US 20150259464A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0259464 A1 BeZWada et al. (43) Pub. Date: Sep. 17, 2015

(54) BIO-BASED MONOMERS AND POLYMERS C08G 7L/02 (2006.01) C08G 69/00 (2006.01) (71) Applicant: Bezwada Biomedical, LLC, C07C 225/22 (2006.01) Hillsborough, NJ (US) A69/70 (2006.01) (72) Inventors: Rao S. Bezwada, Hillsborough, NJ (52) U.S. Cl. (US); Neeti Srivastava, Hillsborough, CPC ...... C08G 18/7657 (2013.01); C07C 225/22 NJ (US) (2013.01); A61 K9/70 (2013.01); C08G 71/02 (21) Appl. No.: 14/645,522 (2013.01); C08G 69/00 (2013.01); C08G 73/02

(22) Filed1C Mara. 12,A 2015 (2013.01); C07C 2101/16 (2013.01) Related U.S. Application Data (57) ABSTRACT (60) Provisional application No. 61/951,617, filed on Mar. 12, 2014. Described are novel bio-based bioabsorbable/non-absorb Publication Classification able and biodegradable monomer compounds, bioabsorbable (51) Int. Cl. and biodegradable polymers therefrom, and methods of mak C08G 8/76 (2006.01) ing Such monomers and polymers, which are useful interalia C08G 73/02 (2006.01) as medical devices, implantable or otherwise. US 2015/0259464 A1 Sep. 17, 2015

BO-BASED MONOMERS AND POLYMERS able chemical versatility. While polyurethane polymers have certain useful properties, shaped articles based on these poly FIELD OF THE INVENTION mers are not typically absorbable or biodegradable and may therefore be unacceptable in circumstances that require 0001. The present invention relates to the discovery of a absorption or biodegradation. For example, certain biomedi new class of bio-based monomers and polymers. Using these cal applications, such as Surgical devices including but not bio-based monomers and their functionalized derivatives, limited to monofilament and multifilament Sutures, films, novel bio-based absorbable/biodegradable and non-absorb sheets, plates, clips, staples, pins, screws, stents, stent coat able polymers (or partially asborbable/biodegradable poly ings, and the like, generally require the use of a material that mers) can be prepared. is asborbable. Hence, the vast majority of research devoted to the development of biomedical polyurethanes has focused on BACKGROUND OF THE INVENTION long-term applications such as vascular grafts and pacemaker 0002 Bio-based and/or biodegradable polymers are lead insulators. increasingly being used in applications that currently rely on 0007. Despite progress in the general development of petroleum based feedstocks. These biobased and/or biode polyurethanes and similar polymers for use in biomedical gradable monomers and polymers have become increasingly applications, relatively little research have been directed to important for a variety of consumer products, durable goods developing absorbable polyurethanes for temporary, rather and biomedical applications including tissue engineering than longer-term implantation. See Fuller et al., U.S. Pat. No. scaffolds, Surgical adhesives, foams, medical device coatings 4,829,099: Beckmann et al., U.S. Patent Publication Nos. and drug delivery matrices, etc. They are also increasingly 2005/0013793, 2004/0170597, and 2007/0014755; Bruinet being used for disposable medical device applications. For al., PCT Publication No. WO95/26762; Woodhouse et al., example, isocyanate-based adhesive/sealant compositions U.S. Pat. No. 6,221.997: Cohn et al., U.S. Pat. No. 4,826,945, are described in U.S. Pat. Nos. 6,894,140; 5,173,301: 4,994, which generally discuss recent advances made in the field of 542; and, 4,740,534, the disclosures of which are incorpo absorbable polyurethanes. rated herein by reference in their entirety. 0008 Subsequent work by Bruin et al., PCT No. WO 0003 Polymers that are derived from monomers from 95/26762, describes the synthesis of crosslinked polyure renewable biobased sources are referred to as bio-based poly thane networks incorporating lactide or glycolide and e-ca mers. Polymers that breakdown into carbon dioxide, water prolactone joined by a lysine-based diisocyanate. Bruin dis and biomass from the action of naturally occurring microor closes that these polymers display good elastomeric ganism Such as bacteria, fungi etc over a period of time are properties and degrade within about 26 weeks in vitro and referred to as biodegradable polymers. A majority of the about 12 weeks in Vivo (Subcutaneous implantation in guinea biobased polymers are also biodegradable. Polymers that are pigs). Despite their disclosed desirable flexibility and degra designed to degrade under physiological conditions are dation characteristics, these highly crosslinked polymers are referred to as absorbable polymers. These polymers are not extensively used in Some biomedical applications because sometimes also referred to as, bioerodible, bioabsorbable, or in some cases they cannot be readily processed into Surgical hydrolyzable polymers. Synthetic absorbable polymers are articles, for example, using standard techniques such as solu generally classified into polyesters, polyorthoesters, polyan tion casting or melt processing, as is the case for the more hydrides, polyesteramides, and polyoxaesters. typical linear, segmented polyurethanes. 0004 Absorbable polymers are increasingly used in a 0009 Cohn et al., EP295055 describes a series of elasto wide range of biomedical applications including tissue engi meric polyester-polyether-polyurethane block copolymers neering scaffolds, stents, stent coatings, foams, highly porous intended for use as Surgical articles. However, these polymers foams, reticulated foams, and adhesion prevention barriers. may be relatively stiff and may have low tensile strength, This increased utilization is, in part, a function of the transient which may preclude their use as elastomeric biomaterials. nature of these polymers when used as biomedical implants Beckmann et al., U.S. Patent Publication No. 2005/0013793 or drug carriers. Medical devices made from absorbable poly describes polyurethane-based biodegradable adhesives from mers can mitigate the inevitable and usually negative physi multi-isocyanate functional molecules and multifunctional ologic responses (e.g., fibrous encapsulation), which limit precursor molecules with terminal groups selected from long-term device success. Hence, an array of asborbable hydroxyl and amino groups. Woodhouse et al. describes polymers have been developed and studied in various bio absorbable polyurethanes derived from amino acids. How medical applications. While significant research and devel ever, all these absorbable polyurethanes may suffer from one opment activity has been carried out on bioasborbable poly or more of the following drawbacks: (a) the very slow rate of mers, such polymers may suffer from performance formation of polyurethane that may be attributed to the low deficiencies which are typically not fully recognized until reactivity of the polyisocyanates and (b) the lack of tunable new applications are identified and in-use testing has been physical and/or mechanical properties and/or controllable carried out. hydrolytic degradation profiles for biodegradable polyisocy 0005 Of the synthetic asborbable polymers, polyesters anates or absorbable polyurethanes derived therefrom. find numerous applications in medical, Surgical and con 0010 Despite advancements in the art of producing poly trolled delivery applications and are the key components of a meric materials and methods for making polymers Suitable majority of bioasborbable medical devices, ranging from for use in drug delivery, tissue adhesives, adhesion prevention Sutures, staples, orthopedic screws and implantable Surgical barrier, foams, highly porous foams, reticulated foams, bone devices to tissue engineering scaffolds. wax formulations, stents, Stent coatings, scaffolds, films, 0006. In addition to polyesters, segmented polyurethane molded devices, and similar Surgical articles, presently avail elastomers have also enjoyed wide use as biomaterials gen able polymers generally lack adequate performance proper erally due to their excellent mechanical properties and desir ties desirable in Surgical articles, for example, those related to US 2015/0259464 A1 Sep. 17, 2015 bioabsorption, flex fatigue life, strength in use, flexibility, 0018. In an embodiment, the present invention provides a and/or durability. Thus, there continues to be a need for new novel class of bio-based monomers and materials derived devices and polymers having tunable physical and/or biologi therefrom (e.g., polymers, pre-polymers, polyols, and/or oli cal properties, so that medical devices and Surgical articles gomers). The bio-based materials may be biodegradable, having a variety of end uses can be prepared. absorbable, and/or non-absorbable. The bio-based monomers 0011. With more uses being envisioned for polymers and are derived from starting compounds that includebutane diol. an increased demand for absorbable polymers with new and Succinic acid, L-lactic acid, amino acids such as L-lysine, improved properties targeted to address performance defi castor oil-based monomers (e.g., ricinoleic acid, 12-hydroxy ciencies, there still is a need for bio-based monomers and Stearic acid, and sebacic acid), and Soybean oil-based mono polymers with beneficial properties. CS. 0019. In an embodiment, the present invention provides a SUMMARY OF THE INVENTION novel class of polymers formed by polymerizing a bio-based 0012. In an embodiment, the present invention provides a monomer with an appropriate additional monomer (e.g., a novel class of bio-based monomers and materials (e.g., pre diol/polyol, or diamine), the polymers being selected from: polymers, polymers, polyols, and/or oligomers) derived polyamides, polyesters, polyureas, polyepoxides, polyestera therefrom. The bio-based materials may be biodegradable, mides, and polyurethanes. The polymers are biodegradable, absorbable, and/or non-absorbable. absorbable, and/or non-absorbable. For the preparation of 0013. In another embodiment, the present invention pro bio-based polyamides, bio-based diamines such as 1.5-pen vides novel bio-based materials useful for a variety of medi tane diamine and L-lysine can be reacted with bio-based cal (e.g., stent coatings), pharmaceutical (e.g., drug formula dicarboxylic acids, such as sebacic acid or Succinic acid. tions), and cosmetic (e.g., cosmetic packaging) uses. Absorbable bio-based polyamides can be prepared by func 0014. In another embodiment, the present invention pro tionalizing sebacic acid with a group Such as lactic acid and vides novel bio-based vegetable oil (e.g., castor or soybean) reacting with diamines. The absorbable polymers are charac derived hydroxyl acids diacids, diamines, and diisocyanates terized by having a controllable degradation profile. and the resulting polymers including bio-based polyamides, 0020. In another embodiment, the present invention pro polyesters, polyureas, polyepoxides, polyesteramides, and vides novel bio-based materials useful for drug delivery polyurethanes. matrices (e.g., controlled drug delivery or site-specific or 0015. In another embodiment, the present invention pro systemic drug delivery systems or matrices), pharmaceutical vides novel bio-based materials and methods of making Such drug formulations, tissue engineering (e.g., tissue scaffold), materials that would ultimately be useful for drug delivery tissue adhesives, adhesion prevention barriers, and other matrices (e.g., controlled drug delivery or site-specific or implantable medical devices including foams (including systemic drug delivery systems or matrices), pharmaceutical reticulated foams, lyophilized foams, highly porous foams, drug formulations, tissue engineering (e.g., tissue scaffold), regular foams, foams with Vertical channels, architecturally tissue adhesives, adhesion prevention barriers, and other gradient foams, trans-compositional foams, and trans-struc implantable medical devices including foams (including tural foams) for wound healing and/or drug delivery, bone reticulated foams, lyophilized foams, highly porous foams, hemostats, bone fillers, bone void fillers, bone wax formula regular foams, foams with Vertical channels, architecturally tions, tissue adhesives and sealants, adhesion prevention bar gradient foams, trans-compositional foams, and trans-struc riers, meshes, filters, Surgical devices (e.g., stents, staples, tural foams) for wound healing and/or drug delivery, bone Sutures (e.g., monofilament and multifilament Sutures), hemostats, bone fillers, bone void fillers, bone wax formula screws (e.g., orthopedic screws), sheets, plates, clips, films, tions, tissue adhesives and sealants, adhesion prevention bar Staples, pins, hooks, buttons, Snaps, tubes, vascular grafts, riers, meshes, filters, Surgical devices (e.g., stents, staples, bone plates, implantable sensors, and molded devices), medi Sutures (e.g., monofilament and multifilament Sutures), cal device coatings (e.g., for endoscopic instruments, Sutures, screws (e.g., orthopedic screws), sheets, plates, clips, films, stents, and needles), cosmetic and pharmaceutical packaging Staples, pins, hooks, buttons, Snaps, tubes, vascular grafts, (e.g., blister packaging films, cast films, extruded films and bone plates, implantable sensors, and molded devices), medi containers), apparels, infusion devices, blood collection cal device coatings (e.g., for endoscopic instruments, Sutures, tubes and devices, tubes, skin care products, transdermal drug stents, and needles), cosmetic and pharmaceutical packaging delivery, consumer product packaging, and disposable medi (e.g., blister packaging films, cast films, extruded films and containers), apparels, infusion devices, blood collection cal devices, durable goods, knitted products, foodstuffs, tubes and devices, tubes, skin care products, transdermal drug nutritional Supplements, nutraceuticals, biodegradable chew delivery, consumer product packaging, and disposable medi ing gums, and reinforced composites. cal devices, durable consumer goods, knitted products, food 0021 Examples of knitted products, woven or non-woven, stuffs, nutritional Supplements, nutraceuticals, biodegradable and molded products include: burn dressings; hernia patches; chewing gums, and reinforced composites. medicated dressings; fascial Substitutes; gauze, fabric, sheet, 0016. These and other embodiments, which will become felt, or sponge for liver hemostasis; gauze bandages; arterial apparent during the following detailed description, have been graft or Substitutes; bandages for skin Surfaces; Suture knot clip; hooks, buttons, and Snaps; bone Substitutes (e.g., man achieved by the inventors’ discovery of the presently claimed dible prosthesis); intrauterine devices (e.g., spermicidal bio-based monomers and polymers thereof. devices); draining or testing tubes or capillaries; Surgical DETAILED DESCRIPTION OF PREFERRED instruments; vascular implants or Supports; vertebral discs; EMBODIMENTS extracorporeal tubing for kidney and heart-lung machines; 0017. The entire disclosures of all cited patents and patent and, artificial skin. publications are incorporated in their entirety herein by ref 0022. As described herein, the functionalized monomers CCC. and polymers of the present invention are useful in medical US 2015/0259464 A1 Sep. 17, 2015

applications/medical devices. Medical application/medical 0035 CHCHCHCH-CHCOO (caprolactone devices, as used herein, encompass medical and biomedical moiety); applications and include all types of applications involved in 10036) -(CH2)COO where y is selected from 2, 3, 4, the practice of medicine that would benefit from a material and 6-24; and that decomposes harmlessly within a known period of time. 0037 –(CHCHO). CHCOO– where Z is selected 0023. In another embodiment, the present invention pro from 2-24; vides a novel diisocyanate selected from formula (I), (II), or 0038 each X" independently is selected from: (III): 0039) —OCH2CO— (glycolic acid moiety);

(I) St. 2 NCO

(II) 1.2 NCO

(III)

-RS1 (Spa, 2X? k O O R X.

RN yN OCN

0024 wherein: 0040 –OCH(CH)CO (lactic acid moiety): 0.025 variable A, the dashed bond, is absent or is a double 0041 —OCHCHOCH2CO— (dioxanone moiety); bond; 0042 –OCHCHCHCH-CHCO- (caprolactone 0026 R is the diacyl residue of a diacid; moiety); 0027) R' is absent or each R" is independently a C- alky lene group: 10043) —O(CH2)CO where y is selected from 2, 3, 4, 0028 R" is the residue of a diol or polyol; and 6-24; and, 0029 from 1-4 R, are present; 0044 – O(CHCHO). CHCO - where Z is selected 0030 each R, is independently selected from: H. C. from 2-24; alkyl, C. alkoxy, benzyloxy, halogen, —CHO. —COH, 0045 each p is independently selected from 0, 1,2,3,4, 5, and —NO, and each R, is independently attached directly to and 6; and, aromatic ring or attached through a —(CH2) -linker; 0046 each p' is independently selected from 0, 1,2,3,4, 5, 0031 each X independently is selected from: and 6: 0032 —CHCOO (glycolic acid moiety); 0047 provided that p--p' total from 0 to 12. 0033 –CH(CH)COO– (lactic acid moiety): 0048. As noted, R is the diacyl (i.e., C(O) R' C(O)) 0034) –CHCHOCHCOO (dioxanone moiety); residue of a diacid. US 2015/0259464 A1 Sep. 17, 2015

I0049) R' is independently selected from: alkylene, derived from vegetable oils including castor oil (e.g., ricino cycloalkylene-alkylene, arylene-alkylene, arylene-alkylene leic acid, 12-hydroxy Stearic acid, and sebacic acid) and Soy arylene, cycloalkylene-alkylene-cycloalkylene, and arylene bean oil. alkylene-cycloalkylene, wherein: 0053 As noted, R" is the residue of a diolor polyol. When 0050 (1) one or more of the methylene (—CH2—) moi R" is the residue of a diol, then it is the R" portion of eties in the alkylene chain portions of the R'group are option HO-R-OH. Alternatively, when R" is the residue of a ally replaced by —O— or —S-, or polyol, it is, excluding the terminal hydroxy groups, selected 0051 (2) one or more of the ethylene (—CH2CH2—) moi from polyalkylene oxides having weight average molecular eties in the alkylene chain portions of the R'group are option weights from about 500-10,000. ally replaced by a carboxyl group ( C(=O)C)— or —OC 0054 Examples of suitable diols from which R" can be (=O)—). derived include diols with up to 8 carbon atoms or diols 0052 Examples of diacids from which R can be derived having repeating units each with up to 8 carbon atoms. Diol include oxalic acid, malonic acid, Succinic acid, glutaric acid, examples include 1.2-ethanediol (ethylene glycol); 1,2-pro adipic acid, pimelic acid, Suberic acid, azelaic acid, sebacic panediol (propylene glycol); 1,3-propanediol; 1,4-butane acid, phthalic acid, isophthalic acid, terephthalic acid, maleic diol: 1,5-pentanediol, 1.3-cyclopentanediol; 1.6-hexanediol; acid, fumaric acid, glutaconic acid, traumatic acid, muconic 1,4-cyclohexanediol: 1.8-octanediol; and, combinations acid, diglycolic acid, 3,6-dioxaoctanedioic acid, 3.6.9-triox thereof. aundecanoic acid, functionalized Oxaacids, polyethylenegly 0055 Examples of suitable polyols from which R" can be col diacids of average molecular weight from 300 to 2000 and derived include polyethylene glycol and polypropylene gly blends thereof, symmetrical/unsymmentrical ether acids, as col with weight average molecular weights of 500-10,000. well as bio-based diacids and their precursors, including, 0056. In another embodiment, the present invention pro Succinic acid, sebacic acid, hydroxyl acids, and diacids vides a novel diisocyanate selected from formulae (Ia)-(IIIa):

