W IB2013058454 W IB 2013058454W WO 2014041486 A1 WO2014041486 A1 WO 2014041486A1
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- production method
- monomer mixture
- biodegradable elastomer
- acid
- biodegradable
- Prior art date
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- 229920001971 elastomer Polymers 0.000 title claims abstract description 52
- 239000000806 elastomer Substances 0.000 title claims abstract description 52
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 23
- 150000003077 polyols Chemical class 0.000 claims abstract description 21
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 19
- 150000002148 esters Chemical class 0.000 claims abstract description 19
- 229920005862 polyol Polymers 0.000 claims abstract description 19
- 238000004132 cross linking Methods 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000000178 monomer Substances 0.000 claims description 25
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 5
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 4
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 4
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 claims description 4
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 claims description 4
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 3
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- HEBKCHPVOIAQTA-QWWZWVQMSA-N D-arabinitol Chemical compound OC[C@@H](O)C(O)[C@H](O)CO HEBKCHPVOIAQTA-QWWZWVQMSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 239000004386 Erythritol Substances 0.000 claims description 2
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- 239000001361 adipic acid Substances 0.000 claims description 2
- 235000011037 adipic acid Nutrition 0.000 claims description 2
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 claims description 2
- 235000019414 erythritol Nutrition 0.000 claims description 2
- 229940009714 erythritol Drugs 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- -1 poly(alpha-hydroxyacids) Polymers 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- KSBAEPSJVUENNK-UHFFFAOYSA-L tin(ii) 2-ethylhexanoate Chemical compound [Sn+2].CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O KSBAEPSJVUENNK-UHFFFAOYSA-L 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 125000002947 alkylene group Chemical group 0.000 claims 1
- 239000012467 final product Substances 0.000 claims 1
- 230000035876 healing Effects 0.000 claims 1
- 230000005923 long-lasting effect Effects 0.000 claims 1
- 238000004904 shortening Methods 0.000 claims 1
- 239000000463 material Substances 0.000 abstract description 12
- 239000001257 hydrogen Substances 0.000 abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 9
- 229920001187 thermosetting polymer Polymers 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 2
- 229920000642 polymer Polymers 0.000 description 15
- 238000006116 polymerization reaction Methods 0.000 description 4
- 239000007789 gas Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 239000012620 biological material Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 150000001991 dicarboxylic acids Chemical class 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000017423 tissue regeneration Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M acrylate group Chemical group C(C=C)(=O)[O-] NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 238000005452 bending Methods 0.000 description 1
- 239000003462 bioceramic Substances 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000009477 glass transition Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000005499 meniscus Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- 239000003106 tissue adhesive Substances 0.000 description 1
- 229940075469 tissue adhesives Drugs 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
- C08G63/60—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from the reaction of a mixture of hydroxy carboxylic acids, polycarboxylic acids and polyhydroxy compounds
-
- 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
- C08G63/78—Preparation processes
Definitions
- the present invention relates to biodegradable elastomers comprising crosslinks and/or hydrogen bonds, and a production method thereof.
- Elastomers are polymers exhibiting viscoelastic features. Biodegradable polymers and elastomers are being commonly used in many applications both in medical and environmental field. Recently, especially pioneered by Langer et al. (Wang et al., Nature Biotechnology, Volume:20, 602-606, 2002), hard biodegradable elastomers have been synthesized and studies have been started to be performed in very different applications especially in medical field and tissue engineering. Furthermore, Lui and Cai (Liu L., Cai W., Materials Letters, 63, 1656-1658, 209) have synthesized shaped memory biodegradable elastomers.
- prepolymerization stage continues for at least 2 to 3 days, and it requires continuous purge of valuable gases such as Argon (Ar), Nitrogen (N 2 ) and keeping the reaction at high temperatures, resulted in an increase in the total cost.
- Argon Ar
- Nitrogen N 2
- Langer et al. discloses this kind of elastomers and field of use in patent document no US2009/0011486 Al.
