“POE IV POLYMERS AND ITS FUNCTIONAL ANALOGS WITH STRUCTURAL ATUNEMENT FOR ADVANCED BIOMEDICAL APPLICATIONS”

Abstract

The present invention relates to the synthesis of and development of novel class of POE-IV copolymers and its various function derivates with suitable weight average molecular weights (Mw) for various bio medical applications. The invention deals with functional derivatives with suitable weight average molecular weights (Mx) for various biomedical applications.

Specification

Description:The present invention is to provide a polymer of two structural units comprising of the following


wherein,

R1, R2 is H, C1-C4 alkyl, -OH, -O-C1-C6 alkyl, O-C1-C12 alkylene; k = 1 - 3.

R is a C1-C12 alkyl, preferably C2-C10 alkyl, and more preferably C2 alkyl;

i is between 1-10, preferably 2-8, more preferably i = 3-5;

m is between 20 and 120, preferably between 40 and 100, and more preferable between 80 and 90;

n is between 5 and 30, preferably between 15 and 25, and more preferable between 20 and 22;

x is between 1 and 12, preferably between 1 and 8, and more preferable between 1 and 4;

y is between 1 and 12, preferably between 1 and 9, and more preferable between 1 and 4;

x+y is between 2 and 24, preferably between 2 and 10, and more preferable between 2 and 6;

m/n is between 1 and 100; preferable between 1 and 50, and more preferable between 1 and 5;

the polymer has a weight-average molecular weight (Mw) between 1500 Da to 70000 Dalton, preferably in the range 4000 Dalton to 30000 Dalton, and more preferably in the range 4000 Dalton to 20000 Dalton;

the polydispersity index (PDI) of the polymers is in the range of 1.05 to 3.5, preferably in the range 1.1 to 3.2, more preferably in the range 1.15 to 2.5.

The main embodiment of the present invention is to provide a synthesis and development of a novel class of POE-IV copolymers and its various functional derivatives with suitable weight average molecular weights (Mw) for various biomedical applications, wherein the constituent monomers, the latent acid linker monomer is synthesized via a combination of at least "one non--hydroxy carboxyl" system with "one or more -hydroxy carboxyl" systems usually used in equivalent molar feed ratios.

DEFINITION OF TERMS:

Unless otherwise stated, all technical and scientific terminologies used in this invention disclosure have the same meaning as commonly understood by one with ordinary skill in the art. In case of any conflict, the present document will clearly specify the contexts including definitions. Details of the preferred methods and materials used and developed herein are described below. However, any other methods and materials similar or equivalent in their reactivity and quality to those described herein can be in principle used for testing the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety.

The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

The terminologies used in this invention disclosure such as "comprise(s)," "include(s)," "having," "has," "can," "contain(s)," and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures.

The singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise.

The present disclosure also contemplates other embodiments "comprising," "consisting of" and "consisting essentially of," the embodiments or elements presented herein, whether explicitly set forth or not.

The conjunctive term "or" includes any and all combinations of one or more listed elements associated by the conjunctive term. For example, in the phrase "an apparatus comprising A or B" may refer to an apparatus including A where B is not present, an apparatus including B where A is not present, or an apparatus where both A and B are present.

The phrases "at least one of A, B, . . . and N" or "at least one of A, B, . . . N, or combinations thereof are defined in the broadest sense to mean one or more elements selected from the group comprising A, B, . . . and N, that is to say, any combination of one or more of the elements A, B, . . . or N including any one element alone or in combination with one or more of the other elements which may also include, in combination, additional elements not listed.

The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity).

The modifier "about" should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression "from about 2 to about 4" also discloses the range "from 2 to 4." The term "about" may refer to plus or minus 10% of the indicated number. For example, "about 10%" may indicate a range 10 of 9% to 11%, and "about 1" may mean from 0.9-1.1. Other meanings of "about" may be apparent from the context, such as rounding off, so, for example "about 1" may also mean from 0.5 to 1.4. The term "wt. %" means weight percent.

The term "w/w" means weight per weight. The term "weight average molecular weight (Mw)" means a measuring system of the polymer weight that includes the mass of individual chains, which contributes to the overall molecular weight of the polymer.

The term "latent acid" means short acid segments in the polymer backbone consisting of a combination of at least one non-a-hydroxy carboxyl system with one or more a-hydroxy carboxyl systems such as units derived from ring opening of glycolide and g-valerolactone, units derived from ring opening of glycolide and d-valerolactone, units derived from ring opening of glycolide and e-caprolactone; units derived from ring opening of glycolide, lactide and g-valerolactone; units derived from ring opening of glycolide, lactide and e-caprolactone and so on.