(Ia) N NCO e R 2

(IIa) NCO N R 21

NCO (IIIa) N R O1 R no-1 (X) Pa R 2 US 2015/0259464 A1 Sep. 17, 2015 5

0057. In another embodiment, the present invention pro vides a novel diisocyanate selected from formulae (Ia)- (IIIa):

(Ia) NCO

O s a Yn 21 o1 ^es 2

R (X). RN N r O O OCN 21

(Ia2) NCO

O N.- Yn 1'N, 2

R (X)p's RN N r O O OCN 2

(IIa) NCO N O - Rn 21 O 1. ^en 21

1s1">x,R O SR1 O OCN 2

(IIa) N NCO O - Rn o1 Xen 2

N1">x,R O SR1 O US 2015/0259464 A1 Sep. 17, 2015 6

-continued (IIIa) NCO

- RYn O R (X) C. c no-1 NR 2 1s1 R Nx, O NR1 O I OCN 2

(IIIa) NCO. O N - RYin R (X) c no1 NR 2

R n1 O N1 O RN N (X), R OCN 2

0058. In another embodiment, the present invention pro vides a novel diisocyanate selected from formulae (Ia)- (IIIa):

(Ia 1A) NCO

O X O s (x)'s O OCN (Ia2A) NCO O

(X). O OCN US 2015/0259464 A1 Sep. 17, 2015 7

-continued (IIa 14) NCO O 21 o1 (X) NR

R Nox21N1 O NR O

OCN

(IIa2A) NCO O o1 (X) NR

R Nix1 O NR1 O

OCN

(IIIa 14) NCO O 21 1 R No1'n(X)

R Nox21 O NR1 O

OCN

(IIIa) NCO. O O1 R no1 (X) NR

Nox2 NR1 O

OCN US 2015/0259464 A1 Sep. 17, 2015

0059. In another embodiment, the present invention pro vides a novel diisocyanate selected from formulae (1)–(20):

(1) O 21 o1 O O NCO -O (X) OCN O's O (2) 21 o1 O O NCO (X)es. O

O OCN O (3) 21 -X) OCN NCO Ol (x),.1 O ror O O O

(4) O

OCN 21 o1 O NCO

O O Ol (X), 1N1

(5) NCO O 21 -X)

OCN

OUI(X), US 2015/0259464 A1 Sep. 17, 2015 9

-continued (6) O 21 rol O NCO (X),1 O

OCN (7) NCO O 21 -X) OCN Ou (X). -->O O (8) O 21 rol O NCO (X). --> O OCN (9) NCO O

-O O (X) ror O O OCN

O 21 o1 (X)

OCN NCO Srir O US 2015/0259464 A1 Sep. 17, 2015 10

-continued (11) O o1 (X)

O NCO -O (X)

OCN O (12) o1 (X) Ol O NCO Xes, O

O OCN

O (13)

o1 (X)

OCN NCO Ol (X)1 O ro ~ O O O

(14) O

OCN o1 (X) Ol NCO

O O Ol (X),1N1

(15) NCO O

OCN

Clu (X), O US 2015/0259464 A1 Sep. 17, 2015 11

-continued (16) O

O NCO (X),1 O OCN cr's (17) NCO O

OCN Outsu(X). O

(18) O

O NCO (X). O

O OCN (19) NCO O

-O O (X) ror O O OCN (20) O -X) OCN NCO. -O O (X) rsr O O US 2015/0259464 A1 Sep. 17, 2015

0060. In another embodiment, the present invention pro polymerizing at least one diisocyanate as described above vides a novel diisocyanate selected from formulae (1)A-(20) with a compound selected from a diol, an ester-diol, diamide A, which correspond to diisocyanates (1)-(20) except that diol and a diamine. each phenyl ring of (1)A-(22)A is independently substituted 0078. In another embodiment, the present invention pro with 1-4R, and provided that at least one R, is other than H. vides a novel polymer as described above, wherein: 0061. In another embodiment, the present invention pro 0079 each X independently is selected from the group vides a novel diisocyanate as described above, wherein: consisting of: 0062 each X independently is selected from the group 0080 —CHCOO (glycolic acid moiety); consisting of: I0081 -CH(CH)COO– (lactic acid moiety): I0082 —CH2CHOCH2COO (dioxanone moiety); and, 0063 —CHCOO (glycolic acid moiety); 0.083 CHCHCHCH-CHCOO (caprolactone 0064 -CH(CH)COO– (lactic acid moiety): moiety); 0065 —CH2CHOCH2COO (dioxanone moiety); and, 0.066 –CHCHCHCH-CHCOO– (caprolactone I0084 each X" independently is selected from the group moiety); consisting of: 0067 each X" independently is selected from the group I0085 —OCH2CO— (glycolic acid moiety); consisting of: I0086 —OCH(CH)CO (lactic acid moiety): I0087 —OCHCHOCH2CO— (dioxanone moiety); and, 0068 —OCH2CO— (glycolic acid moiety); I0088 –OCHCHCHCH-CHCO (caprolactone 0069 –OCH(CH)CO (lactic acid moiety): moiety); and, 0070 –OCHCHOCH2CO (dioxanone moiety); and, I0089 provided that p--p' total from 2-6. (0071 – OCHCHCHCH-CHCO (caprolactone 0090. In another embodiment, the present invention pro moiety); and, vides a novel polymer as described above, wherein: 0072 provided that p--p' total from 2-6. 0091 each p is independently selected from 0, 1, 2, 3, and 0073. In another embodiment, the present invention pro 4; and, vides a novel diisocyanate as described above, wherein: 0092 each p' is independently selected from 0, 1, 2, 3, and 0074 each p is independently selected from 0, 1, 2, 3, and 4: 4; and, 0093 provided that p--p' total from 2-4. 0075 each p' is independently selected from 0, 1, 2, 3, and 0094. In another embodiment, the present invention pro 4: vides a novel polymeras described above, wherein: the poly 0076 provided that p+p' total from 2-4. mer is a bioasborbable polymer. 0077. In another embodiment, the present invention pro 0095. In another embodiment, the present invention pro vides a novel polymer, comprising: a polyurethane, polyes vides a novel diamine selected from formula (IV), (V), or ter-urethane, polyurea-urethane, or polyurea, formed by (VI):

(IV)

1. R C'.2.

(V)

o1's 1.al US 2015/0259464 A1 Sep. 17, 2015

-continued (VI) S. o1 R no.1's(X) eNH2

0.096 wherein: 0109) —(CHCHO). CHCOO– where Z is selected 0097 variable A, the dashed bond, is absent or is a double from 2-24; bond; 0110 each X" independently is selected from: 0098 R is independently the diacyl residue of a diacid; 0111 —OCH2CO— (glycolic acid moiety); 0099 R' is absent or each R" is independently a C- alky 0112 —OCH(CH)CO (lactic acid moiety); lene group: 0113 —OCHCHOCH2CO— (dioxanone moiety); 0100 R" is the residue of a diol or polyol; 0114 –OCHCHCHCH-CHCO- (caprolactone 0101 from 1-4R, are present; moiety); 0102 each R, is independently selected from: H. C. alkyl, C. alkoxy, benzyloxy, halogen, —CHO. —COH, I0115 - O(CH2)CO where y is selected from 2, 3, 4, and —NO, and each R, is independently attached directly to and 6-24; and, aromatic ring or attached through a —(CH) - linker; 0116 – O(CHCHO). CHCO - where Z is selected 0103 each X independently is selected from: from 2-24; 01.04 -CHCOO– (glycolic acid moiety); 0117 each p is independently selected from 0, 1, 2, 3, 4, 5, 0105 -CH(CH)COO– (lactic acid moiety): and 6; and, 0106 —CH2CHOCH2COO (dioxanone moiety); 0118 each p' is independently selected from 0, 1,2,3,4, 5, 01.07 - CHCHCHCH-CHCOO (caprolactone and 6: moiety); 0119 provided that p--p' total from 0 to 12. I0108) —(CH), COO where y is selected from 2, 3, 4, I0120 In another embodiment, the present invention pro and 6-24; and vides a novel diamine selected from formulae (IVa)-(VIa):

NH (IVa) N R 2 1. 2

NH (Va) N R 2 1. 2 US 2015/0259464 A1 Sep. 17, 2015 14

-continued NH (VIa) N R 2. R (X) 1 in 1 No1''n. 2

N RN HN 2

0121. In another embodiment, the present invention pro vides a novel diamine selected from formulae (IVa)-(VIa):

(IVa) NH O N." 1. i: 21 O 1. Xen 2

N R (X).

R. O HN 2

(IVa) NH O N1. 2 1. i: o1 ^en 21

N s (X). RN O HN 21

NH (Va.) O N1 2 1. i: 21 O 18 a 2

R O O RN N Noxi 1 n1R US 2015/0259464 A1 Sep. 17, 2015 15

-continued NH (Va) O N1 2 1. pi o1 ^es 2

R O O RN N N,(X), 1N1 R HN 2

(VIa) NH O N1. 2 it 1. i: 21 -N1's 2

R O O RN N Noxi 1 n1R HN 2

(VIa) NH. O N R 2 R (X) 1 O1 No1 NR 2

R O O RN N Noxi 1 n1R HN 2

0122. In another embodiment, the present invention pro vides a novel diamine selected from formulae (IVa)- (VIa):

(IVal) - H c 'nr, s's O HN US 2015/0259464 A1 Sep. 17, 2015 16

-continued (IVa2) NH2 O

st O HN (Vala) NH2 O

R O O

HN r (Va2) NH2 O

R O O

HN r (VIa) NH2 O

R O O c

HN r (VIa) NH2. c O R no1'''n.(X) O R O O

HN r US 2015/0259464 A1 Sep. 17, 2015 17

0123. In another embodiment, the present invention pro vides a novel diamine selected from formulae (21)-(40):

21. O 21 -X) Ol NH2 x 1" HN c 22. O 21 o1 O O NH2 O

HN Or 23.

HN NH2 Ol (X),1 O ^r O O O 24. O

HN 21 o1 O NH2 O O Ol (X),1N1 25. NH2 O

HN Clu O US 2015/0259464 A1 Sep. 17, 2015 18

-continued 26. O 21 rol O NH2 (x).51 O

HN 27. NH2 O 21 o1 su HN O

O 28. O 21 o1 rol O NH2 (X).NO O

O HN 29. NH2 O

(X)1 O ^o ~ O O O HN 30. O 21 -X) HN (X)1 O r r O O O US 2015/0259464 A1 Sep. 17, 2015 19

-continued 31. O (X) o1 p

O NH2

O O's (X),1. HN 32. O (X) o1 Ol O NH2 Xes, O

O HN

33. O 1(X)p

HN NH2 (X),1 O ^r O O O

34. O

HN NH2 O O (X),1 n R1 35. NH2 O -X) HN O

O US 2015/0259464 A1 Sep. 17, 2015 20

-continued 36. O o1 (X) rC O NH2 (x),1 O

HN 37. NH2 O -X)