- the elastomer in this patent comprises one polyol and one dicarboxylic acid, and the first step of the production method thereof lasts 48 hours.
- United States Patent document no US 2001 1/0008277 Al also discloses this kind of polymers, in which the cross linking can be started with an extrinsic effect thanks to the acrylate groups added to the polymer primary chain.
- thermoset/ceramic composites that are prepared by reacting one polyol and one dicarboxylic acid in the presence of a bioceramic according to the method mentioned above. Again the first step of the method mentioned in this patent document takes substantially elongated periods of time, and it is also costly in terms of the gases used and the energy required.
- the present invention provides savings in terms of energy and raw materials, and in addition to those polymers obtained via the reaction of only one diol and one dicarboxylic acid, other structures which are different than those mentioned in the aforementioned examples can be obtained via addition of an ester such as epsilon-caprolacton.
- the obtained biodegradable elastomers comprise cross links and/or hydrogen bonds.
- the objective of the present invention is to obtain polymers including cross links and/or hydrogen bonds from at least two molecules selected from the group comprising one polyol, one dicarboxylic acid and one ester by using radio waves and high temperature under vacuum.
- Another objective of the present invention is to obtain biodegradable elastomers that can be used for medical and non-medical purposes.
- Yet another objective of the present invention is to provide a method for obtaining the said elastomers economically.
- a further objective of the present invention is to obtain tissue engineering scaffolds from the obtained structures comprising polyol-dicarboxylic acid-ester.
- Figure 1 is the view of the Hydrogen-Nuclear Magnetic Resonance spectrum of Poly(glycerol-co-sebacate-co-e-caprolacton) polymers.
- Figure 2 is the view of the Fourier Transform Infrared spectrum of Poly(glycerol- co-sebacate-co-8-caprolacton) polymers.
- Figure 3 is the view of the Differential Scanned Calorimeter thermogram of Poly(glycerol-co-sebacate-co-s-caprolacton) polymers.
- the elastomers prepared according to the method disclosed in the present invention, and formed via crosslinking the prepolymers obtained by exposing at least two of the materials from the group comprising one polyol, onedicarboxylic acid and oneester to radio waves under vacuum and by using temperature are completely biodegradable and can be used in medical and non-medical areas.
- the production method of the elastomers disclosed in the present invention provides savings in terms of using purge gas, energy and raw material compared to the methods similar to the ones known in the state of the art.
- elastomer comprising only a polyol and a dicarboxylic acid
- the prepolymer synthesis times such as 24 or 48 hours are reduced under 10 minutes via radio waves.
- the frequency of the radio waves is between 1 GHz and 1000 GHz, and their wavelength varies between 0.1 and 100cm.
- the mole ratios of polyol/dicarboxylic acid/ester when the mole ratios of polyol/dicarboxylic acid/ester are referred as x/y/z, it is preferably x > y and x > z.
- the ratios of polyol can be less than the ratios of ester, the final physical features of the structures formed in these cases will vary.
- a catalyst can be utilized during polymerization of the said elastomers. In case a catalyst is used, the said catalyst is intended to be used for ester structure. In this case, the ester groups are preferred to be reacted at the same time with polyol and dicarboxylic acid.
- the biodegradable elastomer structure disclosed in the invention and comprised of one polyol, one dicarboxylic acid and one ester essentially comprises x, y and z parts next to each other on the same chain.
- the said primary chains are crosslinked with each other from exposed hydroxyl regions in x groups or with smaller polymer chains or with ester structures in form of oligomer.
- the crosslinking structure preferred in the present invention is the crosslinkings performed through exposed hydroxyls from polyol groups which are used. Except from this kind of crosslinks, possible crosslinking scenarios which are known by the person skilled in the art such as oligomer structures comprising at least two of monomers forming the inventive biodegradable elastomer bridging between the primary chains are in the scope of the invention.
- the crosslinking amounts or the percentages can be changed through the ratios f monomers used by mole and by using parameters such as temperature, pressure and time in second stage of the polymerization.
- the ratio of crosslink in the elastomers that are obtained may theoretically be 0.1% to 100%.
