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WO2003062298A1 - Co-poly(ester amide) et co-poly(ester urethane) compositions presentant une biodegradabilite, procedes de production et utilisation associes - Google Patents

Co-poly(ester amide) et co-poly(ester urethane) compositions presentant une biodegradabilite, procedes de production et utilisation associes Download PDF

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Publication number
WO2003062298A1
WO2003062298A1 PCT/US2002/001258 US0201258W WO03062298A1 WO 2003062298 A1 WO2003062298 A1 WO 2003062298A1 US 0201258 W US0201258 W US 0201258W WO 03062298 A1 WO03062298 A1 WO 03062298A1
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formula
moles
bis
composition
toluenesulfonic acid
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Ramaz Katsarava
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POLYRAVA LLC
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POLYRAVA LLC
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    • 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
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic 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
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
    • C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
    • C08G69/10—Alpha-amino-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
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/44—Polyester-amides

Definitions

  • the invention described herein relates generally to polymeric compositions which can be used to form a variety of biodegradable objects and to methods for making the same.
  • the present invention relates to polymers made from: (1) the combination of at least two di-p-toluenesulfonic acid salts of a bis-( ⁇ - amino acid) ⁇ , ⁇ -alkylene diester with at least one active diester; (2) the combination of at least two di-p-toluenesulfonic acid salts of a bis-( ⁇ -amino acid) ⁇ , ⁇ -alkylene diester with at least one active bis-carbonate of a diol; (3) the combination of at least one di-p-toluenesulfonic acid salts of a bis-( ⁇ -amino acid) ⁇ , ⁇ -alkylene diester and at least one di-p-toluenesulfonic acid salt of an ester (e.g., a diamino ester) with at least one active diester
  • PAAs poly- ⁇ -amino acids
  • the present invention relates to polymers made using: (1) the combination of at least two di-p-toluenesulfonic acid salts of a bis-( ⁇ -amino acid) ⁇ , ⁇ -alkylene diester with at least one active diester; (2) the combination of at least two di-p- toluenesulfonic acid salts of a bis-( ⁇ amino acid) ⁇ , ⁇ -alkylene diester with at least one active bis-carbonate of a diol; (3) the combination of at least one di-p- toluenesulfonic acid salts of a bis-( ⁇ -amino acid) ⁇ , ⁇ -alkylene diester and at least one di-p-toluenesulfonic acid salt of an ester (e.g., a diamino ester) with at least one active diester; and (4) the combination of at least one di-p-toluenesulfonic acid salts of a bis-( ⁇ -amino
  • the present invention relates to co-poly(ester amide) compositions which contain at least two amino acid subcomponents comprising repeating units according to the following formula:
  • R ⁇ R 2 , R 4 and R 5 are independently selected from -CH 3 , -CH 2 CH 3 , linear and branched C 3 to C 20 alkyl, C 2 to C 3 thioalkyl, linear or branched C 4 to C 20 thioalkyl, -CH 2 -C 6 H 5 , -CH 2 -CH 2 -C 6 H 5 , and linear and branched C 3 -C 20 alkyl with at least one terminal phenyl group;
  • R 3 and R 6 are independently selected from -(CH 2 ) X -, where x is from 2 to about 40;
  • R 7 is selected from -(CH 2 ) y -, where y is from 2 to about 40;
  • n is from about 20 to about 500; the ratio of a/b is in the range of about 90:10 to about 10:90; and at least one of R ⁇ R 2 , R 3 or the first R 7 is different from at least one of R 4 , R 5
  • the at least two amino acid sub-components of Formula (A) are different.
  • the present invention relates to co-poly(ester amide) compositions which contain at least two amino acid sub-components comprising repeating units according to the following formula:
  • R 1 and R 2 are independently selected from -CH 3 , -CH 2 CH 3 , linear and branched C 3 to C 20 alkyl, C 2 to C 3 thioalkyl, linear or branched C 4 to C 20 thioalkyl,
  • R 3 is selected from -(CH 2 ) X ⁇ , where x is from 2 to about 40;
  • R 7 is independently selected from -(CH 2 ) y -, where y is from 2 to about 40;
  • R 9 is selected from -(CH 2 ) r -, where r is from 1 to about 40;
  • R 10 is selected from -C(0)-O-C m H 2m+1 where m is 1 to about 60, and -C(0)-0-R" where R" is selected from hydrogen, - CH 2 -C 6 H 5 , -CH 2 -CH 2 -C 6 H 5 , linear and branched C 3 -C 20 alkyl with at least one terminal phenyl group;
  • n is about 10 to about 1 ,000; and the ratio of c/d is
  • the at least two amino acid sub-components of Formula (B) are different.
  • the first R 7 in Formula (B) is identical to the second R 7 in Formula (B).
  • the present invention relates to co-poly(ester urethane) compositions which contain at least two amino acid sub-components comprising repeating units according to the following formula:
  • R 1 , R 2 , R 4 and R 5 are independently selected from -CH 3 , -CH 2 CH 3 , linear and branched C 3 to C 20 alkyl, C 2 to C 3 thioalkyl, linear or branched C 4 to C 20 thioalkyl, -CH 2 -C 6 H 5 , -CH 2 -CH 2 -C 6 H 5 , and linear and branched C 3 -C 20 alkyl with at least one terminal phenyl group;
  • R 3 and R 6 are independently selected from -(CH 2 ) X -, where x is from 2 to about 40;
  • R 8 is selected from -(CH 2 ) Z -, where z is from 2 to about 40, and -(CH 2 ) r O-(CH 2 ) k -, where j and k are independently selected from 1 to about 20;
  • n is about 10 to about 1 ,000; and the ratio of e/f is in the range of about
  • the present invention relates to co-poly(ester urethane) compositions which contain at least two amino acid sub-components comprising repeating units according to the following formula: -H-C(0)-0-R 8 -0-C(0)-NH-CH(R 1 )-CO-0-R 3 -0-CO-CH(R 2 )-NH-] g
  • R 1 and R 2 are independently selected from -CH 3 , -CH 2 CH 3 , linear and branched C 3 to C 20 alkyl, C 2 to C 3 thioalkyl, linear or branched C 4 to C 20 thioalkyl, -CH 2 -C 6 H 5 , -CH 2 -CH 2 -C 6 H 5 , and linear and branched C 3 -C 20 alkyl with at least one terminal phenyl group;
  • R 3 is selected from -(CH 2 ) X -, where x is from 2 to about 40;
  • each R 8 is independently selected from -(CH 2 ) 2 -, where z is from 2 to about 40, and - (CH 2 ) j -0-(CH 2 ) k -, where j and k are independently selected from 1 to about 20;
  • R 9 is selected from -(CH 2 ) r -, where r is from 1 to about 40;
  • R 10 is selected from
  • the at least two amino acid sub-components of Formula (D) are different.
  • the first R 8 in Formula (D) is identical to the second R 8 in Formula (D).
  • the present invention relates to a method for producing biodegradable polymers comprising the steps of: (A) combining at least one di-p-toluenesulfonic acid salt of a bis-( ⁇ -amino acid) ⁇ , ⁇ - alkylene diesters according to Formulas (la) and/or (lb) and optionally at least one di-p-toluenesulfonic acid salt of an ester according to Formula (IV) with at least one active diester according to Formula (II) or at least one active bis-carbonate of a diol according to Formula (III):
  • R ⁇ R 2 , R 4 and R 5 are independently selected from -CH 3 , -CH 2 CH 3 , linear and branched C 3 to C 20 alkyl, C 2 to C 3 thioalkyl, linear or branched C 4 to C 20 thioalkyl, -CH 2 -C 6 H 5 , -CH 2 -CH 2 -C 6 H 5 , and linear and branched C 3 -C 20 alkyl with at least one terminal phenyl group;
  • R 3 and R 6 are independently selected from -(CH 2 ) X -, where x is from 2 to about 40;
  • R 7 is selected from -(CH 2 ) y -, where y is from 2 to about 40;
  • X is -0-C 6 H 4 -N0 2 ;
  • R 8 is selected from -(CH 2 ) Z -, where z is from 2 to about 40
  • the present invention relates to a method for producing biodegradable polymers using a combination in step (A) of one diester according to Formula (la), one diester according to Formula (lb) and one active diester according to Formula (II), wherein at least one of R ⁇ R 2 or R 3 is different from at least one of R 4 , R 5 or R 6 .
  • the present invention relates to a method for producing biodegradable polymers using a combination in step (A) of one diester according to Formula (la) or (lb) and two active diesters according to Formula (II), wherein the R 7 groups in the active diesters according to
  • the present invention relates to a method for producing biodegradable polymers using a combination in step (A) of one diester according to Formula (la) or (lb), one diester according to Formula (IV) and one active diester according to Formula (II).
  • the present invention relates to a method for producing biodegradable polymers using a combination in step (A) of one diester according to Formula (la), one diester according to Formula (lb) and one active bis-carbonate according to Formula (III), wherein at least one of R 1 , R 2 or R 3 is different from at least one of R 4 , R 5 or R 6 .
  • the present invention relates to a method for producing biodegradable polymers using a combination in step (A) of one diester according to Formula (la) or (lb) and two active bis- carbonates according to Formula (III), wherein the R 8 groups in the active diesters according to Formula (III) are different.
  • the present invention relates to a method for producing biodegradable polymers using a combination in step (A) of one diester according to Formula (la) or (lb), one diester according to Formula (IV) and one active bis-carbonate according to Formula (III).
  • the foregoing compositions and/or methods provide any number of advantages.
  • the present biodegradable compositions and methods for providing the same are cost effective
  • the present invention provides both biodegradable polymers and methods for making the same which have a variety of desirable chemical, biological and/or mechanical properties.
  • the amino acid based bioanalogous polymers yielded by the reactions of the present invention are easy to process using solution casting (using, for example, common organic solvents) and/or melt casting techniques.
  • Figure 1 illustrates wound covering formed using a polymer according to the present invention
  • Figure 2 summarizes a method by which to produce polymers films from a polymer according to the present invention
  • Figure 3 illustrates the function of the various portions of the wound covering of Figure 1.
  • the present invention involves a method for producing a variety of amino acid based bioanalogous polymers made from derivatives of ⁇ -amino acids and/or other nontoxic compounds.