38. US 2015/0259464 A1 Sep. 17, 2015

0.124. In another embodiment, the present invention pro 0159. In another embodiment, the present invention pro vides a novel diamine selected from formulae (21)A-(40)A, vides a novel controlled drug delivery system comprising: which correspond to diamines (21)-(40) except that each 0160 (a) one or more of the polymers described above, phenyl ring of (21)A-(40)A is independently substituted with and 1-4R, and provided that at least one R, is other than H. 0.161 (b) one or more biologically or pharmacologically 0.125. In another embodiment, the present invention pro active agents. vides a novel diamine as described above, wherein: 0162. In another embodiment, the present invention pro 0126 each X independently is selected from the group vides a novel controlled drug delivery system described consisting of: above, wherein the one or more biologically or pharmaco 0127 —CHCOO (glycolic acid moiety); logically active agents are physically embedded or dispersed 0128 -CH(CH)COO– (lactic acid moiety): in a polymeric matrix, comprising: the one or more polymers. I0129 —CHCHOCHCOO (dioxanone moiety); and, 0163. In another embodiment, the present invention pro 0130 CHCHCHCH-CHCOO (caprolactone vides a novel tissue scaffold, comprising: one or more poly moiety); mers described above, wherein the tissue scaffold has a 0131 each X" independently is selected from the group porous structure for the attachment and proliferation of cells consisting of: either in vitro or in vivo. (0132) —OCHCO— (glycolic acid moiety); 0164. In another embodiment, the polymer is further poly 0.133 –OCH(CH)CO (lactic acid moiety): merized on at least one end with at least one lactone monomer 0134 —OCHCHOCH2CO— (dioxanone moiety); and, selected from the group consisting of glycolide, lactide, I0135 –OCHCHCHCH-CHCO- (caprolactone caprolactone, p-dioxanone, TMC, 6-Valerolactone, 3-butyro moiety); and, lactone, morpholinedione, pivalolactone, e-decalactone, 2.5- 0.136 provided that p--p' total from 2-6. diketomorpholine and combinations thereof in order to con 0.137 In another embodiment, the present invention pro trol physical and biological properties. vides a novel diamine as described above, wherein: 0.165. In another embodiment, the present invention pro 0138 each p is independently selected from 0, 1, 2, 3, and vides a novel article, comprising: a metal or polymeric Sub 4; and, strate and further comprising: at least one polymer described above, wherein said article is selected from: 0139 each p' is independently selected from 0, 1, 2, 3, and 0166 a medical device, an implantable medical device, a 4: pharmaceutical delivery system, a consumer product includ 0140 provided that p--p' total from 2-4. ing durable articles, a cosmetic, a tissue engineering applica 0141. In another embodiment, the present invention pro tion, a foam, a reticulated foam, a Suture, a bone hemostat, a vides a novel polymer, comprising: polyamide, polyester bone filler, a bone void filler, a bone cement, a tissue adhesive, amide, polyepoxide, or polyurea formed by polymerizing at a tissue sealant, an adhesion prevention barrier, a mesh, a least one diamine as described above with a compound filter, a stent, a medical device coating, a pharmaceutical drug selected from a dicarboxylic acid, diepoxide, and diisocyan formulation, a cosmetic packaging, a pharmaceutical pack ate. aging, an apparel, an infusion device, a blood collection 0142. In another embodiment, the present invention pro device, a skin care product, and a transdermal drug delivery vides a novel polymer as described above, wherein: material, drug delivery matrices, pharmaceutical drug formu 0143 each X independently is selected from the group lations, tissue engineering, tissue adhesives, adhesion pre consisting of: vention barriers, and other implantable medical devices 0144) —CHCOO (glycolic acid moiety); including foams for wound healing and/or drug delivery, bone (0145 -CH(CH)COO– (lactic acid moiety): hemostats, bone fillers, bone void fillers, bone wax formula 0146 —CHCHOCHCOO (dioxanone moiety); and, tions, tissue adhesives and sealants, adhesion prevention bar 0147 CHCHCHCH-CHCOO (caprolactone riers, meshes, filters, Surgical devices, medical device coat moiety); ings, cosmetic and pharmaceutical packaging, apparel, 0148 each X" independently is selected from the group infusion devices, blood collection tubes and devices, tubes, consisting of: skin care products, transdermal drug delivery, consumer 0149 —OCH2CO— (glycolic acid moiety); product packaging, and disposable medical devices, knitted products, foodstuffs, nutritional Supplements, nutraceuticals, 0150 —OCH(CH)CO (lactic acid moiety): biodegradable chewing gums, and reinforced composites. 0151 —OCHCHOCH2CO— (dioxanone moiety); and, 0167. In another embodiment, the metal or polymeric sub 0152 – OCHCHCHCH-CHCO (caprolactone strate has a coating, comprising: the at least one polymer, moiety); and, wherein said article is suitable for contacting mammalian 0153 provided that p--p' total from 2-6. tissue. 0154) In another embodiment, the present invention pro 0.168. In another embodiment, the article is an implantable vides a novel polymer as described above, wherein: medical device. 0155 each p is independently selected from 0, 1, 2, 3, and (0169. In another embodiment, the article is reticulated 4; and, foam for wound healing and/or controlled drug delivery. 0156 each p' is independently selected from 0, 1, 2, 3, and 0170 In another embodiment, the present invention pro 4: vides a novel Surgical article or component thereof or poly 0157 provided that p--p' total from 2-4. meric carrier, comprising: a polymer described above, 0158. In another embodiment, the present invention pro wherein the article is selected from: vides a novel polymeras described above, wherein: the poly 0171 a stent, Stent coating, wound covering, burn cover mer is a bioasborbable polymer. ing, foam, highly porous foams, reticulated foams, tissue US 2015/0259464 A1 Sep. 17, 2015 22 engineering scaffold, film, adhesion prevention barrier, delivery matrices (e.g., controlled drug delivery), pharmaceu implantable medical device, controlled drug delivery system, tical drug formulations, tissue engineering, tissue adhesives, Suture, ligature, needle and Suture combination, Surgical clip, adhesion prevention barriers, and other implantable medical Surgical staple, Surgical prosthesis, textile structure, cou devices including but not limited to tissue engineering scaf pling, tube, Support, screw, pin, bone wax formulation or an folds, foams (including reticulated foams, lyophilized foams, adhesion prevention barrier. highly porous foams, regular foams, foams with vertical 0172. In another embodiment, the present invention pro channels, architecturally gradient foams, trans-composi vides a novel Surgical article or component thereof as tional foams, and trans-structural foams) for wound healing described above, wherein a biologically active agent is physi and/or drug delivery, bone hemostats, bone fillers, bone void cally embedded or dispersed into the polymer matrix of the fillers, bone wax formulations, tissue adhesives and sealants, controlled delivery system. adhesion prevention barriers, meshes, filters, Surgical devices 0173. In another embodiment, the present invention pro (e.g., Stents, staples, Sutures (e.g., monofilament and mul vides methods of making novel bio-based materials. tifilament Sutures), Screws (e.g., orthopedic screws), sheets, 0.174. In another embodiment, the present invention pro plates, clips, films, staples, pins, tubes, and molded devices), vides novel bio-based castor oil or soybean oil derived medical device coatings (e.g., Stent coatings), cosmetic and hydroxyl acids diacids, diamines, and diisocyanates and pharmaceutical packaging (e.g., blister packaging films, cast polymers formed therefrom that include bio-based polya films, extruded films and containers), apparels, infusion mides, polyureas, polyepoxides, polyester amides, and poly devices, blood collection tubes and devices, tubes, skin care urethanes. These polymers can be biodegradable or biostable. products, transdermal drug delivery, consumer product pack 0.175. In another embodiment, the present invention pro aging, and disposable medical devices. vides novel bioabsorbable and biodegradable polyamides 0182. In another embodiment, in the synthesis of a diiso containing repeating units based on the novel aromatic di cyanate described in the above Bezwada Biomedical Patents, amine monomeric units of the present invention. Methods for the 4-nitrophenol (ortho, meta, para) can be replaced by preparing the novel biodegradable and biocompatible polya 4-NO-phenyl-CH-OH and/or 4-NO-phenyl-CHCH-OH. mides are also provided. Similarly, the 4-nitrobenzoic acid (ortho, meta, para) can be 0176). In another embodiment, the present invention pro replaced by 4-NO-phenyl-CHCOH and/or 4-NO-phenyl vides novel biodegradable and biocompatible polymers hav CHCHCO.H. Alternatively, the 4-nitrophenol can be ing a controllable degradation profile. These polymers are replaced or substituted with 4-NO-(aromatic ring)-P OH useful for medicinal and therapeutic uses, such as tissue engi and 4-NO-(aromatic ring)-P-OH. Similarly, the 4-ni neering. trobenzoic acid can be replaced or substituted with 4-NO 0177. In another embodiment, the present invention pro (aromatic ring)-P COH and 4-NO-(aromatic ring)-P- vides novel aromatic diisocyanates. COH wherein the aromatic rings can be monocyclic, 0178. In another embodiment, the present invention pro bicyclic or polycyclic. The aromatic rings can also be fused. vides novel absorbable and/or biodegradable polyurethanes The aromatic rings can also be heterocyclic containing non and polyurethane esters containing repeating units based on carbon ring atoms such as oxygen, nitrogen and Sulfur. P is the novel aromatic diisocyanates of the present invention. selected from an alkylene, alkylene-arylene, and an alicyclic Methods for preparing the novel biodegradable and biocom chain. Further, the present invention also provides hydrolys patible polyurethanes and polyurethane esters are also pro able diisocyanates derived from these molecules further func vided. tionalized with one or more groups selected from glycolic 0179. In another embodiment, the present invention pro acid, lactic acid, caprolactone, and a p-dioxanone moiety. The vides novel bio-based novel biodegradable and biostable ali positions of nitro to hydroxyl or carboxyl can be ortho meta or phatic polyester polyols. para on the aromatic ring. The present invention also provides 0180. In another embodiment, the present invention pro asborbable polyurethanes derived from the above diisocyan vides novel biobased and/or biodegradable, biocompatible ates. and absorbable a polyurethane and polyurethane esters con 0183 In another embodiment, the present invention pro taining repeating units based on the novel diisocyanate-con vides asborbable polyurethane foams with open and closed taining monomeric units of the present invention. The diiso cell structures, including reticulated foams, foams with Ver cyanates used to prepare polyurethanes and polyurethane tical channels, architecturally gradient foams, trans-compo esters can also be aliphatic or cycloaliphatic. Methods for sitional foams, and trans-structural foams and the process of preparing Such biobased and/or biodegradable and absorb preparing these absorbable foams using the novel hydrolys able aliphatic and aromatic polyurethanes and polyurethane able diisocyanates, diamines, biodegradable and biocompat esters are also provided. ible polyurethanes described herein. Optionally the novel 0181. In another embodiment, the novel diisocyanates, hydrolysable diisocyanates, diamines, biodegradable and diamines, biodegradable and biocompatible polyurethanes, biocompatible polyurethanes described herein are used in and biodegradable and biocompatible polyamides of the combination with those described in patents/patent publica present invention can be used in combination with those tions U.S. Pat. No. 7,772,352, U.S. Pat. No. 8,048,980, U.S. described in patents/patent publications U.S. Pat. No. 7,772, Pat. No. 8,143,325, U.S. Pat. No. 8,367,747, US 2010/ 352, U.S. Pat. No. 8,048,980, U.S. Pat. No. 8,143,325, U.S. 0260702 A1, US 2009/0292029 A1, US 2009/0082540, US Pat. No. 8,367,747, US 2010/0260702A1, US 2009/0292029 2006/0288547 A1, EP 1937182 B1, EP 2298.235 A1, EP A1, US 2009/0082540, US 2006/0288547 A1 EP 1937182 1937182 A4 EP 1937182 A2, and WO 27030464 A2, all of B1, EP229.8235A1 EP 1937182 A4, EP 1937182 A2, and which have been assigned to Bezwada Biomedical, and U.S. WO 27030464 A2, all of which have been assigned to Pat. No. 4,829,099, assigned to Fuller, et al., via lyophiliza Bezwada Biomedical (Bezwada Biomedical Patents), and tion wherein the bioasborbable polyurethane polymers and/ U.S. Pat. No. 4,829,099 assigned to Fuller, et al., for use drug or blends thereofare dissolved in a suitable solvent including US 2015/0259464 A1 Sep. 17, 2015 23 dioxane, N-methylpyrrolidone, dichloromethane and/or mix 0204 a) forming a solution comprising a solvent tures thereof, to form a homogeneous solution which is Sub soluble absorbable elastomer in a solvent; jected to a lyophilization process, comprising: a solution of a 0205 b) at least partially solidifying the solution to bioabsorbable elastomer in a solvent which is substantially, form a solid, optionally by cooling the Solution; and but not necessarily completely, solidified, then the solvent is 0206 c) removing the non-polymeric material, option removed from that which is lyophilized under reduced pres ally by evaporating the solvent from the solid under Sure to form a foam. reduced pressure, to provide an at least partially reticu 0184 In another embodiment, the novel diisocyanates of lated elastomeric matrix comprising the elastomer. the present invention provide a true reticulated, flexible, and 0207. In another embodiment, the invention provides a resilient, bioasborbable elastomeric matrix, suitable for process for preparing a reticulated composite elastomeric implantation and having Sufficient porosity to encourage cel implantable device for implantation into a patient, the process lular ingrowth and proliferation in vivo. comprising: Surface coating or endoporously coating a 0185. In another embodiment, the present invention pro vides a polymerization process for preparing a bioasborbable absorbable reticulated elastomeric matrix with a coating reticulated elastomeric matrix, comprising the steps of: material selected to encourage cellular ingrowth and prolif 0186 (1) admixing eration. The coating material can, for example, comprise: a 0187 a) a polyol component, foamed coating of absorbable polyurethane and optionally, 0188 b) a diisocyanate component, collagen, fibronectin, elastin, hyaluronic acid or a mixture 0189 c) a blowing agent, thereof. Alternatively, the coating comprises: absorbable 0.190 d) optionally, a crosslinking agent, polyurethane and an inorganic component (e.g., calcium car 0191 e) optionally, a chain extender, bonate, tricalcium phosphate, magnesium carbonate, as well 0.192 f) optionally, one or more catalysts, as other inorganic salts). 0208. In another embodiment, the invention provides 0193 g) optionally, one or more cell openers, novel, safe, bio-based, biocompatible and absorbable aro 0194 h) optionally, a surfactant, and matic diisocyanate-based adhesives. For example, such adhe 0.195 i) optionally, a viscosity modifier; sives are metabolically-acceptable Surgical adhesives and to provide a crosslinked elastomeric matrix, and have controllable degradation profiles. In another embodi 0196) (2) reticulating the elastomeric matrix by a reticula ment, the invention provides methods for closing wounds in tion process to provide the reticulated elastomeric matrix. living tissue by use of novel, metabolically-acceptable Surgi The ingredients are present in quantities and the elastomeric cal adhesives having low toxicity. matrix is prepared under conditions So as to: (i) provide a crosslinked resiliently-compressible absorbable elastomeric 0209. In another embodiment, the invention provides matrix, (ii) control formation of biologically undesirable resi diamines that can provide hydrophilic bioasborbable polyes dues, and (iii) reticulate the foam by a reticulation process, to ter amides that are biocompatible and useful for bioasborb provide the reticulated elastomeric matrix. able Sutures, Staples clips, and adhesion prevention barriers. 0197) In another embodiment, the invention provides a 0210. In another embodiment, the invention provides lyophilization process for preparing a reticulated elastomeric novel polyurethanes, polyesters, and polyester amides that matrix, comprising: lyophilizing a flowable polymeric mate are biodegradable and biocompatible and useful for tissue rial. engineering, drug delivery, tissue adhesives, adhesion pre 0198 In another embodiment, the polymeric material, vention, and other implantable medical devices. comprises: a solution of a solvent-soluble absorbable elas 0211. In another embodiment, the invention provides tomer in a solvent. novel hydrolysable diisocyanates for use in the formation of 0199. In another embodiment, the flowable polymeric polyurethanes and other polymers. material is subjected to a lyophilization process, comprising: 0212. In another embodiment, the invention provides solidifying the flowable polymeric material to form a solid, novel hydrolysable branched diisocyanates with pendant e.g., by cooling a solution, then removing the non-polymeric long chain alkyl groups that are hydrophobic or pendant long material, e.g., by evaporating the solvent from the Solid under chain PEG that are hydrophilic. reduced pressure, to provide an at least partially reticulated 0213. In another embodiment, the invention provides elastomeric matrix. novel bioasborbable polyesters, polyurethanes, polyureas, 0200. In another embodiment, a solution of a absorbable and polyester amides that can be further polymerized with elastomer in a solvent is Substantially, but not necessarily lactone monomers. Examples of lactone monomers include completely, solidified, then the solvent is evaporated from glycolide, lactide, caprolactone, p-dioxanone, TMC (trimeth that material to provide an at least partially reticulated elas ylene carbonate), Ö-Valerolactone, B-butyrolactone, morpho tomeric matrix. linedione, pivalolactone, e-decalactone, 2,5-diketomorpho 0201 In another embodiment, the temperature to which line, and combinations thereof. These lactone monomers the solution is cooled is below the freezing temperature of the allow one to control physical and biological properties. Solution. 0214. As noted above, the bio-based monomers of the 0202 In another embodiment, the temperature to which present invention, which have at least two reactive sites, can the solution is cooled is above the apparent glass transition be polymerized with difunctional molecules (e.g., dialcohols temperature of the solid and below the freezing temperature (diols), ester-diols, diamide-diols, diamines, dicarboxylic of the solution. acids (diacids), diexopides, and diisocyanates) to form poly 0203. In another embodiment, the present invention pro mers of the present invention, including polyurethanes, poly vides a lyophilization process for producing an elastomeric ester-urethanes, polyurea-urethanes, polyureas, polyamides, matrix having a reticulated structure, the process comprising polyester amides, and polyepoxides by simple polyconden the steps of: sation reactions. US 2015/0259464 A1 Sep. 17, 2015 24

0215 Examples of diols that can be used to form polymers with the bio-based monomers of the present invention have O O the following structure: D-R-() HO R OH wherein R is independently selected from: alkylene, wherein R is as defined previously. cycloalkylene-alkylene, arylene-alkylene, arylene-alkylene 0224 Examples of diisocyanates that can be used to form arylene, cycloalkylene-alkylene-cycloalkylene, and arylene polymers with the bio-based monomers of the present inven alkylene-cycloalkylene, wherein: tion have the following structure: 0216 (1) one or more of the methylene (—CH2—) moi OCN R NCO eties in the alkylene chain portions of the R group are option wherein R is as defined previously. Other examples include ally replaced by —O— or —S-, or hexamethylene diisocyante, lysine diisocyanate, methylene diphenyl diisocyanate (e.g., MDI), methylene dicyclohexyl 0217 (2) one or more of the ethylene (—CH2CH2—) moi diisocyanate, and isophorone diisocyanate. eties in the alkylene chain portions of the R group are option 0225. In another embodiment, the present invention pro ally replaced by a carboxyl group ( C(=O)C)— or —OC vides polymers from which a medical device or a component (=O)—). of the device is formed, and the polymers exhibit a percent 0218. Alternatively, polyalkylene oxides having weight elongation greater than about 200 or even greater than about average molecular weights from about 500-10,000 can be 500. The polymers can also exhibit a modulus (Young's used as a diol (i.e., a polydiol). Examples of Suitable diols or Modulus) of less than about 40,000 psi, or even less than polydiols for use in the present invention are diols with up to about 20,000 psi. These properties, which measure the degree 8 carbonatoms ordiols having repeating units each with up to of elasticity of the bioabsorbable elastomer, are achieved 8 carbon atoms. Examples of suitable diols include 1.2- while maintaining a tensile strength greater than about 500 ethanediol (ethylene glycol); 1.2-propanediol (propylene psi, or even greater than about 1,000 psi, and a tear strength of glycol); 1,3-propanediol; 1,4-butanediol; 1.5-pentanediol; greater than about 50 lbs/inch, or even greater than about 80 1.3-cyclopentanediol; 1.6-hexanediol; 1,4-cyclohexanediol; lbs/inch 1.8-octanediol; and, combinations thereof. Examples of poly 0226 Generally the functionality of the aromatic mono diols include polyethylene glycol and polypropylene glycol mers is selected from amine- and/or carboxylic acid-contain with weight average molecular weights of 500-10,000. ing phenols, such as amino phenols and amino Salicylic acids, 0219. Examples of ester-diols that can be used to form and from amino benzoic acids, (4-aminophenyl)methanol, polymers with the bio-based monomers of the present inven 2-(4-aminophenyl)ethanol. 2(4-aminophenyl)acetic acid, tion have the following structure: and 3-(4-aminophenyl)propionic acid as Summarized below. Glycolic acid is used as a functionalization moiety for pur HO R OH poses of illustration. wherein R is defined previously, provided that R contains at 0227. The biological properties of the bioasborbable poly least one internal carboxyl group (C(O)O). mers of the present invention used to form devices or parts thereof, as measured by its absorption rate and its breaking 0220 Examples of diamide-diols that can be used to form strength retention in vivo (BSR), can be varied to suit the polymers with the bio-based monomers of the present inven needs of the particular application for which the fabricated tion are have the following structure: medical device or component is intended. This can be conve HO. R OH niently accomplished by varying the ratio of components of the polymer chosen. wherein R'R'' as defined previously, provided that two or 0228. The materials (e.g., polymers) of the present inven more of the ethylene ( CHCH ) moieties in the alkylene tion comprise: cleavable sites (e.g., see the X group of the chain portions of the R group are replaced by amide groups structures provided herein). Depending on the formation (C(O)NH or NHC(O)). route selected, these cleavable sites may be regular along the 0221 Examples of diamines that can be used to form length of a chain extender, thereby giving the segmented polymers with the bio-based monomers of the present inven polyurethane or polyester or the like a biodegradability that tion include have the following structure: is, by some measure, predictable. 0229 Biodegradability is influenced by a number of fac H2N-R-NH2 tors, including crystallinity. The hydrophilicity of the poly wherein R is as defined previously. Alternatively, polyalky mer may also influence the degradability, that is, the extent to lene oxides that are diamines with weight average molecular which water is accessible to the polymer matrix. The number weights from about 500-5,000 can be used. of cleavage sites may also influence biodegradability. Gener ally speaking, the higher the number of cleavage sites, the 0222 Examples of dicarboxylic acids that can be used to greater the rate of degradation. Typically, the cleavable site is form polymers with the bio-based monomers of the present an ester site. For example, the cleavable ester site can be invention have the following structure: derived from a hydroxy acid precursor. This provides seg HOOC- R COOH mented polyurethanes and polyesters or the like with cleav able sites that may be arranged to be recognizable by wherein R is as defined previously. enzymes. 0223 Examples of diepoxides that can be used to form 0230. The polyester amides of the present invention may polymers with the bio-based monomers of the present inven be prepared by reacting an amide acid of the present invention tion have the following structure: with diols in the presence of an organometallic catalyst at US 2015/0259464 A1 Sep. 17, 2015