- the biodegradable elastomer disclosed in the present invention comprises a large number of hydrogen bonds together with the crosslinks.
- the number of the hydrogen bonds varies according to the crosslinking ratios, this situation is caused as a result of the abovementioned conformational changes.
- crosslinking is generally disclosed in this invention, it should be noted that there is always hydrogen bonds present along with the crosslinks in the inventive biodegradable elastomer.
- Obtaining prepolymers by subjecting at least two of the group comprising one polyol, one dicarboxylic acid and one ester to radio waves as disclosed in the present invention takes quite short time than the long periods known in the state of the art via radio waves.
- the said periods used in synthesizing prepolymers are preferably less than 1 hour, more preferably less than 30 minutes, and most preferably less than 10 minutes.
- the reaction times can be reduced to 30 seconds.
- the time for the reaction of crosslinking the said prepolymers via temperature and vacuum is preferably more than 4 hours, more preferably more than 18 hours, and most preferably 24 hours or longer.
- the time period for the said second stage reaction wherein the amount/percentage of crosslinking is changed according to the final use is optimized via the methods known in the state of the art (calculating the acid numbers via titration, gel permeability chromatography, and the like) such that it will be suitable for the field of use.
- mixer can preferably be used in the reactors.
- a vacuum line can be added for the condensation products moving apart from the medium.
- the ester molecules mentioned in the present invention are preferably epsilon- caprolacton, and they can be directly added to the polyol-dicarboxylic acid primary chain as monomer or oligomer by its ring structure being opened with the ring opening structure or they can from branches.
- ester used in prepolymers formed via radio wave method mentioned in here is preferably epsilon-caprolacton
- the monomers which are known by the person skilled in thart and have the binary functional group that can be added to the structure to be obtained, and which are in other biodegradable ester structure are in the scope of the present invention.
- the temperature applied during crosslinking the said prepolymers is preferably in the range of 105 °C to 165 °C, more preferably 105 °C to 165 °C, and the most preferably it is 150 °C.
- the vacuum value used during crosslinking the said prepolymers is preferably less than 100 mbar, more preferably less than lOmbar, and most preferably less than lmbar.
- the polyols are the alcohols comprising more than one hydroxyl group by their nature, and the polyols that can be used in the present invention are selected from the group comprising glycerol, erythritol, arabitol, mannitol, sorbitol, xylitol and the like, but they are not limited to these.
- the polyol used in the present invention is preferably glycerol.
- the dicarboxylic acids are the organic compounds comprising two carboxylic acid groups by their definition, and the dicarboxylic acids that can be used in the present invention are selected from the group comprising malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, and the like, but they are not limited to these
- the dicarboxylic acid used in the present invention is preferably sebasic acid.
- Cyclic or non-cyclic esters added to the polymer chain via a catalyst which is used in the inventive biodegradable elastomers and preferably tin octoate is known well by the person skilled in the art.
- the ester which is especially preferred in the present invention is epsilon-caprolacton.
- the infrared spectroscopy given in Figure 2 also confirms the polymerization.
- the peaks at 3350 cm “1 belong to hydroxy strain vibration in the molecules, showing hydroxyl groups consumed for ester based crosslinking. Methyl groups showed up at 2930 and 2850 cm “1 , and the peak of carbonyl ester showed up at 1734 cm “1 .
- the absorbance peak of methylene group showed up at 1429 cm “1 , while C-0 bending and absorption peaks showed up at 926 and 1185 cm “1 .
- Tissue engineering and biomaterial applications orthopedic hard tissue repair materials, soft tissue repair materials such as meniscus repair materials, biodegradable stents, cartilage repair materials, tendon repair materials, drug carrying systems, catguts and tissue adhesives are amongst the medical fields in which the biodegradable elastomers comprising at least two of the group comprising one polyol, one dicarboxylic acid and one ester, and which is obtained with the method disclosed in the present invention, however the fields of use are not limited to these.