The term "anti-solvent precipitation" means a purification process by mixing the polymer solution and the antisolvent.

The term "reaction feeding or feed ratio" means the molar ratio of used DETOSU monomer to the total moles of triethylene glycol (TEG) and triethylene glycol-latent acid wherein the term "latent acid" means short acid segments in the linker consisting of a combination of at least one non-a-hydroxy carboxyl system with one or more a-hydroxy carboxyl systems such as units derived from ring opening of glycolide and g-valerolactone, units derived from ring opening of glycolide and d-valerolactone, units derived from ring opening of glycolide and e-caprolactone; units derived from ring opening of glycolide, lactide and g-valerolactone; units derived from ring opening of glycolide, lactide and e-caprolactone and so on.

The term "polyol" refers to a chemical compound having more than one hydroxy (-OH) functional group. The term "diol" refers to a chemical compound having two hydroxy (-OH) groups.

The term "alkyl" refers a branched or unbranched saturated hydrocarbon chain with one carbon atom to the number of carbon atoms designated (e.g., C1-C14 alkyl). Examples of alkyl include methyl, ethyl, n-propyl, n-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and so on.

The term "alkylene' refers to a branched or unbranched saturated hydrocarbon chain with one carbon atom to the number of carbon atoms designated (e.g., C1-C14 alkylene). Examples of alkylene include methylene (-CH2-), ethylene (-CH2CH2-), isopentylene (-CH2-CH(CH3-)-CH2-CH2-), n-octylene (-(CH2)8-) and so on.

The terms "bioerodible" or "bioerodibility" refers to the overall mechanism of polymer degradation in a biological environment due to the action of living organisms and the degradation process most likely occurs at physiological pH and temperature.

The novel POE-IV based copolymers reported in this invention disclosure are synthesized via a step-growth polymerization. Molecular weights of polymers obtained from step-growth polymerizations critically depend on the stoichiometric ratios of the monomers used, the purity of the chemicals, reaction conditions, and the degree of polymerization. The most common limitation for obtaining high Mw polymer or high degree of polymerization is usually monomer or reaction solvent impurities.

In the present invention, all monomers and solvents were purified by recrystallization or distillation techniques (as needed and as suitable) to ensure high purity and quality of the materials used and methods developed. The ideal stoichiometric balance for two bifunctional monomers, A-A and B-B, used was 1.0.

However, in this current invention, it was found that varying the stoichiometric ratios between different bifunctional monomers in certain cases favors a higher degree of polymerization thereby resulting in a high molecular weight POE IV.

The polymers disclosed in this invention can be prepared via synthetic processes or methods typically known by those skilled in the art.

In certain embodiments, oxygen, moisture (or both) is excluded during the reaction processes via inert gas purging or vacuum or both or performing the reaction inside a glove box.

A mixture of at least one non--hydroxy cyclic carboxylic ester, one or more -hydroxy cyclic carboxylic esters and a diol linker are mixed and dissolved in pure organic solvent and allowed to react at an elevated temperature. After certain amount of time, monomers (or monomer solutions separately prepared) are added to the same reaction mixture in the same pot at room temperature. Typical preferred reaction temperature for complete conversion of step 1 was found to be 120 C and the preferred reaction temperature for step 2 to synthesize the final polymer was found to be room temperature (25 °C). However, both the steps were carefully and diligently monitored via thin layer chromatography (TLC) over a time necessary for complete conversion to the desired respective products. Final purified polymer product is obtained after filtration followed by repeated re-precipitation in an antisolvent and vacuum drying.

Molecular weight of synthesized polymer was characterized with gel permeation chromatography (GPC). Test was performed on Waters HPLC system with a refractive index detector (2414) utilizing Shodex GPC KF-804 column (Length 300 mm, ID8.0mm) (elution range 7 kDa - 120 kDa). Merck, HPLC grade THF was used as the eluent at a flow rate of 1.0 mL/min at 40°C. The molecular weight calibration was performed with monodisperse linear polystyrene (0.6 kDa to 300 kDa). For molecular weights, the entire signal of a major peak including its shoulder at a lower retention volume was integrated.