  • the present invention relates to co-poly(ester amide)s made using: (1) the combination of at least two di-p-toluenesulfonic acid salts of a bis-( ⁇ -amino acid) ⁇ , ⁇ -alkylene diester with at least one active diester; and
  • compositions, and methods to produce the same, yield polymers which can be used to produce a wide range of biodegradable objects including, but not limited to, sutures, scaffolds (be they medical or otherwise), ligating clips and staples, surgical tubes or catheters, orthopedic implants, barriers to prevent tissue adhesion, vascular grafts, stent coatings (medicated or non- medicated), artificial skin (medicated or non-medicated), bone substitutes, self- reinforced composites, temporary templates for cell growth, temporary contraceptives (e.g., stoppers for closing a fallopian tube, etc.), tampons, biodegradable time release patches (e.g., patches for use with one or more drugs, physiologically active substances and bactericides) and artificial glands for releasing bio-active peptides and/or proteins.
  • biodegradable time release patches e.g., patches for use with one or more drugs, physiologically active substances and bactericides
  • artificial glands for releasing bio-active peptides and
  • biodegradable polymers and methods for making the same which have a variety of desirable chemical, biological and/or mechanical properties.
  • amino acid based bioanalogous polymers obtained by the reactions of the present invention are easy to process using solution casting (using, for example, common organic solvents) and/or melt casting techniques.
  • solution casting using, for example, common organic solvents
  • melt casting techniques range and ratio limits and/or range and time limits may be combined.
  • biodegradable biodegradability
  • biodegradation and the like means the capability of undergoing natural processes in which a material is broken down by metabolic processes of living organisms (e.g., humans, other mammals or animals, fungi, bacteria, etc.). In the presence of oxygen (aerobic biodegradation), these metabolic processes yield carbon dioxide, water, biomass, and minerals. Under anaerobic conditions (anaerobic biodegradation), methane may additionally be produced.
  • room temperature means a temperature in the range of about 20 °C to about 27 °C
  • an amino acid means any naturally occurring or artificially produced amino acid.
  • TosOH is shorthand for the following formula:
  • the present invention relates to co-poly(ester amide)s and co-poly(ester urethane)s made from various combinations, as will be explained below, of Formulas
  • R ⁇ R 2 , R 4 and R 5 are independently selected from -CH 3 , -CH 2 CH 3 , linear and branched C 3 to C 20 alkyl, C 2 to C 3 thioalkyl (e.g., -CH 2 -S-CH 3 , -CH 2 -S-CH 2 -CH 3 , and -CH 2 -CH 2 -S-CH 3 ), linear or branched C 4 to C 20 thioalkyl, -CH 2 -C 6 H 5 , -CH 2 -CH 2 -C 6 H 5 , and linear and branched C 3 -C 20 alkyl with at least one terminal phenyl (-C 6 H 5 ) group; R 3 and R 6 are independently selected from -(CH 2 ) X -, where x is from 2 to about 40;
  • R 7 is selected from -(CH 2 ) y -, where y is from 2 to about 40;
  • R 8 is selected from - (CH 2 ) Z -, where z is from 2 to about 40, and -(CH 2 ) j -0-(CH 2 ) k -, where j and k are independently selected from 1 to about 20;
  • R 9 is selected from -(CH 2 ) r -, where r is from 1 to about 40; and
  • R 10 is selected from -C(0)-0-C m H 2rn+ ⁇ , where m is 1 to about 60, and -C(0)-0-R" where R" is selected from hydrogen, -CH 2 -C 6 H 5 , -CH 2 -CH 2 -C 6 H 5 , linear and branched C 3 -C 20 alkyl with at least one terminal phenyl (-C 6 H 5 ) group.
  • X is selected from -0-C 6 H 4 -N0 2 , phenols or thiophenols with one more electron-withdrawing substituents (e.g., one or more of F, CI, Br, N0 2 , CN, etc.) such as, but not limited to, those groups shown below:
  • X can also be selected from benzazols, imidazols, pyrazols, lactams or thiolactams groups. Exemplary structures for such groups are shown below. It should be noted that X is not limited to the structures of the groups shown above, rather X can be any group having the same basic chemical structure as those shown either above or below. For example,
  • Q is selected from O or S
  • A is selected from NH, O or S.
  • R 1 , R 2 or R 3 is different from at least one of R 4 , R 5 or R 6 (i.e., (la) is different from (lb)) in order for there to be present two different di-p-toluenesulfonic acid salts of a bis-( ⁇ -amino acid) ⁇ , ⁇ -alkylene diester in the reaction mixture.
  • the active diesters when two or more active diesters according to Formula (II) are utilized in the reaction mixture, the active diesters differ in that each active diester has a different R 7 group. In another embodiment, when two or more active bis-carbonates according to Formula (III) are utilized in the reaction mixture, the active bis-carbonates differ in that each active bis-carbonates has a different R 8 group.
  • R ⁇ R 2 , R 4 and R 5 are independently selected from -CH 3 , -CH 2 CH 3 , linear and branched C 3 to C 6 alkyl, -CH 2 -CH 2 -S-CH 3 , and -CH 2 -C 6 H 5 .
  • R 3 and R 6 are independently selected from -(CH 2 ) X -, where x is from 2 to about 20, even where x is from 2 to about 12.
  • R 7 is selected from -(CH 2 ) y -, where y is from 2 to about 30, even where y is from 2 to about 20.
  • R 8 is selected from -(CH 2 ) Z -, where z is from 2 to about 20, even where z is from 2 about 12, and -(CH 2 ) 2 -0-(CH 2 ) 2 -.
  • R 9 is selected from -(CH 2 ) r -, where r is from 2 to about 10, even where r is from 2 to about 6, or even where r is 4.
  • R" is selected from hydrogen, -CH 2 -C 6 H 5 , and -C(0)-0-C m H 2rn+ ⁇ where m is 1 to about 40, even where m is 4, 8, 12, 16 or 20.
  • Co-Poly(ester amide)s in one embodiment, relates to co-poly(ester amide)s according to Formula (A) made from the combination of at least two different di-p- toluenesulfonic acid salts of bis-( ⁇ -amino acid) ⁇ , ⁇ -alkylene diester according to Formulas (la) and (lb) and at least one active diester according to Formula (II).
  • the above compounds are reacted using a suitable polymerization reaction (e.g., a polycondensation reaction) to yield co-poly(ester amide) polymers according to Formula (A) below:
  • n is from about 10 to about 1000 and the ratio of a/b is in the range of about 90:10 to about 10:90. In another embodiment, the ratio of a/b is from about 75:25 to about 25:75; or even from about 60:40 to about 40:60. In another embodiment, n is from about 20 to about 500, or even from about 30 to about 300.
  • the polymers according to Formula (A) have a Mw of about 5,000 to about 400,000 daltons. In another embodiment, the polymers according to Formula (A) have a Mw of about 10,000 to about 200,000 daltons, even about 20,000 to about 100,000 daltons. In another embodiment, when two active diesters according to Formula (II) are reacted with two different di-p-toluenesulfonic acid salts of bis-( ⁇ -amino acid) ⁇ , ⁇ -alkylene diester according to Formulas (la) and (lb) the polymers produced thereby have a formula according to Formula (A) above except that the first R 7 group and the second R 7 group are different from one another.
  • the present invention relates to co-poly(ester amide)s according to Formula (B) made from the combination of at least one di-p- toluenesulfonic acid salt of a bis-( ⁇ -amino acid) ⁇ , ⁇ -alkylene diester according to Formula (la) and/or (lb), at least one di-p-toluenesulfonic acid salt of an ester according to Formula (IV) and at least one active diester according to Formula (II).
  • Formula (lb) can be substituted for Formula (la) by changing the appropriate R groups in Formula (la) to match those contained in Formula (lb).
  • the above compounds are reacted using a suitable polymerization reaction (e.g., a polycondensation reaction) to yield co- poly(ester amide) polymers according to Formula (B) below:
  • n is from about 10 to about 1000 and the ratio of c/d is in the range of about 80:20 to about 20:80. In another embodiment, the ratio of c/d is from about 70:30 to about 30:70; or even from about
  • n is from about 20 to about 500, or even from about 30 to about 300.
  • the polymers according to Formula (B) have a Mw of about 5,000 to about 400,000 daltons. In another embodiment, the polymers according to Formula (B) have a Mw of about 10,000 to about 200,000 daltons, even about 205,000 to about 100,000 daltons.
  • the copolymers according to Formulas (A) and (B) contain three or more different repeating units rather than just two as shown above.
  • each repeating unit of a polymer according to Formula (A) should make up at least about 10 percent of all of the repeating units present in the polymer according to Formula (A).
  • each repeating unit of a polymer according to Formula (B) should make up at least about 20 percent of all of the repeating units present in the polymer according to Formula (B). In all instances, the total of all dissimilar repeating units in such polymers adds up to 100 percent.
  • the present invention relates to co-poly(ester urethane)s according to Formula (C) made from the combination of at least two different di-p- toluenesulfonic acid salts of bis-( ⁇ -amino acid) ⁇ , ⁇ -alkylene diester according to Formulas (la) and (lb) and at least one active bis-carbonate diester of a diol according to Formula (III).
  • the above compounds are reacted using a suitable polymerization reaction (e.g., a polycondensation reaction) to yield co-poly(ester urethane) polymers according to Formula (C) below:
  • n is from about 10 to about 1000 and the ratio of e/f is in the range of about 90:10 to about 10:90. In another embodiment, the ratio of e/f is from about 75:25 to about 25:75; or even from about 60:40 to about 40:60. In another embodiment, n is from about 20 to about 500, or even from about 30 to about 300.
  • the polymers according to Formula (C) have a Mw of about 5,000 to about 400,000 daltons. In another embodiment, the polymers according to Formula (C) have a Mw of about 10,000 to about 200,000 daltons, even about 20,000 to about 100,000 daltons.
  • the present invention relates to co-poly(ester urethane)s according to Formula (D) made from the combination of at least one di-p- toluenesulfonic acid salt of a bis-( ⁇ -amino acid) ⁇ , ⁇ -alkylene diester according to Formula (la) and/or (lb), at least one di-p-toluenesulfonic acid salt of an ester according to Formula (IV) and at least one active bis-carbonate diester of a diol according to Formula (III).
  • Formula (la) is used.
  • Formula (lb) can be substituted for Formula (la) by changing the appropriate R groups in Formula (D) to match those contained in Formula (lb).
  • the above compounds are reacted using a suitable polymerization reaction (e.g., a polycondensation reaction) to yield co-poly(ester urethane) polymers according to
  • n is from about 10 to about 1000 and the ratio of g/h is in the range of about 80:20 to about 20:80. In another embodiment, the ratio of g/h is from about 70:30 to about 30:70; or even from about 60:40 to about 40:60. In another embodiment, n is from about 20 to about 500, or even from about 30 to about 300.