- the said elastomers can also be used in non-medical fields wherein conventional plastic material such as garbage bags, food and drink boxes are used since they are biodegradable.
- the said elastomers are also be synthesized by mixing with filling materials, pain materials, lubricants, antioxidants and the like in both medical fields and non-medical fields.
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Biological Depolymerization Polymers (AREA)
- Polyesters Or Polycarbonates (AREA)
- Materials For Medical Uses (AREA)
Abstract
The present invention relates to elastomers comprising biodegradable cross links and/or hydrogen bonds having a polyol, one ester and one dicarboxylic acid, and the production method thereof. The method comprises the steps of processing the molecules comprising the said groups with radio waves and then processing thermally under vacuum. In the second step of the said method, the ratio of crosslinking and thus the main features in the biodegradable elastomers are changed by applying different reaction times, thus a wide variety of products can be manufactured from medical field to non-medical fields wherein thermoset and/or materials having hydrogen bonds are used.
Description
DESCRIPTION
BIODEGRADABLE ELASTOMER AND A PRODUCTION METHOD
THEREOF Field of the Invention
The present invention relates to biodegradable elastomers comprising crosslinks and/or hydrogen bonds, and a production method thereof. Background of the Invention
Elastomers are polymers exhibiting viscoelastic features. Biodegradable polymers and elastomers are being commonly used in many applications both in medical and environmental field. Recently, especially pioneered by Langer et al. (Wang et al., Nature Biotechnology, Volume:20, 602-606, 2002), hard biodegradable elastomers have been synthesized and studies have been started to be performed in very different applications especially in medical field and tissue engineering. Furthermore, Lui and Cai (Liu L., Cai W., Materials Letters, 63, 1656-1658, 209) have synthesized shaped memory biodegradable elastomers. Especially they obtained a prepolymer via condensation from one diol and one polyol and then they obtained a cross-linked thermoset material by applying heat and vacuum, and they were able to change the crosslinking rates within the acquired final polymer by providing suitable conditions depending on the final application. However in the techniques which are already known in the state of the art, prepolymerization stage continues for at least 2 to 3 days, and it requires continuous purge of valuable gases such as Argon (Ar), Nitrogen (N2) and keeping the reaction at high temperatures, resulted in an increase in the total cost.
Langer et al. discloses this kind of elastomers and field of use in patent document no US2009/0011486 Al. The elastomer in this patent comprises one polyol and
one dicarboxylic acid, and the first step of the production method thereof lasts 48 hours.
United States Patent document no US 2001 1/0008277 Al also discloses this kind of polymers, in which the cross linking can be started with an extrinsic effect thanks to the acrylate groups added to the polymer primary chain.
United States Patent document no US 201 1/0142790 Al discloses thermoset/ceramic composites that are prepared by reacting one polyol and one dicarboxylic acid in the presence of a bioceramic according to the method mentioned above. Again the first step of the method mentioned in this patent document takes substantially elongated periods of time, and it is also costly in terms of the gases used and the energy required.
According to the abovementioned examples and the examples of particular relevance to the ones known in the state of the art, the present invention provides savings in terms of energy and raw materials, and in addition to those polymers obtained via the reaction of only one diol and one dicarboxylic acid, other structures which are different than those mentioned in the aforementioned examples can be obtained via addition of an ester such as epsilon-caprolacton. The obtained biodegradable elastomers comprise cross links and/or hydrogen bonds.
Summary of the Invention The objective of the present invention is to obtain polymers including cross links and/or hydrogen bonds from at least two molecules selected from the group comprising one polyol, one dicarboxylic acid and one ester by using radio waves and high temperature under vacuum. Another objective of the present invention is to obtain biodegradable elastomers that can be used for medical and non-medical purposes.
Yet another objective of the present invention is to provide a method for obtaining the said elastomers economically. A further objective of the present invention is to obtain tissue engineering scaffolds from the obtained structures comprising polyol-dicarboxylic acid-ester.