In TEG POE-IV represented in Formula III, R, R`, R`` refers to a branched or unbranched saturated and unsaturated hydrocarbon chain like "alkyl" and "alkeylene". Examples of alkyl include methyl, ethyl, n-propyl, n-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and so on. Examples of alkylene include methylene (-CH2-), ethylene (-CH2CH2-), isopentylene (-CH2-CH(CH3-)-CH2-CH2-), n-octylene (-(CH2)8-) and so on.

Typically, POE-IV based copolymers or TEG-POE IV is synthesized using a step-growth polymerization. Important factors that influence the molecular weights of polymers via step-growth polymerizations are the stoichiometric ratios of the monomers used in the polymerization step, the purity of the chemical resources, reaction conditions, and the degree of polymerization. Impurities present in the monomer or reaction solvent has been cited as the most common limitations for achieving high degree of polymerization in step-growth polymerization process. In this invention, high purity of all materials utilized as all monomers and solvents were purified by recrystallization or distillation techniques (as needed and as suitable). Ideally, the stoichiometric equivalence for two bifunctional monomers, A-A and B-B, should be 1.0. However, through our method, it was invented that on using higher stoichiometric ratio of one of the bifunctional monomers in certain cases favored a higher degree of polymerization thereby resulting in a high molecular weight TEG-POE IV.

Following the general polymerization procedures, the single-pot synthesis also works to generate other functional analogs to TEG-POE IV wherein the TEG-GL linker can be modified to TEG-LA linker or TEG-GL-LA or LA-TEG-GL followed by in-situ same pot polymerization to obtain various functional derivatives of TEG-POE IV polymers. Similar to TEG-POE IV, the Mw of these polymers increased with increase of DETUSO/Diol content in the polymerization reactions.

This method for synthesis of TEG1 latent acid linker via Method A can be considered as a general representative of all the functional analogs of the new class of latent acid linker synthesis consisting of at least one non--hydroxy carboxyl unit and one or more -hydroxy carboxyl units. In case of TEG1 linker, the non--hydroxy carboxyl unit is the -valerolactone and the -hydroxy carboxyl unit is the glycolide.


Following the general polymerization procedures, this single-pot syntheis also works to generate a wide variety of functional analogs to TEG-POE IV wherein instead of TEG, other diol systems including but not limited to 1.6-hexane diol, 1,10-decane diol and trans-cyclohexanedimethanol (t-CDM) were used. The Mw of these type of polyorthoesters (POE IV) also greatly depended on DETUSO/Diol content in the polymerization reactions.

According to the present invention, we state to clarify that the overall conclusions obtained through our experiments and observations and the concepts developed through the detailed studies described herein are not limited to specific processes, compounds, products, synthetic methods, articles, devices, or uses as such which can of course vary and can be utilized in much broader aspects or fields. It is expected to be understood that the terminologies used herein are meant to describe particular aspects only, and unless specifically defined herein, are not intended to be limiting.

Unless otherwise stated, all technical and scientific terminologies used in this present invention disclosure have the same meaning as commonly understood by one with ordinary skill in the art. In case of any conflict, the present document will clearly specify the contexts including definitions. Details of the preferred methods and materials used and developed herein are described below. However, any other methods and materials similar or equivalent in their reactivity and quality to those described herein can be in principle used for testing the present invention.

The following examples as described below illustrates the present invention as claimed. These examples are only intended as possible methods without limiting the invention to their contents.

EXAMPLES

Preparation of the DETOSU monomer


Figure 2 represents the schematic synthesis of DETOSU monomer.

600 mL of Ethylenediamine was added into a round bottom flask under inert atmosphere followed by addition of 175 gm of potassium tert-butoxide. After the reaction mass dissolved, 100 gm of 3,9-Divinyl-2,4,8,10-tetraoxaspiro[5.5]undecane (DVTOSU) was added to the reaction mass at room temperature. Gradually, the temperature was raised to 120oC and maintained for 30 hours. Reaction mass turned colorless to brown color during the course of reaction. Completion of reaction was monitored with the help of TLC.

After completion of reaction, reaction mass was brought to room temperature and hexane was added. Then, the reaction mass was poured into chilled water and the compound was extracted into organic layer, followed by repeated washing with water to remove impurities. Organic compound was then dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain the crude product which was purified by distillation followed by crystallization in hexane at -20 C to obtain the pure product as white solid (60% yield).

EXAMPLE 1: TEG1-POE IV (TEG1: TEG-GL-VL) via Method A

Method A: Synthesis via conventional two pot method.

Step 1 is synthesis of DETOSU and the procedure is same for both Method A and Method B as given above.