  • the polymers according to Formula (D) have a Mw of about 5,000 to about 400,000 daltons. In another embodiment, the polymers according to Formula (D) have a Mw of about 10,000 to about 200,000 daltons, even about 20,000 to about 100,000 daltons.
  • the copolymers according to Formulas (A) and (B) contain three or more different repeating units rather than just two as shown above.
  • each repeating unit of a polymer according to Formula (A) should make up at least about 10 percent of all of the repeating units present in the polymer according to Formula (A).
  • each repeating unit of a polymer according to Formula (B) should make up at least about 20 percent of all of the repeating units present in the polymer according to Formula (B).
  • the total of all dissimilar repeating units in such polymers adds up to 100 percent.
  • the copolymers according to Formulas (C) and (D) contain three or more different repeating units rather than just two as shown above. In such an instance, each repeating unit of a polymer according to Formula (C) and (D) contain three or more different repeating units rather than just two as shown above. In such an instance, each repeating unit of a polymer according to Formula (C) and (D) contain three or more different repeating units rather than just two as shown above. In such an instance, each repeating unit of a polymer according to Formula (C) and (D) contain three or more different repeating units rather than just two as shown above. In such an instance, each repeating unit of a polymer according to Formula (C) and (D) contain three or more different repeating units rather than just two as shown above. In such an instance, each repeating unit of a polymer according to Formula (C) and (D) contain three or more different repeating units rather than just two as shown above. In such an instance, each repeating unit of a polymer according to Formula (C) and (
  • each repeating unit of a polymer according to Formula (D) should make up at least about 20 percent of all of the repeating units present in the polymer according to Formula (D). In all instances, the total of all dissimilar repeating units in such polymers adds up to 100 percent.
  • the polymers of the present invention are produced using a polycondensation reaction.
  • suitable amounts of the chosen starting materials are added to a suitable solvent (e.g., N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), methyl pyrrolidone (MP), hexamethyl phosphortriamide (HMPT), dimethyl sulfoxide
  • a suitable solvent e.g., N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), methyl pyrrolidone (MP), hexamethyl phosphortriamide (HMPT), dimethyl sulfoxide
  • DMSO dimethylcaprolactame
  • alcohols such as trifluoroethanol
  • a suitable amount of a tertiary amine initiator e.g., triethylamine (Et 3 N)
  • a tertiary fatty amine e.g., N-methyl-morpholine, N.N'-dimethylpyperazine, N ⁇ methylpyperidine, sodium or potassium carbonates and/or hydrocarbonates, etc.
  • the chosen reaction mixture is then mixed at a temperature of about 10 °C to about 40 °C in order to begin the polycondensation polymerization reaction.
  • the reaction components are mixed at a temperature of about 15 °C to about 35 °C, or even at a temperature of about 20 °C to about 30 °C.
  • the temperature of the reaction mixture is raised and held there for a suitable amount of time so as to complete the polycondensation polymerization reaction.
  • the reaction is conducted at a temperature in the range of about 60 °C to about 120 °C, or in the range of about 80 °C to about 100 °C, or even in the range of about 85 °C to about 95 °C.
  • the reaction is carried out for about 8 to about 16 hours, or for about 10 to about 14 hours, or even for about 11 to about 13 hours.
  • the reaction product is allowed to cool to room temperature, and the product is cast as a thin film onto any suitably smooth surface (e.g., a metal or plastic plate), and washed with water (distilled, de-ionized, etc.).
  • the polymer film obtained thereby is dried at a temperature in the range of about 20 °C to about 50 °C, or from about 25 °C to about 45 °C, or even from about
  • a reduced pressure e.g., a pressure in the range of about 0.1 x 10 "3 atms. to about 10 x 10 "3 atms., or even a pressure in the range of about 0.5 x 10 "3 atms. to about 8 x 10 3 atms., or even in the range of about 1 x 10 3 atms. to about 5 x 10 "3 atms.).
  • the polymer After drying, the polymer is purified using an extraction technique with any suitable organic solvent (e.g., ethylacetate, butylacetate, diethyl ether, acetone, benzene, toluene, etc.) in a Soxhlett apparatus until a negative test for p-toluenesulfonic acid and p-nitrophenol is obtained (see the testing and purification procedures below).
  • any suitable organic solvent e.g., ethylacetate, butylacetate, diethyl ether, acetone, benzene, toluene, etc.
  • the molar ratio of the total molar amount of Formulas (la) and (lb) to the molar amount of Formula (II) needs to be approximately 1:1. This is necessary to produce high molecular weight polymers via the above described polycondensation reaction.
  • the molar ratio of the total molar amount of Formulas (la) and (lb) needs to be approximately 1:1. This is necessary to produce high molecular weight polymers via the above described polycondensation reaction.
  • the molar ratio of the total molar amount of Formulas (la) and (lb) to the molar amount of Formula (II) is in the range of about 5:1 to about 1 :5. In another embodiment, the molar ratio of the total molar amount of Formulas (la) and (lb) to the molar amount of Formula (II) is about 2.5:1 to about 1:2.5. Furthermore, in the polymers according to Formula (A) the molar ratio of Formula (la) to Formula (lb) is in the range of about 9:1 to about 1:9. In another embodiment, the molar ratio of Formula (la) to Formula (lb) is about 7.5:2.5 to about 2.5:7.5; or even about 6:4 to about 4:6.
  • the molar ratio of Formula (la) to Formula (lb) is about 1:1.
  • the molar amount of Formula (II) present in the reaction mixture is at least equal to the total molar amount of Formulas (la) and (lb).
  • the molar ratio of the total molar amount of Formula (la) and/or (lb) (if both are present) to the molar amount of Formula (IV) is in the range of about 8:2 to about 2:8.
  • the molar ratio of the total molar amount of Formula (la) and/or (lb) to the molar amount of Formula (IV) is about 7:3 to about 3:7; or even about 6:4 to about 4:6. In yet another embodiment, the molar ratio of the total molar amount of Formula (la) and/or (lb) to the molar amount of Formula (IV) is about 1:1.
  • the molar amount of Formula (II) present in the reaction mixture to produce polymers according to Formula (B) again depends on whether or not high molecular weight polymers are desired. If so, then the ratio of the total molar amount of
  • Formula (la) and/or (lb) and Formula (IV) to the molar amount of Formula (II) needs to be approximately 1 :1. This is necessary to produce high molecular weight polymers via the above described polycondensation reaction. In another embodiment, when low molecular weight polymers are desired, the ratio of the total molar amount of Formula (la) and/or (lb) and Formula (IV) to the molar amount of
  • Formula (II) is in the range of about 5:1 to about 1:5. In another embodiment, the molar ratio of the total molar amount of Formula (la) and/or (lb) and Formula (IV) to the molar amount of Formula (II) is about 2.5:1 to about 1:2.5.
  • the molar ratio of Formula (la) to Formula (lb) is in the range of about 9:1 to about 1 :9. In another embodiment, the molar ratio of Formula (la) to Formula (lb) is about 7.5:2.5 to about 2.5:7.5; or even about 6:4 to about 4:6. In yet another embodiment, the molar ratio of Formula (la) to Formula (lb) is about 1:1.
  • the molar amount of Formula (III) present in the reaction mixture to produce polymers according to Formula (C) again depends on whether or not high molecular weight polymers are desired. If so, then the ratio of the total molar amount of Formulas (la) and (lb) to the molar amount of Formula (III) needs to be approximately 1:1. This is necessary to produce high molecular weight polymers via the above described polycondensation reaction. In another embodiment, when low molecular weight polymers are desired, the ratio of the total molar amount of
  • Formulas (la) and (lb) to the molar amount of Formula (III) is in the range of about 5:1 to about 1:5. In another embodiment, the molar ratio of the total molar amount of Formulas (la) and (lb) to the molar amount of Formula (III) is about 2.5:1 to about 1 :2.5.
  • Formula (IV) is in the range of about 8:2 to about 2:8.
  • the molar ratio of the total molar amount of Formula (la) and/or (lb) to the molar amount of Formula (IV) is about 7:3 to about 3:7; or even about 6:4 to about 4:6.
  • the molar ratio of the total molar amount of Formula (la) and/or (lb) to the molar amount of Formula (IV) is about 1:1.
  • the molar amount of Formula (III) present in the reaction mixture to produce polymers according to Formula (D) again depends on whether or not high molecular weight polymers are desired. If so, then the ratio of the total molar amount of Formula (la) and/or (lb) and Formula (IV) to the molar amount of Formula (III) needs to be approximately 1:1. This is necessary to produce high molecular weight polymers via the above described polycondensation reaction.
  • the ratio of the total molar amount of Formula (la) and/or (lb) and Formula (IV) to the molar amount of Formula (III) is in the range of about 5:1 to about 1 :5.
  • the molar ratio of the total molar amount of Formula (la) and/or (lb) and Formula (IV) to the molar amount of Formula (III) is about 2.5:1 to about 1 :2.5.
  • the concentration of the combination of the solvent and the tertiary amine is in the range of about 0.6 moles/L to about 1.8 moles/L in view of the amount of any one of Formulas (la), (lb), (II), (III) and/or (IV) which is/are present in the reaction mixture.
  • the concentration of the combination of the solvent and the tertiary amine is in the range of about 0.8 moles/L to about 1.6 moles/L in view of the molar amount of any one of Formulas (la), (lb), (II), (III) and/or (IV) which is/are present in the reaction mixture.
  • the concentration of the solvent and the tertiary amine is in the range of about 0.9 moles/L to about 1.3 moles/L in view of the amount of any one of Formulas (la), (lb), (II), (III) and/or (IV) which is/are present in the reaction mixture.
  • the reactants of the polymerization reaction are a combination of two di-p-toluenesulfonic acid salts of bis-( ⁇ -amino acid) ⁇ , ⁇ - alkylene diester according to Formulas (la) and (lb) (where (la) and (lb) can be the same compound or different compounds) and with two active diesters according to Formula (II) or two active bis-carbonates according to Formula (III), the polycondensation polymerization reaction is carried out in a two step process.
  • one of the above di-p-toluenesulfonic acid salt compounds according to Formula (la) or (lb) is combined with one of the active diesters according to Formula (III) in a solvent.
  • a suitable amount of a tertiary amine initiator is then added to this mixture.