elevated temperatures. The organometallic catalyst is typi invention does not depend upon the theoretical correctness of cally a tin-based catalyst, e.g. stannous octoate, and is present these formulae, in whole or in part. Thus it is understood that in the monomer mixture at a mole ratio of monomer-to the formulas used herein, as well as the chemical names catalyst ranging from 15,000 to 80,000/1. The polymerization attributed to the correspondingly indicated compounds, are is typically carried out at a temperature ranging from 120 not intended to limit the invention in any way, including 200° C. or 160-190° C., until the desired molecular weight restricting it to any specific tautomeric form, except where and Viscosity are achieved. such limit is clearly defined. 0231. The polyurethanes and other polymers of the present invention may be prepared by reacting the diisocyan Precursors of the Compounds and Monomeric Units ates of the present invention with a branched chain extender 0240 Glycolic acid and lactic acid are known as alpha ora chain extender and polyols of the present invention and/or hydroxy acids (AHAs) and are present in fruits and other generic polyols including polyethylene glycols, polyesterdi foods. The chemical formula of glycolic acid is ols, and polyetherdiols. HOCHCOOH. This compound is biodegradable. When gly 0232. The polyamides of the present invention may be colic acid is heated it readily loses water by self-esterification prepared by reacting diamines of the present invention with to form polyglycolic acid. Glycolic acid can function as both diacids of the present invention and/or generic diacids includ an acid and an alcohol. This dual functionality leads to a ing polyethylene diacids, polyesterdiacids, and polyetherdi variety of chemical reactions and valuable physical proper acids. ties. Many Surgical devices are made from polyglycolic acid. 0233. The polyepoxides of the present invention may be The process of attaching a glycolic acid moiety to a phenolic prepared by reacting diamines of the present invention with compound is defined as glycolation. epoxides. 0241 Lactic acid is a fermentation product of lactose. It is 0234. In another embodiment, the present invention pro present in Sour milk, koumiss, leban, yogurt, and cottage vides monomers wherein the diisocyanate groups are cheese. Lactic acid is also produced in the muscles during replaced with isothiocyanates; and polymers produced there intense activity. Many Surgical and orthopedic devices are from. Specifically, this embodiment of the invention is made from polylactic acid. The esters of lactic acid are useful directed to isothiocyanate analogs of the above. as emulsifying agents in baking foods; examples include 0235. In another embodiment, the present invention pro Stearoyl-2-lactylate, glyceryl lactostearate, and glyceryl lac vides novel biodegradable and biocompatible aliphatic and topalmitate. The process of attaching a lactic acid moiety to a cyclic aliphatic diisocyanate-based monomers. Examples of phenolic compound is defined as lactolation. cyclic aliphatic diisocyanate-based monomers are the cyclo 0242 Epsilon-caprolactone is a reactive cyclic monomer, hexane-containing compounds which are related to their aro and the polymers derived therefrom are useful for tailoring matic counterparts formally by reduction of the benzene rings specialty polyols and hydroxy-functional polymer resins with to cyclohexane rings. The polymers prepared from Such satu enhanced flexibility. The monomer polymerizes under mild rated monomers have beneficially reduced color, improved conditions to give low viscosity products Superior to conven transparency and are non-yellowing. tional aliphatic polyesters. Copolymers of caprolactone with 0236 Examples of cyclic aliphatic diamine-based mono glycolide and lactide exhibit unique physical and biological mers are the cyclohexane-containing compounds, which are properties as well as different hydrolysis profiles based on the related to their aromatic counterparts 21-40 formed by reduc composition of the monomers. The process of attaching an tion of the benzene rings to cyclohexane rings. As for the open chain e-caprolactone moiety to a phenolic compound is corresponding cycloaliphatic diisocyanate monomers, the defined as caprolation. polymers prepared from Such saturated diamine monomers 0243 p-Dioxanone (1,4-dioxan-2-one) is a cyclic mono have beneficially reduced color, improved transparency and mer, and polymers are made therefrom via ring opening poly are non-yellowing. merization. Polyesters derived from this monomer are used in 0237 Abeneficial property of the polymers of the present making bioasborbable Surgical devices with a longer absorp invention that contain ester linkages is that the ester linkages tion profile (slower hydrolysis) compared to polyglycolic are hydrolytically unstable, and therefore the polymer is acid. The bioasborbable surgical devices made from 1,4- absorbable because it readily breaks down into small seg dioxan-2-one have proved to be biologically safe, and bio ments when exposed to moist bodily tissue. compatible. The process of attaching an open chain p-diox 0238 When any variable occurs more than one time in any anone moiety to a phenolic compound is defined as constituent or in any formula, its definition in each occurrence dioxonation. is independent of its definition at every other occurrence. 0244 Embodiments of the new functionalized bio-based Combinations of substituents and/or variables are permis diamines and diisocyanates have controllable hydrolysis pro sible only if Such combinations result in stable compounds. files, improved bioavailability, improved efficacy, and Within the context of the present invention, compounds are enhanced functionality. The difunctional compounds of the stable if they do not degrade significantly prior to their present invention can readily polymerize into biodegradable intended use under normal conditions. In some instances, polyamides, polyesters, polyureas, polyepoxides, polyestera compounds of the invention may be designed or required to be mides and polyurethanes, which are useful for many applica bioabsorbed or biodegraded as part of their intended function. tions that are described herein. Absorbability and/or biodegradability, which may be an 0245 “Absorbable” refers to a monomer or product advantageous property of the present polymers, is not derived therefrom that readily reacts or enzymatically intended to mean that the polymeric compound are unstable. degrades upon exposure to bodily tissue for a relatively short 0239. It is believed the chemical formulas and names used period of time, thus providing a significant weight loss of the herein correctly and accurately reflect the underlying chemi original material in that short time period. Examples of time cal compounds. However, the nature and value of the present periods include, up to 12 months, up to 9 months, 3-9 months, US 2015/0259464 A1 Sep. 17, 2015 26 up to 6 months, and 2-8 weeks. Therefore, the polymers of the atoms include 6-10. Examples include phenyl, naphthyl, present invention can be fabricated into medical and Surgical anthracenyl, and phenanthrenyl. devices, foams, bioadhesives, coatings, etc., (described pre 0256 "Arylene' refers to a bivalent aryl moiety, wherein viously) that are useful for a vast array of applications requir aryl is as previously defined. The ring system may be mono ing complete absorption within the relatively short time peri cyclic or fused polycyclic (e.g., bicyclic, tricyclic, etc.). An ods as defined above. example is phneylene. In various embodiments, the arylene, 0246 “Monomers’ includes macromers, unless the con e.g., phenylene, may be a 1.2-, 1.3-, or 1.4-Substituted moiety. text clearly indicates otherwise. 0257 “Cycloalkyl refers to an optionally substituted, 0247 “Elastomer' is a material that at room temperature mono-, di-, tri-, or other multicyclic alicyclic ring system can be stretched repeatedly to at least twice its original length moiety having from 3-20 carbonatoms (and all combinations and, upon immediate release of the stress, will return with and Subcombinations of ranges of carbon atoms and specific force to its approximate original length. numbers of carbon atoms therein). Examples of carbon 0248 "Prepolymer is a low molecular weight polymer ranges include 3-8, and 3-6. Multi-ring structures may be usually an intermediate between that of the monomer and the bridged or fused ring structures, wherein the additional final polymer that is capable of further polymerization. groups fused or bridged to the cycloalkyl ring may include optionally Substituted cycloalkyl, aryl, heterocycloalkyl, or 0249 “Monomeric unit is defined as a small molecule heteroaryl rings. Examples of cycloalkyl groups include that can chemically react with other monomers to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, polymer. adamantyl, 2-4-isopropyl-1-methyl-7-Oxa-bicyclo[2.2.1 0250) “Polymer is a molecule that is formed by joining heptanyl, and 2-1,2,3,4-tetrahydro-naphthalenyl. repeating monomeric units. 0258 “Cycloalkylene' refers to a bivalent cycloalkyl moi 0251. The polymers of the present invention can be, with ety, wherein cycloalkyl is as previously defined. Cycloalky out limitation, linear, branced, star or comb polymers. lene is a type of alkylene group which is a cycloalkyl group 0252 A“biologically active' is a substance that can act on with two open bonding sites. a cell, virus, organ, or organism, including but not limited to (0259 “Cycloalkylenealkylene' refers to a bivalent moi drugs (i.e., pharmaceuticals) to create a change in the func ety, wherein a cycloalkylene group is bonded to a non-cyclic tioning of the cell, virus, organ, or organism. In certain alkylene group, wherein each of the cycloalkylene and non embodiments of the invention, the biologically active sub cyclic alkylene groups has one open bonding site, and stances are organic molecules having molecular weight of wherein cycloalkylene and alkylene are each as previously about 600 or less, or are polymeric species such as proteins, defined. “Cycloalkylenealkylene' includes moieties having nucleic acids, and the like. A biologically active Substance -cycloalkylene-alkylene-and-alkylene-cycloalkylene-bond can be a substance used for therapy of an animal, preferably ing orders or configurations. a human. In the present invention, a biologically active Sub 0260 Arylenealkylene' refers to a bivalent moiety, stance bears, or has a functional homolog that bears, one or wherein an arylene group is bonded to a non-cyclic alkylene more hydroxyl, amino, and/or carboxylic acid substituents, group, and each of the arylene and non-cyclic alkylene group including functional derivatives such as esters, amides, has one open bonding site, wherein arylene and alkylene are methyl ethers, glycosides, and other derivatives that are each as previously defined. "Arylenealkylene' includes moi apparent to those skilled in the art. Examples of biologically eties having -arylene-alkylene-and-alkylene-arylene-bond active compounds that can be used in the present invention ing orders or configurations. include Capsaicin, Vitamin E. Resveratrol, and isoflavonoids. 0261 Arylenealkylenearylene' refers to bivalent moi 0253 “Alkyl refers to an optionally substituted, saturated eties, wherein two arylene groups are bonded to a non-cyclic straight, or branched hydrocarbon moiety having from 1-20 alkylene group, and each of the arylene groups has one open carbon atoms (and all combinations and Subcombinations of bonding site, wherein arylene and alkylene are each as pre ranges of carbonatoms and specific numbers of carbonatoms viously defined. therein). Examples of ranges of carbon atoms include 1-8, 0262 “Cycloalkylenealkylenecycloalkylene' refers to a 1-6, and 1-4. Examples include methyl, ethyl, n-propyl, iso bivalent moiety, wherein two cycloalkylene groups are propyl. n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopen bonded to a non-cyclic alkylene group, and each of the tyl, n-hexyl, isohexyl, 3-methylpenty1, 2,2-dimethylbutyl, cycloalkylene groups has one open bonding site, wherein and 2,3-dimethylbutyl. cycloalkylene and alkylene are each as previously defined. 0254 Alkylene' refers to a bivalent alkyl moiety having 0263 Arylenealkylenecycloalkylene' refers to a bivalent the general formula —(CH), , where n is from 1 to 150. moiety, wherein an arylene and a cycloalkylene group are Examples of carbon ranges include 1-20, 1-16, and 1-10. By each bonded to a non-cyclic alkylene group, and each of the bivalent, it is meant that the group has two open sites each of arylene and cycloalkylene groups has one open bonding site, which bonds to another group. Examples include methylene, wherein arylene, cycloalkylene, and alkylene are as previ ethylene, trimethylene, pentamethylene, and hexamethylene. ously defined. Arylenealkylenecycloalkylene' includes Alkylene groups can be optionally Substituted with alkyl, moieties having -arylene-alkylene-cycloalkylene- and wherein alkyl is as previously defined. “Lower alkylene’ cycloalkylene-alkylene-arylene-bonding orders or configu herein refers to those alkylene groups having from 1-6 carbon rations. atOmS. 0264 “Chain Extenders.” The nature of the chain extender 0255 'Aryl refers to an optionally substituted, mono-, group in the polymers of the present invention can vary pro di-, tri-, or other multicyclic aromatic ring system moiety vided that the polymer of the invention possesses acceptable having from 6-50 carbon atoms (and all combinations and mechanical properties and release kinetics for the selected Subcombinations of ranges of carbonatoms and specific num therapeutic application. The chain extendergroup R* is typi bers of carbon atoms therein). Examples of ranges of carbon cally a divalent organic radical having a molecular weight of US 2015/0259464 A1 Sep. 17, 2015 27 about 60 to about 5000. Additional examples include R* -continued having a molecular weight of about 100 to about 1000, and O may contain oxygenatoms, Sulfur atoms and/or ester groups. 0265. The chain extendergroup may be biologically inac OH tive, or may itself possess biological activity. The chain extender group can also be a polyalkylene oxide. Such as polyethylene oxide. The chain extender group can also be OH polyester derived from at least one lactone monomer, Such as O glycolide, lactide, p-dioxanone, trimethylenecarbonate, or caprolactone. The chain extender group can also comprise 21 OH other functional groups (including hydroxy groups, amine groups, carboxylic acids, and the like) that can be used to modify the properties of the polymer (e.g. for branching, for O cross linking). O 0266. When any variable occurs more than one time in any HO constituent or in any formula, its definition in each occurrence O is independent of its definition at every other occurrence. O Combinations of substituents and/or variables are permis sible only if Such combinations result in stable compounds. OH Within the context of the present invention, compounds are stable if they do not degrade significantly prior to their O intended use under normal conditions. In some instances, compounds of the invention are may be designed or required O to be bioabsorbed or biodegraded as part of their intended HO function. Absorbability and/or biodegradability, which may O be an advantageous property of the present polymers, is not O intended to mean that the polymeric compound are unstable. OH OH HO HO Bio-Based Polyester and Polyesteramide Polyols and Methods of Preparation Thereof O O HO 1N1-N- 2NS-1a1n-NH2 0267 O HN OH NH2

0268. Using the above bio-based monomers, one can make bio-based polyester and polyamide ester polyols for the preparation of bio-based polyurethanes. Examples of bio OH based polyols that can be prepared are shown below (BDO=1, 4-butane diol):

“Y” O O US 2015/0259464 A1 Sep. 17, 2015 28

-continued O O

'''" O O O

21 OH

O O --> O O

HO 21

O O

OH

O O --> O O

HO

O O O

O

O O HO c

O O US 2015/0259464 A1 Sep. 17, 2015 29

-continued

OH

+ BDO -- Polyester Diol (100% Bio derived)

HO

OH

+ BDO -- Polyester Diol (100% Bio , derived) HO

OH

-- 14 Butanediol -e-

HO

Polyester Diol (100% Bio-derived)

OH

cOO -- 14 Butanediol -e-

HO

Polyester Diol (100% Bio-derived) US 2015/0259464 A1 Sep. 17, 2015 30

-continued

21 OH

Functionalized 14 Butanediol

HO

Polyester Diol (100% Bio-derived, bioabsorbable Polymer)

OH

Functionalized 14 Butanediol

HO

Polyester Diol (100% Bio-derived, bioabsorbable Polymer) wherein functionalized 1,4-butanediol is prepared by react films, coatings, microspheres and fibers with different geo ing 1,4-butanediol with lactic acid, glycolic acid, p-diox metric shapes for the design of various medical implants, and anone and/or caprolactone. may also be processed by compression molding and extru S1O. 0269. In another embodiment, copolymers of asborbable 0271 Polyamides, polyesters, polyureas, polyepoxides, polymers of the present invention can be prepared by prepar polyesteramides, and polyurethanes prepared in accordance ing a prepolymer under melt poly-condensation conditions, with the present invention have average molecular weights of followed by adding at least one lactone monomer or lactone about 1500 to about 100,000 calculated by Gel Permeation prepolymer. The mixture is then subjected to the desired Chromatography (GPC) relative to narrow molecular weight conditions of temperature and time to copolymerize the pre polystyrene standards. Other examples of Polyamides, poly polymer with the lactone monomers. esters, polyureas, polyepoxides, polyesteramides, and poly 0270. The polymers of the invention are prepared in accor urethanes have average molecular weights of about 1500 up dance with methods commonly employed in the field of syn to about 40,000. thetic polymers to produce a variety of useful products with 0272 Processes for preparing polyamides of the invention valuable physical and chemical properties. The polymers are are provided as further embodiments of the invention and are readily processed into pastes or can be solvent cast to yield illustrated by the following general method:

HN + HOOC-R-COOH -> Polyamide

Recinoleic acide based amine US 2015/0259464 A1 Sep. 17, 2015 31

-continued NH2 O

O

HN + HOOC-R -COOH -> Polyamide

O

O 12-Hydroxy Steric acid based amine

0273. The diamines can also be reacted with diisocyanates (OCN R NCO) to prepare biodegradable polyureas. 0274 Processes for preparing polyurethanes of the inven tion are provided as further embodiments of the invention and are illustrated by the following general procedure:

