US009328192B2

(12) United States Patent (10) Patent No.: US 9,328,192 B2 BeZWada et al. (45) Date of Patent: May 3, 2016

(54) BO-BASED MONOMERS AND POLYMERS (58) Field of Classification Search CPC ... C08G 18/7657; C08G 71/02: C08G 73/02: (71) Applicant: Bezwada Biomedical, LLC, C08G 69/00; C08G 18/8125; C08G 18/771; Hillsborough, NJ (US) C08G 18/603; C07C 265/14 See application file for complete search history. (72) Inventors: Rao S Bezwada, Hillsborough, NJ (US); Neeti Srivastava, Hillsborough, NJ (US) (56) References Cited (73) Assignee: Bezwada Biomedical, LLC, U.S. PATENT DOCUMENTS HIllsborough, NJ (US) 3.427,346 A * 2/1969 Brotherton ...... CO7C 263/16 (*) Notice: Subject to any disclaimer, the term of this 521,162 4,740,534 A 4, 1988 Matsuda et al. patent is extended or adjusted under 35 4,826,945 A 5/1989 Cohn et al. U.S.C. 154(b) by 0 days. 4,829,099 A 5/1989 Fuller et al. 4,994,542 A 2f1991 Matsuda et al. (21) Appl. No.: 14/645,522 5,173,301 A 12/1992 Itoh et al. 6,221,997 B1 4/2001 Woodhouse et al. (22) Filed: Mar 12, 2015 6,894,140 B2 5/2005 Roby 8,309,132 B2 11/2012 Bezwada 8,551,519 B2 10/2013 Bezwada (65) Prior Publication Data 8,664,429 B2 3/2014 Bezwada US 2015/O259464 A1 Sep. 17, 2015 8,901,341 B2 12/2014 Bezwada 8,901,347 B1 12/2014 Bezwada 2004/0170597 A1 9/2004 Beckman et al. Related U.S. Application Data 2005/OO 13793 A1 1/2005 Beckman et al. (60) Provisional application No. 61/951,617, filed on Mar. 2007/OO 14755 A1 1/2007 Beckman et al. 12, 2014. FOREIGN PATENT DOCUMENTS Int. C. (51) EP O295055 A2 12/1988 C08G 8/76 (2006.01) WO 95.26762 A1 10, 1995 C08G 7L/02 (2006.01) C08G 69/00 (2006.01) OTHER PUBLICATIONS C08G 73/02 (2006.01) C08G 18/60 (2006.01) Krishnamurti. “Vinyl monomers from 12-hydroxystearic acid.” Pig C08G 8/77 (2006.01) ments and Resin Technology (1980), 9, (4), 15-17.* C08G 18/8 (2006.01) CD7C 265/4 (2006.01) * cited by examiner (52) U.S. C. CPC ...... C08G 18/7657 (2013.01); C07C 265/14 Primary Examiner — Paul A Zucker (2013.01); C08G 18/603 (2013.01); C08G Assistant Examiner — Mark Luderer 18/771 (2013.01); C08G 18/8125 (2013.01); (74) Attorney, Agent, or Firm — Vance Intellectual Property, C08G 69/00 (2013.01); C08G 71/02 (2013.01); PC C08G 73/02 (2013.01); C08G 2230/00 (2013.01); Y10T 428/1352 (2015.01); Y10T (57) ABSTRACT 428/1355 (2015.01); Y10T 428/1393 (2015.01); Described are novel ricinoleic acid/12-hydroxy stearic acid Y10T 428/24999 (2015.04): Y10T 428/249991 based diisocyanates, which are useful as monomers to form (2015.04); Y10T 428/2804 (2015.01); Y10T polymers, which have applications inter alia as medical 428/2896 (2015.01); Y10T 428/31551 devices. (2015.04); Y10T 428/31605 (2015.04): Y10T 442/20 (2015.04) 30 Claims, No Drawings US 9,328,192 B2 1. 2 BO-BASED MONOMERS AND POLYMERS mers are not typically absorbable or biodegradable and may therefore be unacceptable in circumstances that require FIELD OF THE INVENTION absorption or biodegradation. For example, certain biomedi cal applications, such as Surgical devices including but not The present invention relates to the discovery of a new class limited to monofilament and multifilament Sutures, films, of bio-based monomers and polymers. Using these bio-based sheets, plates, clips, staples, pins, screws, stents, stent coat monomers and their functionalized derivatives, novel bio ings, and the like, generally require the use of a material that based absorbable/biodegradable and non-absorbable poly is absorbable. Hence, the vast majority of research devoted to mers (or partially absorbable/biodegradable polymers) can be the development of biomedical polyurethanes has focused on prepared. 10 long-term applications such as vascular grafts and pacemaker lead insulators. BACKGROUND OF THE INVENTION Despite progress in the general development of polyure thanes and similar polymers for use in biomedical applica Bio-based and/or biodegradable polymers are increasingly tions, relatively little research have been directed to develop being used in applications that currently rely on petroleum 15 ing absorbable polyurethanes for temporary, rather than based feedstocks. These biobased and/or biodegradable longer-term implantation. See Fuller et al., U.S. Pat. No. monomers and polymers have become increasingly impor 4,829,099: Beckmann et al., U.S. Patent Publication Nos. tant for a variety of consumer products, durable goods and 2005/0013793, 2004/0170597, and 2007/0014755; Bruinet biomedical applications including tissue engineering scaf al., PCT Publication No. WO95/26762; Woodhouse et al., folds, Surgical adhesives, foams, medical device coatings and U.S. Pat. No. 6,221.997: Cohn et al., U.S. Pat. No. 4,826,945, drug delivery matrices, etc. They are also increasingly being which generally discuss recent advances made in the field of used for disposable medical device applications. For absorbable polyurethanes. example, isocyanate-based adhesive/sealant compositions Subsequent work by Bruinet al., PCT No. WO95/26762, are described in U.S. Pat. Nos. 6,894,140; 5,173,301: 4,994, describes the synthesis of crosslinked polyurethane networks 542; and, 4,740,534, the disclosures of which are incorpo 25 incorporating lactide or glycolide and e-caprolactone joined rated herein by reference in their entirety. by a lysine-based diisocyanate. Bruin discloses that these Polymers that are derived from monomers from renewable polymers display good elastomeric properties and degrade biobased sources are referred to as bio-based polymers. Poly within about 26 weeks in vitro and about 12 weeks in vivo mers that breakdown into carbon dioxide, water and biomass (Subcutaneous implantation in guinea pigs). Despite their from the action of naturally occurring microorganism Such as 30 disclosed desirable flexibility and degradation characteris bacteria, fungi etc over a period of time are referred to as tics, these highly crosslinked polymers are not extensively biodegradable polymers. A majority of the biobased poly used in some biomedical applications because in some cases mers are also biodegradable. Polymers that are designed to they cannot be readily processed into Surgical articles, for degrade under physiological conditions are referred to as example, using standard techniques such as Solution casting absorbable polymers. These polymers are sometimes also 35 or melt processing, as is the case for the more typical linear, referred to as, bioerodible, bioabsorbable, or hydrolyzable segmented polyurethanes. polymers. Synthetic absorbable polymers are generally clas Cohn et al., EP 295055 describes a series of elastomeric sified into polyesters, polyorthoesters, polyanhydrides, poly polyester-polyether-polyurethane block copolymers esteramides, and polyoxaesters. intended for use as Surgical articles. However, these polymers Absorbable polymers are increasingly used in a wide range 40 may be relatively stiff and may have low tensile strength, of biomedical applications including tissue engineering scaf which may preclude their use as elastomeric biomaterials. folds, stents, stent coatings, foams, highly porous foams, Beckmann et al., U.S. Patent Publication No. 2005/0013793 reticulated foams, and adhesion prevention barriers. This describes polyurethane-based biodegradable adhesives from increased utilization is, in part, a function of the transient multi-isocyanate functional molecules and multifunctional nature of these polymers when used as biomedical implants 45 precursor molecules with terminal groups selected from or drug carriers. Medical devices made from absorbable poly hydroxyl and amino groups. Woodhouse et al. describes mers can mitigate the inevitable and usually negative physi absorbable polyurethanes derived from amino acids. How ologic responses (e.g., fibrous encapsulation), which limit ever, all these absorbable polyurethanes may suffer from one long-term device success. Hence, an array of absorbable or more of the following drawbacks: (a) the very slow rate of polymers have been developed and studied in various bio 50 formation of polyurethane that may be attributed to the low medical applications. While significant research and devel reactivity of the polyisocyanates and (b) the lack of tunable opment activity has been carried out on bioabsorbable poly physical and/or mechanical properties and/or controllable mers, such polymers may suffer from performance hydrolytic degradation profiles for biodegradable polyisocy deficiencies which are typically not fully recognized until anates or absorbable polyurethanes derived therefrom. new applications are identified and in-use testing has been 55 Despite advancements in the art of producing polymeric carried out. materials and methods for making polymers Suitable for use Of the synthetic absorbable polymers, polyesters find in drug delivery, tissue adhesives, adhesion prevention bar numerous applications in medical, Surgical and controlled rier, foams, highly porous foams, reticulated foams, bone wax delivery applications and are the key components of a major formulations, Stents, stent coatings, Scaffolds, films, molded ity of bioabsorbable medical devices, ranging from Sutures, 60 devices, and similar Surgical articles, presently available Staples, orthopedic screws and implantable Surgical devices polymers generally lack adequate performance properties to tissue engineering scaffolds. desirable in Surgical articles, for example, those related to In addition to polyesters, segmented polyurethane elas bioabsorption, flex fatigue life, strength in use, flexibility, tomers have also enjoyed wide use as biomaterials generally and/or durability. Thus, there continues to be a need for new due to their excellent mechanical properties and desirable 65 devices and polymers having tunable physical and/or biologi chemical versatility. While polyurethane polymers have cer cal properties, so that medical devices and Surgical articles tain useful properties, shaped articles based on these poly having a variety of end uses can be prepared. US 9,328,192 B2 3 4 With more uses being envisioned for polymers and an acid, L-lactic acid, amino acids such as L-lysine, castor oil increased demand for absorbable polymers with new and based monomers (e.g., ricinoleic acid, 12-hydroxy Stearic improved properties targeted to address performance defi acid, and sebacic acid), and Soybean oil-based monomers. ciencies, there still is a need for bio-based monomers and In an embodiment, the present invention provides a novel polymers with beneficial properties. class of polymers formed by polymerizing a bio-based mono mer with an appropriate additional monomer (e.g., a diol/ SUMMARY OF THE INVENTION polyol, or diamine), the polymers being selected from: polya mides, polyesters, polyureas, polyepoxides, In an embodiment, the present invention provides a novel polyesteramides, and polyurethanes. The polymers are bio class of bio-based monomers and materials (e.g., pre-poly 10 degradable, absorbable, and/or non-absorbable. For the mers, polymers, polyols, and/or oligomers) derived there preparation of bio-based polyamides, bio-based diamines from. The bio-based materials may be biodegradable, absorb able, and/or non-absorbable. Such as 1.5-pentane diamine and L-lysine can be reacted with In another embodiment, the present invention provides bio-based dicarboxylic acids, such as sebacic acid or Succinic novel bio-based materials useful for a variety of medical (e.g., 15 acid. Absorbable bio-based polyamides can be prepared by stent coatings), pharmaceutical (e.g., drug formulations), and functionalizing sebacic acid with a group Such as lactic acid cosmetic (e.g., cosmetic packaging) uses. and reacting with diamines. The absorbable polymers are In another embodiment, the present invention provides characterized by having a controllable degradation profile. novel bio-based vegetable oil (e.g., castor or soybean) derived In another embodiment, the present invention provides hydroxyl acids diacids, diamines, and diisocyanates and the novel bio-based materials useful for drug delivery matrices resulting polymers including bio-based polyamides, polyes (e.g., controlled drug delivery or site-specific or systemic ters, polyureas, polyepoxides, polyesteramides, and polyure drug delivery systems or matrices), pharmaceutical drug for thanes. mulations, tissue engineering (e.g., tissue scaffold), tissue In another embodiment, the present invention provides adhesives, adhesion prevention barriers, and other implant novel bio-based materials and methods of making Such mate 25 rials that would ultimately be useful for drug delivery matri able medical devices including foams (including reticulated ces (e.g., controlled drug delivery or site-specific or systemic foams, lyophilized foams, highly porous foams, regular drug delivery systems or matrices), pharmaceutical drug for foams, foams with vertical channels, architecturally gradient mulations, tissue engineering (e.g., tissue scaffold), tissue foams, trans-compositional foams, and trans-structural adhesives, adhesion prevention barriers, and other implant 30 foams) for wound healing and/or drug delivery, bone hemo able medical devices including foams (including reticulated foams, lyophilized foams, highly porous foams, regular stats, bone fillers, bone void fillers, bone wax formulations, foams, foams with vertical channels, architecturally gradient tissue adhesives and sealants, adhesion prevention barriers, foams, trans-compositional foams, and trans-structural meshes, filters, Surgical devices (e.g., stents, staples, Sutures foams) for wound healing and/or drug delivery, bone hemo 35 (e.g., monofilament and multifilament Sutures), Screws (e.g., stats, bone fillers, bone void fillers, bone wax formulations, orthopedic screws), sheets, plates, clips, films, staples, pins, tissue adhesives and sealants, adhesion prevention barriers, hooks, buttons, Snaps, tubes, vascular grafts, bone plates, meshes, filters, Surgical devices (e.g., stents, staples, Sutures implantable sensors, and molded devices), medical device (e.g., monofilament and multifilament Sutures), Screws (e.g., coatings (e.g., for endoscopic instruments, Sutures, Stents, orthopedic screws), sheets, plates, clips, films, staples, pins, 40 hooks, buttons, Snaps, tubes, vascular grafts, bone plates, and needles), cosmetic and pharmaceutical packaging (e.g., implantable sensors, and molded devices), medical device blister packaging films, cast films, extruded films and con coatings (e.g., for endoscopic instruments, Sutures, Stents, tainers), apparels, infusion devices, blood collection tubes and needles), cosmetic and pharmaceutical packaging (e.g., and devices, tubes, skin care products, transdermal drug blister packaging films, cast films, extruded films and con 45 delivery, consumer product packaging, and disposable medi tainers), apparels, infusion devices, blood collection tubes cal devices, durable goods, knitted products, foodstuffs, and devices, tubes, skin care products, transdermal drug delivery, consumer product packaging, and disposable medi nutritional Supplements, nutraceuticals, biodegradable chew cal devices, durable consumer goods, knitted products, food ing gums, and reinforced composites. stuffs, nutritional Supplements, nutraceuticals, biodegradable 50 Examples of knitted products, woven or non-woven, and chewing gums, and reinforced composites. molded products include: burn dressings; hernia patches; These and other embodiments, which will become appar medicated dressings; fascial Substitutes; gauze, fabric, sheet, ent during the following detailed description, have been felt, or sponge for liver hemostasis; gauze bandages; arterial achieved by the inventors’ discovery of the presently claimed graft or Substitutes; bandages for skin Surfaces; Suture knot bio-based monomers and polymers thereof. 55 clip; hooks, buttons, and Snaps; bone Substitutes (e.g., man dible prosthesis); intrauterine devices (e.g., spermicidal DETAILED DESCRIPTION OF PREFERRED devices); draining or testing tubes or capillaries; Surgical EMBODIMENTS instruments; vascular implants or Supports; vertebral discs; extracorporeal tubing for kidney and heart-lung machines; The entire disclosures of all cited patents and patent pub 60 and, artificial skin. lications are incorporated in their entirety herein by reference. As described herein, the functionalized monomers and In an embodiment, the present invention provides a novel polymers of the present invention are useful in medical appli class of bio-based monomers and materials derived therefrom cations/medical devices. Medical application/medical (e.g., polymers, pre-polymers, polyols, and/or oligomers). devices, as used herein, encompass medical and biomedical The bio-based materials may be biodegradable, absorbable, 65 applications and include all types of applications involved in and/or non-absorbable. The bio-based monomers are derived the practice of medicine that would benefit from a material from starting compounds that include butane diol. Succinic that decomposes harmlessly within a known period of time. US 9,328,192 B2 5 6 In another embodiment, the present invention provides a novel diisocyanate selected from formula (I), (II), or (III):