  • the reaction components are mixed at a temperature of about 10 °C to about 40 °C, or at a temperature of about 15 °C to about 35 °C, or even at a temperature of about 20 °C to about 30 °C.
  • the reaction is carried out for about 2 to about 6 hours, or for about 3 to about 5 hours, or even fro about 4 hours, in order to begin a portion of the overall polycondensation reaction.
  • the remaining di-p-toluenesulfonic acid salt compound according to Formula (la) or (lb) and the remaining active diester according to Formula (II) are added to the above reaction mixture.
  • the combined reaction mixture is mixed and the temperature of the reaction mixture is raised and held there for a suitable amount of time so as to complete the polycondensation polymerization reaction.
  • the reaction is conducted at a temperature in the range of about 60 °C to about 120 °C, or in the range of about 80 °C to about 100 °C, or even in the range of about 85 °C to about 95 °C. This reaction is carried out for about 8 to about 16 hours, or for about 10 to about 1 hours, or even for about 11 to about 13 hours.
  • the above reaction produces a polymer with only two types of repeating units because the first step ensures almost complete reaction of the first di-p- toluenesulfonic acid salt compound according to Formula (la) or (lb) with one of the active diesters according to Formula (III).
  • the second step accomplishes the reaction of the second di-p-toluenesulfonic acid salt compound according to Formula (la) or (lb) with the second active diesters according to Formula (III) and the linking of the first and second repeating units to form a polymer according to Formula (A).
  • This same process can also be used to form polymers according to Formula (C) when two bis-carbonates according to Formula (III) are used instead of two active diesters according to Formula (II).
  • Co-PEAs Co-Poly(ester amide)s
  • the following process is used to purify the Co-PEAs according to the present invention.
  • the co-poly(ester amide) polymer obtained according to the present invention is dissolved in a sufficient amount of chloroform (usually about 50 to about 100 ml of solvent per about 10 grams of polymer). This solution is filtered and the polymer is precipitated in butyl acetate (about 1.0 L), upon which the polymer separates as a tar like mass, and is then kept overnight in a refrigerator.
  • butyl acetate is removed and a fresh portion of butyl acetate (again about 1.0 L) is added to the tar like mass and it is again kept overnight in a refrigerator again.
  • This procedure is repeated until a negative test for p-nitrophenol and p-toluenesulfonic acid (see below) is obtained. In one embodiment, it is repeated 2 to 10 times, in another 2 to 8 times, in another 2 to 4 times. However, it should be realized that it can take more repetitions than stated above to purify the polymer(s) obtained using the present inventive methods.
  • the following process is used to purify the Co-PEURs according to the present invention.
  • the film obtained is dissolved in a suitable solvent (e.g., DMF), and then the polymer is precipitated in water.
  • a rubber-like polymer is collected and is dried at about 35 °C to about 40 °C under reduced pressure (e.g., a pressure in the range of about 0.1 x 10 "3 atms.
  • the polymers of the present invention can be tested for the presence of p- nitrophenol by a variety of methods.
  • the testing procedure utilized herein for p-toluenesulfonic acid is identical to that used to test for p-nitrophenol (i.e., UV determination).
  • the phenyl group present in TosOH absorbs in the region of 240 to 260 nm.
  • the testing procedure is utilized on co-poly(ester amide)s (PEAs) and co-poly(ester urethane)s (PEURs) free of phenylalanine. In all the cases studied, no absorbance of TosOH was observed when the absorbance of p-nitrophenol was not observed.
  • Di-p-toluenesulfonic acid salts of bis-( ⁇ -amino acid) ⁇ , ⁇ -alkylene diesters useful in the above-mentioned processes can be synthesized by a variety of methods. For example, one such method is shown below:
  • Di-p-toluenesulfonic acid salts of an ester useful in the above-mentioned processes can be synthesized by a variety of methods. For example, one such method for synthesizing such compounds is shown below:
  • Active diesters for use in the present invention can be synthesized by a variety of methods. For example, one such method for synthesizing such diesters is shown below. The reaction is conducted in a suitable organic solvent.
  • Active bis-carbonates for use in the present invention can be synthesized by a variety of methods. For example, one such method for synthesizing such bis- carbonates is shown below. The reaction is conducted in a suitable solvent (e.g., chlorobenzene).
  • a suitable solvent e.g., chlorobenzene
  • the Examples below are illustrative of the above-mentioned polymer reactions and are not to be construed as limiting.
  • the reduced viscosity data ( ⁇ re ) of the polymers is obtained in m-cresol at a concentration of 0.5 g/dL and a temperature of about 25 °C.
  • the term a reduced pressure in the Examples below is equal to a pressure in the range of about 1 x 10 3 to about 5 x 10 3 atms.
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture a di-p- toluenesulfonic acid salt of bis-(L-phenylalanine)-1 ,2-ethylene diester (Formula (la), where R and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 2 -) (56.0672 g, 0.08 moles); di-p- toluenesulfonic acid salt of bis-(L-leucine)-1 ,3-propylene diester (Formula (lb), where R 4 and R 5 both are -CH 2 CH(CH 3 ) 2 and R 6 is -(CH 2 ) 3 -) (12.9766 g, 0.02 moles) (total amount of the salts is 0.1 moles); and a di-p-nitrophenyl adipate (Formula (II), where X is -0-C 6 H 4 -N0 2 and R 7 is
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of bis(L-phenilalanine)-1 ,3-propylene diester (Formula (la), where R 1 and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 3 -) (57.1888 g, 0.08 moles); a di-p- toluenesulfonic acid salt of bis-(L-leucine)-1 ,4-butylene diester (Formula (lb), where R 4 and R 5 both are -CH 2 CH(CH 3 ) 2 and R 6 is -(CH 2 ) 4 -) (13.2170 g, 0.02 moles) (total amount of the salts is 0.1 moles); and a di-p-nitrophenyl sebacinate (Formula (II), where X is -0-C 6 H 4 -N0 2 and
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, THF, DMF, DMA, and DMSO.
  • Example 3 Co-poly- ⁇ [N,N'-adipoyl-[bis-(L-phenylalaine)-1 ,4-butylene diester]] 080 -[N,N'- adipoyl-[bis-(L-valine)-1 ,4-butylene diester]] 020 ⁇
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of bis-(L-phenylalanine)-1 ,4-butylene diester (Formula (la), where R 1 and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 4 -) (58.3112 g, 0.08 moles); a di-p- toluenesulfonic acid salt of bis(L-valine)-1 ,4-butylene diester (Formula (lb), where R 4 and R 5 both are -CH 2 (CH 3 ) 2 and R 6 is -(CH 2 ) 4 -) (12.6560 g, 0.02 moles) (total amount of the salts is 0.1 moles); and a di-p-nitrophenyl adipate (Formula (II), where X is -O- C 6 H 4 -N0 2
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, DMF, DMA, and DMSO; and insoluble in THF.
  • Example 4 Co-poly- ⁇ [N,N'-sebacoyl-[bis-(L-phenylalanine)-1 ,6-hexylene diester]] 080 -[N,N'- sebacoyl-[bis-(L-valine)-1 ,6-hexylene diester]] 0 . 20 ⁇
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of di-p- toluenesulfonic acid salt of a bis(L-phenylalanine)-1 ,6-hexylene diester (Formula (la), where R and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 6 -) (60.5552 g, 0.08 moles); a di-p-toluenesulfonic acid salt of a bis-(L-valine)-1 ,6-hexylene diester (Formula (lb), where R 4 and R 5 both are -CH 2 (CH 3 ) 2 and R 6 is -(CH 2 ) 6 -) (13.2170 g, 0.02 moles) (total amount of the salts is 0.1 moles); and a di-p-nitrophenyl sebacinate (Formula (II), where X is -0-C 6 H 4 -N
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • Example 5 Example 5:
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of di-p- toluenesulfonic acid salt of a bis(L-phenylalanine)-1 ,6-hexylene diester (Formula (la), where R 1 and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 6 -) (60.5552 g, 0.08 moles) and a di-p-toluenesulfonic acid salt of a bis-(L-isoleucine)-1 ,4-butylene diester (Formula (lb), where R 4 and R 5 both are -CH(CH 3 )CH 2 CH 3 and R 6 is -(CH 2 ) 4 -)
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, THF, DMF, DMA, and DMSO.
  • Example 6 Co-poly- ⁇ [N,N'-adipoyl-(bis-(L-phenylalanine)-1 ,4-butylene diester]] 08 o-[N,N'- adipoyl-[bis(L-isoleucine)-1 ,6-hexylene diester]] 020 ⁇
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenylalanine)-1 ,4-butylene diester (Formula (la), where R 1 and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 4 -) (58.3112 g, 0.08 moles); a di-p-toluenesulfonic acid salt of a bis-(L-isoleucine)-1 ,6-hexylene diester (Formula
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • Example 7 Example 7:
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenylalanine)-1 ,4-butylene diester (Formula (la), where R 1 and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 4 -) (58.3112 g, 0.08 moles); a di-p-toluenesulfonic acid salt of a bis(DL-norleucine)-1 ,4-butylene diester (Formula (lb), where R 4 and R 5 both are -CH 2 CH 2 CH 2 CH 3 and R 6 is -(CH 2 ) 4 -) (13.2170 g, 0.02 moles) (total amount of the salts is 0.1 mole); and a di-p-nitrophenyl adipate (Formula (II), where X is -0-C 6
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • Example 8 Co-poly- ⁇ [N,N'-adipoyl-[bis-(L-phenylalanine)-1 ,4-butylene diester]] 080 -[N,N'- adipoyl-[bis-(L-leucine)-1 ,6-hexylene diester]] 020 ⁇
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenylalanine)-1 ,4-butylene diester (Formula (la), where R 1 and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 4 -) (58.3112 g, 0.08 moles); a di-p-toluenesulfonic acid salt of a bis-(L-leucine)-1 ,6-hexylene diester (Formula (lb), where R 4 and R 5 both are -CH 2 CH(CH 3 ) 2 and R 6 is -(CH 2 ) 6 -) (13.7782 g, 0.02 moles) (total amount of the salts is 0.1 mole); and a di-p-nitrophenyl adipate (Formula (II), where X is -0-C
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, THF, DMF, DMA, and DMSO.