Step 2: Synthesis of Latent Acid Linker TEG1 (TEG1: TEG-GL-VL)

2.2 g of Glycolide, 19.14 g of -valerolactone and 57.43 g of triethylene glycol were added into a round bottom flask under nitrogen atmosphere. Then, the temperature of the reaction mixture was gradually raised to 120oC and stirred at that temperature for 18 hours under nitrogen atmosphere. The progress of the reaction to form the linker product, TEG1: TEG-GL-VL latent acid linker was monitored via thin layer chromatography (TLC). After completion of the reaction, the product was carefully transferred into another flask without touching the walls of the flask under nitrogen atmosphere. The isolated TEG1 latent acid linker was cooled and stored in a freezer (-20 oC) under nitrogen atmosphere and used as it is for the next step without further purification (70% yield).

Step 3: Synthesis of the final polymer TEG1-POE IV (TEG1: TEG-GL-VL)

2 g of TEG1 linker as synthesized in step 2 was dissolved in 20 ml of dry THF and was added to a round bottom flask containing 2.96 g of triethylene glycol under nitrogen atmosphere at room temperature. Then 6.93 g of DETOSU was dissolved in 40 ml of dry THF and was added portion-wise to the above reaction mass. Then ~2-3 drops of p-TSA solution (Conc.:10 mg of PTSA in 1 ml dry THF) was added to the above reaction mass and stirred for ~2 hours at 30oC under inert atmosphere. After completion of the reaction, reaction mass was slowly added to 500 ml of vigorously stirred dried hexane under inert atmosphere. The polymerized product was observed as a colorless precipitate at the bottom of the flask. After complete precipitation, the hexane layer was decanted and the polymer precipitate was dissolved in minimum amount of dry THF and reprecipitated into hexane. The reprecipitation process was repeated 2-3 times to remove all the unwanted unreacted impurities from the polymer. The purified polymer was dried under reduced pressure under high vacuum pump to give a colorless viscous TEG1-POE IV polymer (50% yield).

EXAMPLE 2: TEG1-POE IV (TEG1: TEG-GL-VL) via Method A

Step 1 is synthesis of DETOSU and the procedure is same for both Method A and Method B as given above.

Step 2: Synthesis of Latent Acid Linker TEG1 (TEG1: TEG-GL-VL)

35.0 g of Glycolide, 30.2 g of -valerolactone and 90.75 g of triethylene glycol were added into a round bottom flask under nitrogen atmosphere. Then, the temperature of the reaction mixture was gradually raised to 120oC and stirred at that temperature for 18 hours under nitrogen atmosphere. The progress of the reaction to form the linker product, TEG1: TEG-GL-VL latent acid linker was monitored via thin layer chromatography (TLC). After completion of the reaction, the product was carefully transferred into another flask without touching the walls of the flask under nitrogen atmosphere. The isolated TEG1 latent acid linker was cooled and stored in a freezer (-20 oC) under nitrogen atmosphere and used as it is for the next step without further purification (72% yield).

Step 3: Synthesis of the final polymer TEG1-POE IV (TEG1: TEG-GL-VL)

5 g of TEG1 linker as synthesized in step 2 was dissolved in 55 ml of dry THF and was added to a round bottom flask containing 7.5 g of triethylene glycol under nitrogen atmosphere at room temperature. Then 17 g of DETOSU was dissolved in 100 ml of dry THF and was added portion-wise to the above reaction mass. Then ~2-3 drops of p-TSA solution (Conc.:10 mg of PTSA in 1 ml dry THF) was added to the above reaction mass and stirred for ~2 hours at 30oC under inert atmosphere. After completion of the reaction, reaction mass was slowly added to 1500 ml of vigorously stirred dried hexane under inert atmosphere. The polymerized product was observed as a colorless precipitate at the bottom of the flask. After complete precipitation, the hexane layer was decanted and the polymer precipitate was dissolved in minimum amount of dry THF and reprecipitated into hexane. The reprecipitation process was repeated 2-3 times to remove all the unwanted unreacted impurities from the polymer. The purified polymer was dried under reduced pressure under high vacuum pump to give a colorless viscous TEG1-POE IV polymer (48 % yield).

EXAMPLE 3: TEG1-POE IV (TEG1: TEG-GL-VL) VIA METHOD B

Method B: Polymer synthesis via a single-pot method. Method B consists of essentially two steps: Step 1: Synthesis of DETOSU; Step 2: Synthesis of Latent acid linker followed by in-situ synthesis of the polymer.

Step 1 is synthesis of DETOSU and the procedure is same for both Method A and Method B as given above.