NCO O

21 O

OCN + HO-R-OH -- Polyurethane

O

O Recinoleic acide based amine NCO O

O

OCN + HO-R-OH -- Polyurethane

O

O 12-Hydroxy Steric acid based amine

0275. These diisocyanates can also be reacted with reacted with the previously synthesized pre-polymer to gen diamines (HN R NH) to prepare biodegradable poly erate a high molecular weight polymer, polyurethane for leaS example. However, the formation of polyurethanes may also 0276. The diamines of this invention can also be reacted be carried out using Such processes as a single step process with diepoxides to prepare biodegradable polyepoxides. involving reaction of the chain extender together with the 0277. The mechanical properties, such as ultimate tensile diisocyanate and the polyol, without the formation of a pre strength, of the polyurethanes of the present invention can in polymer. Some cases be influenced primarily by the polyol component 0279. The polyol component of a polymer of the present as opposed to the hard segment as in typical segmented poly invention is often selected according to the components tox urethanes. icity, which is liberated when the polymer is broken down. 0278. One type of polyurethane of the present invention is Two examples of typical polyols are polyethylene oxide and the type known as segmented polyurethane, which is charac polycaprolactone diol. Others may be suitable in some cases. terized by a formation of repeating soft and hard blocks 0280. The constituents making up the polyurethanes of the formed from a polyol component, a diisocyanate component, present invention can be selected so as to be biodegradable to and an optional chain extender, and can occur in a linear, substantially nontoxic constituents. The term substantially branched or networked form. The chain extender may be non-toxic refers to materials which when present in the body US 2015/0259464 A1 Sep. 17, 2015 32 are physically tolerated and, more specifically, do not cause dissolved. The mixture may be deposited into a dish causing appreciable cell death (cytotoxicity) or detrimental alteration the solvent to evaporate, with the salt material being removed of normal cell function (such as a mutagenic response). This by Subsequent washing with water. would of course depend on where and how the material is 0287. In another embodiment, the present invention pro applied. Detailed in vivo tests may be appropriate to deter vides methods and processes for preparing the biodegradable mine the effect of the material on the neighboring cells. and absorbable polymers of the present invention from the 0281. Depending on the synthesis route selected for the monomers disclosed, vide Supra, with or without the inclu segement polyurethane, the cleavable sites of the present sion of other monomers. The polymerization processes typi invention may be regularly spaced along the length of the cally used for the formation of polyurethanes, polyamides, chain extender, thereby giving the segmented polyurethane a etc., are well-known to those skilled in the art. Representative biodegradability which is, by Some measure, predictable. processes are provided in U.S. Pat. No. 7,772,352, U.S. Pat. Biodegradability is influenced by a number of factors, includ No. 8,048,980, U.S. Pat. No. 8,143,325, U.S. Pat. No. 8,367, ing the number of Susceptible sites and crystallinity. 747, US 2010/0260702A1, US 2009/0292029A1, US 2009/ 0282. The hydrophilicity of a polymer, that is, the extent to 0082540, US 2006/0288547 A1, EP 1937182 B1, EP which water is accessible to the polymer matrix and the 229.8235 A1 EP 1937182 A4, EP 1937182 A2, and WO Susceptible sites, may also influence its degradability. In those 27030464 A2, all of which have been assigned to Bezwada cases where the chain extender has enzyme recognizable side Biomedical. groups, the access of water to the Surface of the matrix should 0288 The polyurethane materials disclosed herein may be increase the rate at which the enzyme can catalyze the reac used in a number of different forms and in a range of appli tion between water and the hydrolyzable cleavage sites. cations, both in the biomedical field and others. The material 0283. The number of cleavage sites also influences biode can be fabricated by casting or other molding techniques to gradability. The higher the number of sites generally, the form a substrate, which can be used alone or combined with greater the rate of degradation. Typically, the cleavable site is other Substrates to form homogenous multi-layered materi an ester site. For example, the cleavable ester site can be als. Such multilayered homogeneous polyurethane materials adjacent one or more amino acids. This provides segmented may be formed with layers having different degrees of polyurethanes with cleavable sites in its chain extender that degradability. Such substrates may range in thickness from may be engineered to be recognizable by an enzyme. In this about 1 micron to about 5 millimeters for applications suit embodiment of the invention, the rate of degradation is con able for skin repair and the like, and more particularly from trolled to achieve a desired therapeutic indication. about 10 microns to about 3.5 millimeters, and still more 0284. In another embodiment, the diisocyanate is reacted particularly from about 50 microns to about 2 millimeters. with the polyol under suitable conditions to form a prepoly The thinner the substrate, the more care is needed in handling mer; the prepolymer is then reacted with the chain extender, it. again under Suitable conditions, to form the polyurethane. 0285 Alternatively, multi-functional components can be 0289 Forbone regeneration and the like, the polyurethane employed to produce a cross-linked network, and hence non material may range in thickness from about 1 cm to about 5 linear, segmented polyurethane. This could be achieved by cm or more, depending on the specific application, including the use of a branched complex bearing more than two the dimensions of the bone being regenerated. hydroxyl groups, such as for example a triol, for example. In 0290. In another embodiment, the present invention pro another case, certain amino acids may also contribute to the vides polymers that can be used as a pharmaceutical carrier in formation of a networked polymer. Lysine for example, hav a drug delivery matrix. The matrix is formed by mixing the ing an amine group on its side chain, may be reacted with Such polymer with a therapeutic agent. sites as a isocyanate group on the diisocyanate. Additionally, 0291. A variety of different therapeutic agents can be used several lysines may be present in the amino acid segment in conjunction with the polymers of the invention. In general, thereby providing potential bonding sites between each cor therapeutic agents administered via the pharmaceutical com responding amine and another site such as an isocyanate positions of the invention include, without limitation antiin group. Thus, such multi-functional components readily allow fectives Such as antibiotics and antiviral agents; analgesics for the formation of nonlinear segmented polyurethanes. and analgesic combinations; anorexics; antihelmintics; anti 0286. In another embodiment, substantially non-toxic arthritics; anti-asthmatic agents; anticonvulsants; antidepres degradable polyurethanes can be formed from amino acids sants; antidiuretic agents; antidiarrheals; antihist-amines; and Substantially non-toxic diols, in Such a manner, to be antiinflammatory agents; antimigraine preparations; antinau useful as biomaterials for a variety of applications such as seants; antineo-plastics; antiparkinsonism drugs; antiprurit artificial skin, wound dressings, tissue engineering scaffolds ics; antipsychotics; antipyretics, antispas-modics; anticholin and the like. The polyurethane materials may be formed by ergics; sympathomimetics; Xanthine derivatives; melt or solvent processing techniques such as dissolving the cardiovascular preparations including calcium channel polymer into a solvent, pouring the mixture onto a flat sheet or blockers and beta-blockers such as pindolol and antiarrhyth into a mold and evaporating the solvent, with the polymer mics; antihypertensives: diuretics; vasodilators including remaining therein. Other melt processing techniques may be general coronary, peripheral and cerebral; central nervous available by melting a blank of polyurethane and manipulat system stimulants; cough and cold preparations, including ing it into a shape as desired, including tubes or fibers. Porous decongestants; hormones Such as estradiol and other steroids, polyurethane may be formed in a number of ways, including including corticosteroids; hypnotics; immunosuppressives; the addition of a gas (typically carbon dioxide) into the poly muscle relaxants; para-sympatholytics; psychoStimulants; merization reaction, and trapping the gas into the polymer sedatives; tranquilizers; and naturally derived or genetically structure. Alternatively, salt crystals can be added to the sol engineered proteins, polysaccharides, glycoproteins or lipo vent polymer mixture during casting wherein the salt is not proteins. US 2015/0259464 A1 Sep. 17, 2015

0292. The drug delivery matrix may be administered in (0309 1. staples, any suitable dosage form such as oral, parenteral, Subcutane 0310 m. hooks, buttons, and snaps, ously as an implant, vaginally or as a Suppository. Matrix formulations containing polymers of the invention is formu 0311 n. bone substitutes (e.g., mandible prosthesis), lated by mixing one or more therapeutic agents with the 0312 o. intrauterine devices (e.g., spermicidal devices), polymer. The therapeutic agent may be present as a liquid, a 0313 p. draining or testing tubes or capillaries, finely divided solid, or any other appropriate physical form. 0314 q. Surgical instruments, Typically, the matrix will include one or more additives, e.g., 0315 r. vascular implants or supports, nontoxic auxiliary Substances Such as diluents, carriers, excipients, stabilizers or the like. However, the presence of 0316 s. vertebral discs, such additives is entirely optional. Other suitable additives 0317 t, extracorporeal tubing for kidney and heart-lung may be formulated with the polymers of this invention and machines, pharmaceutically active agents or compounds, however, if 0318 u. artificial skin, and the like. water is to be used it should be added immediately before 0319. The polyurethanes, polyureas, polyesterurethanes, administration. polyamides, polyesteramides of the invention may be formed 0293. The amount of therapeutic agent will be dependent into Surgical articles using any known technique, Such as, for upon the particular drug employed and medical condition example, extrusion, molding and/or solvent casting. The being treated. Typically, the amount of drug represents about polyurethanes, polyureas, polyesterurethanes, may be used 0.001% to about 70%, more typically about 0.01% to about alone, blended with other bioabsorbable compositions, or in 50%, and most typically about 0.1% to about 20% by weight combination with non-bioabsorbable components. A wide of the matrix. variety of Surgical articles may be manufactured from the 0294 The quantity and type of polymer incorporated into polyurethanes, polyureas, polyamideurethanes, and/or poly a parenteral dosage form will vary depending on the release ureaurethanes described herein. These include but are not profile desired and the amount of drug employed. The product limited to clips and other fasteners, staples, Sutures, pins, may contain blends of polymers of this invention to provide screws, prosthetic devices, wound dressings or coverings, the desired release profile or consistency to a given formula burn dressings or coverings, drug delivery devices, anasto tion. mosis rings, stents, stent coatings, films, scaffolds, polyure 0295 The polymers of this invention, upon contact with thane foams, reticulated foams and other implantable medical body fluids including blood or the like, undergoes gradual devices. Examples of medical implantable devices include degradation (mainly through hydrolysis) with concomitant prosthetic devices, stents, Sutures, staples, clips and other release of the dispersed drug for a Sustained or extended fasteners, screws, pins, films, meshes, drug delivery devices period (as compared to the release from an isotonic saline or systems, anastomosis rings, Surgical dressings and the like. Solution). This can result in prolonged delivery (over one to In some preferred embodiments, the Surgical articles or com 2,000 hours, including 2 to 800 hours) of effective amounts ponents thereof include stents, stent coatings, wound cover (0.0001 mg/kg/hour to 10 mg/kg/hour) of the drug. This ings, burn coverings, foams, tissue engineering scaffolds, dosage form can be administered as necessary depending on films, implantable medical devices, and/or controlled drug the subject being treated, the severity of the affliction, the delivery systems, more preferably stents, stent coatings, judgment of the prescribing physician, and the like. wound and/or burn coverings, and/or controlled delivery sys 0296 Individual formulations of drugs and polymers of tems. In certain other preferred embodiments, the Surgical this invention may be tested in appropriate in vitro and/or in articles or components thereof include Sutures, ligatures, vivo models to achieve the desired drug release profiles. For needle and Suture combinations, Surgical clips, Surgical example, a drug could be formulated with a polymer of this Staples, Surgical prosthetic devices, textile structures, cou invention and orally administered to an animal. The drug plings, tubes, Supports, screws, or pins. In certain preferred release profile is monitored by appropriate means, such as by drug delivery systems, the systems comprise a polyurethane, taking blood samples at specific times and assaying the polyurea, polyamideurethane, and/or polyureaurethane in samples for drug concentration. Following this or similar admixture with a biologically or pharmaceutically active procedures, those skilled in the art are able to formulate a agent. Non-limiting examples of polymeric carriers in Such variety of formulations having the desired release profile. drug delivery systems and/or pharmaceutical compositions 0297. The polyurethanes, polyureas, polyamideurethanes, include self-supporting films, hollow tubes, beads, and/or and/or polyureaurethanes of the invention may beformed into gels. Other preferred uses of the surgical articles include their various articles for Surgical and medical uses including, with use as Scaffolds for tissue engineering comprising a porous out limitation: structure for the attachment and proliferation of cells. 0298 a... burn dressings, 0320 Additional examples of the surgical and medical 0299 b. hernia patches, uses of the filaments, films, and molded articles of the present 0300 c. medicated dressings, invention include knitted products, woven or non-woven, and 0301 d. fascial substitutes, molded products including, burn dressings, hernia patches, 0302 e. gauze, fabric, sheet, felt or sponge for liver hemo medicated dressings, facial Substitutes, gauze, fabric, sheet, Stasis, felt or sponge for liver homeostasis, gauze bandages, arterial 0303 f. gauze bandages, graft or Substitutes, bandages for skin Surfaces, Suture knot 0304 g. arterial graft or substitutes, clip, orthopedic pins, clamps, screws, and plates, clips (e.g., 0305 h. bandages for skin surfaces, for Vena cava), staples, hooks, buttons, and Snaps, bone Sub 0306 i. Suture knot clip, stitutes (e.g., mandible prosthesis), bone Void fillers, bone 0307 j. Orthopedic pins, clamps, screws, and plates, cements, intrauterine devices (e.g., spermicidal devices), 0308 k. clips (e.g., for vena cava), draining or testing tubes or capillaries, Surgical instruments, US 2015/0259464 A1 Sep. 17, 2015 34 vascular implants or Supports, Vertebral discs, extracorporeal deurethanes, and/or polyureaurethanes described herein. tubing for kidney and heart-lung machines, artificial skin and Examples of Such medico-Surgically useful Substances others. include, for example and without limitation, those which 0321. The polyurethanes, polyureas, polyamideurethanes, accelerate or beneficially modify the healing process when and/or polyureaurethanes disclosed herein may also be used particles are applied to a Surgical repair site. For example, to fabricate degradable containers and packaging materials articles made from compositions containing the presently which can degrade in landfills in contrast to existing non disclosed polyurethanes, polyureas, polyamideurethanes, degradable materials which present environmental concerns. and/or polyureaurethanes may carry a therapeutic agent 0322 The polyurethane material is believed to be espe which will be deposited at the repair site. The therapeutic cially useful for use as a tissue engineering scaffold, i.e., as a agent may be chosen for its antimicrobial properties, capabil structure for the growth or regeneration of tissue. Polyure ity for promoting repair or reconstruction and/or new tissue thanes may lend themselves to Such uses since enzyme-cata growth. Antimicrobial agents such as broad spectrum antibi lyzed degradation may in some cases occur concurrently with otics, for example and without limitation, gentamycin Sulfate, the migration or growth of cells into the material, while desir erythromycin, or derivatized glycopeptides which are slowly ably degrading in the process into its Substantially non-toxic released into the tissue, may be applied in this manner to aid constituents. It is also possible, in Some cases, that cells in combating clinical and Sub-clinical infections in a tissue migrating into or located adjacent the matrix may themselves repair site. To promote repair and/or tissue growth, one or exude proteolytic enzymes that will mediate hydrolytic cleav several growth promoting factors may be introduced into the age. articles, e.g., fibroblast growth factor, bone growth factor, 0323 Such tissue engineering scaffolds may have appli epidermal growth factor, platelet-derived growth factor, mac cations in the regeneration of skin and other organs, bone, rophage-derived growth factor, alveolar-derived growth fac cartilage, ligaments, tendons, bladder and other tissues. The tor, monocyte-derived growth factor, magainin, and the like. polyurethane material may also be useful in the production of Examples of therapeutic indications include, without limita Sutures, which require good mechanical strength, as well as in tion, glycerol with tissue or kidney plasminogen activator to the production of drug release matrices, in view of their need cause thrombosis, Superoxide dismutase to Scavenge tissue for degradation to non-toxic materials. The polyurethane damaging free radicals, tumor necrosis factor for cancer material may also be useful for non-biomedical applications, therapy or colony stimulating factor and interferon, interleu where degradability into Substantially non-toxic constituents kin-2 or other lymphokine to enhance the immune system. is an asset. The polyurethane material lends itself to steriliza 0328. In another embodiment, branched or linear bioas tion by Such techniques as gamma radiation and ethylene borbable polyurethanes and the like of the present invention oxide treatments. may also be derived from diisocyanates based on 0324 Fibers made from the present polyurethanes, poly cycloaliphatic amino acids such as aminocyclohexanecar ureas, polyamideurethanes, and/or polyureaurethanes can be boxylic acid as well as cycloaliphatic amino alcohols such as knitted or woven with other fibers, either bioabsorbable or aminocyclohexanol. Polyurethanes and the like from these non-bioabsorbable, to form meshes or fabrics. Compositions diisocyanates can be prepared according to the procedures including these polyurethanes, polyureas, polyamideure described in U.S. Patent Application Publication Nos. thanes, and/or polyureaurethanes may also be used as bioab 20060188547, 20090292029, European Patent Publication Sorbable coatings for Surgical devices. No. EP 1937182 and WO 2007030464. Polyurethanes and the 0325 Another embodiment of the invention is directed to like resulting from cycloaliphatic amino acids as well as compositions containing the polyurethanes, polyureas, cycloaliphatic amino alcohols will find use in a variety of polyamideurethanes, and/or polyureaurethanes described applications including biomedical applications wherein con herein which may be used to make reinforced composites. trolled hydrolytic degradation is desired. Thus, for example, the polyurethane, polyurea, polyami 0329. In another embodiment, absorbable polyester deurethane, and/or polyureaurethane composition may form amides can be prepared by reaction of amide diols, and/or the matrix of the composite and may be reinforced with bioasborbable polyols, with diacids including but not limited bioabsorbable or non-bioabsorbable fibers or particles. Alter to oxalic acid, Succinic acid, malonic acid, butanedioic acid, natively, a matrix of any bioabsorbable or non-bioabsorbable adipic acid, azelaic acid, sebacic acid, diglycolic acid, 3.6- polymer composition may be reinforced with fibers or par dioxaoctanedioic acid, 3.6.9-trioxaundecanoic acid, func ticulate material made from compositions containing the tionalized Oxaacids, polyethyleneglycol diacids of average polyurethanes, polyureas, polyamideurethanes, and/or poly molecular weight from 300 to 2000 and blends thereof. ureaurethanes described herein. 0330. In another embodiment, bioasborbable polyamides 0326 In another embodiment, the polyurethanes, poly will be prepared by reaction of diamines with diacids includ ureas, polyamideurethanes, and/or polyureaurethanes ing but not limited to oxalic acid. Succinic acid, malonic acid, described herein may be admixed with filler. The filler may be butanedioic acid, adipic acid, azelaic acid, sebacic acid, dig in any particulate form, including granulate or staple fibers. lycolic acid, 3,6-dioxaoctanedioic acid, 3.6.9-trioxaunde While any known filler may be used, hydroxyapatite, trical canoic acid, functionalized Oxaacids, polyethyleneglycol cium phosphate, bioglass or other bioceramics are the pre diacids of average molecular weight from 300 to 2000 and ferred fillers. Normally, from about 10 grams to about 400 blends thereof. grams of filler are mixed with about 100 grams of polymer. 0331. The monomers of the present invention can be poly The filled, cross-linked polymers are useful, for example, as merized to form absorbable polymers (e.g., polyesters, polya molding compositions. mides, polyester amides, polyurethanes, and polyanhy 0327. It is further contemplated that one or more medico drides). It can be advantageous for the monomers that are to Surgically useful Substances may be incorporated into com be polymerized to have at least two active sites (e.g., 2 or 3) positions containing the polyurethanes, polyureas, polyami for polymerization. These active sites include amino, isocy US 2015/0259464 A1 Sep. 17, 2015 anate and carboxylic acid groups. The monomers with at least 0334. The drug delivery matrix may be administered in two active sites can also be copolymerized with selected any suitable dosage form such as oral, parenteral, Subcutane difunctional molecules (e.g., dicarboxylic acids, dialcohols, ously as an implant, vaginally or as a Suppository. Matrix diisocyanates, amino-alcohols, hydroxy-carboxylic acids, formulations containing polymers of the invention may be and diamines) based on the starting functionalized amino acid formulated by mixing one or more therapeutic agents with the to form bioasborbable polymers. The polymers (and copoly polymer. The biologically active agent may be present as a mers) of the present invention can also be further reacted/ liquid, a finely divided solid, or any other appropriate physi polymerized to form additional useful polymers of the cal form. Typically, the matrix will include one or more addi present invention. tives, e.g., nontoxic auxiliary Substances Such as diluents, carriers, excipients, stabilizers or the like. However, the pres 0332. It would be readily apparent to one of ordinary skill ence of such additives is optional. Other suitable additives in the art once armed with the teachings in the present appli may be formulated with the polymers of this invention and cation that the diisocyanates of the present invention may be pharmaceutically active agent or compound. If water is to be reacted with a variety of reactants that are typically employed used as an additive, it is preferably be added immediately in the preparation of bioabsorbable and biocompatible poly before administration. urethanes and/or polyester urethanes, preferably with tunable 0335 The amount of biologically active agent will be physical, mechanical properties and/or hydrolytic degrada dependent upon the particular agent employed and medical tion profiles. It would also be apparent to the ordinarily condition being treated. Typically, the amount of drug repre skilled artisan that the terminal groups for given polyure sents about 0.001% to about 70%, more typically about thane, or polyester may be derivatized by further reacting the 0.01% to about 50%, and most typically about 0.1% to about polyurethane and/or polyesters with additional derivatizing 20% by weight of the matrix. agents. Polyurethanes terminated with —NCO or hydroxyl 0336. The quantity and type of polymer incorporated into groups can be prepared by varying the ratio of isocyanates: a parenteral dosage form will vary depending on release hydroxyl groups in the reaction mixture i.e. (isocyanates, profile desired and the amount of drug employed. The product chain extender and polyol). Polyurethanes with high molecu may contain blends of polymers of this invention to provide lar weights are formed when the ratio of isocyanates: hy the desired release profile or consistency to a given formula droxyl group is 1. Furthermore, by varying the ratio of iso tion. cyanates: hydroxyl groups in the reaction mixture, 0337 The polymers of this invention, upon contact with polyurethanes with tunable physical and mechanical proper body fluids including blood or the like, undergo gradual deg ties can be obtained. It would also be apparent to the ordi radation (mainly through hydrolysis) with concomitant narily skilled artisan that the terminal groups for given poly release of the dispersed drug for a Sustained or extended urethane, or polyester may be derivatized by further reacting period (as compared to the release from an isotonic saline the polyurethane and/or polyesters with additional derivatiz solution). This may result in prolonged delivery (over about ing agents. one to about 2,000 hours, preferably about two to about 800 0333. The polymers of the present invention may be used hours) of effective amounts (including, for example, about as pharmaceutical carriers in a drug delivery matrix, i.e., a 0.0001 mg/kg/hour to about 10 mg/kg/hour) of the drug. This matrix for a biologically active Substance (i.e., agent). The dosage form may be administered as necessary depending on matrix may be formed by mixing the polymer with a biologi the subject being treated, the severity of the affliction, the cally active agent. The biologically active agent can be dis judgment of the prescribing physician, and the like. persed into the polymer Solution for example during prepa 0338 Individual formulations of drugs and polymers of ration of matrix or via melt blending. A vast variety of this invention may be tested in appropriate in vitro and in vivo different biologically active agents may be used in conjunc models to achieve the desired drug release profiles. For tion with the polymers of the invention. In general, therapeu example, a drug may be formulated with a polymer of this tic agents administered via the pharmaceutical compositions invention and administered to an animal (e.g., orally). The of the invention include, without limitation: anti-infectives drug release profile may be monitored by appropriate means, Such as antibiotics and antiviral agents; analgesics and anal Such as by taking blood samples at specific times and assaying gesic combinations; anorexics; anti-helmintics; anti-arthrit the samples for drug concentration. Following this or similar ics; anti-asthmatic agents; anticonvulsants; antidepressants; procedures, those skilled in the art may formulate a variety of anti-diuretic agents; anti-diarrheals; anti-histamines; anti-in formulations. flammatory agents; anti-migraine preparations; anti-nause 0339. It is further contemplated that one or more medico ants; anti-neoplastics; anti-parkinsonism drugs; anti-prurit Surgically useful Substances (biologically active agents) may ics; anti-psychotics; anti-pyretics, anti-spasmodics; anti be incorporated into compositions containing the bioasborb cholinergics; sympathomimetics: Xanthine derivatives; able polyurethanes and/or polyester amides described herein. cardiovascular preparations including calcium channel Examples of Such biologically active agents include, for blockers and beta-blockers such as pindolol and anti-arrhyth example, those which accelerate or beneficially modify the mics; anti-hypertensives; diuretics; vasodilators including healing process when particles are applied to a Surgical repair general coronary, peripheral and cerebral; central nervous site. For example, articles made from compositions contain system stimulants; cough and cold preparations, including ing the present polyurethanes and/or polyesters may carry a decongestants; hormones Such as estradiol and other steroids, therapeutic agent which will be deposited at the repair site. including corticosteroids; hypnotics; immunosuppressives; The biologically active agent may be chosen for its antimi muscle relaxants; para-sympatyholytics; psychoStimulants; crobial properties, capability for promoting repair or recon sedatives; and tranquilizers; and naturally derived or geneti struction and/or new tissue growth. Antimicrobial agents cally engineered proteins, polysaccharides, glycoproteins or Such as broad spectrum antibiotic, for example, gentamycin lipoproteins. Sulfate, erythromycin, or derivatized glycopeptides which are US 2015/0259464 A1 Sep. 17, 2015 36 slowly released into the tissue may be applied in this manner edrine, picotamide, pimobendan, prenalterol, primaquine, to aid in combating clinical and Sub-clinical infections in a progabide, propanidid, protokylol, proxymetacaine, ralox tissue repair site. To promote repair and/or tissue growth, one ifene hydrochloride, repaglinide, reproterol, rimiterol, rito or several growth promoting factors may be introduced into drine, Salacetamide, Salazosulfapyridine, Salbutamol, salicy the articles, e.g., fibroblast growth factor, bone growth factor, lamide, Salicylic acid, salmeterol, Salsalate, sildenafil. epidermal growth factor, platelet derived growth factor, mac silibinin, Sulmetozin, tamsulosin, teraZosin, terbutaline, rophage derived growth factor, alveolar derived growth fac tetroxoprim, theodrenaline, tioclomarol, tioXolone, alpha-to tor, monocyte derived growth factor, magainin, and the like. copherol (vitamin E), tofisopam, tolcapone, tolterodine, tra Some therapeutic indications are: glycerol with tissue or kid nilast, tretoquinol, triclosan, trimaZosin, trimetazidine, tri ney plasminogen activator to cause thrombosis, Superoxide methobenzamide, trimethoprim, trimetozine, trimetrexate dismutase to scavenge tissue damaging free radicals, tumor glucuronate, troXipide, Verapamil, Vesnarinone, Vetrabutine, necrosis factor for cancertherapy or colony stimulating factor Viloxazine, warfarin, Xamoterol. and interferon, interleukin-2 or other lymphokine to enhance 0342. Other biologically active phenolics that can be used the immune system. include acacetin, 4-acetamido-2-methyl-1-naphthol, 0340. It is contemplated that it may be desirable to dye acetaminophen, albuterol, allenolic acid, aloe emodin, aloin, articles made from compositions containing the present B-amino-4-hydroxy-3,5-di-iodohydrocinnamic acid, N-(5- branched bioasborbable polyurethanes and/or polyesters in amino-2-hydroxyphenyl)-benzeneacetamide, 4-amino-1- order to increase visibility of the article in the surgical field. naphthol, 3-aminosalicylic acid, 4-aminosalicylic acid, anac Dyes, such as those known to be suitable for incorporation in ardic acid, p-anol, anthragallol, anthralin, anthranol, sutures, may be used. Such dyes include but are not limited to anthrarobin, anthrarufin, apigenin, apiin, apocynin, aspidi carbon black, bone black, D&C Green No. 6, and D&C Violet nol, aspirin, baptigenin, benzestrol, benzoresorcinol, bisphe No. 2 as described in the handbook of U.S. Colorants for nol a, bisphenol b, butylated hydroxylanisole, butylated Food, Drugs and Cosmetics by Daniel M. Marrion (1979), the hydroxytoluene, capobenic acid, trans-1-(3'-carboxy-4-hy disclosures of which are hereby incorporated herein by ref droxyphenyl)-2-(2".5"-dihydroxyphenyl)ethane, catechin, erence, in their entireties. Preferably, articles in accordance chlorogenic acid, m-chlorophenol, 5-chloro-8-quinolinol, with this disclosure may be dyed by adding up to about a few chloroxylenol, chlorquinaldol, chromo-nar, chrysin, percent and preferably about 0.2% dye to the resin composi cinametic acid, clorophene, coniferyl alcohol, p-coumaric tion prior to extrusion. acid, coumes-trol, coumetarol, daphnetin, datiscetin, deox 0341 Biologically active hydroxy compounds that can be yepinephrine, 3,5-diiodothyronine, 3,5-di-iodotyrosine, used as a pendant group or covalently bonded to the amino dimethophrine, dioSmetin, diresorcinol, disoprofol, dopa, acid of present invention of the present invention include dopamine, drosophilin a, efloxate, ellagic acid, embelin, acenocoumarol, acetarsol, actinoquinol, adrenalone, aliben Equol. eriodictyol, esculetin, esculin, ethylnorepinephrine, dol, amodiaquine, anethole, balsalazide, bamethan, benser ethyl Vanillin, eugenol, eupatorin, fenadiazole, ferulic acid, azide, bentiromide, benzarone, benzquinamide, bevantolol. fisetin, 3-fluoro-4-hydroxyphenylacetic acid, fraxetin, fustin, bifluranol, buclosamide, bupheniode, chlorotrianisene, galangin, gallacetophe-none, gallic acid, gardenins, chloroxylenol, cianidanol, cinepazide, cinitapride, genistein, gentisyl alcohol, gepefrine, geranylhydroqui-none, cinepazide, cinmetacin, clebopride, clemastine, clioquinol, 6-gingerol, gossypol, guaiacol, guaifenesin, harmalol, cyclovalone, cynarine, denopamine, dextroy thyroxine, hematoxylin, hinderin, homoeriodictyol, homogentisic acid, diacerein, dichlorophen, dienestrol, diethylstilbestrol, homoVanillic acid, hydroxyamphetamine, 2-hydroxy-5-(2,5- diflunisal, diiodohydroxyquinoline, dilaZep, dilevalol, dihydroxybenzylamino)-2-hydroxybenzoic acid, 4-hydroxy dimestrol, dimoxyline, dioSmin, dithranol, dobutamine, 3-methoxy-mandelic acid, n-(p-hydroxyphenyl)glycine, donepezil, dopamine, dopexamine, doxazosin, entacapone, hydroxyprocaine, 8-hydroxyquinoline, hypericin, irigenin, epanolol, epimestrol, epinephrine, estradiol Valerate, estriol, isoproterenol, isoquercitrin, isothebaine, kaempferol, liothy estriol Succinate, estrone, etamivan, etamsylate, ethaverine, ronine, luteolin, mangostin, 5.5'-methylenedisalicylic acid, ethoXZolamide, ethyl biscoumacetate, etillefrine, etiroXate, n-methylepinephrine, metyrosine, morin, mycophenolic exalamide, exifone, fendosal, fenoldopam mesilate, fenot acid, myricetin, naringenin, nylidrin, orcinol, osalmid, ost erol, fenoxedil, fenticlor, flopropione, floredil, fluorescein, hole, oxantel, paroxypropione, pentachlorophenol, 3-penta folescutol, formoterol, gallopamil, gentistic acid, glaziovine, decylcatechol, p-pentyloxy-phenol, phloretin, phlorogluci glibenclamide, glucametacin, guajacol, halquinol, hexachlo nol, pinosylvine, plumbagin, pyrocatechol, pyrogallol, rophene, hexestrol, hexobendine, hexoprenaline, hexylresor quercetagetin, quercetin, resacetophenone, rhamnetin, rhein, cinol, hydroxyethyl salicylate, hydroxystilbamidineisethion Sakuranetin, Salicyl alcohol, salicylanilide, 4-salicyloylmor ate, hymecromone, ifenprodil, indomethacin, ipriflavone, pholine, Salsalate, Scopoletin, Scutellarein, serotonin, (3,4,5- isoetarine, isoprenaline, isoxSuprine, itopride hydrochloride, trihydroxyphenyl)methylenepropanedinitrile, thymol, thyro ketobemidone, khellin, labetalol, lactylphenetidin, levodopa. propic acid, thyroXine, tiratricol, tyrosine, Vanillic acid, and levomepromazine, levorphanol, levothyroxine, mebeverine, vanillin. medrylamine, mefexamide, mepacrine, mesalazine, mestra 0343 Further biologically active carboxylic acid and/or nol, metaraminol, methocarbamol, methoxamine, methox amine compounds that can be used as a pendant group or salen, methyldopa, midodrine, mitoxantrone, morclofone, covalently bonded to the amino acid of the present invention nabumetone, naproxen, nitroxoline, norfenefrine, normo include Acemetacin, Aceclofenac, Acediasulfone, Adipi laxol, octopamine, omeprazole, orciprenaline, OXilofrine, odone, Alminoprofen, Amisulpride, AmlexanoX, Amodi oxitriptan, oxyfedrine, oxypertine, oxyphenbutaZone, aquine, Amosulalol. Amoxicillin, Amsacrine, Anileridine, oxyphenisatin acetate, oxyquinoline, papaverine, paracet AZacyclonol, Baccofen, Balsalazide Sodium, Bentiromide, anol, parethoxycaine, phenacaine, phenacetin, phenazocine, Benzocaine, Bromopride, Bumetanide, Carprofen, phenolphthalein, phenprocoumon, phentolamine, phlo Carvedilol, Carzenide, Cefprozil, Cinitapride, Cinmetacin, US 2015/0259464 A1 Sep. 17, 2015 37