  • Example 9 Co-poly- ⁇ [N,N'-adipoyl-[bis-(L-phenylalanine)-1 ,4-butylene diester]]o. 8o -[N,N'- adipoyl-[bis-(L-leucine)-1 ,8-octylene diester]] 020 ⁇
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenylalanine)-1 ,4-butylene diester (Formula (la), where R 1 and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 4 -) (58.3112 g, 0.08 moles); a di-p-toluenesulfonic acid salt of a bis-(L-leucine)-1 ,8-octylene diester (Formula (lb), where R 4 and R 5 both are -CH 2 CH(CH 3 ) 2 and R 6 is -(CH 2 ) 8 -) (14.3392 g, 0.02 moles) (total amount of the salts is 0.1 moles); and a di-p-nitrophenyl adipate (Formula (II), where X is -0-
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • Example 10 Co-poly- ⁇ [N,N'-adipoyl-[bis-(L-phenylalanine)-1 ,4-butylene diester]] 080 -[N,N'- adipoyl-[bis-(L-leucine)-1 ,12-dodecylene diester]] 020 ⁇
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenylalanine)-1 ,4-butylene diester (Formula (la), where R 1 and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 4 -) (58.3112 g, 0.08 moles); a di-p-toluenesulfonic acid salt of a bis-(L-leucine)-1 ,12-dodecylene diester (Formula
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenylalanine)-1 ,4-butylene diester (Formula (la), where R 1 and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 4 -) (58.3112 g, 0.08 moles); a di-p-toluenesulfonic acid salt of a bis(DL-methionine)-1 ,4-butylene diester (Formula (lb), where R 4 and R 5 both are -CH 2 CH 2 SCH 3 and R 6 is -(CH 2 ) 4 -) (13.9386 g, 0.02 moles) (total amount of the salts is 0.1 moles); and a di-p-nitrophenyl adipate (Formula (II), where X is -0-C 6 H 4
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • Example 12 Co-poly- ⁇ [N,N , -adipoyl-[bis-(L-phenylalanine)-1 ,4-butylene diester]]o .8 o-[N,N'- adipoyl-[bis-(DL-methionine)-1 ,6-hexylene diester]] 020 ⁇
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenylalanine)-1 ,4-butylene diester (Formula (la), where R 1 and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 4 -) (58.3112 g, 0.08 moles); a di-p-toluenesulfonic acid salt of a bis(DL-methionine)-1 ,4-butylene diester (Formula
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.-
  • Example 13 Example 13:
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenylalanine)-1 ,6-hexylene diester (Formula (la), where R 1 and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 6 -) (68.1246 g, 0.09 moles); di-p-toluenesulfonic acid salt of a bis-(L-leucine)-1 ,6-hexylene diester (Formula (lb), where R 4 and R 5 both are -CH 2 CH(CH 3 ) 2 and R 6 is -(CH 2 ) 6 -) (6.8891 g, 0.01 moles) (total amount of the salts is 0.1 moles); and a di-p-nitrophenyl sebacinate (Formula (II), where X is -0-C 6 H 4
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • Example 14 Co-poly- ⁇ [N,N'-sebacoyl-[bis-(L-phenylalanine)-1 ,6-hexylene diesterj] 080 -[N,N'- sebacoyl-[bis-(L-leucine)-1 ,6-hexylene diester]] 020 ⁇
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenilalanine)-1 ,6-hexylene diester (Formula (la), where R 1 and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 6 -) (60.5552 g (0.08 moles); a di-p-toluenesulfonic acid salt of a bis-(L-leucine)-1 ,6-hexylene diester (Formula (lb), where R 4 and R 5 both are -CH 2 CH(CH 3 ) 2 and R 6 is -(CH 2 ) 6 -) (13.7782 g, 0.02 moles) (total amount of the salts is 0.1 moles); and a di-p-nitrophenyl sebacinate (Formula (II), where X is -0-C
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, THF, DMF, DMA, and DMSO.
  • Example 15 Co-poly- ⁇ [N,N'-sebacoyl-[bis-(L-phenylalanine)-1 ,6-hexylene diester]] 060 -[N,N'- sebacoyl-[bis-(L-leucine)-1 ,6-hexylene diester]] 040 ⁇
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis(L-phenylalanine)-1 ,6-hexylene diester (Formula (la), where R 1 and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 6 -) (45.4146 g, 0.06 moles); a di-p-toluenesulfonic acid salt of a bis-(L-leucine)-1 ,6-hexylene diester (Formula (lb), where R 4 and R 5 both are -CH 2 CH(CH 3 ) 2 and R 6 is -(CH 2 ) 6 -) (27.5564 g, 0.04 moles) (total amount of the salts is 0.1 moles); and a di-p-nitrophenyl sebacinate (Formula (II), where X is -0-C 6 H 4
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, THF, DMF, DMA, and DMSO.
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenylalanine)-1 ,6-hexylene diester (Formula (la), where R 1 and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 6 -) (30.2776 g, 0.04 moles); a di-p-toluenesulfonic acid salt of a bis-(L-leucine)-1 ,6-hexylene diester (Formula (lb), where R 4 and R 5 both are -CH 2 CH(CH 3 ) 2 and R 6 is -(CH 2 ) 6 -) (41.3346 g, 0.06 moles) (total amount of the salts is 0.1 moles); and a di-p-nitrophenyl sebacinate (Formula (II), where X is -0-C 6
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, THF, DMF, DMA, and DMSO.
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenylalanine)-1 ,6-hexylene diester (Formula (la), where R 1 and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 6 -) (15.1388 g, 0.02 moles); a di-p-toluenesulfonic acid salt of a bis-(L-leucine)-1,6-hexylene diester (Formula (lb), where R 4 and R 5 both are -CH 2 CH(CH 3 ) 2 and R 6 is -(CH 2 ) 6 -) (55.1128 g, 0.08 moles) (total amount of the salts is 0.1 moles); and a di-p-nitrophenyl sebacinate (Formula (II), where X is -0-C 6 H
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, THF, DMF, DMA, and DMSO.
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenilalanine)-1 ,6-hexylene diester (Formula (la), where R 1 and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 6 -) (7.5694 g, 0.01 moles); a di-p-toluenesulfonic acid salt of a bis-(L-leucine)-1 ,6-hexylene diester (Formula (lb), where R 4 and R 5 both are -CH 2 CH(CH 3 ) 2 and R 6 is -(CH 2 ) 6 -) (62.0019 g, 0.09 moles) (total amount of the salts is 0.1 mole); and a di-p-nitrophenyl sebacinate (Formula (II), where X is -0-C 6 H
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salts of a bis-(L-phenylalanine)-1 ,6-hexylene diester (Formula (la), where R 1 and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 6 -) (60.5552 g, 0.08 moles); a di-p-toluenesulfonic acid salts of a bis-(L-leucine)-1 ,6-hexylene diester (Formula (lb), where R 4 and R 5 both are -CH 2 CH(CH 3 ) 2 and R 6 is -(CH 2 ) 6 -) (13.7782 g, 0.02 moles) (total amount of the salts is 0.1 moles); and a di-p-nitrophenyl docosanedioate (Formula (II),
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • Example 21 Co-poly- ⁇ [N,N'-sebacoyl-[bis-(L-phenylalanine)-1 ,6-hexylene diester]] 050 -[N,N'- adipoyl-[bis-(L-leucine)-1 ,6-hexylene diester]] 050 ⁇
  • Dry triethylamine (15.4 ml, 0.11 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenylalanine)-1 ,6-hexylene diester (Formula (la), where R 1 and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 6 -) (37.8470 g, 0.05 moles) and a di-p-nitrophenyl sebacinate (Formula (II), where X is -0-C 6 H 4 -N0 2 and R 7 is
  • a di-p-toluenesulfonic acid salt of a bis-(L-leucine)- 1 ,6-hexylene diester (Formula (lb), where R 4 and R 5 both are -CH 2 CH(CH 3 ) 2 and R 6 is -(CH 2 ) 6 -) (34.4455 g, 0.05 moles) (total amount of the salts is 0.1 moles); a di-p- nitrophenyl sebacinate (Formula (II), where X is -0-C 6 H 4 -N0 2 and R 7 is -(CH 2 ) 8 -) (22.2220 g, 0.05 moles), and an additional 15.4 ml (0.11 moles) of Et 3 N (total volume of DMF and Et 3 N is 83.3 ml) is added to the reaction mixture and the temperature is increased up to about 90 °C and is stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • Et 3 N is 83.3 ml) at room temperature.
  • the temperature of the reaction mixture is increased to about 80 °C and stirred for about 12 hours.
  • the viscous reaction solution is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenylalanine)-1,3-propylene diester (Formula (la) where R 1 and R 2 are both -CH 2 Ph and R 3 is -(CH 2 ) 3 -) (57.1888 g, 0.08 moles); a di-p-toluenesulfonic acid salt of a L-lysine n-octyl ester (Formula (IV) where R 9 is -CH- and R 10 is -C(0)-0-C 8 H 17 ) (12.0563 g, 0.02 moles) (total amount of the salts is 0.1 moles); and a di-p-nitrophenyl sebacinate (Formula (II) where X is -0-C 6 H 4 -N0 2 and R 7 is -(CH 2 ) 8
  • the temperature of the reaction mixture is increased to about 80 °C and stirred for about 12 hours.
  • the viscous reaction solution is cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, THF, DMF, DMA, DMSO.
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenylalanine)-1 ,4-butylene diester (Formula (la) where R 1 and R 2 are both -CH 2 Ph and R 3 is -(CH 2 ) 4 -) (58.3112 g, 0.08 moles); a di-p- toluenesulfonic acid salt of a L-lysine n-octyl ester (Formula (IV) where R 9 is -CH- and R 10 is -C(0)-0-C 8 H 17 ) (12.0563 g, 0.02 moles) (total amount of the salts is 0.1 moles); and a di-p-nitrophenyl adipate (Formula (II) where X is -0-C 6 H 4 -N0 2 and R 7 is -(CH 2
  • Et 3 N is 83.3 ml) at room temperature.
  • the temperature of the reaction mixture is increased to about 80 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, DMF, DMA, and DMSO.
  • Example 26 adipoyl-L-lysine n-octyl ester] 0 10 ⁇
  • the temperature of the reaction mixture is increased to about 80 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, DMF, DMA, and DMSO.