Detailed Description of the Invention A biomaterial system developed to fulfill the objectives of the present invention is illustrated in the accompanying figures, in which:
Figure 1 is the view of the Hydrogen-Nuclear Magnetic Resonance spectrum of Poly(glycerol-co-sebacate-co-e-caprolacton) polymers.
Figure 2 is the view of the Fourier Transform Infrared spectrum of Poly(glycerol- co-sebacate-co-8-caprolacton) polymers.
Figure 3 is the view of the Differential Scanned Calorimeter thermogram of Poly(glycerol-co-sebacate-co-s-caprolacton) polymers.
The elastomers prepared according to the method disclosed in the present invention, and formed via crosslinking the prepolymers obtained by exposing at least two of the materials from the group comprising one polyol, onedicarboxylic acid and oneester to radio waves under vacuum and by using temperature are completely biodegradable and can be used in medical and non-medical areas. The production method of the elastomers disclosed in the present invention provides savings in terms of using purge gas, energy and raw material compared to the methods similar to the ones known in the state of the art. The production of elastomer comprising only a polyol and a dicarboxylic acid is in the scope of this invention with the superiority to the similar methods to the ones known in the state of the art is that the prepolymer synthesis times such as 24 or 48 hours are reduced under 10 minutes via radio waves. The frequency of the radio waves is
between 1 GHz and 1000 GHz, and their wavelength varies between 0.1 and 100cm.
In production of the elastomers disclosed in the present invention, when the mole ratios of polyol/dicarboxylic acid/ester are referred as x/y/z, it is preferably x > y and x > z. The ratios of polyol can be less than the ratios of ester, the final physical features of the structures formed in these cases will vary. A catalyst can be utilized during polymerization of the said elastomers. In case a catalyst is used, the said catalyst is intended to be used for ester structure. In this case, the ester groups are preferred to be reacted at the same time with polyol and dicarboxylic acid. After the polyol and dicarboxylic acid are reacted, obtaining crosslinked elastomers is risked by adding ester groups and catalyst; in this case the oligomers comprised of esters will attach to polyol-dicarboxylic acid polymer backbone as branches in exposed hydroxyl parts in polyol groups.
In both cases, positions and numbers of the hydrogen bonds will naturally exhibit differences through the associated groups known by the people skilled in the the art, and all these conformational combinations are in the scope of the invention. The biodegradable elastomer structure disclosed in the invention and comprised of one polyol, one dicarboxylic acid and one ester essentially comprises x, y and z parts next to each other on the same chain. The said primary chains are crosslinked with each other from exposed hydroxyl regions in x groups or with smaller polymer chains or with ester structures in form of oligomer. When the ratios selected by mole are suitable and the crosslinking parameters are selected right, other groups that can still form a bond within polymer after the reaction, and through the preferred hydroxyl or carbonyl group can added to the structure in the following reactions.
The crosslinking structure preferred in the present invention is the crosslinkings performed through exposed hydroxyls from polyol groups which are used. Except
from this kind of crosslinks, possible crosslinking scenarios which are known by the person skilled in the art such as oligomer structures comprising at least two of monomers forming the inventive biodegradable elastomer bridging between the primary chains are in the scope of the invention. The crosslinking amounts or the percentages can be changed through the ratios f monomers used by mole and by using parameters such as temperature, pressure and time in second stage of the polymerization. The ratio of crosslink in the elastomers that are obtained may theoretically be 0.1% to 100%. The biodegradable elastomer disclosed in the present invention comprises a large number of hydrogen bonds together with the crosslinks. The number of the hydrogen bonds varies according to the crosslinking ratios, this situation is caused as a result of the abovementioned conformational changes. Even though crosslinking is generally disclosed in this invention, it should be noted that there is always hydrogen bonds present along with the crosslinks in the inventive biodegradable elastomer.
Obtaining prepolymers by subjecting at least two of the group comprising one polyol, one dicarboxylic acid and one ester to radio waves as disclosed in the present invention takes quite short time than the long periods known in the state of the art via radio waves. In first stage, the said periods used in synthesizing prepolymers are preferably less than 1 hour, more preferably less than 30 minutes, and most preferably less than 10 minutes. In cases wherein x and y among the compounds are for example 0.2 mole, the reaction times can be reduced to 30 seconds.