(I) St. 2 NCO

(II) 1.2 NCO

(III) N -RS1 (pa, 2x1 O O R xCO

wherein: O(CH2)CO wherey is selected from 2,3,4, and 6-24: variable A, the dashed bond, is absent or is a double bond; and, R is the diacyl residue of a diacid; 45 —O(CH2CH2O). CHCO— where Z is selected from 2-24: R" is absent or each R" is independently a C- alkylene each p is independently selected from 0, 1,2,3,4, 5, and 6: group; and, R" is the residue of a diol or polyol; each p' is independently selected from 0, 1,2,3,4, 5, and 6: from 1-4 R, are present: provided that p--p' total from 0 to 12. each R, is independently selected from: H. C. alkyl, C. 50 As noted, R is the diacyl (i.e., C(O) R' C(O)) residue alkoxy, benzyloxy, halogen, —CHO. —COH, and —NO, of a diacid. and each R, is independently attached directly to aromatic R is independently selected from: alkylene, cycloalky ring or attached through a —(CH2) -linker, lene-alkylene, arylene-alkylene, arylene-alkylene-arylene, each X independently is selected from: cycloalkylene-alkylene-cycloalkylene, and arylene-alky —CHCOO (glycolic acid moiety); 55 lene-cycloalkylene, wherein: —CH(CH)COO (lactic acid moiety); (1) one or more of the methylene (—CH2—) moieties in —CHCHOCHCOO (dioxanone moiety); the alkylene chain portions of the R' group are optionally —CH2CH2CHCH-CHCOO— (caprolactone moiety); replaced by —O— or —S—; or (2) one or more of the ethylene ( CHCH ) moieties in -(CH2)COO wherey is selected from 2,3,4, and 6-24: 60 the alkylene chain portions of the R' group are optionally and replaced by a carboxyl group ( C(=O)C)— or —OC —(CH2CH2O). CHCOO where Z is selected from 2-24: (=O)—). each X" independently is selected from: Examples of diacids from which R can be derived include —OCH2CO (glycolic acid moiety); oxalic acid, malonic acid, Succinic acid, glutaric acid, adipic —OCH(CH)CO (lactic acid moiety); 65 acid, pimelic acid, Suberic acid, azelaic acid, sebacic acid, —OCH2CHOCH2CO— (dioxanone moiety); phthalic acid, isophthalic acid, terephthalic acid, maleic acid, —OCH2CH2CHCH-CHCO— (caprolactone moiety); fumaric acid, glutaconic acid, traumatic acid, muconic acid, US 9,328,192 B2 7 8 diglycolic acid, 3,6-dioxaoctanedioic acid, 3.6.9-trioxaunde Examples of suitable diols from which R" can be derived canoic acid, functionalized oxaacids, polyethyleneglycol diacids of average molecular weight from 300 to 2000 and include diols with up to 8 carbon atoms or diols having blends thereof, symmetrical/unsymmentrical ether acids, as repeating units each with up to 8 carbonatoms. Diol examples well as bio-based diacids and their precursors, including, include 12-ethanediol (ethylene glycol); 1.2-propanediol Succinic acid, sebacic acid, hydroxyl acids, and diacids 5 (propylene glycol); 1,3-propanediol, 1,4-butanediol; 1.5- derived from vegetable oils including castor oil (e.g., ricino leic acid, 12-hydroxy Stearic acid, and sebacic acid) and Soy pentanediol, 1.3-cyclopentanediol, 1.6-hexanediol; 1,4-cy bean oil. clohexanediol; 1.8-octanediol; and, combinations thereof. As noted, R" is the residue of a diol or polyol. When R" is Examples of suitable polyols from which R" can be derived the residue of a diol, then it is the R" portion of HO R' 1 O OH. Alternatively, when R" is the residue of a polyol, it is, include polyethylene glycol and polypropylene glycol with excluding the terminal hydroxy groups, selected from poly weight average molecular weights of 500-10,000. alkylene oxides having weight average molecular weights In another embodiment, the present invention provides a from about 500-10,000. novel diisocyanate selected from formulae (Ia)-(IIIa): (Ia) N NCO R 2

(IIa) NCO N - Rn 21

(IIIa) NCO. N R 1 R no-1'n(X) 21

In another embodiment, the present invention provides a novel diisocyanate selected from formulae (Ia)-(IIIa):

(Ia) N NCO O - Rn o1 Xen 2

US 9,328,192 B2 11 12 In another embodiment, the present invention provides a novel diisocyanate selected from formulae (Ia)-(IIIa):

(Ia 1A) NCO 1PS

s scpa O

OCN (Ia2A) NCO

o1'n(X) O s "es c O OCN (IIa 14) NCO O

R O O c

OCN Or (IIa2A) NCO O

R Nix1 O NR1 O

OCN

(IIIa 14) NCO

1. R no-1 (X) NR

O O c Nox2 NR1

OCN US 9,328,192 B2 13 14 -continued (IIIa) NCO. O c R'Sno1'''n. - (X)p R Nix1 O NR1 O

OCN

In another embodiment, the present invention provides a novel diisocyanate selected from formulae (1)–(20):

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

O NCO Xps, O

O OCN (3) O 21 -X)

OCN

Ol O O NCO (X)1 rr O O

O (4) 21 -X) OCN Ol Ol O O NCO (X), 1. N1 US 9,328,192 B2 15 16 -continued (5) NCO O 21 -X) OCN O (X), O O (6)

21 o1 (X) rC O NCO (x)51 O

OCN

(7) NCO O 21 -X) OCN O (X)'no O

O

(8) O 21 rol O NCO (X). O

O OCN

(9) NCO O

-O O (X) Srir O O OCN US 9,328,192 B2 17 18 -continued (10) O 21 -X) OCN

Olus -O O NCO (X) r r O O (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 Sr. ~" (14)

OCN

O O x 1 NR1n (15) NCO O -X) OCN O (X), US 9,328,192 B2 19 20 -continued (16) O -X) rC NCO (x),1 O OCN cr's (17) NCO O -X) OCN O Clu (X). --- O O (18)

O NCO (X).

OCN Crs (19)

O

(X) -O r r O O O OCN Or (20)

O

OCN rol NCO. Clus (X) -O r r O O O

In another embodiment, the present invention provides a In another embodiment, the present invention provides a novel diisocyanate selected from formulae (1)A-(20)A, novel R th A. St. which correspond to diisocyanates (1)-(20) except that each 6S O eac Xindependently is selected from the group consisting phenyl ring of (1)A-(22)A is independently substituted with —CHCOO (glycolic acid moiety); 1-4R, and provided that at least one R, is other than H. —CH(CH)COO (lactic acid moiety); US 9,328,192 B2 21 22 —CHCHOCHCOO— (dioxanone moiety); and, —CH2CH2OCHCOO— (dioxanone moiety); and, —CHCHCHCH-CHCOO (caprolactone moiety); —CH2CH2CHCH-CHCOO— (caprolactone moiety); each X" independently is selected from the group consist ing of each X" independently is selected from the group consist —OCH2CO (glycolic acid moiety); ing of —OCH(CH)CO— (lactic acid moiety); —OCH2CO— (glycolic acid moiety); —OCHCHOCH2CO (dioxanone moiety); and, —OCH(CH)CO— (lactic acid moiety); —OCH2CH2CHCH-CHCO— (caprolactone moiety); —OCHCHOCH2CO— (dioxanone moiety); and, and, —OCH2CH2CH2CH2CH2CO— (caprolactone moiety); provided that p-p' total from 2-6. 10 and, In another embodiment, the present invention provides a novel diisocyanate as described above, wherein: provided that p--p' total from 2-6. each p is independently selected from 0, 1, 2, 3, and 4; and, In another embodiment, the present invention provides a each p' is independently selected from 0, 1, 2, 3, and 4: novel polymer as described above, wherein: provided that p-p' total from 2-4. 15 each p is independently selected from 0, 1, 2, 3, and 4; and, In another embodiment, the present invention provides a each p' is independently selected from 0, 1, 2, 3, and 4: novel polymer, comprising: a polyurethane, polyester-ure thane, polyurea-urethane, or polyurea, formed by polymeriZ provided that p--p' total from 2-4. ing at least one diisocyanate as described above with a com In another embodiment, the present invention provides a pound selected from a diol, an ester-diol, diamide-diol and a novel polymeras described above, wherein: the polymer is a diamine. bioabsorbable polymer. In another embodiment, the present invention provides a In another embodiment, the present invention provides a novel polymer as described above, wherein: novel diamine selected from formula (IV), (V), or (VI):

(IV)

(V)

18's

(VI)

1N1it (X). 2

each Xindependently is selected from the group consisting wherein: of: variable A, the dashed bond, is absent or is a double bond; 65 R is independently the diacyl residue of a diacid; —CHCOO (glycolic acid moiety); R" is absent or each R" is independently a C- alkylene —CH(CH)COO (lactic acid moiety); group; US 9,328,192 B2 23 24 R" is the residue of a diol or polyol; each X" independently is selected from: from 1-4 R, are present: —OCHCO— (glycolic acid moiety); each R, is independently selected from: H. C. alkyl, C. —OCH(CH)CO— (lactic acid moiety); alkoxy, benzyloxy, halogen, —CHO. —COH, and —NO, —OCHCHOCH2CO— (dioxanone moiety); and each R, is independently attached directly to aromatic 5 —OCH2CH2CH2CH2CH2CO— (caprolactone moiety); ring or attached through a —(CH2) -linker, O(CH2)CO wherey is selected from 2,3,4, and 6-24: each X independently is selected from: and, —CHCOO (glycolic acid moiety); —O(CH2CH2O). CHCO— where Z is selected from 2-24: —CH(CH)COO (lactic acid moiety); each p is independently selected from 0, 1,2,3,4, 5, and 6: —CHCHOCHCOO— (dioxanone moiety); 10 and, —CH2CH2CHCH-CHCOO— (caprolactone moiety); each p' is independently selected from 0, 1,2,3,4, 5, and 6: -(CH2)COO wherey is selected from 2,3,4, and 6-24: provided that p--p' total from 0 to 12. and In another embodiment, the present invention provides a —(CHCHO). CHCOO where Z is selected from 2-24: novel diamine selected from formulae (IVa)-(VIa):

(IVa)

(Va)

NH (VIa) 2. N R it 1. o-No-1 ^en 21

S1 R N1 O NR1 R.N. (X), HN 2

In another embodiment, the present invention provides a novel diamine selected from formulae (IVa)-(VIa): (IVa) NH O N1. 2 1 i: 21 o1 X'ns 21

N s (X). RN 21 O

US 9,328,192 B2 27 28 In another embodiment, the present invention provides a novel diamine selected from formulae (IVa)-(VIa): O (IVal) R r (X)scp's O HN (IVa2) O c (X)"NR

O HN (Va.) NH2 O

R O a.