  • Example 27 Co-poly- ⁇ [N,N'-adipoyl-bis-(L-phenylalanine)-1 ,6-hexylene diester] ⁇ 80 -[N ⁇ ,N ⁇ - adipoyl-L-lysine n-octyl ester] 020 ⁇
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenylalanine)-1 ,6-hexylene diester (Formula (la) where R 1 and R 2 are both -CH 2 Ph and R 3 -(CH 2 ) 6 -) (60.5552 g, 0.08 moles); a di- p-toluenesulfonic acid salt of a L-lysine n-octyl ester (Formula (IV) where R 9 is -CH- and R 10 is -C(0)-0-C 8 H 17 ) (12.0563 g, 0.02 moles) (total amount of the salts is 0.1 moles); and a di-p-nitrophenyl adipate (Formula (II) where X is -0-C 6 H 4 -N0 2 and R 7 is -(CH
  • the temperature of the reaction mixture is increased to about 80 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, DMF, DMA, and DMSO.
  • the temperature of the reaction mixture is increased to about 80 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, DMF, DMA, and DMSO.
  • R 7 is -(CH 2 ) 4 -) (38.833 g, 0.1 moles) in dry DMF (52.5 ml; total volume of DMF and Et 3 N is 83.3 ml) at room temperature.
  • the temperature of the reaction mixture is increased to about 80 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, DMF, DMA, and DMSO.
  • the temperature of the reaction mixture is increased to about 80 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, DMF, DMA, and DMSO.
  • Example 31 Co-poly- ⁇ [N,N'-adipoyl-bis-(L-phenylalanine)-1 ,6-hexylene diester] 10 -[N ⁇ ,N ⁇ - adipoyl-L-lysine n-octyl ester] 090 ⁇
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenylalanine)-1 ,6-hexylene diester (Formula (la) where R 1 and R 2 are both -CH 2 Ph and R 3 is -(CH 2 ) 6 -) (7.5694 g, 0.01 moles); a di-p-toluenesulfonic acid salt of a L-lysine n-octyl ester (Formula (IV) where R 9 is
  • -CH- and R 10 is -C(0)-0-C 8 H 17 ) (54.2538 g, 0.09 moles) (total amount of the salts is 0.1 moles); and a di-p-nitrophenyl adipate (Formula (II) where X is -0-C 6 H 4 -N0 2 and R 7 is -(CH 2 ) 4 -) (38.833 g, 0.1 moles) in dry DMF (52.5 ml; total volume of DMF and Et 3 N is 83.3 ml) at room temperature.
  • the temperature of the reaction mixture is increased to about 80 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, DMF, DMA, and DMSO.
  • R 7 is -(CH 2 ) 8 -) (44.444 g, 0.1 moles) in dry DMF (52.5 ml) (total volume of DMF and Et 3 N is 83.3 ml) at room temperature.
  • the temperature of the reaction mixture is increased to about 80 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, DMF,
  • the temperature of the reaction mixture is increased to about 80 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, THF, DMF, DMA, and DMSO.
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenylalanine)-1 ,6-hexylene diester (Formula (la) where R 1 and R 2 are both -CH 2 Ph and R 3 is -(CH 2 ) 6 -) (60.5552 g, 0.08 moles); di-p-toluenesulfonic acid salt of a L-lysine n-octyl ester (Formula (IV) where R 9 is
  • -CH- and R 10 is -C(0)-0-C 8 H 17 ) (12.0563 g, 0.02 moles) (total amount of the salts is 0.1 moles); and a di-p-nitrophenyl tetradecandioate (Formula (II) where X is -O- C 6 H 4 -N0 2 and R 7 is -(CH 2 ) 12 -) (50.055 g, 0.1 moles) in dry DMF (52.5 ml) (total volume of DMF and Et 3 N is 83.3 ml) at room temperature. The temperature of the reaction mixture is increased to about 80 °C and stirred for about 12 hours.
  • the temperature of the reaction mixture is increased to about 80 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, THF, DMF, DMA, and DMSO.
  • the temperature of the reaction mixture is increased to about 80 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, ethanol, THF, DMF, DMA, and DMSO.
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-leucine)-1 ,6-hexylene diester (Formula (la) where R 1 and R 2 are both -CH 2 CH(CH 3 ) 2 and R 3 is -(CH 2 ) 6 -) (55.1128 g, 0.08 moles); a di-p-toluenesulfonic acid salt of a L-lysine n-octyl ester (Formula (IV) where R 9 is -CH- and R 10 is -C(0)-0-C 8 H 17 ) (12.0563 g, 0.02 moles) (total amount of the salts is 0.1 moles); and a di-p-nitrophenyl sebacinate (Formula (II) where X is -0-C 6 H 4 -N0 2 and R 7 is
  • the temperature of the reaction mixture is increased to about 80 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, ethanol, THF, DMF, DMA, and DMSO.
  • the temperature of the reaction mixture is increased to about 80 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, ethanol, THF, DMF, DMA, and DMSO.
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-leucine)-1 ,6-hexylene diester (Formula (la) where R and R 2 are both -CH 2 CH(CH 3 ) 2 and R 3 is -(CH 2 ) 6 -) (27.5564 g, 0.04 moles); a di-p-toluenesulfonic acid salt of a L-lysine n-octyl ester (Formula (IV) where R 9 is -CH- and R 10 is -C(0)-0-C 8 H 17 ) (36.1692 g, 0.06 moles) (total amount of the salts is
  • the temperature of the reaction mixture is increased to about 80 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, ethanol, THF, DMF, DMA, and DMSO.
  • the temperature of the reaction mixture is increased to about 80 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, ethanol, THF, DMF, DMA, and DMSO.
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-leucine)-1 ,6-hexylene diester (Formula (la) where R 1 and R 2 are both -CH 2 CH(CH 3 ) 2 and R 3 is -(CH 2 ) 6 -) (8.8891 g (0.01 moles); a di-p-toluenesulfonic acid salt of a L-lysine n-octyl ester (Formula (IV) where R 9 is -CH- and R 0 is -C(0)-0-C 8 H 17 ) (54.2538 g, 0.09 moles) (total amount of the salts is 0.1 moles); and a di-p-nitrophenyl sebacinate (Formula (II) where X is -0-C 6 H 4 -N0 2 and R 7 is
  • the temperature of the reaction mixture is increased to about 80 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, ethanol, THF, DMF, DMA, and DMSO.
  • Example 43 Co-poly- ⁇ [N,N'-sebacoyl-bis-(L-valine)-1 ,6-hexylene diester] 080 -[N ⁇ ,N ⁇ - sebacoyl-L-lysine n-octyl ester] 020 ⁇
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-valine)-1 ,6-hexylene diester (Formula (la) where R 1 and R 2 are both -CH(CH 3 ) 2 and R 3 is -(CH 2 ) 6 -) (52.8680 g, 0.08 moles); a di-p- toluenesulfonic acid salt of a L-lysine n-octyl ester (Formula (IV) where R 9 is -CH- and R 10 is -C(0)-0-C 8 H 17 ) (12.0563 g, 0.02 moles) (total amount of the salts is 0.1 moles); and a di-p-nitrophenyl sebacinate (Formula (II) where X is -0-C 6 H 4 -N0 2 and R 7 is -(CH
  • the temperature of the reaction mixture is increased to about 80 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, THF, DMF, DMA, and DMSO.
  • Example 44 Co-poly- ⁇ [N,N'-sebacoyl-bis-(L-isoleucine)-1 ,6-hexylene diester] 080 -[N ⁇ ,N ⁇ - sebacoyl-L-lysine n-octyl ester] ⁇ 20 ⁇
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-isoleucine)1,6-hexylene diester (Formula (la) where R 1 and R 2 are both -CH(CH 3 )CH 2 CH 3 and R 3 is -(CH 2 ) 6 -) (55.1128 g, 0.08 moles); a di-p-toluenesulfonic acid salt of a L-lysine n-octyl ester (Formula (IV) where R 9 is -CH- and R 10 is -C(0)-0-C 8 H 17 ) (12.0563 g, 0.02 moles) (total amount of the salts is 0.1 moles); and a di-p-nitrophenyl sebacinate (Formula (II) where X is -O- C 6 H 4 -N0 2 and R 7 is
  • the temperature of the reaction mixture is increased to about 80 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, THF, DMF, DMA, and DMSO.
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenylalanine)-1 ,6-hexylene diester (Formula (la) where R 1 and R 2 are both -CH 2 Ph and R 3 is -(CH 2 ) 6 -) (45.4164 g, 0.06 moles); a di-p-toluenesulfonic acid salt of a bis-(L-leucine)-1 ,6-hexylene diester (Formula (lb) where R 4 and R 5 are both -CH 2 CH(CH 3 ) 2 and R 6 is -(CH 2 ) 6 -) (13.7782 g, 0.02 moles); a di-p-toluenesulfonic acid salt of a L-lysine n-octyl ester (Formula (IV) where R 9 is
  • the temperature of the reaction mixture is increased to about 80 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, THF, DMF, DMA, and DMSO.
  • Example 46 Co-poly- ⁇ [N,N l -sebacoyl-bis-(L-phenylalanine)-1 ,6-hexylene diester] 040 -[N,N'- sebacoyl-bis-(L-leucine)-1 ,6-hexylene diester] 040 -[N ⁇ ,N ⁇ -sebacoyl-L-lysine n-octyl ester] ⁇ 20 ⁇
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenylalanine)-1 ,6-hexylene diester (Formula (la) where R 1 and R 2 are both -CH 2 Ph and R 3 is -(CH 2 ) 6 -) (30.2776 g, 0.04 moles); a di-p-toluenesulfonic acid salt of a bis-(L-leucine)-1 ,6-hexylene diester (Formula (lb) where R 4 and R 5 are both -CH 2 CH(CH 3 ) 2 and R 6 -(CH 2 ) 6 -) (27.5564 g, 0.04moles); a di-p-toluenesulfonic acid salt of a L-lysine n-octyl ester (Formula (IV) where R 9
  • R 7 is -(CH 2 ) 8 -) (44.444 g, 0.1 moles) in dry DMF (52.5 ml) (total volume of DMF and Et 3 N is 83.3 ml) at room temperature.
  • the temperature of the reaction mixture is increased to about 80 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, THF, DMF, DMA, and DMSO.
  • Co-Polv(ester urethane) (Co-PEUR) Examples:
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • Example 49 Co-poly- ⁇ [N,N'-trimethylenedioxydicarbonyl-[bis-(L-phenylalanine)-1 ,6- hexylene diester]] 090 -[N,N'-trimethylenedioxydicarbonyl-[bis-(L-leucine)-1 ,6-hexylene diester]] 0,10 ⁇
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenylalanine)-1 ,6-hexylene diester (Formula (la), where R 1 and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 6 -) (68.1246 g, 0.09 moles); a di-p-toluenesulfonic acid salt of a bis-(L- leucine)-1 ,6-hexylene diester (Formula (lb), where R 4 and R 5 both are -CH 2 CH(CH 3 ) 2 and R 6 is -(CH 2 ) 6 -) (6.8891 g, 0.01 moles) (total amount of the salts is 0.1 mole); and an active bis-carbonate (Formula (III), where X is -0-C 6 H 4 -N0 2 and
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • Example 50 Example 50:
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, THF, DMF, DMA, and DMSO.