After the prepolymer is produced, the time for the reaction of crosslinking the said prepolymers via temperature and vacuum is preferably more than 4 hours, more preferably more than 18 hours, and most preferably 24 hours or longer. The time period for the said second stage reaction wherein the amount/percentage of crosslinking is changed according to the final use is optimized via the methods
known in the state of the art (calculating the acid numbers via titration, gel permeability chromatography, and the like) such that it will be suitable for the field of use. In stages of producing the prepolymers and crosslinked elastomers mentioned in the present invention, mixer can preferably be used in the reactors. In first stage wherein the prepolymers are synthesized and which takes short time, a vacuum line can be added for the condensation products moving apart from the medium. The ester molecules mentioned in the present invention are preferably epsilon- caprolacton, and they can be directly added to the polyol-dicarboxylic acid primary chain as monomer or oligomer by its ring structure being opened with the ring opening structure or they can from branches. Even though the ester used in prepolymers formed via radio wave method mentioned in here is preferably epsilon-caprolacton, the monomers which are known by the person skilled in thart and have the binary functional group that can be added to the structure to be obtained, and which are in other biodegradable ester structure are in the scope of the present invention. The temperature applied during crosslinking the said prepolymers is preferably in the range of 105 °C to 165 °C, more preferably 105 °C to 165 °C, and the most preferably it is 150 °C.
The vacuum value used during crosslinking the said prepolymers is preferably less than 100 mbar, more preferably less than lOmbar, and most preferably less than lmbar.
The polyols are the alcohols comprising more than one hydroxyl group by their nature, and the polyols that can be used in the present invention are selected from the group comprising glycerol, erythritol, arabitol, mannitol, sorbitol, xylitol and
the like, but they are not limited to these. The polyol used in the present invention is preferably glycerol.
The dicarboxylic acids are the organic compounds comprising two carboxylic acid groups by their definition, and the dicarboxylic acids that can be used in the present invention are selected from the group comprising malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, and the like, but they are not limited to these The dicarboxylic acid used in the present invention is preferably sebasic acid.
Cyclic or non-cyclic esters added to the polymer chain via a catalyst which is used in the inventive biodegradable elastomers and preferably tin octoate is known well by the person skilled in the art. The ester which is especially preferred in the present invention is epsilon-caprolacton.
The polymer synthesis is confirmed in 1H-NMR given in Figure 1 and from the calculation of the peak areas given in boxes A and B , and as a result of the calculations made according to the areas, it has been found that the ratio of glycerol, sebasic acid and ε-caprolacton monomer is 50:16:34.
The infrared spectroscopy given in Figure 2 also confirms the polymerization. The peaks at 3350 cm"1 belong to hydroxy strain vibration in the molecules, showing hydroxyl groups consumed for ester based crosslinking. Methyl groups showed up at 2930 and 2850 cm"1, and the peak of carbonyl ester showed up at 1734 cm"1. The absorbance peak of methylene group showed up at 1429 cm"1, while C-0 bending and absorption peaks showed up at 926 and 1185 cm"1.
Figure 3 is DSC thermogram showing thermal behaviors of the synthesized polymers, the glass transition temperature of the obtained elastomers is Tg= -36,96 °C. Elastomers do not have melting and crystallization temperature. With the heating performed in second stage of DSC analysis (over 250 °C), the amount of
crosslinking increased in the structure and became final, and the polymerization reaction continued for a while. The said data indicates the amorphous structure of the elastomers and shows elastic feature. Tissue engineering and biomaterial applications, orthopedic hard tissue repair materials, soft tissue repair materials such as meniscus repair materials, biodegradable stents, cartilage repair materials, tendon repair materials, drug carrying systems, catguts and tissue adhesives are amongst the medical fields in which the biodegradable elastomers comprising at least two of the group comprising one polyol, one dicarboxylic acid and one ester, and which is obtained with the method disclosed in the present invention, however the fields of use are not limited to these. The said elastomers can also be used in non-medical fields wherein conventional plastic material such as garbage bags, food and drink boxes are used since they are biodegradable. The said elastomers are also be synthesized by mixing with filling materials, pain materials, lubricants, antioxidants and the like in both medical fields and non-medical fields.