HN (Va2A)

R

R O O n c

HN (VIa)

O1 R no-1 (X) NR O

R O n c

HN US 9,328,192 B2 29 30 -continued (VIa2) NH2. O O1 R no-1 (X) NR

R O O O Nix-NR-1n HN

In another embodiment, the present invention provides a novel diamine selected from formulae (21)-(40):

21 O 21 -X)

O NH2 (x),1 O

HN 22 O 21 -X)

O NH2 Xes, O

O HN 23 O 21 -X) HN

Ol O O NH2 (X)1 ^o~ O O

24 O 21 o1 (X) HN

Ol O O NH2 (X), 1N1 US 9,328,192 B2 31 32 -continued 25 NH2 O 21 -X) HN O (X),1 O 26 O 21 -X)

O NH2 (x),1 O

HN 27 NH2 O (X) 21 o1 p HN O Xps, O

O

28 O 21 -X)

O NH2 Xes, O

O HN

29 NH2 O

(X),1 O ^r O O O HN US 9,328,192 B2 33 34 -continued 30

HN

O O Olus 1. NH2 (X), ^r O O 31

O

O O's (X),1. HN 32

HN 33

HN NH2 s^ ~ 34

HN

35

HN

(X),1 US 9,328,192 B2 35 36 -continued 36 O -X) rC NH2 (x),1 O HN cr's 37 NH2 O

HN Outs O

38 O

O

rol NH (X)p. O

HN Crs

NH2 O c (X) (x),.1 O ror O O O HN Or

40 O -X) HN NH2. O O Clus (X),1. ->~ O O US 9,328,192 B2 37 38 In another embodiment, the present invention provides a described above, wherein the tissue scaffold has a porous novel diamine selected from formulae (21)A-(40)A, which structure for the attachment and proliferation of cells either in correspond to diamines (21)-(40) except that each phenyl ring vitro or in vivo. of (21)A-(40)A is independently substituted with 1-4R, and In another embodiment, the polymer is further polymer provided that at least one R, is other than H. 5 ized on at least one end with at least one lactone monomer In another embodiment, the present invention provides a selected from the group consisting of glycolide, lactide, novel diamine as described above, wherein: caprolactone, p-dioxanone, TMC, 6-Valerolactone, 3-butyro each Xindependently is selected from the group consisting lactone, morpholinedione, pivalolactone, e-decalactone, 2.5- of: diketomorpholine and combinations thereof in order to con —CHCOO (glycolic acid moiety); 10 trol physical and biological properties. —CH(CH)COO (lactic acid moiety); In another embodiment, the present invention provides a —CHCHOCHCOO— (dioxanone moiety); and, novel article, comprising: a metal or polymeric Substrate and —CH2CH2CHCH-CHCOO— (caprolactone moiety); further comprising: at least one polymer described above, each X" independently is selected from the group consist wherein said article is selected from: ing of 15 a medical device, an implantable medical device, a phar —OCHCO (glycolic acid moiety); maceutical delivery system, a consumer product including —OCH(CH)CO— (lactic acid moiety); durable articles, a cosmetic, a tissue engineering application, —OCH2CHOCH2CO— (dioxanone moiety); and, a foam, a reticulated foam, a Suture, a bone hemostat, a bone —OCH2CH2CHCH-CHCO— (caprolactone moiety); filler, a bone void filler, a bone cement, a tissue adhesive, a and, tissue sealant, an adhesion prevention barrier, a mesh, a filter, provided that p-p' total from 2-6. a stent, a medical device coating, a pharmaceutical drug for In another embodiment, the present invention provides a mulation, a cosmetic packaging, a pharmaceutical packaging, novel diamine as described above, wherein: an apparel, an infusion device, a blood collection device, a each p is independently selected from 0, 1, 2, 3, and 4; and, skin care product, and a transdermal drug delivery material, each p' is independently selected from 0, 1, 2, 3, and 4: 25 drug delivery matrices, pharmaceutical drug formulations, provided that p-p' total from 2-4. tissue engineering, tissue adhesives, adhesion prevention bar In another embodiment, the present invention provides a riers, and other implantable medical devices including foams novel polymer, comprising: polyamide, polyester amide, for wound healing and/or drug delivery, bone hemostats, bone polyepoxide, or polyurea formed by polymerizing at least one fillers, bone void fillers, bone wax formulations, tissue adhe diamine as described above with a compound selected from a 30 sives and Sealants, adhesion prevention barriers, meshes, fil dicarboxylic acid, diepoxide, and diisocyanate. ters, Surgical devices, medical device coatings, cosmetic and In another embodiment, the present invention provides a pharmaceutical packaging, apparel, infusion devices, blood novel polymer as described above, wherein: collection tubes and devices, tubes, skin care products, trans each Xindependently is selected from the group consisting dermal drug delivery, consumer product packaging, and dis of: 35 posable medical devices, knitted products, foodstuffs, nutri —CHCOO (glycolic acid moiety); tional Supplements, nutraceuticals, biodegradable chewing —CH(CH)COO (lactic acid moiety); gums, and reinforced composites. —CHCHOCHCOO— (dioxanone moiety); and, In another embodiment, the metal or polymeric substrate —CH2CH2CHCH-CHCOO— (caprolactone moiety); has a coating, comprising: the at least one polymer, wherein each X" independently is selected from the group consist 40 said article is Suitable for contacting mammalian tissue. ing of In another embodiment, the article is an implantable medi —OCHCO (glycolic acid moiety); cal device. —OCH(CH)CO— (lactic acid moiety); In another embodiment, the article is reticulated foam for —OCH2CHOCH2CO— (dioxanone moiety); and, wound healing and/or controlled drug delivery. —OCH2CH2CHCH-CHCO— (caprolactone moiety); 45 In another embodiment, the present invention provides a and, novel Surgical article or component thereof or polymeric car provided that p-p' total from 2-6. rier, comprising: a polymer described above, wherein the In another embodiment, the present invention provides a article is selected from: novel polymer as described above, wherein: a stent, stent coating, wound covering, burn covering, each p is independently selected from 0, 1, 2, 3, and 4; and, 50 foam, highly porous foams, reticulated foams, tissue engi each p' is independently selected from 0, 1, 2, 3, and 4: neering scaffold, film, adhesion prevention barrier, implant provided that p-p' total from 2-4. able medical device, controlled drug delivery system, Suture, In another embodiment, the present invention provides a ligature, needle and Suture combination, Surgical clip, Surgi novel polymeras described above, wherein: the polymer is a cal Staple, Surgical prosthesis, textile structure, coupling, bioabsorbable polymer. 55 tube, Support, screw, pin, bone wax formulation or an adhe In another embodiment, the present invention provides a sion prevention barrier. novel controlled drug delivery system comprising: In another embodiment, the present invention provides a (a) one or more of the polymers described above, and novel Surgical article or component thereof as described (b) one or more biologically or pharmacologically active above, wherein a biologically active agent is physically agents. 60 embedded or dispersed into the polymer matrix of the con In another embodiment, the present invention provides a trolled delivery system. novel controlled drug delivery system described above, In another embodiment, the present invention provides wherein the one or more biologically or pharmacologically methods of making novel bio-based materials. active agents are physically embedded or dispersed in a poly In another embodiment, the present invention provides meric matrix, comprising: the one or more polymers. 65 novel bio-based castor oil or soybean oil derived hydroxyl In another embodiment, the present invention provides a acids diacids, diamines, and diisocyanates and polymers novel tissue scaffold, comprising: one or more polymers formed therefrom that include bio-based polyamides, poly US 9,328,192 B2 39 40 ureas, polyepoxides, polyester amides, and polyurethanes. In another embodiment, in the synthesis of a diisocyanate These polymers can be biodegradable or biostable. described in the above Bezwada Biomedical Patents, the 4-ni In another embodiment, the present invention provides trophenol (ortho, meta, para) can be replaced by 4-NO novel bioabsorbable and biodegradable polyamides contain phenyl-CH-OH and/or 4-NO-phenyl-CH2CH2OH. Simi ing repeating units based on the novel aromatic di-amine larly, the 4-nitrobenzoic acid (ortho, meta, para) can be monomeric units of the present invention. Methods for pre replaced by 4-NO-phenyl-CHCO2H and/or 4-NO-phenyl paring the novel biodegradable and biocompatible polya CHCHCO.H. Alternatively, the 4-nitrophenol can be mides are also provided. replaced or substituted with 4-NO-(aromatic ring)-P OH In another embodiment, the present invention provides and 4-NO-(aromatic ring)-P OH. Similarly, the 4-ni novel biodegradable and biocompatible polymers having a 10 trobenzoic acid can be replaced or substituted with 4-NO (aromatic ring)-P COH and 4-NO-(aromatic ring)-P - controllable degradation profile. These polymers are useful COH wherein the aromatic rings can be monocyclic, for medicinal and therapeutic uses, such as tissue engineer bicyclic or polycyclic. The aromatic rings can also be fused. 1ng. The aromatic rings can also be heterocyclic containing non In another embodiment, the present invention provides 15 carbon ring atoms such as oxygen, nitrogen and Sulfur. P is novel aromatic diisocyanates. selected from an alkylene, alkylene-arylene, and an alicyclic In another embodiment, the present invention provides chain. Further, the present invention also provides hydrolys novel absorbable and/or biodegradable polyurethanes and able diisocyanates derived from these molecules further func polyurethane esters containing repeating units based on the tionalized with one or more groups selected from glycolic novel aromatic diisocyanates of the present invention. Meth acid, lactic acid, caprolactone, and a p-dioxanone moiety. The ods for preparing the novel biodegradable and biocompatible positions of nitro to hydroxyl or carboxyl can be ortho meta or polyurethanes and polyurethane esters are also provided. para on the aromatic ring. The present invention also provides In another embodiment, the present invention provides absorbable polyurethanes derived from the above diisocyan novel bio-based novel biodegradable and biostable aliphatic ates. polyester polyols. 25 In another embodiment, the present invention provides In another embodiment, the present invention provides absorbable polyurethane foams with open and closed cell novel biobased and/or biodegradable, biocompatible and structures, including reticulated foams, foams with vertical absorbable a polyurethane and polyurethane esters contain channels, architecturally gradient foams, trans-composi ing repeating units based on the novel diisocyanate-contain tional foams, and trans-structural foams and the process of ing monomeric units of the present invention. The diisocyan 30 preparing these absorbable foams using the novel hydrolys ates used to prepare polyurethanes and polyurethane esters able diisocyanates, diamines, biodegradable and biocompat can also be aliphatic or cycloaliphatic. Methods for preparing ible polyurethanes described herein. Optionally the novel such biobased and/or biodegradable and absorbable aliphatic hydrolysable diisocyanates, diamines, biodegradable and and aromatic polyurethanes and polyurethane esters are also biocompatible polyurethanes described herein are used in provided. 35 combination with those described in patents/patent publica In another embodiment, the novel diisocyanates, diamines, tions U.S. Pat. No. 7,772,352, U.S. Pat. No. 8,048,980, U.S. biodegradable and biocompatible polyurethanes, and biode Pat. No. 8,143,325, U.S. Pat. No. 8,367,747, US 2010/ gradable and biocompatible polyamides of the present inven 0260702 A1, US 2009/0292029 A1, US 2009/0082540, US tion can be used in combination with those described in 2006/0288547 A1, EP 1937182 B1, EP 2298.235 A1, EP patents/patent publications U.S. Pat. No. 7,772,352, U.S. Pat. 40 1937182 A4 EP 1937182 A2, and WO 27030464 A2, all of No. 8,048,980, U.S. Pat. No. 8,143,325, U.S. Pat. No. 8,367, which have been assigned to Bezwada Biomedical, and U.S. 747, US 2010/0260702A1, US 2009/0292029A1, US 2009/ Pat. No. 4,829,099, assigned to Fuller, et al., via lyophiliza 0082540, US 2006/0288547 A1, EP 1937182 B1, EP tion wherein the bioabsorbable polyurethane polymers and/ 2298235 A1 EP 1937182 A4, EP 1937182 A2, and WO or blends thereofare dissolved in a suitable solvent including 27030464 A2, all of which have been assigned to Bezwada 45 dioxane, N-methylpyrrolidone, dichloromethane and/or mix Biomedical (Bezwada Biomedical Patents), and U.S. Pat. No. tures thereof, to form a homogeneous solution which is Sub 4,829,099 assigned to Fuller, et al., for use drug delivery jected to a lyophilization process, comprising: a solution of a matrices (e.g., controlled drug delivery), pharmaceutical drug bioabsorbable elastomer in a solvent which is substantially, formulations, tissue engineering, tissue adhesives, adhesion but not necessarily completely, solidified, then the solvent is prevention barriers, and other implantable medical devices 50 removed from that which is lyophilized under reduced pres including but not limited to tissue engineering scaffolds, Sure to form a foam. foams (including reticulated foams, lyophilized foams, In another embodiment, the novel diisocyanates of the highly porous foams, regular foams, foams with vertical present invention provide a true reticulated, flexible, and channels, architecturally gradient foams, trans-composi resilient, bioabsorbable elastomeric matrix, suitable for tional foams, and trans-structural foams) for wound healing 55 implantation and having Sufficient porosity to encourage cel and/or drug delivery, bone hemostats, bone fillers, bone void lular ingrowth and proliferation in vivo. fillers, bone wax formulations, tissue adhesives and Sealants, In another embodiment, the present invention provides a adhesion prevention barriers, meshes, filters, Surgical devices polymerization process for preparing a bioabsorbable reticu (e.g., Stents, staples, Sutures (e.g., monofilament and mul lated elastomeric matrix, comprising the steps of tifilament Sutures), Screws (e.g., orthopedic screws), sheets, 60 (1) admixing plates, clips, films, staples, pins, tubes, and molded devices), a) a polyol component, medical device coatings (e.g., stent coatings), cosmetic and b) a diisocyanate component, pharmaceutical packaging (e.g., blister packaging films, cast c) a blowing agent, films, extruded films and containers), apparels, infusion d) optionally, a crosslinking agent, devices, blood collection tubes and devices, tubes, skin care 65 e) optionally, a chain extender, products, transdermal drug delivery, consumer product pack f) optionally, one or more catalysts, aging, and disposable medical devices. g) optionally, one or more cell openers, US 9,328,192 B2 41 42 h) optionally, a Surfactant, and invention provides methods for closing wounds in living tis i) optionally, a viscosity modifier, Sue by use of novel, metabolically-acceptable Surgical adhe to provide a crosslinked elastomeric matrix, and sives having low toxicity. (2) reticulating the elastomeric matrix by a reticulation In another embodiment, the invention provides diamines process to provide the reticulated elastomeric matrix. The 5 that can provide hydrophilic bioabsorbable polyester amides ingredients are present in quantities and the elastomeric that are biocompatible and useful for bioabsorbable sutures, matrix is prepared under conditions So as to: (i) provide a Staples clips, and adhesion prevention barriers. crosslinked resiliently-compressible absorbable elastomeric In another embodiment, the invention provides novel poly matrix, (ii) control formation of biologically undesirable resi urethanes, polyesters, and polyester amides that are biode dues, and (iii) reticulate the foam by a reticulation process, to 10 gradable and biocompatible and useful for tissue engineering, provide the reticulated elastomeric matrix. In another embodiment, the invention provides a lyo drug delivery, tissue adhesives, adhesion prevention, and philization process for preparing a reticulated elastomeric other implantable medical devices. matrix, comprising: lyophilizing a flowable polymeric mate In another embodiment, the invention provides novel rial. 15 hydrolysable diisocyanates for use in the formation of poly In another embodiment, the polymeric material, com urethanes and other polymers. prises: a solution of a solvent-soluble absorbable elastomer in In another embodiment, the invention provides novel a solvent. hydrolysable branched diisocyanates with pendant long chain In another embodiment, the flowable polymeric material is alkyl groups that are hydrophobic or pendant long chain PEG Subjected to a lyophilization process, comprising: Solidifying that are hydrophilic. the flowable polymeric material to form a solid, e.g., by In another embodiment, the invention provides novel bio cooling a solution, then removing the non-polymeric mate absorbable polyesters, polyurethanes, polyureas, and polyes rial, e.g., by evaporating the solvent from the Solid under ter amides that can be further polymerized with lactone reduced pressure, to provide an at least partially reticulated monomers. Examples of lactone monomers include gly elastomeric matrix. 25 collide, lactide, caprolactone, p-dioxanone, TMC (trimethyl In another embodiment, a solution of a absorbable elas ene carbonate), Ö-Valerolactone, B-butyrolactone, morpho tomer in a solvent is substantially, but not necessarily com linedione, pivalolactone, e-decalactone, 2.5- diketomorpholine, and combinations thereof. These lactone pletely, solidified, then the solvent is evaporated from that monomers allow one to control physical and biological prop material to provide an at least partially reticulated elastomeric erties. matrix. 