Clebopride, Clenbuterol, Clometacin, Cromoglicic acid, Carzenide, Diclofenac, Flufenamic acid, Furosemide, Ioben Diclofenac, Diflunisal, Eprosartan, EthoXZolamide, Fen Zamic acid, locetamic acid, and Mefenamic acid. dosal, Flufenamic acid, Furosemide, Ibuprofen, Indometacin, Iobenzamic acid, locarmic acid, locetamic acid, lodoxamic 0351 Examples of biologically active diamino com acid, loglycamic acid, lophenoic acid, lotroXic acid, Mefe pounds useful in the present invention include Amisulpride, namic acid, Nadoxolol, Naproxen, Nedocromil, D-Norpseu Amodiaquine. Amosulalol, Amoxicillin, Amsacrine, AZacy doephedrine, paracetamol Repaglinide, Salazosulfapyridine, clonol, Bromopride, Carvedilol, Cefprozil, Cinitapride, Salicylic Acid, Salsalate and Sarpogrelate. Clebopride, Nadoxolol, 0344 Examples of biologically active dihydroxy com Clenbuterol, EthoXZolamide, pounds that can be used to as a pendant group or covalently D-Norpseudoephedrine, amino acids (L-lysine), and natural bonded to the amino acid of present invention of present products. invention include Adrenalone, Alfuzosin, Alibendol, Amru 0352 Examples of naturally occurring biologically active bicin, Apomorphine, Bamethan, BenZquinamide, Bevan tolol, Bifluranol, Bisacodyl, Brodimoprim, Bunazosin, phenolics include bergaptol, caffeic acid, capsaicin, cou Bupheniode, Carbidopa, Carbuterol, Cyclofenil, Cyclova marin, daidzein, 2.5-dihydroxy-benzoic acid, ferulic acid, lone, Daunorubicin, Dichlorophen, Dienestrol, Diethylstil flavonoids, glycitein (isoflavone), 4-hydroxycinnamic acid, bestrol, Dimestrol, Dithranol, Donepezil, Doxefazepam, 4-hydroxy-coumarin, isopimpinellin, resveratrol, synapic Doxorubicin, Entacapone, Epinepheine, Epirubicin, Esome acid, Vanillic acid, Vanillin, chalcones, soybean flavonoids prazole, Etamivan, Etamsylate, Etilefrine, EZetimibe, Fenti and derivatives thereof. clor, Fluorescein, Folescutol, Formoterol, Gefitinib, Hex estrol, Hexylresorcinol, Hydroxyethyl salicylate, Ifenprodil, 0353 Capsaicin is a biologically active phenolic that is the Isoetarine, IsoxSuprine, Itopride. HCl, Khellin, Labetalol, active component of cayenne pepper. The capsaicin is an Mitoxantrone, Morclofone, Moxaverine, Normolaxol, Ome amide of Vanillylamine and Cs to C branched fatty acids. prazole, Oxilofrine, Oxepertine, Phenacaine, Phenolphtha Topical application of capsaicin stimulates and blocks Small lein, PraZosin, Tolcapone, Vesnarinone, and Vetradutine. 0345 Examples of biologically active diamino com pain fibers by depleting them of the neurotransmitter sub pounds that can be used as a pendant group or covalently stance P that mediates pain impulses. A cream made from bonded to the amino acid of present invention of present 0.025%-0.075% capsaicin applied 4x daily may help periph invention include Amisulpride. Amodiaquine. Amosul-alol, eral neuropathic pain, post-herpetic neuralgia, trigeminal Amoxicillin, Amsacrine, AZacyclonol, Bromopride, neuralgia, psoriasis and fibromyalgia. It is also useful for Carvedilol, Cefprozil, Cinitapride, Clebopride, Clenbuterol, diabetic neuropathy, cluster headaches, earache, osteo- and EthoXZolamide, Nadoxolol, and D-Norpseudoephedrine. rheumatoid arthritis. Capsaicin is a powerful pain reliever. 0346 Examples of biologically active hydroxy/amino compounds that can be used as a pendant group include 0354 Naproxen, paracetamol, acetaminophen and acetyl Amisulpride. Amodiaquine. Amosulalol. Amoxicillin, Amsa salicylic acid are biologically active phenolics that belong to crine, Azacyclonol, Bromopride, Carvedilol, Cefprozil, Cini the class of drugs called non-steroidal anti-inflammatory tapride, Clebopride, Clenbuterol, Ethoxzolamide, Nadox drugs or NSAIDs. The NSAIDs provide reliefby blocking the olol, D-Norpseudo-ephedrine, and paracetamol. action of prostaglandins, which are hormone-like Substances 0347 Examples of biologically active dicarboxylic acid that contribute to pain, inflammation, fever and muscle compounds that can be used as a pendant group or covalently cramps. Phenolic moieties, synthetic and naturally occurring, bonded to the amino acid of present invention of present are part of many drugs. invention include Adipiodone, Cromoglicic acid, Eprosartan, 0355 The compounds employed in the methods of the locarmic acid, lodoxamic acid, loglycamic acid, lotroXic acid, present invention may be prepared in a number of ways well Nedocromil. known to those skilled in the art. The compounds may be 0348 Examples of biologically active hydroxy/carboxylic synthesized, for example, by the methods described below, or acid compounds that can be used as a pendant group or variations thereon as appreciated by the skilled artisan. All covalently bonded to the amino acid of present invention processes disclosed in association with the present invention include Acemetacin, Bentiromide, Cinmetacin, Clometacin, are contemplated to be practiced on any scale, including Diflunisal, Fendosal, Indometacin, lophenoic acid, milligram, gram, multigram, kilogram, multikilogram or Naproxen, Repaglinide, Salazosulfapyridine, Salicylic Acid, commercial industrial scale. Salsalate, and Sarpogrelate. 0349 Examples of biologically active hydroxyl-acids for 0356. The surgical articles, component thereof, polymeric use as the pendant group or covalently bonded to the amino carrier, or the like can comprise a polymerformed by reacting acid of present invention include 4-hydroxycinnamic acid, an amine of one of the invention with an isocyanate, carboxy caffeic acid, chlorogenic acid, ferulic acid, Sinapic acid, van lic acid, activated carboxylic acid, or epoxide, or an isocyan illic acid, Acemetacin, Bentiromide, Cinmetacin, Clometa ate of the invention with an amine, alcohol, aminoalcohol, cin, Diflunisal, Fendosal, Indometacin, lophenoic acid, thiol or combination thereof, or a carboxylic acid of the Naproxen, Repaglinide, Salazosulfapyridine, Salicylic Acid, invention with an alcohol, amine or combination thereof. Salsalate, and Sarpogrelate. 0357 The following examples are included to further 0350 Examples of useful biologically active amino?car illustrate the invention and are not to be considered as limiting boxylic acid compounds that can be used as a pendant group the invention anyway. Melting points were measured for all of present invention include Aceclofenac, Acediasulfone, products by using a Polmon (MP96) melting point apparatus. Alminoprofen, Amlexanox, Anileridine, Baccofen, Bal For all the products, NMR was run using a Varian 200 MHz Salazide Sodium, Benzocaine, Bumetanide, Carprofen, and tetramethylsilane as an internal standard. US 2015/0259464 A1 Sep. 17, 2015 38

EXAMPLES Example 1 Diisocyanate from Ricinoleic acid, 4-nitro-benzoic acid, and 4-nitro phenol 0358

OH

O

21 OH ON

4-Nitro benzoyl chloride

O

SOCl.