The structures prepared in different geometries from biodegradable elastomers disclosed in the invention for medical use and non-medical fields are also in scope of the present invention, and there is no limitation for these geometries.
Within the framework of these basic concepts, it is possible to develop a wide variety of embodiments of the inventive biodegradable elastomer and a production method thereof (1). The invention cannot be limited to the examples described herein; it is as defined in the claims.
Claims
A biodegradable elastomer and a production method thereof characterized by the steps of subjecting at least two monomer mixture selected from the group comprising one polyol, one dicarboxylic acid and one ester to radio waves in order to prevent time, energy and raw material consumption resulting from the prepolymerization by shortening the long lasting prepolymerization stage first, and then applying heat and vacuum.
A biodegradable elastomer and a production method thereof according to claim 1 characterized in that the polyol monomer mixture is an alcohol comprising more than one hydroxyl group, and it is selected from the group comprising glycerol, erythritol, arabitol, mannitol, sorbitol, xylitol
A biodegradable elastomer and a production method thereof according to claim 1, characterized in that the dicarboxylic acid monomer used in monomer mixture is a monomer selected from the group comprising sebasic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid.
A biodegradable elastomer and a production method thereof according to claim 1, characterized in that the ester monomer used in the monomer mixture is a monomer selected from the group comprising epsilon- caprolacton, poly(alpha-hydroxyacids), poly(3-hydroxyalconates), poly(alkylene dicarboxylates).
A biodegradable elastomer and a production method thereof according to claim 4, characterized in that the number of crosslinks and H bonds are increased by keeping the temperature of the monomer mixture at the range of 100 to 165 °C during reaction in order to provide a final product with self healing features.
A biodegradable elastomer and a production method thereof according to any one of the preceding claims, characterized in that the frequency of the radio waves used to accelerate the prepolymerization stage on the monomer mixture is in between 1 and 1000 GHz.
A biodegradable elastomer and a production method thereof according to any one of the preceding claims, characterized in that the wavelength of the radio waves used on the monomer mixture to accelerate the prepolymerization stage is in between 0.1 and 100 cm.
A biodegradable elastomer and a production method thereof according to any one of the preceding claims, characterized in that the time at which the monomer mixture is subjected to radio waves is between 30 seconds and 1 hour.
A biodegradable elastomer and a production method thereof according to any one of the preceding claims, characterized in that the vacuum pressure applied to the monomer mixture subjected to radio waves is between 0.1 mbar to 100 mbar.
10. A biodegradable elastomer and a production method thereof according to any one of the preceding claims, characterized in that the temperature applied to the monomer mixture subjected to radio waves is between 105 °C to 165 °C.
11. A biodegradable elastomer and a production method thereof according to any one of the preceding claims, characterized in that the time for applying vacuum and heat to the monomer mixture subjected to radio waves is between 2 hours and 120 hours.
12. A biodegradable elastomer and a production method thereof according to any one of the preceding claims, characterized in that tin octoate is added into the monomer mixture as a catalyst in order to accelerate the reaction.
13. A biodegradable elastomer and a production method thereof according to claim 13, characterized in that the ratio of the catalyst added to the monomer mixture to the ester monomer in the monomer mixture is between 0.1% and 0.5% by weight.
14. A biodegradable elastomer and a production method thereof according to any one of the preceding claims, characterized in that the rate of crosslinking is between 0.1 % to 100% in the reaction taking place following the applications performed on the monomer mixture.
15. A biodegradable elastomer obtained via a method according to any one of the preceding claims.
16. A biodegradable elastomer according to claim 16, characterized in that it is a biocompatible elastomer.
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