30 In another embodiment, the temperature to which the solu As noted above, the bio-based monomers of the present tion is cooled is below the freezing temperature of the solu invention, which have at least two reactive sites, can be poly tion. merized with difunctional molecules (e.g., dialcohols (diols), In another embodiment, the temperature to which the solu ester-diols, diamide-diols, diamines, dicarboxylic acids (di tion is cooled is above the apparent glass transition tempera 35 acids), dieXopides, and diisocyanates) to form polymers of ture of the solid and below the freezing temperature of the the present invention, including polyurethanes, polyester Solution. urethanes, polyurea-urethanes, polyureas, polyamides, poly In another embodiment, the present invention provides a ester amides, and polyepoxides by simple polycondensation lyophilization process for producing an elastomeric matrix reactions. having a reticulated structure, the process comprising the 40 Examples of diols that can be used to form polymers with steps of: the bio-based monomers of the present invention have the a) forming a solution comprising a solvent-soluble absorb following structure: able elastomer in a solvent; b) at least partially solidifying the solution to form a solid, HO R OH optionally by cooling the Solution; and 45 wherein R is independently selected from: alkylene, c) removing the non-polymeric material, optionally by cycloalkylene-alkylene, arylene-alkylene, arylene-alkylene evaporating the solvent from the solid under reduced arylene, cycloalkylene-alkylene-cycloalkylene, and arylene pressure, to provide an at least partially reticulated elas alkylene-cycloalkylene, wherein: tomeric matrix comprising the elastomer. (1) one or more of the methylene (—CH2—) moieties in In another embodiment, the invention provides a process 50 the alkylene chain portions of the R group are optionally for preparing a reticulated composite elastomeric implantable replaced by —O— or —S—; or device for implantation into a patient, the process comprising: (2) one or more of the ethylene ( CHCH ) moieties in Surface coating or endoporously coating a absorbable reticu the alkylene chain portions of the R group are optionally lated elastomeric matrix with a coating material selected to replaced by a carboxyl group ( C(=O)C)— or —OC encourage cellular ingrowth and proliferation. The coating 55 (=O)—). material can, for example, comprise: a foamed coating of Alternatively, polyalkylene oxides having weight average absorbable polyurethane and optionally, collagen, fibronec molecular weights from about 500-10,000 can be used as a tin, elastin, hyaluronic acid or a mixture thereof. Alterna diol (i.e., a polydiol). Examples of suitable diols or polydiols tively, the coating comprises: absorbable polyurethane and an for use in the present invention are diols with up to 8 carbon inorganic component (e.g., calcium carbonate, tricalcium 60 atoms ordiols having repeating units each with up to 8 carbon phosphate, magnesium carbonate, as well as other inorganic atoms. Examples of suitable diols include 1.2-ethanediol salts). (ethylene glycol); 1,2-propanediol (propylene glycol); 1,3- In another embodiment, the invention provides novel, safe, propanediol, 1,4-butanediol; 1.5-pentanediol; 1.3-cyclopen bio-based, biocompatible and absorbable aromatic diisocy tanediol; 1.6-hexanediol: 1,4-cyclohexanediol: 1.8-oc anate-based adhesives. For example, such adhesives are 65 tanediol; and, combinations thereof. Examples of polydiols metabolically-acceptable Surgical adhesives and have con include polyethylene glycol and polypropylene glycol with trollable degradation profiles. In another embodiment, the weight average molecular weights of 500-10,000. US 9,328,192 B2 43 44 Examples of ester-diols that can be used to form polymers The biological properties of the bioabsorbable polymers of with the bio-based monomers of the present invention have the present invention used to form devices or parts thereof, as the following structure: measured by its absorption rate and its breaking strength retention in vivo (BSR), can be varied to suit the needs of the HO R OH particular application for which the fabricated medical device wherein R is defined previously, provided that R contains at or component is intended. This can be conveniently accom least one internal carboxyl group (C(O)O). plished by varying the ratio of components of the polymer Examples of diamide-diols that can be used to form poly chosen. mers with the bio-based monomers of the present invention The materials (e.g., polymers) of the present invention are have the following structure: 10 comprise: cleavable sites (e.g., see the X group of the struc tures provided herein). Depending on the formation route HO. R OH selected, these cleavable sites may be regular along the length wherein R'-R as defined previously, provided that two or of a chain extender, thereby giving the segmented polyure more of the ethylene ( CHCH ) moieties in the alkylene thane or polyester or the like a biodegradability that is, by chain portions of the R group are replaced by amide groups 15 Some measure, predictable. (C(O)NH or NHC(O)). Biodegradability is influenced by a number of factors, Examples of diamines that can be used to form polymers including crystallinity. The hydrophilicity of the polymer with the bio-based monomers of the present invention include may also influence the degradability, that is, the extent to have the following structure: which water is accessible to the polymer matrix. The number of cleavage sites may also influence biodegradability. Gener ally speaking, the higher the number of cleavage sites, the wherein R is as defined previously. Alternatively, polyalky greater the rate of degradation. Typically, the cleavable site is lene oxides that are diamines with weight average molecular an ester site. For example, the cleavable ester site can be weights from about 500-5,000 can be used. derived from a hydroxy acid precursor. This provides seg Examples of dicarboxylic acids that can be used to form 25 mented polyurethanes and polyesters or the like with cleav polymers with the bio-based monomers of the present inven able sites that may be arranged to be recognizable by tion have the following structure: enzymes. HOOC- R COOH The polyester amides of the present invention may be pre pared by reacting an amide acid of the present invention with wherein R is as defined previously. 30 diols in the presence of an organometallic catalyst at elevated Examples of diepoxides that can be used to form polymers temperatures. The organometallic catalyst is typically a tin with the bio-based monomers of the present invention have based catalyst, e.g. stannous octoate, and is present in the the following structure: monomer mixture at a mole ratio of monomer-to-catalyst ranging from 15,000 to 80,000/1. The polymerization is typi 35 cally carried out at a temperature ranging from 120-200°C. or 160-190°C., until the desired molecular weight and viscosity D-R-CI are achieved. The polyurethanes and other polymers of the present wherein R is as defined previously. invention may be prepared by reacting the diisocyanates of Examples of diisocyanates that can be used to form poly 40 the present invention with a branched chain extender or a mers with the bio-based monomers of the present invention chain extender and polyols of the present invention and/or have the following structure: generic polyols including polyethylene glycols, polyesterdi ols, and polyetherdiols. OCN R NCO The polyamides of the present invention may be prepared wherein R is as defined previously. Other examples include 45 by reacting diamines of the present invention with diacids of hexamethylene diisocyante, lysine diisocyanate, methylene the present invention and/or generic diacids including poly diphenyl diisocyanate (e.g., MDI), methylene dicyclohexyl ethylene diacids, polyesterdiacids, and polyetherdiacids. diisocyanate, and isophorone diisocyanate. The polyepoxides of the present invention may be prepared In another embodiment, the present invention provides by reacting diamines of the present invention with epoxides. polymers from which a medical device or a component of the 50 In another embodiment, the present invention provides device is formed, and the polymers exhibit a percent elonga monomers wherein the diisocyanate groups are replaced with tion greater than about 200 or even greater than about 500. isothiocyanates; and polymers produced therefrom. Specifi The polymers can also exhibit a modulus (Young's Modulus) cally, this embodiment of the invention is directed to isothio of less than about 40,000 psi, or even less than about 20,000 cyanate analogs of the above. psi. These properties, which measure the degree of elasticity 55 In another embodiment, the present invention provides of the bioabsorbable elastomer, are achieved while maintain novel biodegradable and biocompatible aliphatic and cyclic ing a tensile strength greater than about 500 psi, or even aliphatic diisocyanate-based monomers. Examples of cyclic greater than about 1,000 psi, and a tear strength of greater than aliphatic diisocyanate-based monomers are the cyclohexane about 50 lbs/inch, or even greater than about 80 lbs/inch containing compounds which are related to their aromatic Generally the functionality of the aromatic monomers is 60 counterparts formally by reduction of the benzene rings to selected from amine- and/or carboxylic acid-containing phe cyclohexane rings. The polymers prepared from Such satu nols, such as amino phenols and amino Salicylic acids, and rated monomers have beneficially reduced color, improved from amino benzoic acids, (4-aminophenyl)methanol, 2-(4- transparency and are non-yellowing. aminophenyl)ethanol. 2(4-aminophenyl)acetic acid, and Examples of cyclic aliphatic diamine-based monomers are 3-(4-aminophenyl)propionic acid as Summarized below. Gly 65 the cyclohexane-containing compounds, which are related to colic acid is used as a functionalization moiety for purposes of their aromatic counterparts 21-40 formed by reduction of the illustration. benzene rings to cyclohexane rings. As for the corresponding US 9,328,192 B2 45 46 cycloaliphatic diisocyanate monomers, the polymers pre ing bioabsorbable Surgical devices with a longer absorption pared from Such saturated diamine monomers have benefi profile (slower hydrolysis) compared to polyglycolic acid. cially reduced color, improved transparency and are non The bioabsorbable surgical devices made from 1,4-dioxan-2- yellowing. one have proved to be biologically safe, and biocompatible. A beneficial property of the polymers of the present inven 5 The process of attaching an open chain p-dioxanone moiety tion that contain ester linkages is that the ester linkages are to a phenolic compound is defined as dioxonation. hydrolytically unstable, and therefore the polymer is absorb Embodiments of the new functionalized bio-based able because it readily breaks down into Small segments when diamines and diisocyanates have controllable hydrolysis pro exposed to moist bodily tissue. files, improved bioavailability, improved efficacy, and When any variable occurs more than one time in any con 10 enhanced functionality. The difunctional compounds of the stituent or in any formula, its definition in each occurrence is present invention can readily polymerize into biodegradable independent of its definition at every other occurrence. Com polyamides, polyesters, polyureas, polyepoxides, polyestera binations of substituents and/or variables are permissible mides and polyurethanes, which are useful for many applica only if such combinations result in stable compounds. Within tions that are described herein. the context of the present invention, compounds are stable if 15 “Absorbable' refers to a monomer or product derived they do not degrade significantly prior to their intended use therefrom that readily reacts or enzymatically degrades upon under normal conditions. In some instances, compounds of exposure to bodily tissue for a relatively short period of time, the invention may be designed or required to be bioabsorbed thus providing a significant weight loss of the original mate or biodegraded as part of their intended function. Absorbabil rial in that short time period. Examples of time periods ity and/or biodegradability, which may be an advantageous include, up to 12 months, up to 9 months, 3-9 months, up to 6 property of the present polymers, is not intended to mean that months, and 2-8 weeks. Therefore, the polymers of the the polymeric compound are unstable. present invention can be fabricated into medical and Surgical It is believed the chemical formulas and names used herein devices, foams, bioadhesives, coatings, etc., (described pre correctly and accurately reflect the underlying chemical com viously) that are useful for a vastarray of applications requir pounds. However, the nature and value of the present inven 25 ing complete absorption within the relatively short time peri tion does not depend upon the theoretical correctness of these ods as defined above. formulae, in whole or in part. Thus it is understood that the "Monomers' includes macromers, unless the context formulas used herein, as well as the chemical names attrib clearly indicates otherwise. uted to the correspondingly indicated compounds, are not “Elastomer' is a material that at room temperature can be intended to limit the invention in any way, including restrict 30 stretched repeatedly to at least twice its original length and, ing it to any specific tautomeric form, except where such limit upon immediate release of the stress, will return with force to is clearly defined. its approximate original length. Precursors of the Compounds and Monomeric Units “Prepolymer is a low molecular weight polymer usually Glycolic acid and lactic acid are known as alpha-hydroxy an intermediate between that of the monomer and the final acids (AHAs) and are present in fruits and other foods. The 35 polymer that is capable of further polymerization. chemical formula of glycolic acid is HOCHCOOH. This "Monomeric unit is defined as a small molecule that can compound is biodegradable. When glycolic acid is heated it chemically react with other monomers to form a polymer. readily loses water by self-esterification to form polyglycolic “Polymer is a molecule that is formed by joining repeat acid. Glycolic acid can function as both an acid and an alco ing monomeric units. The polymers of the present invention hol. This dual functionality leads to a variety of chemical 40 can be, without limitation, linear, branced, star or comb poly reactions and valuable physical properties. Many Surgical CS. devices are made from polyglycolic acid. The process of A“biologically active' is a Substance that can act on a cell, attaching a glycolic acid moiety to a phenolic compound is virus, organ, or organism, including but not limited to drugs defined as glycolation. (i.e., pharmaceuticals) to create a change in the functioning of Lactic acid is a fermentation product of lactose. It is present 45 the cell, virus, organ, or organism. In certain embodiments of in Sour milk, koumiss, leban, yogurt, and cottage cheese. the invention, the biologically active Substances are organic Lactic acid is also produced in the muscles during intense molecules having molecular weight of about 600 or less, or activity. Many Surgical and orthopedic devices are made from are polymeric species such as proteins, nucleic acids, and the polylactic acid. The esters of lactic acid are useful as emul like. A biologically active Substance can be a substance used Sifying agents in baking foods; examples include Stearoyl-2- 50 for therapy of an animal, preferably a human. In the present lactylate, glyceryl lactostearate, and glyceryl lactopalmitate. invention, a biologically active Substance bears, or has a func The process of attaching a lactic acid moiety to a phenolic tional homolog that bears, one or more hydroxyl, amino, compound is defined as lactolation. and/or carboxylic acid Substituents, including functional Epsilon-caprolactone is a reactive cyclic monomer, and the derivatives such as esters, amides, methyl ethers, glycosides, polymers derived therefrom are useful for tailoring specialty 55 and other derivatives that are apparent to those skilled in the polyols and hydroxy-functional polymer resins with art. Examples of biologically active compounds that can be enhanced flexibility. The monomer polymerizes under mild used in the present invention include Capsaicin, Vitamin E, conditions to give low viscosity products Superior to conven Resveratrol, and isoflavonoids. tional aliphatic polyesters. Copolymers of caprolactone with Alkyl refers to an optionally substituted, saturated glycolide and lactide exhibit unique physical and biological 60 straight, or branched hydrocarbon moiety having from 1-20 properties as well as different hydrolysis profiles based on the carbon atoms (and all combinations and Subcombinations of composition of the monomers. The process of attaching an ranges of carbonatoms and specific numbers of carbonatoms open chain e-caprolactone moiety to a phenolic compound is therein). Examples of ranges of carbon atoms include 1-8, defined as caprolation. 1-6, and 1-4. Examples include methyl, ethyl, n-propyl, iso p-Dioxanone (1,4-dioxan-2-one) is a cyclic monomer, and 65 propyl. n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopen polymers are made therefrom via ring opening polymeriza tyl, n-hexyl, isohexyl, 3-methylpenty1, 2,2-dimethylbutyl, tion. Polyesters derived from this monomer are used in mak and 2,3-dimethylbutyl. US 9,328,192 B2 47 48 Alkylene' refers to a bivalent alkyl moiety having the arylene and cycloalkylene groups has one open bonding site, general formula —(CH), , where n is from 1 to 150. wherein arylene, cycloalkylene, and alkylene are as previ Examples of carbon ranges include 1-20, 1-16, and 1-10. By ously defined. Arylenealkylenecycloalkylene' includes bivalent, it is meant that the group has two open sites each of moieties having -arylene-alkylene-cycloalkylene- and which bonds to another group. Examples include methylene, 5 cycloalkylene-alkylene-arylene-bonding orders or configu ethylene, trimethylene, pentamethylene, and hexamethylene. rations. Alkylene groups can be optionally Substituted with alkyl, “Chain Extenders.” The nature of the chain extendergroup wherein alkyl is as previously defined. “Lower alkylene’ in the polymers of the present invention can vary provided herein refers to those alkylene groups having from 1-6 carbon that the polymer of the invention possesses acceptable atOmS. 10 mechanical properties and release kinetics for the selected Aryl refers to an optionally substituted, mono-, di-, tri-, therapeutic application. The chain extendergroup R* is typi or other multicyclic aromatic ring system moiety having from cally a divalent organic radical having a molecular weight of 6-50 carbon atoms (and all combinations and subcombina about 60 to about 5000. Additional examples include R* tions of ranges of carbon atoms and specific numbers of having a molecular weight of about 100 to about 1000, and carbon atoms therein). Examples of ranges of carbon atoms 15 may contain oxygenatoms, Sulfur atoms and/or ester groups. include 6-10. Examples include phenyl, naphthyl, anthrace The chain extendergroup may be biologically inactive, or nyl, and phenanthrenyl. may itself possess biological activity. The chain extender Arylene' refers to a bivalentaryl moiety, wherein aryl is as group can also be a polyalkylene oxide, such as polyethylene previously defined. The ring system may be monocyclic or oxide. The chain extendergroup can also be polyester derived fused polycyclic (e.g., bicyclic, tricyclic, etc.). An example is from at least one lactone monomer, such as glycolide, lactide, phneylene. In various embodiments, the arylene, e.g., phe p-dioxanone, trimethylenecarbonate, or caprolactone. The nylene, may be a 1.2-, 1.3-, or 1.4-substituted moiety. chain extender group can also comprise other functional “Cycloalkyl refers to an optionally substituted, mono-, groups (including hydroxy groups, amine groups, carboxylic di-, tri-, or other multicyclic alicyclic ring system moiety acids, and the like) that can be used to modify the properties having from 3-20 carbon atoms (and all combinations and 25 of the polymer (e.g. for branching, for cross linking). Subcombinations of ranges of carbonatoms and specific num When any variable occurs more than one time in any con bers of carbon atoms therein). Examples of carbon ranges stituent or in any formula, its definition in each occurrence is include 3-8, and 3-6. Multi-ring structures may be bridged or independent of its definition at every other occurrence. Com fused ring structures, wherein the additional groups fused or binations of substituents and/or variables are permissible bridged to the cycloalkyl ring may include optionally Substi 30 only if such combinations result in stable compounds. Within tuted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl rings. the context of the present invention, compounds are stable if Examples of cycloalkyl groups include cyclopropyl, cyclobu they do not degrade significantly prior to their intended use tyl, cyclopentyl, cyclohexyl, cyclooctyl, adamanty1, 2-4-iso under normal conditions. In some instances, compounds of propyl-1-methyl-7-Oxa-bicyclo2.2.1]heptanyl, and 2-1.2. the invention are may be designed or required to be bioab 3,4-tetrahydro-naphthalenyl. 35 sorbed or biodegraded as part of their intended function. “Cycloalkylene' refers to a bivalent cycloalkyl moiety, Absorbability and/or biodegradability, which may be an wherein cycloalkyl is as previously defined. Cycloalkylene is advantageous property of the present polymers, is not a type of alkylene group which is a cycloalkyl group with two intended to mean that the polymeric compound are unstable. open bonding sites. Bio-Based Polyester and Polyesteramide Polyols and Meth “Cycloalkylenealkylene' refers to a bivalent moiety, 40 ods of Preparation Thereof wherein a cycloalkylene group is bonded to a non-cyclic alkylene group, wherein each of the cycloalkylene and non cyclic alkylene groups has one open bonding site, and O wherein cycloalkylene and alkylene are each as previously defined. “Cycloalkylenealkylene' includes moieties having 45 21 OH -cycloalkylene-alkylene-and-alkylene-cycloalkylene-bond ing orders or configurations. Arylenealkylene' refers to a bivalent moiety, wherein an arylene group is bonded to a non-cyclic alkylene group, and OH each of the arylene and non-cyclic alkylene group has one 50 O open bonding site, wherein arylene and alkylene are each as previously defined. Arylenealkylene' includes moieties having -arylene-alkylene- and -alkylene-arylene-bonding OH orders or configurations. Arylenealkylenearylene' refers to bivalent moieties, 55 wherein two arylene groups are bonded to a non-cyclic alky OH lene group, and each of the arylene groups has one open O bonding site, wherein arylene and alkylene are each as pre viously defined. 21 OH “Cycloalkylenealkylenecycloalkylene' refers to a bivalent 60 moiety, wherein two cycloalkylene groups are bonded to a non-cyclic alkylene group, and each of the cycloalkylene O groups has one open bonding site, wherein cycloalkylene and O alkylene are each as previously defined. HO Arylenealkylenecycloalkylene' refers to a bivalent moi 65 ety, wherein an arylene and a cycloalkylene group are each O bonded to a non-cyclic alkylene group, and each of the US 9,328,192 B2 49 50 -continued -continued HO 1N1N1 OH 2N-1-N-1-N-NH2