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenylalanine)-1 ,6-hexylene diester (Formula (la), where R 1 and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 6 -) (30.2776 g, 0.04 moles); a di-p-toluenesulfonic acid salt of a bis-(L-leucine)-1 ,6-hexylene diester (Formula (lb), where R 4 and R 5 both are -CH 2 CH(CH 3 ) 2 and R 6 is -(CH 2 ) 6 -) (41.3346 g, 0.06 moles) (total amount of the salts is 0.1 moles), and an active bis-carbonate (Formula (III), where X is -0-C 6 H 4 -N0 2 and
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • Example 53 Co-poly- ⁇ [N,N'-trimethylenedioxydicarbonyl-[bis-(L-phenylalanine)-1 ,6- hexylene diester]] 020 -[N,N'-trimethylenedioxydicarbonyl-bis-(L-leucine)-1 ,6-hexylene diester]] 080 ⁇
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenylalanine)-,6-hexylene diester (Formula (la), where R 1 and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 6 -) (15.1388 g, 0.02 moles); a di-p- toluenesulfonic acid salt of a bis-(L-leucine)-1 ,6-hexylene diester (Formula (lb), where R 4 and R 5 both are -CH 2 CH(CH 3 ) 2 and R 6 is -(CH 2 ) 6 -) (55.1128 g, 0.08 moles) (total amount of the salts is 0.1 mole); and an active bis-carbonate (Formula (III), where X is -0-C 6 H 4 -N0 2 and R
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • Example 54 Co-poly- ⁇ [N,N'-trimethylenedioxydicarbonyl-[bis-(L-phenylalanine)-1 ,6- hexylene diester]] 0 10 -[N,N'-trimethylenedioxydicarbonyl-[bis-(L-leucine)-1 ,6-hexylene diester]] 090 ⁇
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenylalanine)-1 ,6-hexylene diester (Formula (la), where R 1 and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 6 -) (7.5694 g, 0.01 moles); a di-p-toluenesulfonic acid salt of a bis-(L-leucine)-1 ,6-hexylene diester (Formula (lb), where R 4 and R 5 both are -CH 2 CH(CH 3 ) 2 and R 6 is -(CH 2 ) 6 -) (62.0019 g, 0.09 moles) (total amount of the salts is 0.1 moles); and an active bis-carbonate (Formula (III), where X is -0-C 6 H 4 -N0 2 and R
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • total amount of the salts is 0.1 moles
  • an active bis-carbonate (Formula (III), where X is -0-C 6 H 4 -N0 2 and R 8 is -(CH 2 ) 2 -0-(CH 2 ) 2 -) (43.633 g, 0.1 moles) in dry DMF (52.5 ml; total volume of DMF and Et 3 N is 83.3 ml) at room temperature.
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • Example 59 Co-poly- ⁇ [N,N'-(3-oxapentylene-1 ,5-dioxydicarbonyl)-[bis-(L-phenylalanine)-
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenylalanine)-1 ,6-hexylene diester (Formula (la), where R 1 and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 6 -) (30.2776 g, 0.04 moles); a di-p-toluenesulfonic acid salt of a bis-(L-leucine)-1 ,6-hexylene diester (Formula (lb), where R 4 and R 5 both are -CH 2 CH(CH 3 ) 2 and R 6 is -(CH 2 ) 6 -) (41.3346 g, 0.06 moles) (total amount of the salts is 0.1 moles); and an active bis-carbonate (Formula (III), where X is -0-C 6 H 4 -N0 2 and
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • Example 61 Co-poly- ⁇ [N,N'-(3-oxapentylene-1 ,5-dioxydicarbonyl)-[bis-(L-phenylalanine)-
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-phenylalanine)-1 ,6-hexylene diester (Formula (la), where R 1 and R 2 both are -CH 2 Ph and R 3 is -(CH 2 ) 6 -) (7.5694 g, 0.01 moles); a di-p-toluenesulfonic acid salt of a bis-(L-leucine)-1 ,6-hexylene diester (Formula (lb), where R 4 and R 5 both are -CH 2 CH(CH 3 ) 2 and R 6 is -(CH 2 ) 6 -) (62.0019 g, 0.09 moles) (total amount of the salts is 0.1 moles); and an active bis-carbonate (Formula (III), where X is -0-C 6 H 4 -N0 2 and R
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, THF, DMF, DMA, and DMSO.
  • Example 63
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reacfion product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, THF, DMF, DMA, and DMSO.
  • Example 64 Co-poly- ⁇ [N,N'-trimethylenedioxydicarbonyl-bis-(L-leucine)-1 ,6-hexylene diester] 080 -[N ⁇ ,N ⁇ - trimethylenedioxydicarbonyl-L-lysine n-dodecyl ester] 020 ⁇
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, THF, DMF, DMA, and DMSO.
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-leucine)-1 ,6-hexylene diester (Formula (la) where R 1 and R 2 are both -CH 2 CH(CH 3 ) 2 and R 3 is -(CH 2 ) 6 -) (55.1128 g, 0.08 moles); a di-p-toluenesulfonic acid salt of a L-lysine n-hexadecyl ester (Formula (IV) where R 9 is -CH- and R 10 is -C(0)-0-C 16 H 33 ) (14.3008 g, 0.02 moles) (total amount of the salts is 0.1 moles); and an active bis-carbonate (Formula (III) where X is -0-C 6 H 4 -N0 2 and R 8 is -(CH 2
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, THF, DMF, DMA, and DMSO.
  • R 8 is -(CH 2 ) 2 -0-(CH 2 ) 2 -) (43.633 g, 0.1 moles) in dry DMF (52.5 ml) (total volume of DMF and Et 3 N is 83.3 ml) at room temperature.
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, THF, DMF, DMA, and
  • R 8 is -(CH 2 ) 2 -0-(CH 2 ) 2 -) (43.633 g, 0.1 moles) in dry DMF (52.5 ml) (total volume of DMF and Et 3 N is 83.3 ml) at room temperature.
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, THF, DMF, DMA, and
  • Dry triethylamine (30.8 ml, 0.22 moles) is added to a mixture of a di-p- toluenesulfonic acid salt of a bis-(L-leucine)-1 ,6-hexylene diester (Formula (la) where R 1 and R 2 are both -CH 2 CH(CH 3 ) 2 and R 3 is -(CH 2 ) 6 -) (55.1128 g, 0.08 moles); a di-p-toluenesulfonic acid salt of a L-lysine n-dodecyl ester (Formula (IV) where R 9 is -CH- and R 10 is -C(0)-0-C 12 H 25 ) (13.1786 g, 0.02 moles) (total amount of the salts is 0.1 moles); and an active bis-carbonate (Formula (III) where X is -0-C 6 H 4 -N0 2 and R 8 is -(CH 2 )
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, THF, DMF, DMA, and DMSO.
  • R 8 is -(CH 2 ) 2 -0-(CH 2 ) 2 -) (43.633 g, 0.1 moles) in dry DMF (52.5 ml) (total volume of DMF and Et 3 N is 83.3 ml) at room temperature.
  • the temperature of the reaction mixture is increased to about 90 °C and stirred for about 12 hours.
  • the reaction product is then cooled to room temperature, cast as a thin film onto the smooth surface, and washed with water.
  • the polymeric product obtained thereby is dried at 30 to 40 °C under reduced pressure.
  • the copolymer is soluble in chloroform, THF, DMF, DMA, and DMSO.
  • the polymers of the present invention are soluble in organic solvents like chloroform, DMF, DMA, DMSO, and most of them in THF. They have a Mw in the range of about 5,000 to about 400,000 daltons. In another embodiment, the polymers according to Formula (C) have a Mw of about 10,000 to about 200,000 daltons, even about 20,000 to about 100,000 daltons. In one embodiment, the polymers of the present invention have a narrow polydispersity - Mw/Mn equals 1 ,0 to about 2.0, even about 1.25 to about 1.9, or even 1.5 to about 1.8.
  • the glass transition temperature of the polymers of the present invention is determined using a Perkin-Elmer DSC-7 under a nitrogen gas flow. Due to the hydrophilic nature of some PEAs such samples should be heated prior to determining a PEAs glass transition temperature to remove any absorbed water, then cooled, and reheated again at a heating/cooling rate of 20 °C/min. The thermal data from the second DSC scan should be used in such cases.
  • ⁇ red for the polymers of the present invention can be determined in /77-cresol at a concentration of 0.5 g/dL at 25 °C.
  • the polymers of the present invention exhibit a wide range of mechanical properties depending on the composition the monomers used therein to produce the polymers.
  • the homopoly(ester amide)s poly-[N,N'-sebacoyl-bis-(L- phenylalanine)-1 ,6-hexylene diester] and poly-[N,N'-adipoyl-bis-(L-phenylalanine)-
  • the films which are impregnated with enzymes are exposed to pure buffer.
  • the films are removed from the solutions after a predetermined amount time (normally about 24 hours), dried with filter paper and weighed.
  • the buffer or enzyme solution in the buffer is changed every 24 hours.
  • the biodegradation study is conducted for about 120 hours (about 5 days).
  • the biodegradation rate is assessed in mg of weight loss per cm 2 of the film surface in hours (mg/(cm 2 • h).
  • the desired enzyme (2 to 10 mg of enzyme per 1 g of polymer) is added to the polymer solution as a fine powder and then the films are prepared by sinking Teflon ® films into the enzyme/polymer mixture described above.
  • This technique can also be used to produce medicated wound coverings with a variety of additives (i.e., enzymes, antibiotics, pain killers, cancer drugs, etc.).
  • additives i.e., enzymes, antibiotics, pain killers, cancer drugs, etc.
  • the incorporation of various ⁇ -amino acids' residues into polymeric backbones can impart biodegradation to polymers which normally reveal low tendency to biodegradation.
  • a homopoly(ester amide) based on isoleucine and valine reveals a low tendency to ⁇ -chymotrypsin catalyzed biodegradation.
  • phenylalanine residues After the incorporation of phenylalanine residues into the polymeric backbone the biodegradation rate increases, as is shown below in Table 5 with regard to Examples 3 to 6.