Step 2: Synthesis of the TEG1-POE IV (TEG1: TEG-GL-VL) polymer via single pot method
900 mg of Glycolide, 777 mg of -valerolactone and 5.75 gm of triethyleneglycol were added to a flame dried round bottom flask under inert atmosphere. Temperature of the reaction mixture was gradually raised to 120oC and the reaction mixture was allowed to stir at that temperature for 30 hours. The completion of the reaction was monitored with the help of TLC. After completion of the reaction, the temperature of the reaction was allowed to come to room temperature and 20 ml of freshly distilled THF was added to the reaction mixture and allowed to stir under inert atmosphere for 1 hour. Then 10 gm of DETOSU was dissolved in 50 ml of dry THF and was slowly added to the reaction mixture under inert atmosphere. Then ~2-3 drops of p-TSA solution (Conc.:10 mg of PTSA in 1 ml dry THF) was added to the above reaction mass and stirred for ~2 hours at 30oC under inert atmosphere. After completion of the reaction, the reaction mass obtained from the single-pot from two consecutive reactions was slowly added to 500 ml of vigorously stirred dried hexane under inert atmosphere. The polymerized product was observed as a colorless viscous precipitate at the bottom of the flask. After complete precipitation, the hexane layer was decanted and the polymer precipitate was dissolved in minimum amount of dry THF and reprecipitated into hexane. The reprecipitation process was repeated 2-3 times to remove all the unwanted unreacted impurities from the polymer. The purified polymer was dried under reduced pressure under high vacuum pump to give a colorless viscous TEG1-POE IV polymer (55 % yield).

EXAMPLE 4: TEG1-POE IV (TEG1: TEG-GL-VL) VIA METHOD B

Step 1 is synthesis of DETOSU and the procedure is same for both Method A and Method B as given above.

Step 2: Synthesis of the TEG1-POE IV (TEG1: TEG-GL-VL) polymer via single pot method

1.5 gm of Glycolide, 1.3 gm of -valerolactone and 9.5 gm of triethyleneglycol were added to a flame dried round bottom flask under inert atmosphere. Temperature of the reaction mixture was gradually raised to 120oC and the reaction mixture was allowed to stir at that temperature for 30 hours. The completion of the reaction was monitored with the help of TLC. After completion of the reaction, the temperature of the reaction was allowed to come to room temperature and 35 ml of freshly distilled THF was added to the reaction mixture and allowed to stir under inert atmosphere for 1 hour. Then 16.6 gm of DETOSU was dissolved in 85 ml of dry THF and was slowly added to the reaction mixture under inert atmosphere.

Then ~2-3 drops of p-TSA solution (Conc.:10 mg of PTSA in 1 ml dry THF) was added to the above reaction mass and stirred for ~2 hours at 30oC under inert atmosphere. After completion of the reaction, the reaction mass obtained from the single-pot from two consecutive reactions was slowly added to 1000 ml of vigorously stirred dried hexane under inert atmosphere. The polymerized product was observed as a colorless viscous precipitate at the bottom of the flask. After complete precipitation, the hexane layer was decanted and the polymer precipitate was dissolved in minimum amount of dry THF and reprecipitated into hexane. The reprecipitation process was repeated 2-3 times to remove all the unwanted unreacted impurities from the polymer. The purified polymer was dried under reduced pressure under high vacuum pump to give a colorless viscous TEG1-POE IV polymer (58 % yield).

Via using Method A and Method B as illustrated in Example 1 to Example 4 for synthesizing TEG1-POE IV polymer, a range of novel POE IV polymers were successfully synthesized as listed below in Table 1.

Table 1. List of novel POE IV polymers having a combination of various -hydroxy carboxyl and non- -hydroxy carboxyl units in the latent acid linker monomer

S No. Novel POE IV Polymer Latent Acid Linker Cyclic -hydroxy carboxyl ester Cyclic non--hydroxy carboxyl ester Mw/PDI
1 TEG1-POE IV TEG1: TEG-GL-VL Glycolide (GL) VL (-valerolactone) 5300/2.0
2 TEG2-POE IV TEG2: TEG-GL-CL Glycolide (GL) CL (-Caprolactone) 5900/2.1
3 TEG3-POE IV TEG3: TEG-GL-LA-CL Glycolide (GL), Lactide (LA) CL (-Caprolactone) 3600/1.8
4 TEG4-POE IV TEG4: TEG-GL-LA-VL Glycolide (GL), Lactide (LA) VL (-valerolactone) 4300/2.0