OH 5 O

HN OH O ch HO NH2 10 O O Using the above bio-based monomers, one can make bio OH OH based polyester and polyamide ester polyols for the prepara HO HO 15 tion of bio-based polyurethanes. Examples of bio-based poly O ols that can be prepared are shown below (BDO=1,4-butane diol): r O HO N sci cO R O r O O O HO o c

O O O

21 OH

O

O O

O HO c O

OH

O

O O HO c US 9,328,192 B2 51 52 -continued O O

O O O O

O

21 OH

O

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

HO 21

O O

OH

O

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

HO

O O

21 OH

O -- + 14 Butanediol -> O

HO 21

O Polyester Diol (100% Bio-derived) US 9,328,192 B2

-continued O

OH

O

O O + 14 Butanediol ->

O

HO

O Polyester Diol (100% Bio-derived) O

21 OH

O

O Functionalized O 14 Butanediol O

HO 21

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

OH

O

O Functionalized O 14 Butanediol O

HO

O Polyester Diol (100% Bio-derived, bioabsorbable Polymer) wherein functionalized 1,4-butanediol is prepared by react able physical and chemical properties. The polymers are ing 1,4-butanediol with lactic acid, glycolic acid, p-diox 55 readily processed into pastes or can be solvent cast to yield anone and/or caprolactone. films, coatings, microspheres and fibers with different geo In another embodiment, copolymers of absorbable poly metric shapes for the design of various medical implants, and mers of the present invention can be prepared by preparing a may also be processed by compression molding and extru prepolymer under melt poly-condensation conditions, fol 60 lowed by adding at least one lactone monomer or lactone Sion. prepolymer. The mixture is then subjected to the desired Polyamides, polyesters, polyureas, polyepoxides, polyes conditions of temperature and time to copolymerize the pre teramides, and polyurethanes prepared in accordance with polymer with the lactone monomers. the present invention have average molecular weights of The polymers of the invention are prepared in accordance 65 about 1500 to about 100,000 calculated by Gel Permeation with methods commonly employed in the field of synthetic Chromatography (GPC) relative to narrow molecular weight polymers to produce a variety of useful products with valu polystyrene standards. Other examples of Polyamides, poly US 9,328,192 B2 55 56 esters, polyureas, polyepoxides, polyesteramides, and poly- These diisocyanates can also be reacted with diamines urethanes have average molecular weights of about 1500 up (HN R NH) to prepare biodegradable polyureas to about 40,000. The diamines of this invention can also be reacted with Processes for preparing polyamides of the invention are diepoxides to prepare biodegradable polyepoxides. provided as further embodiments of the invention and are 5 The mechanical properties. Such as ultimate tensile illustrated by the following general method: strength, of the polyurethanes of the present invention can in

NH2 O 21 O HN + HOOC-R-COOH -- Polyamide

O O Recinoleic acide based amine NH2 O O O

HN + HOOC-R -COOH -> Polyamide

O

O 12-Hydroxy Steric acid based amine

The diamines can also be reacted with diisocyanates Some cases be influenced primarily by the polyol component (OCN R NCO) to prepare biodegradable polyureas. 35 as opposed to the hard segment as in typical segmented poly Processes for preparing polyurethanes of the invention are urethanes. provided as further embodiments of the invention and are One type of polyurethane of the present invention is the illustrated by the following general procedure: type known as segmented polyurethane, which is character