  • the content of the impregnated enzyme permits regulation of a wide range of biodegradation rates as is shown below for lipase in Table 6.
  • copolymers show an tendency to lipase catalyzed biodegradation similar to that of the corresponding homopolymer, as it is shown below in Table 7.
  • the polymers of the present invention can be used to form, for example, medicated wound coverings using the following process.
  • a suitable solvent e.g., chloroform, THF, DMF, DMA, DMSO, ethanol, etc.
  • a desire amount of any suitable additive e.g., about 2 to about 10 mg of enzyme per about 1 g of polymer
  • any suitable form e.g., a powder, liquid, solid, gas, etc.
  • Such additives include, but are not limited to, enzymes, antibiotics, pain killers, cancer drugs, amino acids and anesthetics.
  • the polymers of the present invention can be used for a wide variety of applications.
  • Such applications include, but are not limited to, sutures, scaffolds (be they medical or otherwise), ligating clips and staples, surgical tubes or catheters, orthopedic implants, barriers to prevent tissue adhesion, vascular grafts, stent coatings (medicated or non-medicated), artificial skin (medicated or non-medicated), bone substitutes, self-reinforced composites, temporary templates for cell growth, temporary contraceptives (e.g., stoppers for closing a fallopian tube, etc.), tampons, biodegradable time release patches (e.g., patches for use with one or more drugs, physiologically active substances and bactericides), artificial glands for releasing bio-active peptides and/or proteins, biodegradable packaging (for agricultural, food service, or any other packaging use), and biodegradable polymer protection films for use in protecting articles from a wide range of environmental factors (e.g., corrosion protection, water
  • Such additives include, but are not limited to, any and all additives which may impart such polymers films with one or more anti-static, anti-mildew and/or anti-corrosion properties.
  • a volatile corrosion inhibitor could be added to a polymer film produced from one or polymers according to the present invention. Any suitable corrosion inhibitor can be used.
  • United States Patent Nos. 4,290,912; 5,320,778; and 5,855,975 disclose vapor phase or volatile corrosion inhibitors and are incorporated herein by reference in their entirety for their teachings of such compounds.
  • the polymer compositions of the present invention can be used to form controlled release devices. Such devices allow for the controlled release of a desired compound and/or compounds over an extended period of time.
  • FIG. 1 shows a cross-sectional view of a wound covering 100 made in accordance with the above method using a polymer 102 according to the present invention and four additives therein (i.e., a bacteriophage 104, an antibiotic 106, an anesthetic 108, and an enzyme 110).
  • additives i.e., a bacteriophage 104, an antibiotic 106, an anesthetic 108, and an enzyme 110.
  • any suitable combination of additives can be used depending upon the final use intended for the polymer product.
  • the wound covering 100 of Figure 1 utilizes can optionally include a support film made of Teflon ® (or any other suitable support film). Alternatively, it is also possible to forego the use of a support film (such as Teflon ® ) and form a film from the solution of biodegradable polymer and any additives added thereto.
  • Figure 2 depicts a process for making a biodegradable polymer film for use as a wound covering using at least one polymer according to the present invention which does not require the use of a support film.
  • the polymer films according to the method of Figure 2 are produced by dissolving one or more polymer composition according to the present invention in a suitable organic solvent and, optionally, adding to the solution 101 any desired additives.
  • the solution is, for example, cast into a thin film by pouring a polymer solution (which may or may not contain additives therein) into, for example, a suitable mold and removing the solvent therefrom by any suitable method (e.g., by evaporation, heating, etc.). If a support layer is utilized, then the support layer can be submerged into the solution of polymer and, optionally, additive(s), and allowing the support layer the dry.
  • the wound covering 100 of Figures 1-3 may be perforated with suitable sized holes 120 to provide breathability and to allow the migration of gases such as water vapor.
  • the holes 120 formed in the wound covering 100 can be any suitable size so long as the serve to not only allow air to pass through the wound covering and reach the wound, but also allow gases such as water vapor to pass through the wound covering in either direction.

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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)
  • Polyurethanes Or Polyureas (AREA)

Abstract

L'invention concerne des compositions polymères qui peuvent être utilisées pour former une pluralité d'objets biodégradables et des procédés de fabrication des ces dernières. L'invention concerne en particulier des polymères produits à partir des combinaisons suivantes : (1) la combinaison d'au moins deux sels d'acide di-p-toluènesulfonique d'un diester bis-(α-aminoacide) α,φ-alkylène avec au moins un diester actif ; (2) la combinaison d'au moins deux sels d'acide di-p-toluènesulfonique d'un diester bis-(α-aminoacide) α,φ-alkylène avec au moins un bicarbonate actif d'un diol ; (3) la combinaison d'au moins un sel d'acide di-p-toluènesulfonique d'un diester bis-(α-aminoacide) α,φ-alkylène et au moins un sel d'acide di-p-toluènesulfonique d'un ester (par exemple un diamino ester) avec au moins un diester actif ; et (4) la combinaison d'au moins un sel d'acide di-p-toluènesulfonique d'un diester bis-(α-aminoacide) α,φ-alkylène et au moins un sel d'acide di-p-toluènesulfonique d'un ester (par exemple un diamino ester) avec au moins un bicarbonate actif d'un diol. L'invention concerne également des procédés de fabrication des polymères précités et leur utilisation.
PCT/US2002/001258 2002-01-17 2002-01-17 Co-poly(ester amide) et co-poly(ester urethane) compositions presentant une biodegradabilite, procedes de production et utilisation associes Ceased WO2003062298A1 (fr)

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US20090274741A1 (en) * 2004-05-26 2009-11-05 Advanced Cardiovascular Systems, Inc. Polymers containing poly(ester amides) and agents for use with medical articles and methods of fabricating the same
US7863406B2 (en) 2004-06-03 2011-01-04 Cornell Research Foundation, Inc. Unsaturated poly(ester-amide) biomaterials
CN102186507A (zh) * 2008-10-15 2011-09-14 梅迪沃什有限公司 可生物降解的脯氨酸基聚合物
EP1848410A4 (fr) * 2005-02-17 2011-11-09 Medivas Llc Compositions d'administration particulaires, polymeriques, et leurs methodes d'utilisation
US8163269B2 (en) 2004-04-05 2012-04-24 Carpenter Kenneth W Bioactive stents for type II diabetics and methods for use thereof
US20130344126A1 (en) * 2012-06-25 2013-12-26 Surmodics, Inc. Bioerodable poly(etheresteramides) and medical article uses
US9102830B2 (en) 2005-09-22 2015-08-11 Medivas, Llc Bis-(α-amino)-diol-diester-containing poly (ester amide) and poly (ester urethane) compositions and methods of use
US9517203B2 (en) 2000-08-30 2016-12-13 Mediv As, Llc Polymer particle delivery compositions and methods of use
US9873765B2 (en) 2011-06-23 2018-01-23 Dsm Ip Assets, B.V. Biodegradable polyesteramide copolymers for drug delivery
US9873764B2 (en) 2011-06-23 2018-01-23 Dsm Ip Assets, B.V. Particles comprising polyesteramide copolymers for drug delivery
US10434071B2 (en) 2014-12-18 2019-10-08 Dsm Ip Assets, B.V. Drug delivery system for delivery of acid sensitivity drugs
CN114456373A (zh) * 2022-01-26 2022-05-10 中山大学 一种基于亮氨酸的聚酯酰胺的纳米递药体系及其制备方法和应用

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USRE40359E1 (en) 2000-01-11 2008-06-03 Surmodics, Inc. Polymer blends as biodegradable matrices for preparing biocomposites
US9517203B2 (en) 2000-08-30 2016-12-13 Mediv As, Llc Polymer particle delivery compositions and methods of use
US8163269B2 (en) 2004-04-05 2012-04-24 Carpenter Kenneth W Bioactive stents for type II diabetics and methods for use thereof
US20090274741A1 (en) * 2004-05-26 2009-11-05 Advanced Cardiovascular Systems, Inc. Polymers containing poly(ester amides) and agents for use with medical articles and methods of fabricating the same
US8808723B2 (en) * 2004-05-26 2014-08-19 Abbott Cardiovascular Systems Inc. Polymers containing poly(ester amides) and agents for use with medical articles and methods of fabricating the same
US7863406B2 (en) 2004-06-03 2011-01-04 Cornell Research Foundation, Inc. Unsaturated poly(ester-amide) biomaterials
EP1848410A4 (fr) * 2005-02-17 2011-11-09 Medivas Llc Compositions d'administration particulaires, polymeriques, et leurs methodes d'utilisation
US9102830B2 (en) 2005-09-22 2015-08-11 Medivas, Llc Bis-(α-amino)-diol-diester-containing poly (ester amide) and poly (ester urethane) compositions and methods of use
CN102186507A (zh) * 2008-10-15 2011-09-14 梅迪沃什有限公司 可生物降解的脯氨酸基聚合物
US9963549B2 (en) 2011-06-23 2018-05-08 Dsm Ip Assets, B.V. Biodegradable polyesteramide copolymers for drug delivery
US9873765B2 (en) 2011-06-23 2018-01-23 Dsm Ip Assets, B.V. Biodegradable polyesteramide copolymers for drug delivery
US9873764B2 (en) 2011-06-23 2018-01-23 Dsm Ip Assets, B.V. Particles comprising polyesteramide copolymers for drug delivery
US9896544B2 (en) 2011-06-23 2018-02-20 Dsm Ip Assets, B.V. Biodegradable polyesteramide copolymers for drug delivery
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WO2014004512A1 (fr) * 2012-06-25 2014-01-03 Surmodics, Inc. Poly(étherestéramides) biodégradables et utilisations dans des articles médicaux
US20130344126A1 (en) * 2012-06-25 2013-12-26 Surmodics, Inc. Bioerodable poly(etheresteramides) and medical article uses
US10434071B2 (en) 2014-12-18 2019-10-08 Dsm Ip Assets, B.V. Drug delivery system for delivery of acid sensitivity drugs
US10888531B2 (en) 2014-12-18 2021-01-12 Dsm Ip Assets B.V. Drug delivery system for delivery of acid sensitivity drugs
US11202762B2 (en) 2014-12-18 2021-12-21 Dsm Ip Assets B.V. Drug delivery system for delivery of acid sensitivity drugs
CN114456373A (zh) * 2022-01-26 2022-05-10 中山大学 一种基于亮氨酸的聚酯酰胺的纳米递药体系及其制备方法和应用

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