ON

4-Nitro phenol

NO

21 O O 1 C ON

O O Reduction US 2015/0259464 A1 Sep. 17, 2015 39

-continued NH2

21 UOO HN

O O Triphosgene 1,4-Dioxane

NCO

21 UOO OCN

O O

Example 1A Example 1B Synthesis of 4-Nitro Benzoyl Chloride Synthesis of Ricinoleic Acid Mono Nitro Acid 0359 0361

O 4-Nitro benzoyl 21 OH chloride, TEA, Acetone COOH COC Hs

SOCl2.Hexane OH Hos O

21 OH NO NO ON

O

O 0360 Thionyl chloride (3.0 L) was added drop wise to 4-Ntro benzoic acid (1.5 kg) at ambient temperature under 0362. To a mixture of ricinoleic acid (1600g), triethy nitrogen atmosphere and heat the mass to reflux and main lamine (1100 mL) in acetone (6 L) at 0-5°C., was added tained for 6 hours at which time TLC shown completion of the 4-nitro benzoyl chloride (1200 g). It was stirred at room reaction. Then distilled out completely excess Thionyl chlo temperature for 16 hours. After the reaction was completed ride under reduced pressure, remove the traces with dichlo then the total reaction mass was poured onto coldwater (12 L) romethane as co solvent under reduced pressure at 55-60° C. and extracted with ethyl acetate (6 liter) and combined total organic layers and washed with 15% NaHCO solution (IL) The resulted residue was precipated with petroleum ether (3 and 15% NaCl solution (1.0 L) followed by water washing L) at 5-10° C. and stirred for 30 minutes at 5-10° C. The (1.0 L), then dry the organic layer with sodium Sulphate and resulting solid was filtered and kept under nitrogen and dried distilled up the solvent under reduced pressure completely till well to yield (1400 g) of pure 4-nitrobenzoyl chloride as pale thick oily mass is obtained. Resulting crude was purified by yellow powder with a melting point of 69-71° C. column chromatography by using hexane: ethyl acetate (9:1) US 2015/0259464 A1 Sep. 17, 2015 40 to yield pure 4-nitro-benzoic acid 11-carboxy-1-hexyl-un Example 1D dec-3-enyl ester product as light yellow thick syrup (750 g). The resulting compound was characterized by "H NMR Synthesis of Ricinoleic Acid Diamine Compound (DMSO-d) & 0.85 (t,3H, CH), 1.12-1.6 (m,22H, 11xCH), 1.91 (m,2H, CH), 2.2-2.32 (m, 4H,2xCH), 3.5 (m. 1H, CH) 0365 5.52 (m. 1H, CH), 5.65 (m. 1H, CH), 8.25-8.35 (m, 4H, Ar). O Example 1C Synthesis of Ricinoleic Acid Di-Nitro Compound ON sc-O- 0363 O O

Reduction

O ON HN sc-O-

O O ON DCCTHF 0366. To a solution of 4-nitro-benzoic acid 1-hexyl-11-(4- nitro-phenoxy carbonyl)-undec-3-enyl ester (300 g) in ethyl OH acetate (1.5 L) in a pressure vessel was added Raney Nickel O (120 g) added, and the mixture stirred under an atmosphere of Hydrogen (8-10 Kg) for 8 hours at a temperature of 60-65°C. a o–K)-No, The catalyst was removed by filtration. The solvent was dis ON tilled off completely under reduced pressure at 65-70° C. and removed traces for 1 hour at 85-90° C. to get pure 4-ami O nobenzoic acid 11-(4-amino-phenoxycarbonyl)-1-hexyl-un O dec-3-enyl ester product as deep yellow thick syrup (190 g). The resulting compound was characterized by "H NMR (CDC1) & 0.88 (t, 3H, CH), 1.2-1.65 (m, 24H, 12xCH), 0364 To a solution of 4-Nitro-benzoic acid 11-carboxy 2.12 (t, 2H, COCH), 3.5 (m, 1H, CH) 5.12 (m, 1H, CH), 5.45 1-hexyl-undec-3-enyl ester (700 g) in dry THF (2 L), Di (m. 1H, CH), 6.55 (m, 4H, Ar), 6.85 (m,2H, Ar), 7.75 (m,2H, azabicyclo-undecane (DBU) (24 g) at 5-10°C., was added a Ar). solution of N,N'dicyclohexylcarbodiimide DCC (390 g) in 600 ml THF under nitrogen atmosphere, and later stirred at Example 1E room temperature for 24 hours. Check TLC and filtered off the DCU salts wash with hot THF 400 ml, combined total Synthesis of Ricinoleic Acid Diisocyanate filtrate mass and THF solvent was distilled off around 75% Compound under reduced pressure at 60-65° C., the resulted mass was poured into ice water (3 L) and extracted with ethyl acetate (3 0367 L) and combined total organic layers and wash with 15% NaHCO, solution (IL) and 15% NaCl solution (1.0 L) fol lowed by water washing (1.0 L), then dry the organic layer O with sodium sulphate and distill up the solvent under reduced pressure completely till get thick oily mass. The resulted HN crude was purified by column chromatography by using hex ane: ethyl acetate (9.5:0.5) as eluant to get the pure 4-nitro benzoic acid 1-hexyl-11-(4-nitro-phenoxycarbonyl)-undec O O 3-enyl ester product as deep yellow thick syrup (300 g). The resulting compound was characterized by H NMR (CDC1) 8 0.86 (t, 3H, CH), 1.35-1.65 (m, 20H, 10xCH), 1.78 (m, Triphosgene 2H, CH), 2.31-2.42 (m 4H2xCH), 3.5 (m. 1H, CH)5.52(m, 1H, CH), 5.65 (m, 1H, CH), 7.25-7.35 (m, 4H, Ar), 8.28-7.32 (m, 4H. Ar). US 2015/0259464 A1 Sep. 17, 2015

-continued was taken for further purification in 650 ml of 9:1 toluene: O heptane mixture under nitrogen and heated up to 85-90° C. (mass temp) with thorough shaking and allow for settle the a o-()-Nco brown impurity layer at bottom and decant the top clear layer OCN and given charcoal & Sodium Sulphate treatment for the clear decanted layer at 90-95° C. and filtered through hyflow and O washed with toluene 100 ml, distilled up total solvent under reduced pressure and kept for traces removal under vacuum O for 1 hour at 90-95°C. to get Diisocyanate as syrup and the resulted syrup was taken for next purification as follows. This 0368 To a solution of 44-Amino-benzoic acid 11-(4- purification procedure is repeated for one more time to get the amino-phenoxycarbonyl)-1-hexyl-undec-3-enyl ester (160 pure diisocyanate (100 g) as deep yellow syrup (98.8% g) in dry 1,4-dioxane (1.8 L) Triphosgene (158 g) was added NCO). The resulting compound was characterized by 'H 320 ml of 1,4 dioxane. The solution was heated up to 60-65° NMR (CDC1) 80.84 (t, 3H, CH), 1.21-1.43 (m, 24H, C. followed by cooling to room temperature at which tem 12xCH), 2.12 (t, 2H, COCH), 3.5 (m, 1H, CH).5.12 (m. 1H, perature the mass became clear Solution. The solution was CH), 5.45 (m. 1H, CH), 7.12-7.32 (m, 4H, Ar) 7.85-8.15 (m, then again heated up to 100-105° C. and stirred for 3 to 4 4H, Ar). The hydrolytic degradation of the urethane prepared hours. The solvent was distilled off completely under reduced from this isocyanate was carried out in pH 9.0 buffer solution. pressure at 85-90° C. The traces of solvent were completely The study showed that 1% solution is 100% hydrolyzed in 14 removed by using 1,4 dioxane (600 mL) followed by Toluene hours at 50° C. (300 mL) under reduced pressure at 85-90° C. The resulting residue was dissolved in toluene (360 mL) and given charcoal Example 2 and sodium sulphate treatment then distilled up total solvent under reduced pressure at 95-100° C. and kept for traces Diisocyanate from Ricinoleic Acid, Mono Glycolate removal for 2 hours at 95-100° C. to get 125 grams of the Extended 4-Nitro-Phenol, and 4-Nitro-Benzoic Acid crude diisocyanate product as deep yellow thick syrup which 0369

OH O O

21 OH ON --4-Nitro benzoyl chloride O

O \ OH

ON R = BriC

NO

21 O O O ON

O O Reduction US 2015/0259464 A1 Sep. 17, 2015

-continued NH2

21 O O O HN

O O Triphosgene 1,4-Dioxane

NCO

21 O O O

OCN

O O

Example 3 Diisocyanate from Di-Glycolic Acid Extended Ricinoleic Acid, 4-Nitro Benzoic Acid, and 4-Nitro-Phenol 0370

O O

21 OH 21 OH -e- CICH2COCl OH ar O O 4-Nitrobenzoic Acid, TEA, Acetone

O

21 OH

O~ O O ON ON O

O --- US 2015/0259464 A1 Sep. 17, 2015 43

-continued O 21 r O O NO

O ON estin O 21 r O O O NH2 r O O HN Triphosgene 1,4-Dioxane O 21 r O O O NCO r O O OCN

Example 4 -continued O Diisocyanate from 12-Hydroxy Stearic Acid, OH 4-Nitro-Benzoic Acid, and 4-Nitro-Phenol ON 0371

OH SOCl O O

OH ON -e- O O

C O Nin phenol OH ON US 2015/0259464 A1 Sep. 17, 2015 44

-continued dilute HCl, and resulting solid was filtered off and washed NO with chilled water. The solid was converted into slurry with 500 ml diisopropyl ether. The DIPE was filtered off and the O resulting solid was dried in vacuum oven at 70-75° C. to yield ON pure 4-nitrobenzoic acid 11-carboxy-1-hexyl-undecyl ester product as white powder with a melting point of 98-101° C. The resulting compound was characterized by "H NMR (DMSO-d) & 0.85 (t, 3H, CH), 1.2-1.6 (m. 28H, 14xCH), O O 1.8 (m, 2H, CH), 2.32 (t, 2H, COCH), 3.2 (m. 1H, CH) chain 8.1-8.25 (m, 4H, Ar). O NH2 Example 4B

O Synthesis of 12-Hydroxy Stearic Di-Nitro HN Compound 0374 O O Triphosgene 1,4-Dioxane O NCO OH

O ON OCN O

O O O ON Example 4A OH

Synthesis of 12-Hydroxy Stearic Mono Nitro Acid O 0372 ON o–K)-No, O

OH O O -e-4-Nitro benzoyl chloride, TEA, Acetone 0375 To a solution of 4-Nitro-benzoic acid 11-carboxy OH 1-hexyl-undecyl ester (350 g) in dry THF (2 L), Di-azabicy O cloundecane (DBU) (23 gr) at 5-10°C., was added a solution of N,N'Dicyclohexyl carbodiimide DCC (192 g) in 600 ml OH THF under nitrogen atmosphere, and later stirred at room temperature for 16-18 hours. DCU salts were filtered off and ON washed with tetrahydofuran. THF solvent was distilled off completely under reduced pressure at 60-65° C. and the O resulting mass was poured into ice water (2 L). The resulting solid was filtered and washed with chilled water. The result O ing crude was turned into slurry with 500 ml diisopropyl ether. DIPE was filtered off and then the material was dried in 0373) To a mixture of 12-Hydroxy stearic acid (450grams, vacuum oven at 80-90° C. to yield pure 4-Nitro-benzoic acid 1.5 moles), Triethylamine (313 ml, 2.35 moles) in Acetone (1 1-hexyl-11-(4-nitro-phenoxy carbonyl)-undecyl ester prod L) at 10-15° C., was added 4-Nitro Benzoyl Chloride (332 uct as white powder with a melting point of 142-145° C. The grams, 1.78 moles) and later stirred at room temperature for resulting compound was characterized by H NMR (CDC1) 10 hours. 75% of the solvent was distilled off. The resulting & 0.88 (t, 3H, CH), 1.3-1.6 (m, 26H, 13xCH), 1.78 (m. 2H, Solution was cooled to room temperature and poured onto CH), 2.12 (t, 2H, COCH), 3.45 (m, 1H, CH), 7.52 (m, 2H, cold water. The pH of the solution was adjusted to 4-5 with Ar) 7.75 (m, 1H, Ar) 8.3-8.52 (m, 5H, Ar). US 2015/0259464 A1 Sep. 17, 2015 45

Example 4C Example 4D Synthesis of 12-Hydroxy Stearic Diamino Synthesis of 12-Hydroxy Stearic Diisocyanate Compound 0378 0376

O o–K)-Ni,

O o-()-No, O O ON n phosgene O O O elein o–K)-Nco

O O

O 0379 To a solution of 4-Amino-benzoic acid 11-(4- amino-phenoxycarbonyl)-1-hexyl-undecyl ester (180 g) in o-()-NH. dry 1,4-dioxane (1.4 L) was added tri-phosgene (201 g) by dissolving in 360 ml of 1.4 dioxane. The solution was heated up to 60-65° C. followed by cooling to room temperature. The solution was again heated up to 100-105° C. and stirred for O O 3-4 hours. The solvent was distilled off completely under reduced pressure at 85-90° C. The traces were completely removed by using 14 dioxane followed by toluene (300 mL) under reduced pressure at 85-90°C. The resulting residue was dissolved in toluene and given charcoal and Sodium Sulphate treatment followed by distillation of the total solvent under 0377 To a solution of 4-Nitro-benzoic acid 1-hexyl-11 reduced pressure at 95-100° C. and kept for removal of trace (4-nitro-phenoxy carbonyl)-undecyl ester (290 g) in a mix solvent for 2 hours at 95-100° C. to get 130 grams of the crude product as deep yellow thick syrup which was taken for ture of Ethyl acetate (1.5 L) and DMF (300 mL) taken in a further purification in 650 ml of 6:4 toluene: hexane mixture pressure vessel was added Raney Nickel (80 g). The reaction under nitrogen and heated up to 85-90° C. with thorough mixture was stirred under an atmosphere of Hydrogen (8-10 shaking. The resulting solution was allowed to sit to enable Kg) for 4 hours at a temperature of 60-65°C. The catalyst was brown impurity layer to settle down at bottom. The top clear removed by filtration. 75% of the solvent was distilled off and layer was decanted off and given charcoal & Sodium Sulphate poured into cold water (2 L). The resulting solid was filtered treatment for the clear decanted layer at 90-95°C. and filtered off and washed with chilled water (100 mL) and do the slurry and washed with toluene. The solvent was distilled off under reduced pressure and kept for removal of trace solvent under with 1 lit diisopropylether and filtered off, then dried the vacuum for 1 hour at 90-95°C. It was then allowed to cool to material properly in vacuum oven at 60-80°C. to yield pure 40-45° C. and added 200 ml of dry n-Hexane and cooled to 4-amino-benzoic acid 11-(4-amino-phenoxycarbonyl)-1- 0-5°C. under nitrogen with proper stirring for 30 minutes hexyl-undecyl ester product as off white powder (190 g) with with glass rod in a beaker. The resulting solid was filtered off a melting point of 156-159°C. The resulting compound was to yield the pure diisocyanate as off white powder 85 grams characterized by "H NMR (CDC1) & 0.83 (t, 3H, CH), (99.25% NCO) with a melting point of 98-101° C. The prod 1.2-1.65 (m, 26H, 13xCH), 1.81 (m. 2H, CH), 2.12 (t, 2H, uct was characterized by "H NMR (CDC1) & 0.82 (t, 3H, CH), 1.21-1.43 (m, 26H, 13xCH), 1.83 (m. 2H, CH), 2.12 COCH), 3.50 (m. 1H, CH), 5.5-6.1 (m, 4H, 2xNH) 6.8-7.2 (t, 2H, COCH), 3.82 (m. 1H, CH), 7.12-7.32 (m, 4H, Ar) (m, 4H. Ar), 7.2-7.8 (m, 4H. Ar). The hydrolytic degradation 7.75-8.15 (m, 4H. Ar). The hydrolytic degradation of the of the compound was carried out in pH 9.0 buffer solution. urethane prepared from this isocyanate was carried out in pH The study showed that 1% solution is 100% hydrolyzed in 15 9.0 buffer solution. The study showed that 1% solution is hours at 50° C. 100% hydrolyzed in 16 hours at 50° C. US 2015/0259464 A1 Sep. 17, 2015 46

Example 5 Diisocyanate from 12-Hydroxy Stearic Acid, Mono-Glycolate Extended-4-Nitro Phenol, and 4-Nitro-Benzoic Acid 0380