NCO O 21 O OCN + HO-R-OH -> Polyurethane

O O Recinoleic acide based amine NCO O O O

OCN + HO-R-OH -> Polyurethane

O

O 12-Hydroxy Steric acid based amine US 9,328,192 B2 57 58 ized by a formation of repeating soft and hard blocks formed In another embodiment, Substantially non-toxic degrad from a polyol component, a diisocyanate component, and an able polyurethanes can be formed from amino acids and optional chain extender, and can occur in a linear, branched or Substantially non-toxic diols, in Such a manner, to be useful as networked form. The chain extender may be reacted with the biomaterials for a variety of applications such as artificial previously synthesized pre-polymer to generate a high 5 skin, wound dressings, tissue engineering scaffolds and the molecular weight polymer, polyurethane for example. How like. The polyurethane materials may be formed by melt or ever, the formation of polyurethanes may also be carried out Solvent processing techniques such as dissolving the polymer using such processes as a single step process involving reac into a solvent, pouring the mixture onto a flat sheet or into a tion of the chain extender together with the diisocyanate and mold and evaporating the solvent, with the polymer remain 10 ing therein. Other melt processing techniques may be avail the polyol, without the formation of a prepolymer. able by melting a blank of polyurethane and manipulating it The polyol component of a polymer of the present inven into a shape as desired, including tubes or fibers. Porous tion is often selected according to the components toxicity, polyurethane may be formed in a number of ways, including which is liberated when the polymer is broken down. Two the addition of a gas (typically carbon dioxide) into the poly examples of typical polyols are polyethylene oxide and poly 15 merization reaction, and trapping the gas into the polymer caprolactone diol. Others may be suitable in Some cases. structure. Alternatively, salt crystals can be added to the sol The constituents making up the polyurethanes of the vent polymer mixture during casting wherein the salt is not present invention can be selected so as to be biodegradable to dissolved. The mixture may be deposited into a dish causing Substantially nontoxic constituents. The term Substantially the solvent to evaporate, with the salt material being removed non-toxic refers to materials which when present in the body 20 by Subsequent washing with water. are physically tolerated and, more specifically, do not cause In another embodiment, the present invention provides appreciable cell death (cytotoxicity) or detrimental alteration methods and processes for preparing the biodegradable and of normal cell function (such as a mutagenic response). This absorbable polymers of the present invention from the mono would of course depend on where and how the material is mers disclosed, vide supra, with or without the inclusion of applied. Detailed in vivo tests may be appropriate to deter- 25 other monomers. The polymerization processes typically mine the effect of the material on the neighboring cells. used for the formation of polyurethanes, polyamides, etc., are Depending on the synthesis route selected for the segment well-known to those skilled in the art. Representative pro polyurethane, the cleavable sites of the present invention may cesses are provided in U.S. Pat. No. 7,772,352, U.S. Pat. No. be regularly spaced along the length of the chain extender, 8,048,980, U.S. Pat. No. 8,143,325, U.S. Pat. No. 8,367,747, thereby giving the segmented polyurethane a biodegradabil- 30 US 2010/0260702 A1, US 2009/0292029 A1, US 2009/ ity which is, by some measure, predictable. Biodegradability 0082540, US 2006/0288547 A1, EP 1937182 B1, EP is influenced by a number of factors, including the number of 229.8235 A1 EP 1937182 A4, EP 1937182 A2, and WO Susceptible sites and crystallinity. 27030464 A2, all of which have been assigned to Bezwada The hydrophilicity of a polymer, that is, the extent to which Biomedical. water is accessible to the polymer matrix and the susceptible 35 The polyurethane materials disclosed herein may be used sites, may also influence its degradability. In those cases in a number of different forms and in a range of applications, where the chain extender has enzyme recognizable side both in the biomedical field and others. The material can be groups, the access of water to the Surface of the matrix should fabricated by casting or other molding techniques to form a increase the rate at which the enzyme can catalyze the reac substrate, which can be used alone or combined with other tion between water and the hydrolyzable cleavage sites. 40 Substrates to form homogenous multi-layered materials. Such The number of cleavage sites also influences biodegrad multilayered homogeneous polyurethane materials may be ability. The higher the number of sites generally, the greater formed with layers having different degrees of degradability. the rate of degradation. Typically, the cleavable site is an ester Such Substrates may range in thickness from about 1 micron site. For example, the cleavable ester site can be adjacent one to about 5 millimeters for applications suitable for skin repair or more amino acids. This provides segmented polyurethanes 45 and the like, and more particularly from about 10 microns to with cleavable sites in its chain extender that may be engi about 3.5 millimeters, and still more particularly from about neered to be recognizable by an enzyme. In this embodiment 50 microns to about 2 millimeters. The thinner the substrate, of the invention, the rate of degradation is controlled to the more care is needed in handling it. achieve a desired therapeutic indication. For bone regeneration and the like, the polyurethane mate In another embodiment, the diisocyanate is reacted with 50 rial may range in thickness from about 1 cm to about 5 cm or the polyol under suitable conditions to form a prepolymer; the more, depending on the specific application, including the prepolymer is then reacted with the chain extender, again dimensions of the bone being regenerated. under Suitable conditions, to form the polyurethane. In another embodiment, the present invention provides Alternatively, multi-functional components can be polymers that can be used as a pharmaceutical carrier in a employed to produce a cross-linked network, and hence non- 55 drug delivery matrix. The matrix is formed by mixing the linear, segmented polyurethane. This could be achieved by polymer with a therapeutic agent. the use of a branched complex bearing more than two A variety of different therapeutic agents can be used in hydroxyl groups, such as for example a triol, for example. In conjunction with the polymers of the invention. In general, another case, certain amino acids may also contribute to the therapeutic agents administered via the pharmaceutical com formation of a networked polymer. Lysine for example, hav- 60 positions of the invention include, without limitation antiin ing an amine group on its side chain, may be reacted with Such fectives Such as antibiotics and antiviral agents; analgesics sites as a isocyanate group on the diisocyanate. Additionally, and analgesic combinations; anorexics; antihelmintics; anti several lysines may be present in the amino acid segment arthritics; anti-asthmatic agents; anticonvulsants; antidepres thereby providing potential bonding sites between each cor sants; antidiuretic agents; antidiarrheals; antihist-amines; responding amine and another site such as an isocyanate 65 antiinflammatory agents; antimigraine preparations; antinau group. Thus, such multi-functional components readily allow seants; antineo-plastics; antiparkinsonism drugs; antiprurit for the formation of nonlinear segmented polyurethanes. ics; antipsychotics; antipyretics, antispas-modics; anticholin US 9,328,192 B2 59 60 ergics; sympathomimetics; Xanthine derivatives; e. gauze, fabric, sheet, felt or sponge for liver hemostasis, cardiovascular preparations including calcium channel f gauze bandages, blockers and beta-blockers such as pindolol and antiarrhyth g. arterial graft or Substitutes, mics; antihypertensives: diuretics; vasodilators including h. bandages for skin Surfaces, general coronary, peripheral and cerebral; central nervous i. Suture knot clip, system stimulants; cough and cold preparations, including j. Orthopedic pins, clamps, screws, and plates, decongestants; hormones Such as estradiol and other steroids, k. clips (e.g., for Vena cava), including corticosteroids; hypnotics; immunosuppressives; 1. Staples, muscle relaxants; para-sympatholytics; psychoStimulants; m. hooks, buttons, and Snaps, sedatives; tranquilizers; and naturally derived or genetically 10 n.bone Substitutes (e.g., mandible prosthesis), engineered proteins, polysaccharides, glycoproteins or lipo o. intrauterine devices (e.g., spermicidal devices), proteins. p. draining or testing tubes or capillaries, The drug delivery matrix may be administered in any Suit q. Surgical instruments, able dosage form Such as oral, parenteral, Subcutaneously as r. Vascular implants or Supports, an implant, vaginally or as a Suppository. Matrix formulations 15 S. vertebral discs, containing polymers of the invention is formulated by mixing t. extracorporeal tubing for kidney and heart-lung one or more therapeutic agents with the polymer. The thera machines, peutic agent may be present as a liquid, a finely divided solid, u. artificial skin, and the like. or any other appropriate physical form. Typically, the matrix The polyurethanes, polyureas, polyesterurethanes, polya will include one or more additives, e.g., nontoxic auxiliary mides, polyesteramides of the invention may be formed into Substances such as diluents, carriers, excipients, stabilizers or Surgical articles using any known technique, such as, for the like. However, the presence of such additives is entirely example, extrusion, molding and/or solvent casting. The optional. Other suitable additives may beformulated with the polyurethanes, polyureas, polyesterurethanes, may be used polymers of this invention and pharmaceutically active agents alone, blended with other bioabsorbable compositions, or in or compounds, however, if water is to be used it should be 25 combination with non-bioabsorbable components. A wide added immediately before administration. variety of Surgical articles may be manufactured from the The amount of therapeutic agent will be dependent upon polyurethanes, polyureas, polyamideurethanes, and/or poly the particular drug employed and medical condition being ureaurethanes described herein. These include but are not treated. Typically, the amount of drug represents about limited to clips and other fasteners, staples, Sutures, pins, 0.001% to about 70%, more typically about 0.01% to about 30 screws, prosthetic devices, wound dressings or coverings, 50%, and most typically about 0.1% to about 20% by weight burn dressings or coverings, drug delivery devices, anasto of the matrix. mosis rings, stents, stent coatings, films, scaffolds, polyure The quantity and type of polymer incorporated into a thane foams, reticulated foams and other implantable medical parenteral dosage form will vary depending on the release devices. Examples of medical implantable devices include profile desired and the amount of drug employed. The product 35 prosthetic devices, stents, Sutures, staples, clips and other may contain blends of polymers of this invention to provide fasteners, screws, pins, films, meshes, drug delivery devices the desired release profile or consistency to a given formula or systems, anastomosis rings, Surgical dressings and the like. tion. In some preferred embodiments, the Surgical articles or com The polymers of this invention, upon contact with body ponents thereof include stents, stent coatings, wound cover fluids including blood or the like, undergoes gradual degra 40 ings, burn coverings, foams, tissue engineering scaffolds, dation (mainly through hydrolysis) with concomitant release films, implantable medical devices, and/or controlled drug of the dispersed drug for a Sustained or extended period (as delivery systems, more preferably stents, stent coatings, compared to the release from an isotonic saline Solution). wound and/or burn coverings, and/or controlled delivery sys This can result in prolonged delivery (over one to 2,000 hours, tems. In certain other preferred embodiments, the Surgical including 2 to 800 hours) of effective amounts (0.0001 45 articles or components thereof include Sutures, ligatures, mg/kg/hour to 10 mg/kg/hour) of the drug. This dosage form needle and Suture combinations, Surgical clips, Surgical can be administered as necessary depending on the Subject Staples, Surgical prosthetic devices, textile structures, cou being treated, the severity of the affliction, the judgment of the plings, tubes, Supports, screws, or pins. In certain preferred prescribing physician, and the like. drug delivery systems, the systems comprise a polyurethane, Individual formulations of drugs and polymers of this 50 polyurea, polyamideurethane, and/or polyureaurethane in invention may be tested in appropriate in vitro and/or in vivo admixture with a biologically or pharmaceutically active models to achieve the desired drug release profiles. For agent. Non-limiting examples of polymeric carriers in Such example, a drug could be formulated with a polymer of this drug delivery systems and/or pharmaceutical compositions invention and orally administered to an animal. The drug include self-supporting films, hollow tubes, beads, and/or release profile is monitored by appropriate means, such as by 55 gels. Other preferred uses of the surgical articles include their taking blood samples at specific times and assaying the use as Scaffolds for tissue engineering comprising a porous samples for drug concentration. Following this or similar structure for the attachment and proliferation of cells. procedures, those skilled in the art are able to formulate a Additional examples of the Surgical and medical uses of the variety of formulations having the desired release profile. filaments, films, and molded articles of the present invention The polyurethanes, polyureas, polyamideurethanes, and/ 60 include knitted products, woven or non-woven, and molded or polyureaurethanes of the invention may be formed into products including, burn dressings, hernia patches, medi various articles for Surgical and medical uses including, with cated dressings, facial Substitutes, gauze, fabric, sheet, felt or out limitation: sponge for liver homeostasis, gauze bandages, arterial graft or a. burn dressings, Substitutes, bandages for skin Surfaces, Suture knot clip, b.hernia patches, 65 orthopedic pins, clamps, Screws, and plates, clips (e.g., for c. medicated dressings, Vena cava), Staples, hooks, buttons, and Snaps, bone Substi d. fascial Substitutes, tutes (e.g., mandible prosthesis), bone Void fillers, bone US 9,328,192 B2 61 62 cements, intrauterine devices (e.g., spermicidal devices), example and without limitation, those which accelerate or draining or testing tubes or capillaries, Surgical instruments, beneficially modify the healing process when particles are vascular implants or Supports, Vertebral discs, extracorporeal applied to a Surgical repair site. For example, articles made tubing for kidney and heart-lung machines, artificial skin and from compositions containing the presently disclosed poly others. urethanes, polyureas, polyamideurethanes, and/or poly The polyurethanes, polyureas, polyamideurethanes, and/ ureaurethanes may carry a therapeutic agent which will be or polyureaurethanes disclosed herein may also be used to deposited at the repair site. The therapeutic agent may be fabricate degradable containers and packaging materials chosen for its antimicrobial properties, capability for promot which can degrade in landfills in contrast to existing non ing repair or reconstruction and/or new tissue growth. Anti degradable materials which present environmental concerns. 10 microbial agents such as broad spectrum antibiotics, for The polyurethane material is believed to be especially use example and without limitation, gentamycin Sulfate, erythro ful for use as a tissue engineering scaffold, i.e., as a structure mycin, or derivatized glycopeptides which are slowly for the growth or regeneration of tissue. Polyurethanes may released into the tissue, may be applied in this manner to aid lend themselves to Such uses since enzyme-catalyzed degra in combating clinical and Sub-clinical infections in a tissue dation may in Some cases occur concurrently with the migra 15 repair site. To promote repair and/or tissue growth, one or tion or growth of cells into the material, while desirably several growth promoting factors may be introduced into the degrading in the process into its Substantially non-toxic con articles, e.g., fibroblast growth factor, bone growth factor, stituents. It is also possible, in Some cases, that cells migrating epidermal growth factor, platelet-derived growth factor, mac into or located adjacent the matrix may themselves exude rophage-derived growth factor, alveolar-derived growth fac proteolytic enzymes that will mediate hydrolytic cleavage. tor, monocyte-derived growth factor, magainin, and the like. Such tissue engineering scaffolds may have applications in Examples of therapeutic indications include, without limita the regeneration of skin and other organs, bone, cartilage, tion, glycerol with tissue or kidney plasminogen activator to ligaments, tendons, bladder and other tissues. The polyure cause thrombosis, Superoxide dismutase to Scavenge tissue thane material may also be useful in the production of sutures, damaging free radicals, tumor necrosis factor for cancer which require good mechanical strength, as well as in the 25 therapy or colony stimulating factor and interferon, interleu production of drug release matrices, in view of their need for kin-2 or other lymphokine to enhance the immune system. degradation to non-toxic materials. The polyurethane mate In another embodiment, branched or linear bioabsorbable rial may also be useful for non-biomedical applications, polyurethanes and the like of the present invention may also where degradability into Substantially non-toxic constituents be derived from diisocyanates based on cycloaliphatic amino is an asset. The polyurethane material lends itself to steriliza 30 acids such as aminocyclohexanecarboxylic acid as well as tion by Such techniques as gamma radiation and ethylene cycloaliphatic amino alcohols such as aminocyclohexanol. oxide treatments. Polyurethanes and the like from these diisocyanates can be Fibers made from the present polyurethanes, polyureas, prepared according to the procedures described in U.S. Patent polyamideurethanes, and/or polyureaurethanes can be knit Application Publication Nos. 200601885.47, 20090292029, ted or woven with other fibers, either bioabsorbable or non 35 European Patent Publication No. EP 1937182 and WO bioabsorbable, to form meshes or fabrics. Compositions 2007030464. Polyurethanes and the like resulting from including these polyurethanes, polyureas, polyamideure cycloaliphatic amino acids as well as cycloaliphatic amino thanes, and/or polyureaurethanes may also be used as bioab alcohols will find use in a variety of applications including Sorbable coatings for Surgical devices. biomedical applications wherein controlled hydrolytic deg Another embodiment of the invention is directed to com 40 radation is desired. positions containing the polyurethanes, polyureas, polyami In another embodiment, absorbable polyester amides can deurethanes, and/or polyureaurethanes described herein be prepared by reaction of amide diols, and/or bioabsorbable which may be used to make reinforced composites. Thus, for polyols, with diacids including but not limited to oxalic acid, example, the polyurethane, polyurea, polyamideurethane, Succinic acid, malonic acid, butanedioic acid, adipic acid, and/or polyureaurethane composition may form the matrix of 45 aZelaic acid, sebacic acid, diglycolic acid, 3,6-dioxaoc the composite and may be reinforced with bioabsorbable or tanedioic acid, 3.6.9-trioxaundecanoic acid, functionalized non-bioabsorbable fibers or particles. Alternatively, a matrix oxaacids, polyethyleneglycol diacids of average molecular of any bioabsorbable or non-bioabsorbable polymer compo weight from 300 to 2000 and blends thereof. sition may be reinforced with fibers or particulate material In another embodiment, bioabsorbable polyamides will be made from compositions containing the polyurethanes, poly 50 prepared by reaction of diamines with diacids including but ureas, polyamideurethanes, and/or polyureaurethanes not limited to oxalic acid, Succinic acid, malonic acid, butane described herein. dioic acid, adipic acid, azelaic acid, sebacic acid, diglycolic In another embodiment, the polyurethanes, polyureas, acid, 3,6-dioxaoctanedioic acid, 3.6.9-trioxaundecanoic acid, polyamideurethanes, and/or polyureaurethanes described functionalized oxaacids, polyethyleneglycol diacids of aver herein may be admixed with filler. The filler may be in any 55 age molecular weight from 300 to 2000 and blends thereof. particulate form, including granulate or staple fibers. While The monomers of the present invention can be polymerized any known filler may be used, hydroxyapatite, tricalcium to form absorbable polymers (e.g., polyesters, polyamides, phosphate, bioglass or other bioceramics are the preferred polyester amides, polyurethanes, and polyanhydrides). It can fillers. Normally, from about 10 grams to about 400 grams of be advantageous for the monomers that are to be polymerized filler