Although, Example 1 to Example 4 illustrated in this invention disclosure used triethylene glycol as the typical diol example, it is just a representative of experimental validation for the proof of concept. These methods are applicable to a much broader range of diols including but not limited to alky- or alkylidene- based diols with straight chain systems, branched chain systems as well as various polymeric systems with diols as the end-group functional moieties. Also, the cyclic non--hydroxy carboxyl esters that can be utilized in the development of these novel type of POE IV polymers are not limited to -valerolactone and -caprolactone only and can broadly include several other non--hydroxy carboxyl ester systems including but not limited to -butyrolactone, -hydroxy--butyrolactone, -valerolactone and so on along with their corresponding various kinds of functional derivatives as well.

Characterization

Molecular weights of synthesized novel POE IV polymers were characterized with gel permeation chromatography (GPC). Test was performed on Waters HPLC system with a refractive index detector (2414) utilizing Shodex GPC KF-804 column (Length 300 mm, ID8.0mm) (elution range 7 kDa - 120 kDa). Merck, HPLC grade THF was used as the eluent at a flow rate of 1.0 mL/min at 40°C. The molecular weight calibration was performed with monodisperse linear polystyrene (0.6 kDa to 300 kDa). For molecular weights, the entire signal of a major peak including its shoulder at a lower retention volume was integrated.
, Claims:1. A polymer comprising of the following two structural units:


wherein, R1, R2 is H, C1-C4 alkyl, -OH, -O-C1-C6 alkyl, O-C1-C12 alkylene; k = 1 - 3.

R is a C1-C12 alkyl, preferably C2-C10 alkyl, and more preferably C2 alkyl;

i is between 1-10, preferably 2-8, more preferably i = 3-5;

m is between 20 and 120, preferably between 40 and 100, and more preferable between 80 and 90;

n is between 5 and 30, preferably between 15 and 25, and more preferable between 20 and 22;

x is between 1 and 12, preferably between 1 and 8, and more preferable between 1 and 4;

y is between 1 and 12, preferably between 1 and 9, and more preferable between 1 and 4;

x+y is between 2 and 24, preferably between 2 and 10, and more preferable between 2 and 6;

m/n is between 1 and 100; preferable between 1 and 50, and more preferable between 1 and 5;
the polymer has a weight-average molecular weight (Mw) between 1500 Da to 70000 Dalton, preferably in the range 4000 Dalton to 30000 Dalton, and more preferably in the range 4000 Dalton to 20000 Dalton;

the polydispersity index (PDI) of the polymers is in the range of 1.05 to 3.5, preferably in the range 1.1 to 3.2, more preferably in the range 1.15 to 2.5.

2. According to the claim 1, the polymer can be synthesized using the conventional three step synthesis (Method A) wherein the linker and the polymer is synthesized separately or it can also be synthesized via a one-pot strategy (Method B) wherein the polymer is synthesized in-situ in the same pot following the synthesis of the linker.
3. According to the claim 1, the polymer can be synthesized via method A and method B with molecular weights ranging from 1.5 kDa to 70 kDa.
4. According to the claim 1, the latent acid linker monomer in polymers comprises combination of at least one non--hydroxy carboxyl unit and one or more -hydroxy carboxyl units.
5. According to the claim 1, the molecular weights (Mw) of the polymers can be controlled via altering the equivalent molar ratio of DETOSU to total molar diol content (total molar diol content = molar equivalents of triethylene glycol + molar equivalents of latent acid diol linker).
6. According to the claim 1, the polymer wherein the ketal monomer is DETOSU: 3,9-Diethylene-2,4,8,10-tetraoxaspiro(5.5)undecane.
7. According to the claim 1, the various physicochemical properties of the polymers include potentially higher drug-loading efficiency, more controlled drug release rates as well as overall polymer degradation can be tuned via altering the molecular weights of the polymers as well as the equivalent molar ratios of -hydroxy carboxyl unit /non--hydroxy carboxyl units incorporated into the latent acid linker fraction of the polymer.
8. According to the claim 1, the polymer preferentially follows a surface erosion-based degradation mechanism wherein the polymer matrix preferentially demonstrates a progressive disintegration via thinning of the drug delivering matrix instead of the usual bulk degradation mechanism.
9. According to the claim 1, the novel class of polymers developed via this invention are used for drug delivery systems, drug eluting implants, medical devices, 3D bio-printing, dental applications, scaffolds for wound healing and other biomedical applications.

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