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.