are mixed with about 100 grams of polymer. The filled, 60 to have at least two active sites (e.g., 2 or 3) for polymeriza cross-linked polymers are useful, for example, as molding tion. These active sites include amino, isocyanate and car compositions. boxylic acid groups. The monomers with at least two active It is further contemplated that one or more medico-Surgi sites can also be copolymerized with selected difunctional cally useful Substances may be incorporated into composi molecules (e.g., dicarboxylic acids, dialcohols, diisocyan tions containing the polyurethanes, polyureas, polyamideure 65 ates, amino-alcohols, hydroxy-carboxylic acids, and thanes, and/or polyureaurethanes described herein. Examples diamines) based on the starting functionalized amino acid to of Such medico-Surgically useful Substances include, for form bioabsorbable polymers. The polymers (and copoly US 9,328,192 B2 63 64 mers) of the present invention can also be further reacted/ such additives is optional. Other suitable additives may be polymerized to form additional useful polymers of the formulated with the polymers of this invention and pharma present invention. ceutically active agent or compound. If water is to be used as It would be readily apparent to one of ordinary skill in the an additive, it is preferably be added immediately before art once armed with the teachings in the present application 5 administration. that the diisocyanates of the present invention may be reacted The amount of biologically active agent will be dependent with a variety of reactants that are typically employed in the upon the particular agent employed and medical condition preparation of bioabsorbable and biocompatible polyure being treated. Typically, the amount of drug represents about thanes and/or polyester urethanes, preferably with tunable 0.001% to about 70%, more typically about 0.01% to about physical, mechanical properties and/or hydrolytic degrada 10 50%, and most typically about 0.1% to about 20% by weight tion profiles. It would also be apparent to the ordinarily of the matrix. skilled artisan that the terminal groups for given polyure The quantity and type of polymer incorporated into a thane, or polyester may be derivatized by further reacting the parenteral dosage form will vary depending on release profile polyurethane and/or polyesters with additional derivatizing desired and the amount of drug employed. The product may agents. Polyurethanes terminated with —NCO or hydroxyl 15 contain blends of polymers of this invention to provide the groups can be prepared by varying the ratio of isocyanates: desired release profile or consistency to a given formulation. hydroxyl groups in the reaction mixture i.e. (isocyanates, The polymers of this invention, upon contact with body chain extender and polyol). Polyurethanes with high molecu fluids including blood or the like, undergo gradual degrada lar weights are formed when the ratio of isocyanates: hy tion (mainly through hydrolysis) with concomitant release of droxyl group is 1. Furthermore, by varying the ratio of iso the dispersed drug for a Sustained or extended period (as cyanates: hydroxyl groups in the reaction mixture, compared to the release from an isotonic saline Solution). polyurethanes with tunable physical and mechanical proper This may result in prolonged delivery (over about one to ties can be obtained. It would also be apparent to the ordi about 2,000 hours, preferably about two to about 800 hours) narily skilled artisan that the terminal groups for given poly of effective amounts (including, for example, about 0.0001 urethane, or polyester may be derivatized by further reacting 25 mg/kg/hour to about 10 mg/kg/hour) of the drug. This dosage the polyurethane and/or polyesters with additional derivatiz form may be administered as necessary depending on the ing agents. subject being treated, the severity of the affliction, the judg The polymers of the present invention may be used as ment of the prescribing physician, and the like. pharmaceutical carriers in a drug delivery matrix, i.e., a Individual formulations of drugs and polymers of this matrix for a biologically active Substance (i.e., agent). The 30 invention may be tested in appropriate in vitro and in vivo matrix may be formed by mixing the polymer with a biologi models to achieve the desired drug release profiles. For cally active agent. The biologically active agent can be dis example, a drug may be formulated with a polymer of this persed into the polymer Solution for example during prepa invention and administered to an animal (e.g., orally). The ration of matrix or via melt blending. A vast variety of drug release profile may be monitored by appropriate means, different biologically active agents may be used in conjunc 35 Such as by taking blood samples at specific times and assaying tion with the polymers of the invention. In general, therapeu the samples for drug concentration. Following this or similar tic agents administered via the pharmaceutical compositions procedures, those skilled in the art may formulate a variety of of the invention include, without limitation: anti-infectives formulations. Such as antibiotics and antiviral agents; analgesics and anal It is further contemplated that one or more medico-Surgi gesic combinations; anorexics; anti-helmintics; anti-arthrit 40 cally useful Substances (biologically active agents) may be ics; anti-asthmatic agents; anticonvulsants; antidepressants; incorporated into compositions containing the bioabsorbable anti-diuretic agents; anti-diarrheals; anti-histamines; anti-in polyurethanes and/or polyester amides described herein. flammatory agents; anti-migraine preparations; anti-nause Examples of Such biologically active agents include, for ants; anti-neoplastics; anti-parkinsonism drugs; anti-prurit example, those which accelerate or beneficially modify the ics; anti-psychotics; anti-pyretics, anti-spasmodics; anti 45 healing process when particles are applied to a Surgical repair cholinergics; sympathomimetics: Xanthine derivatives; site. For example, articles made from compositions contain cardiovascular preparations including calcium channel ing the present polyurethanes and/or polyesters may carry a blockers and beta-blockers such as pindolol and anti-arrhyth therapeutic agent which will be deposited at the repair site. mics; anti-hypertensives; diuretics; vasodilators including The biologically active agent may be chosen for its antimi general coronary, peripheral and cerebral; central nervous 50 crobial properties, capability for promoting repair or recon system stimulants; cough and cold preparations, including struction and/or new tissue growth. Antimicrobial agents decongestants; hormones Such as estradiol and other steroids, Such as broad spectrum antibiotic, for example, gentamycin including corticosteroids; hypnotics; immunosuppressives; Sulfate, erythromycin, or derivatized glycopeptides which are muscle relaxants; para-sympatyholytics; psychoStimulants; slowly released into the tissue may be applied in this manner sedatives; and tranquilizers; and naturally derived or geneti 55 to aid in combating clinical and Sub-clinical infections in a cally engineered proteins, polysaccharides, glycoproteins or tissue repair site. To promote repair and/or tissue growth, one lipoproteins. or several growth promoting factors may be introduced into The drug delivery matrix may be administered in any Suit the articles, e.g., fibroblast growth factor, bone growth factor, able dosage form Such as oral, parenteral, Subcutaneously as epidermal growth factor, platelet derived growth factor, mac an implant, vaginally or as a Suppository. Matrix formulations 60 rophage derived growth factor, alveolar derived growth fac containing polymers of the invention may be formulated by tor, monocyte derived growth factor, magainin, and the like. mixing one or more therapeutic agents with the polymer. The Some therapeutic indications are: glycerol with tissue or kid biologically active agent may be present as a liquid, a finely ney plasminogen activator to cause thrombosis, Superoxide divided solid, or any other appropriate physical form. Typi dismutase to Scavenge tissue damaging free radicals, tumor cally, the matrix will include one or more additives, e.g., 65 necrosis factor for cancertherapy or colony stimulating factor nontoxic auxiliary Substances Such as diluents, carriers, and interferon, interleukin-2 or other lymphokine to enhance excipients, stabilizers or the like. However, the presence of the immune system. US 9,328,192 B2 65 66 It is contemplated that it may be desirable to dye articles hydroxytoluene, capobenic acid, trans-1-(3'-carboxy-4-hy made from compositions containing the present branched droxyphenyl)-2-(2".5"-dihydroxyphenyl)ethane, catechin, bioabsorbable polyurethanes and/or polyesters in order to chlorogenic acid, m-chlorophenol, 5-chloro-8-quinolinol, increase visibility of the article in the surgical field. Dyes, chloroxylenol, chlorquinaldol, chromo-nar, chrysin, Such as those known to be suitable for incorporation in cinametic acid, clorophene, coniferyl alcohol, p-coumaric 5 acid, coumes-trol, coumetarol, daphnetin, datiscetin, deox sutures, may be used. Such dyes include but are not limited to yepinephrine, 3,5-diiodothyronine, 3,5-di-iodotyrosine, carbon black, bone black, D&C Green No. 6, and D&C Violet dimethophrine, dioSmetin, diresorcinol, disoprofol, dopa, No. 2 as described in the handbook of U.S. Colorants for dopamine, drosophilin a, efloxate, ellagic acid, embelin, Food, Drugs and Cosmetics by Daniel M. Marrion (1979), the Equol. eriodictyol, esculetin, esculin, ethylnorepinephrine, disclosures of which are hereby incorporated herein by ref ethyl Vanillin, eugenol, eupatorin, fenadiazole, ferulic acid, erence, in their entireties. Preferably, articles in accordance 10 fisetin, 3-fluoro-4-hydroxyphenylacetic acid, fraxetin, fustin, with this disclosure may be dyed by adding up to about a few galangin, gallacetophe-none, gallic acid, gardenins, percent and preferably about 0.2% dye to the resin composi genistein, gentisyl alcohol, gepefrine, geranylhydroqui-none, tion prior to extrusion. 6-gingerol, gossypol, guaiacol, guaifenesin, harmalol, Biologically active hydroxy compounds that can be used as hematoxylin, hinderin, homoeriodictyol, homogentisic acid, a pendant group or covalently bonded to the amino acid of 15 homoVanillic acid, hydroxyamphetamine, 2-hydroxy-5-(2,5- present invention of the present invention include acenocou dihydroxybenzylamino)-2-hydroxybenzoic acid, 4-hydroxy marol, acetarsol, actinoquinol, adrenalone, alibendol, amodi 3-methoxy-mandelic acid, n-(p-hydroxyphenyl)glycine, aquine, anethole, balsalazide, bamethan, benserazide, ben hydroxyprocaine, 8-hydroxyquinoline, hypericin, irigenin, tiromide, benzarone, benzquinamide, bevantolol, bifluranol, isoproterenol, isoquercitrin, isothebaine, kaempferol, liothy buclosamide, bupheniode, chlorotrianisene, chloroxylenol, ronine, luteolin, mangostin, 5.5'-methylenedisalicylic acid, cianidanol, cinepazide, cinitapride, cinepazide, cinmetacin, n-methylepinephrine, metyrosine, morin, mycophenolic clebopride, clemastine, clioquinol, cyclovalone, cynarine, acid, myricetin, naringenin, nylidrin, orcinol, osalmid, ost hole, oxantel, paroxypropione, pentachlorophenol, 3-penta denopamine, dextroy thyroxine, diacerein, dichlorophen, decylcatechol, p-pentyloxy-phenol, phloretin, phlorogluci dienestrol, diethylstilbestrol, diflunisal, diiodohydrox nol, pinosylvine, plumbagin, pyrocatechol, pyrogallol, yduinoline, dilaZep, dilevalol, dimestrol, dimoxyline, quercetagetin, quercetin, resacetophenone, rhamnetin, rhein, diosmin, dithranol, dobutamine, donepezil, dopamine, 25 Sakuranetin, Salicyl alcohol, salicylanilide, 4-salicyloylmor dopexamine, doxazosin, entacapone, epanolol, epimestrol, pholine, Salsalate, Scopoletin, Scutellarein, serotonin, (3,4,5- epinephrine, estradiol Valerate, estriol, estriol Succinate, trihydroxyphenyl)methylenepropanedinitrile, thymol, thyro estrone, etamivan, etamsylate, ethaverine, ethoXZolamide, propic acid, thyroXine, tiratricol, tyrosine, Vanillic acid, and ethyl biscoumacetate, etillefrine, etiroXate, exalamide, exi vanillin. fone, fendosal, fenoldopam mesilate, fenoterol, fenoxedil, 30 Further biologically active carboxylic acid and/or amine fenticlor, flopropione, floredil, fluorescein, folescutol, for compounds that can be used as a pendant group or covalently moterol, gallopamil, gentistic acid, glaziovine, glibencla bonded to the amino acid of the present invention include mide, glucametacin, guajacol, halquinol, hexachlorophene, Acemetacin, Aceclofenac, Acediasulfone, Adipiodone, hexestrol, hexobendine, hexoprenaline, hexylresorcinol, Alminoprofen, Amisulpride, AmlexanoX, Amodiaquine, hydroxyethyl salicylate, hydroxy stilbamidine isethionate, Amosulalol. Amoxicillin, Amsacrine, Anileridine, AZacy hymecromone, ifenprodil, indomethacin, ipriflavone, isoetar 35 clonol, Baccofen, Balsalazide sodium, Bentiromide, Ben ine, isoprenaline, isoxSuprine, itopride hydrochloride, keto Zocaine, Bromopride, Bumetanide, Carprofen, Carvedilol, bemidone, khellin, labetalol, lactylphenetidin, levodopa. Carzenide, Cefprozil, Cinitapride, Cinmetacin, Clebopride, levomepromazine, levorphanol, levothyroxine, mebeverine, Clenbuterol, Clometacin, Cromoglicic acid, Diclofenac, medrylamine, mefexamide, mepacrine, mesalazine, mestra Diflunisal, Eprosartan, Ethoxzolamide, Fendosal, Flufe nol, metaraminol, methocarbamol, methoxamine, methox 40 namic acid. Furosemide, Ibuprofen, Indometacin, Ioben salen, methyldopa, midodrine, mitoxantrone, morclofone, Zamic acid, Iocarmic acid, Iocetamic acid, Iodoxamic acid, nabumetone, naproxen, nitroxoline, norfenefrine, normo Ioglycamic acid, Iophenoic acid, IotroXic acid, Mefenamic laxol, octopamine, omeprazole, orciprenaline, OXilofrine, acid, Nadoxolol, Naproxen, Nedocromil, D-Norpseudoephe oxitriptan, oxyfedrine, oxypertine, oxyphenbutaZone, drine, paracetamol Repaglinide, Salazosulfapyridine, Sali oxyphenisatin acetate, oxyquinoline, papaverine, paracet cylic Acid, Salsalate and Sarpogrelate. anol, parethoxycaine, phenacaine, phenacetin, phenazocine, 45 Examples of biologically active dihydroxy compounds phenolphthalein, phenprocoumon, phentolamine, phlo that can be used to as a pendant group or covalently bonded to edrine, picotamide, pimobendan, prenalterol, primaquine, the amino acid of present invention of present invention progabide, propanidid, protokylol, proxymetacaine, ralox include Adrenalone, AlfuZosin, Alibendol, Amrubicin, Apo ifene hydrochloride, repaglinide, reproterol, rimiterol, rito morphine, Bamethan, Benzquinamide, Bevantolol, Biflura drine, Salacetamide, Salazosulfapyridine, Salbutamol, salicy 50 nol, Bisacodyl, Brodimoprim, Bunazosin, Bupheniode, Car lamide, salicylic acid, salmeterol, Salsalate, sildenafil. bidopa, Carbuterol, Cyclofenil, Cyclovalone, Daunorubicin, silibinin, Sulmetozin, tamsulosin, teraZosin, terbutaline, Dichlorophen, Dienestrol, Diethylstilbestrol, Dimestrol, tetroxoprim, theodrenaline, tioclomarol, tioxolone, alpha-to Dithranol, Donepezil, Doxefazepam, Doxorubicin, Entaca copherol (vitamin E), tofisopam, tolcapone, tolterodine, tra pone, Epinepheine, Epirubicin, Esomeprazole, Etamivan, nilast, tretoquinol, triclosan, trimaZosin, trimetazidine, tri 55 Etamsylate, Etilefrine, EZetimibe, Fenticlor, Fluorescein, methobenzamide, trimethoprim, trimetozine, trimetrexate Folescutol. Formoterol, Gefitinib, Hexestrol, Hexylresorci glucuronate, troXipide, Verapamil, Vesnarinone, Vetrabutine, nol, Hydroxyethyl salicylate, Ifenprodil, Isoetarine, ISOXSu Viloxazine, warfarin, Xamoterol. prine, Itopride. HCl, Khellin, Labetalol, Mitoxantrone, Mor Other biologically active phenolics that can be used clofone, Moxaverine, Normolaxol. Omeprazole, Oxilofrine, include acacetin, 4-acetamido-2-methyl-1-naphthol, Oxepertine, Phenacaine, Phenolphthalein, Prazosin, Tolca acetaminophen, albuterol, allenolic acid, aloe emodin, aloin, 60 pone, Vesnarinone, and Vetradutine. B-amino-4-hydroxy-3,5-di-iodohydrocinnamic acid, N-(5- Examples of biologically active diamino compounds that amino-2-hydroxyphenyl)-benzeneacetamide, 4-amino-1- can be used as a pendant group or covalently bonded to the naphthol, 3-aminosalicylic acid, 4-aminosalicylic acid, anac amino acid of present invention of present invention include ardic acid, p-anol, anthragallol, anthralin, anthranol, Amisulpride, Amodiaquine. Amosul-alol. Amoxicillin, anthrarobin, anthrarufin, apigenin, apin, apocynin, aspidi 65 Amsacrine, Azacyclonol, Bromopride, Carvedilol, Cefprozil, nol, aspirin, baptigenin, benzestrol, benzoresorcinol, bisphe Cinitapride, Clebopride, Clenbuterol, Ethoxzolamide, nol a, bisphenol b, butylated hydroxylanisole, butylated Nadoxolol, and D-Norpseudoephedrine. US 9,328,192 B2 67 68 Examples of biologically active hydroxy/amino com Vanillylamine and Cs to C branched fatty acids. Topical pounds that can be used as a pendant group include Amisul application of capsaicin Stimulates and blocks Small pain pride, Amodiaquine, Amosulalol. Amoxicillin, Amsacrine, fibers by depleting them of the neurotransmitter substance P Azacyclonol, Bromopride, Carvedilol, Cefprozil, Cinitap that mediates pain impulses. A cream made from 0.025%- ride, Clebopride, Clenbuterol, EthoXZolamide, Nadoxolol. 0.075% capsaicin applied 4x daily may help peripheral neu D-Norpseudo-ephedrine, and paracetamol. ropathic pain, post-herpetic neuralgia, trigeminal neuralgia, Examples of biologically active dicarboxylic acid com psoriasis and fibromyalgia. It is also useful for diabetic neu pounds that can be used as a pendant group or covalently ropathy, cluster headaches, earache, osteo- and rheumatoid bonded to the amino acid of present invention of present arthritis. Capsaicin is a powerful pain reliever. invention include Adipiodone, Cromoglicic acid, Eprosartan, Naproxen, paracetamol, acetaminophen and acetylsali Iocarmic acid, Iodoxamic acid, Ioglycamic acid, Iotroxic 10 cylic acid are biologically active phenolics that belong to the acid, Nedocromil. Examples of biologically active hydroxy/carboxylic acid class of drugs called non-steroidal anti-inflammatory drugs or compounds that can be used as a pendant group or covalently NSAIDs. The NSAIDs provide relief by blocking the action bonded to the amino acid of present invention include Acem of prostaglandins, which are hormone-like Substances that etacin, Bentiromide, Cinmetacin, Clometacin, Diflunisal, 15 contribute to pain, inflammation, fever and muscle cramps. Fendosal, Indometacin, Iophenoic acid, Naproxen, Repaglin Phenolic moieties, synthetic and naturally occurring, are part ide, Salazosulfapyridine, Salicylic Acid, Salsalate, and Sar of many drugs. pogrelate. The compounds employed in the methods of the present Examples of biologically active hydroxyl-acids for use as invention may be prepared in a number of ways well known to the pendant group or covalently bonded to the amino acid of those skilled in the art. The compounds may be synthesized, present invention include 4-hydroxycinnamic acid, caffeic for example, by the methods described below, or variations acid, chlorogenic acid, ferulic acid, Sinapic acid, Vanillic acid, thereon as appreciated by the skilled artisan. All processes Acemetacin, Bentiromide, Cinmetacin, Clometacin, disclosed in association with the present invention are con Diflunisal, Fendosal, Indometacin, Iophenoic acid, templated to be practiced on any scale, including milligram, Naproxen, Repaglinide, Salazosulfapyridine, Salicylic Acid, 25 gram, multigram, kilogram, multikilogram or commercial Salsalate, and Sarpogrelate. industrial scale. Examples of useful biologically active amino/carboxylic The Surgical articles, component thereof, polymeric car acid compounds that can be used as a pendant group of rier, or the like can comprise a polymer formed by reacting an present invention include Aceclofenac, Acediasulfone, Almi amine of one of the invention with an isocyanate, carboxylic noprofen, Amlexanox, Anileridine, Baccofen, BalsalaZide 30 acid, activated carboxylic acid, or epoxide, or an isocyanate Sodium, Benzocaine, Bumetanide, Carprofen, Carzenide, Diclofenac, Flufenamic acid, Furosemide, Iobenzamic acid, of the invention with an amine, alcohol, aminoalcohol, thiol Iocetamic acid, and Mefenamic acid. or combination thereof, or a carboxylic acid of the invention Examples of biologically active diamino compounds use with an alcohol, amine or combination thereof. 35 The following examples are included to further illustrate ful in the present invention include Amisulpride. Amodi the invention and are not to be considered as limiting the aquine, Amosulalol. Amoxicillin, Amsacrine, AZacyclonol, invention anyway. Melting points were measured for all prod Bromopride, Carvedilol, Cefprozil, Cinitapride, Clebopride, ucts by using a Polmon (MP96) melting point apparatus. For Clenbuterol, EthoXZolamide, Nadoxolol, D-Norpseudoephe all the products, NMR was run using a Varian 200 MHz and drine, amino acids (L-lysine), and natural products. tetramethylsilane as an internal standard. Examples of naturally occurring biologically active phe 40 nolics include bergaptol, caffeic acid, capsaicin, coumarin, daidzein, 2.5-dihydroxy-benzoic acid, ferulic acid, fla vonoids, glycitein (isoflavone), 4-hydroxycinnamic acid, EXAMPLES 4-hydroxy-coumarin, isopimpinellin, resveratrol, synapic acid, Vanillic acid, Vanillin, chalcones, soybean flavonoids 45 Example 1 and derivatives thereof. Capsaicin is a biologically active phenolic that is the active Diisocyanate from Ricinoleic acid, 4-nitro-benzoic component of cayenne pepper. The capsaicin is an amide of acid, and 4-nitro phenol OH