O

OH -e- 4-Nitro benzoyl chloride, TEA, Acetone

OH

OH ON

ON O

O ---

O r O ON O NO2 O

chain O r O HN O NH2 O

Triphosgene 1,4-Dioxane US 2015/0259464 A1 Sep. 17, 2015 47

-continued O r O OCN O NCO

O

O

Example 5A Synthesis of Dinitro 12-Hydroxy Stearic Monoglycolate 0381

OH ON

O

O

ON O

O 1- Br

O r O ON O NO O

0382 To a solution of 4-Nitro-benzoic acid 11-carboxy propyl Ether and filtered off. The resulting solid was then 1-hexyl-undecyl ester (500g) in dry Acetone, triethylamine dried in vacuum oven at 60-80° C. to yield pure (R)-18-(2- (232 mL) at 10-15°C. was added Bromoacetic acid 4-nitro (4-nitrophenoxy)-2-oxoethoxy)-18-oxooctadecan-7-yl 4-ni phenyl ester (347 g). The solution was stirred at room tem trobenzoate product as off white powder with a melting point perature for 8 hours. 75% of the solvent was distilled off and of 130-133°C. The resulting compound was characterized by cooled to room temperature. The resulting Solid was poured "H NMR (CDC1,) & 0.86 (t, 3H, CH,), 1.2-1.5 (m. 28H, onto cold water and pH was adjusted to 4-5 with dilute HC1. 14xCH), 1.68 (m, 2H, CH), 2.42 (t, 2H, COCH), 3.52 (m, The resulting solid was filtered off and washed with chilled 1H, CH), 5.2 (s. 2H, CH) 7.42 (m, 2H, Ar) 8.4–8.52 (m, 6H, water (100 mL). The slurry was prepared with 1 lit Di Iso Ar). US 2015/0259464 A1 Sep. 17, 2015 48

Example 5B Synthesis of 12-Hydroxy Stearic Monoglycolate Diamine 0383

O r O ON O NO O

O r O HN O NH2 O

0384. To a solution of (R)-18-(2-(4-nitrophenoxy)-2-oxo compound was characterized by "H NMR (CDC1) & 0.83 (t, ethoxy)-18-oxooctadecan-7-yl 4-nitrobenzoate (380 g) in a 3H, CH), 1.2-1.65 (m. 28H, 14xCH), 1.71 (m, 2H, CH), mixture of Ethyl acetate (1.5 L) and DMF (300 mL) taken in 2.42 (t, 2H, COCH), 3.50 (m. 1H, CH), 5.12 (s. 2H, CH) a pressure vessel was added Raney Nickel (100 g). The result 6.12 (m. 2H, Ar), 6.52 (m, 4H, 2xNH) 6.9-7.52 (m, 6H, Ar). ing mixture was stirred under an atmosphere of hydrogen The hydrolytic degradation of the compound was carried out (8-10 Kg) for 4 hours at a temperature of 60-65° C. The in pH 9.0 buffer solution. The study showed that 1% solution catalyst was removed by filtration. The solvent was distilled is 100% hydrolyzed in 9 hours at 50° C. off by 75%, poured onto cold water (2 L) and filtered off the resulted solid and wash with chilled water (100 mL) and do Example 14 the slurry with 1 lit Di Isopropyl Ether and filtered off, then dry the material properly in vacuum oven at 60-80°C. to yield Synthesis of 12-Hydroxy Stearic Monoglycolate pure (R)-18-(2-(4-amino phenoxy)-2-oxoethoxy)-18-oxooc Diisocyanate tadecan-7-yl 4-amino benzoate product as off white powder (190 g) with a melting point of 124-127°C. The resulting 0385

O r O HN O NH2 O US 2015/0259464 A1 Sep. 17, 2015 49

-continued O r O HN O NCO

O

0386 To a solution of (R)-18-(2-(4-amino phenoxy)-2- 100 ml. The solvent was distilled off under reduced pressure oxoethoxy)-18-oxooctadecan-7-yl 4-amino benzoate (180g) and kept for removal of trace solvent under vacuum for 1-2 in dry 1,4-dioxane (1.4 lit) Triphosgene (160 g) was added by hours at 90-95°C. This purification procedure is repeated for dissolving in 320 ml 1,4 dioxane after heated up to 60-65°C. one more time to get the pure diisocyanate as deep yellow followed by cooling to room temperature at which tempera syrup 95 grams (99.1% NCO). The resulting compound was ture the mass became clear Solution, then again heated up to characterized by H NMR (CDC1) & 0.81 (t, 3H, CH), 100-105°C. and stirred for 3-4 hours, solvent was distilled off 1.21-1.63 (m. 28H, 14xCH), 1.73 (m,2H, CH), 2.22 (t, 2H, completely under reduced pressure at 80-85°C., then remove COCH), 3.62 (m. 1H, CH), 5.22 (s. 2H, CH) 7.15-7.52 (m, the traces completely by using 1,4 dioxane followed by Tolu 8H, Ar). The hydrolytic degradation of the urethane prepared ene (300 mL) under reduced pressure at 85-90° C., then from this isocyanate was carried out in pH 9.0 buffer solution. resulted residue was dissolved in Toluene 350 ml and given The study showed that 1% solution is 100% hydrolyzed in 12 charcoal and Sodium Sulphate treatment then distilled up total hours at 50° C. solvent under reduced pressure at 95-100° C. and kept for traces removal for 2 hours at 95-100° C. to get 150 grams of Example 6 the crude product as deep yellow syrup that was taken for further purification in 750 ml of 6:4 toluene: hexane mixture Diisocyanate from 12-Hydroxy Stearic Acid, under nitrogen and heated up to 85-90° C. and allow for settle Di-Glycolic Acid Extented, 4-Nitro Benzoic Acid, the brown impurity layer at bottom and decant the top clear and 4-Nitro Phenol layer and given charcoal & Sodium Sulphate treatment for the clear layer at 90-95°C. and filtered and washed with toluene 0387

O

OH CICHCOCI OH -e- OH er O O 4-Nitrobenzoic Acid, TEA, Acetone

O

OH

O r O O ON ON O US 2015/0259464 A1 Sep. 17, 2015 50

-continued O r O O O NO r O O ON elein O r O O O NH2 r O O HN Triphosgene 1,4-Dioxane O r O O O NCO r O O OCN

Example 7 0388 Diisocyanate from 12-Hydroxy Stearic-Succinate is prepared using the following scheme

O

OH Succinic anhydride -es

OH O

OH

O

O HO

O | Nin Pheno DCCTHF US 2015/0259464 A1 Sep. 17, 2015 51

-continued O o–O)-so O

O ON O O also O o–K)- O

O HN O O Triphosgene 1,4-Dioxane O o–O)-so O

O OCN O

O

Example 8 Diisocyanate from Ricinoleic Acid-Succinate Prepared According to the Following Scheme 0389)

O

21 OH Succinic anhydride He

OH O

21 OH

O

O HO

O | Nin Pheno DCCTHF US 2015/0259464 A1 Sep. 17, 2015 52

-continued

O ON O also

O HN O

Triphosgene 1,4-Dioxane

21 O -()– NCO

O OCN O

Example 9 Diisocyanate from Ricinoleic Acid-Diglycolic Anhydride Prepared According to the Following Scheme 0390

O

21 OH Diglycolic anhydride Her

OH O

21 OH

HO r r O O O | Nin Pheno DCCTHF US 2015/0259464 A1 Sep. 17, 2015

-continued O

ON O r r O O O estin O 21 O -()– NH2 HN O r r O O O Triphosgene 1,4-Dioxane O 21 o–()-sco os-()- r O O O

Example 10 Diisocyanate from 12 Hydroxystearic Acid-Diglycolic Anhydride Prepared According to the Following Scheme 0391

OH Diglycolic anhydride Hess

OH

OH

HO r r O O O |Nir Pheno DCCTHF US 2015/0259464 A1 Sep. 17, 2015 54

-continued

ON O r r O O O estin

HN O r r O O O Triphosgene 1,4-Dioxane

0392 Numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise that as specifically described herein. What is claimed is: 1. A diisocyanate selected from formula (I), (II), or (III):

(I)

2 1's R 1. NCO US 2015/0259464 A1 Sep. 17, 2015 55

-continued (II) 1. o1's-N- 2NCO

(III) 1. R NCO

wherein: -(CH2)COO where y is selected from 2, 3, 4, and variable A, the dashed bond, is absent or is a double bond; 6-24; and each R is independently the diacyl residue of a diacid; —(CH2CH2O). CHCOO where Z is selected from 2-24, R" is absent or each R" is independently a C- alkylene each X" independently is selected from: group; —OCH2CO— (glycolic acid moiety); R" is the residue of a diol or polyol; —OCH(CH)CO— (lactic acid moiety); from 1-4 R, are present: —OCHCHOCH2CO— (dioxanone moiety); each R, is independently selected from: H. C. alkyl, C. —OCH2CH2CHCH-CHCO— (caprolactone moi alkoxy, benzyloxy, halogen, —CHO. —COH, and ety); and, —NO, and each R, is independently attached directly O(CH2)CO where y is selected from 2, 3, 4, and to aromatic ring or attached through a —(CH2) - 6-24; linker; —O(CH2CH2O). CHCO— where Z is selected from each X independently is selected from: 2-24, each p is independently selected from 0, 1,2,3,4, 5, and 6: —CHCOO (glycolic acid moiety); and, —CH(CH)COO (lactic acid moiety); each p' is independently selected from 0, 1,2,3,4, 5, and 6: —CH2CH2OCHCOO— (dioxanone moiety); provided that p--p' total from 0 to 12. —CH2CH2CHCH-CHCOO— (caprolactone moi 2. The diisocyanate of claim 1, wherein the diisocyanate is ety); selected from formulae (Ia)-(IIIa):

(Ia)

N NCO

| 21 -- US 2015/0259464 A1 Sep. 17, 2015 56

-continued

(IIa)

3. The diisocyanate of claim 1, wherein the diisocyanate is selected from formulae (Ia)-(IIIa):

(Ia)

(Ia2) US 2015/0259464 A1 Sep. 17, 2015 57

-continued (IIa) NCO O | N1.- 21 O1^en 2

1st-NorseR O O OCN 2

(IIa) NCO O | N - R 1^n 2

1st-NorseR O O OCN 2

(IIIa) NCO O N1. it | -- 21 -N-1 ns 21

1s-Nx^1R O O OCN 21

(IIIa) NCO. O N1. R - (X) | - 1 No1'n 21

1s-NX^1R O O 21 US 2015/0259464 A1 Sep. 17, 2015 58

4. The diisocyanate of claim 1, wherein the diisocyanate is selected from formulae (Ia)-(IIIa):

(IalA) NCO O

s (x)'s O OCN (Ia2A) NCO O

s (x)'s O OCN (IIa 14) NCO O

R O O

OCN r (IIa2A) NCO O

R O O

OCN r (IIIa 14) NCO O 21 1 R No1 (X)''n.

R O O

OCN US 2015/0259464 A1 Sep. 17, 2015 59

-continued (IIIa) NCO. O R (X) c No1 "NR R O O O Nix-NR1n OCN

5. The diisocyanate of claim 1, wherein the diisocyanate is selected from formulae (1)–(20):

(1) O 21 o1 O O NCO (x),1 O

OCN O (2) 21 -X)

O NCO Xes, O

O OCN O (3) 21 -X)

OCN

Ol O O NCO (X)1 ^o~ O O O (4) 21 -X)

OCN

Ol O O NCO x 1 NR-1 US 2015/0259464 A1 Sep. 17, 2015 60

-continued (5) NCO O 21 -X)

OCN O (X),1 O (6) O 21 rol O NCO (x),.1 O

OCN (7) NCO O 21 -X)

OCN O Xes, --> O (8)

21 o1 (X) rC O NCO Xps, --> O OCN (9) NCO O 21 -X)

(X)1O ^o~ O O O OCN US 2015/0259464 A1 Sep. 17, 2015 61

-continued (10)

OCN NCO O (X)1 O no ~ O O O (11) O -X)

NCO x," OCN C. (12) O -X)

O NCO

O (X) No

OCN

(13) O -X) OCN NCO (x)51 O r r O O O

(14) O -X) OCN NCO 'N-O US 2015/0259464 A1 Sep. 17, 2015 62

-continued (15) NCO O -X) OCN

Clu (X),1 O (16) O o1 (X) rC O NCO

O

OCN cr's (17) NCO O -X) OCN Outs O

(18)

O NCO Xps, O

O OCN (19) NCO O

OCN US 2015/0259464 A1 Sep. 17, 2015 63

-continued (20) O o1 (X)

OCN NCO. (X), O nor O O O

6. The diisocyanate of claim 1, wherein: —OCH2CH2CHCH-CHCO— (caprolactone moi each Xindependently is selected from the group consisting ety); and, of: provided that p--p' total from 2-6. 7. The diisocyanate of claim 6, wherein: —CHCOO (glycolic acid moiety): each p is independently selected from 0, 1, 2, 3, and 4; and, —CH(CH)COO– (lactic acid moiety); each p' is independently selected from 0, 1, 2, 3, and 4: —CHCHOCHCOO (dioxanone moiety); and, provided that p--p' total from 2-4. —CH2CH2CHCH-CHCOO— (caprolactone moi- 8. A polymer, comprising: a polyurethane, polyester-ure ety); thane, polyurea-urethane, or polyurea, formed by polymeriZ each X" independently is selected from the group consist- 1ng at least one diisocyanate selected from formulae (I)-(III) ing of of claim 1 with a compound selected from a diol, an ester - OCH CO—CO (glycoliclvcolic aciacid moiety):moietv): diol,9. Thediamide-diol polymer andof claim a diamine. 8, wherein the polymer is a bio —OCH(CH)CO— (lactic acid moiety); asborbable polymer. —OCHCHOCH2CO— (dioxanone moiety); and, 10. A diamine selected from formula (IV), (V), or (VI):

(IV)

(V)

US 2015/0259464 A1 Sep. 17, 2015 64

-continued (VI)

e R o1 R No1 (X) NR al

wherein: 14. A tissue scaffold, comprising: one or more polymers of variable A, the dashed bond, is absent or is a double bond; claim 8, wherein the tissue scaffold has a porous structure for each R is independently the diacyl residue of a diacid; the attachment and proliferation of cells either in vitro or in R" is absent or each R" is independently a C- alkylene vivo. group; 15. A polymer of claim 8, wherein the polymer is further R" is the residue of a diol or polyol; polymerized on at least one end with at least one lactone from 1-4 R, are present; monomer selected from the group consisting of glycolide, each R, is independently selected from: H. C. alkyl, C. lactide, caprolactone, p-dioxanone, TMC, 6-Valerolactone, alkoxy, benzyloxy, halogen, —CHO. —COH, and B-butyrolactone, morpholinedione, pivalolactone, e-decallac —NO, and each R, is independently attached directly tone, 2,5-diketomorpholine and combinations thereof in to aromatic ring or attached through a —(CH2) - order to control physical and biological properties. linker; each X independently is selected from: 16. An article, comprising: a metal or polymeric Substrate —CHCOO (glycolic acid moiety); and further comprising: at least one polymer according to —CH(CH)COO (lactic acid moiety); claim 8, wherein said article is selected from: —CH2CH2OCHCOO— (dioxanone moiety); a medical device, an implantable medical device, a phar —CH2CH2CHCH-CHCOO— (caprolactone moi maceutical delivery system, a consumer product includ ety); ing durable articles, a cosmetic, a tissue engineering -(CH2)COO where y is selected from 2, 3, 4, and application, a foam, a reticulated foam, a Suture, a bone 6-24; and hemostat, a bone filler, a bone void filler, a bone cement, —(CH2CH2O). CHCOO where Z is selected from a tissue adhesive, a tissue sealant, an adhesion preven 2-24, tion barrier, a mesh, a filter, a stent, a medical device each X" independently is selected from: coating, a pharmaceutical drug formulation, a cosmetic —OCH2CO— (glycolic acid moiety); packaging, a pharmaceutical packaging, an apparel, an infusion device, a blood collection device, a skin care —OCH(CH)CO— (lactic acid moiety); product, and a transdermal drug delivery material, drug —OCHCHOCH2CO (dioxanone moiety); delivery matrices, pharmaceutical drug formulations, —OCH2CH2CHCH-CHCO— (caprolactone moi tissue engineering, tissue adhesives, adhesion preven ety); tion barriers, and other implantable medical devices O(CH2)CO where y is selected from 2, 3, 4, and including foams for wound healing and/or drug delivery, 6-24; and, bone hemostats, bone fillers, bone void fillers, bone wax —O(CHCHO). CHCO where Z is selected from formulations, tissue adhesives and Sealants, adhesion 2-24, prevention barriers, meshes, filters, Surgical devices, each p is independently selected from 0, 1, 2, 3, 4, 5, and 6: medical device coatings, cosmetic and pharmaceutical and, packaging, apparel, infusion devices, blood collection each p' is independently selected from 0, 1,2,3,4, 5, and 6: tubes and devices, tubes, skin care products, transdermal provided that p-p' total from 0 to 12. drug delivery, consumer product packaging, and dispos 11. A polymer, comprising: a polyamide, polyester amide, able medical devices, knitted products, foodstuffs, nutri polyepoxide, or polyurea formed by polymerizing at least one tional Supplements, nutraceuticals, biodegradable chew diamine of claim 10, with a compound selected from a dicar ing gums, and reinforced composites. boxylic acid, diepoxide, and diisocyanate. 17. The article of claim 16, wherein the metal or polymeric 12. A controlled drug delivery system comprising: Substrate has a coating, comprising: the at least one polymer (c) one or more polymers of claim 8, and of claim 8, wherein said article is suitable for contacting (d) one or more biologically or pharmacologically active mammalian tissue. agents. 13. The controlled drug delivery system of claim 12, 18. The article of claim 16, wherein the article is an wherein the one or more biologically or pharmacologically implantable medical device. active agents are physically embedded or dispersed in a poly 19. The article of claim 16, wherein the article is reticulated meric matrix, comprising: the one or more polymers. foam for wound healing and/or controlled drug delivery. US 2015/0259464 A1 Sep. 17, 2015 65

20. A Surgical article or component thereof or polymeric carrier, comprising: a polymer of claim 8, wherein the article is selected from: a stent, stent coating, wound covering, burn covering, foam, highly porous foams, reticulated foams, tissue engineering scaffold, film, adhesion prevention barrier, implantable medical device, controlled drug delivery system, Suture, ligature, needle and Suture combination, Surgical clip, Surgical staple, Surgical prosthesis, textile structure, coupling, tube, Support, screw, pin, bone wax formulation or an adhesion prevention barrier. 21. A surgical article or component thereof of claim 20, wherein a biologically active agent is physically embedded or dispersed into the polymer matrix of the controlled delivery system.