OH ON

He 4-Nitro benzoyl chloride

OH

SOCl US 9,328,192 B2 69 -continued O

21 C ON

O

O s phenol

NO

21 O O O ON

O O e

NH2

21 O O O HN

O O Triphosgene 1,4-Dioxane

NCO

21 O O Y c

OCN

O O US 9,328,192 B2 71 72 Example 1A (1.0 L), then dry the organic layer with sodium Sulphate and distilled up the solvent under reduced pressure completely till Synthesis of 4-Nitro Benzoyl Chloride thick oily mass is obtained. Resulting crude was purified by column chromatography by using hexane: ethyl acetate (9:1) to yield pure 4-nitro-benzoic acid 11-carboxy-1-hexyl-un dec-3-enyl ester product as light yellow thick syrup (750 g). The resulting compound was characterized by H NMR (DMSO-d) & 0.85 (t,3H, CH), 1.12-1.6 (m, 22H, 11xCH), COOH COC 1.91 (m,2H, CH), 2.2-2.32 (m, 4H,2xCH), 3.5 (m, 1H, CH) 10 5.52 (m. 1H, CH), 5.65 (m. 1H, CH), 8.25-8.35 (m, 4H, Ar). SOCl/Hexane --- Example 1C

15 Synthesis of Ricinoleic Acid Di-Nitro Compound NO NO O

21 OH Thionyl chloride (3.0 L) was added drop wise to 4-Ntro ON benzoic acid (1.5 kg) at ambient temperature under nitrogen atmosphere and heat the mass to reflux and maintained for 6 hours at which time TLC shown completion of the reaction. Then distilled out completely excess Thionyl chloride under 25 reduced pressure, remove the traces with dichloromethane as co solvent under reduced pressure at 55-60° C. The resulted residue was precipated with petroleum ether (3 L) at 5-10°C. ON and stirred for 30 minutes at 5-10°C. The resulting solid was DCCTHF filtered and kept under nitrogen and dried well to yield (1400 30 g) of pure 4-nitro benzoyl chloride as pale yellow powder OH with a melting point of 69-71°C. Example 1B 35 O Synthesis of Ricinoleic Acid Mono Nitro Acid

ON a o–K)-No, 40 O 4-Nitro benzoyl O 21 OH chloride, TEA, Acetone -as

45 OH To a solution of 4-Nitro-benzoic acid 11-carboxy-1-hexyl O undec-3-enyl ester (700 g) in dry THF (2 L), Di-azabicyclo undecane (DBU) (24 g) at 5-10°C., was added a solution of 21 OH N,N'dicyclohexylcarbodiimide DCC (390 g) in 600 ml THF ON under nitrogen atmosphere, and later stirred at room tempera ture for 24 hours. Check TLC and filtered off the DCU salts wash with hot THF 400 ml, combined total filtrate mass and O THF solvent was distilled off around 75% under reduced 55 pressure at 60-65°C., the resulted mass was poured into ice O water (3 L) and extracted with ethyl acetate (3 L) and com bined total organic layers and wash with 15% NaHCO solu tion (1 L) and 15% NaCl solution (1.0 L) followed by water washing (1.0 L), then dry the organic layer with sodium To a mixture of ricinoleic acid (1600 g), triethylamine 60 sulphate and distill up the solvent under reduced pressure (1100 mL) in acetone (6 L) at 0-5°C., was added 4-nitro completely till get thick oily mass. The resulted crude was benzoyl chloride (1200 g). It was stirred at room temperature purified by column chromatography by using hexane: ethyl for 16 hours. After the reaction was completed then the total acetate (9.5:0.5) as eluant to get the pure 4-nitro-benzoic acid reaction mass was poured onto cold water (12 L) and 1-hexyl-11-(4-nitro-phenoxycarbonyl)-undec-3-enyl ester extracted with ethyl acetate (6 liter) and combined total 65 product as deep yellow thick syrup (300 g). The resulting organic layers and washed with 15% NaHCO, solution (IL) compound was characterized by H NMR (CDC1) & 0.86 (t, and 15% NaCl solution (1.0 L) followed by water washing 3H, CH), 1.35-1.65 (m, 20H, 10xCH), 1.78 (m, 2H, CH), US 9,328,192 B2 73 74 2.31-2.42 (m 4H2xCH), 3.5 (m. 1H, CH) 5.52 (m. 1H, CH), -continued 5.65 (m. 1H, CH), 7.25-7.35 (m, 4H, Ar), 8.28-7.32 (m, 4H, Ar). Example 1D Synthesis of Ricinoleic Acid Diamine Compound OCN 10 O

ON sc-O- 15

O O

Reduction To a solution of 44-Amino-benzoic acid 11-(4-amino-phe noxycarbonyl)-1-hexyl-undec-3-enyl ester (160 g) in dry 1,4-

O dioxane (1.8L) Triphosgene (158 g) was added 320 ml of 1.4 dioxane. The solution was heated up to 60-65C. followed by 25 cooling to room temperature at which temperature the mass HN c-O- became clear Solution. The solution was then again heated up to 100-105° C. and stirred for 3 to 4 hours. The Solvent was O O distilled off completely under reduced pressure at 85-90° C. 30 The traces of solvent were completely removed by using 1.4 To a solution of 4-nitro-benzoic acid 1-hexyl-11-(4-nitro dioxane (600 mL) followed by Toluene (300 mL) under phenoxy carbonyl)-undec-3-enyl ester (300 g) in ethyl acetate (1.5 L) in a pressure vessel was added Raney Nickel reduced pressure at 85-90° C. The resulting residue was dis (120 g) added, and the mixture stirred under an atmosphere of 35 Solved in toluene (360 mL) and given charcoal and Sodium Hydrogen (8-10 Kg) for 8 hours at a temperature of 60-65°C. sulphate treatment then distilled up total solvent under The catalyst was removed by filtration. The solvent was dis reduced pressure at 95-100° C. and kept for traces removal for 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 2 hours at 95-100° C. to get 125 grams of the crude diisocy nobenzoic acid 11-(4-amino-phenoxycarbonyl)-1-hexyl-un 40 anate product as deep yellow thick syrup which was taken for dec-3-enyl ester product as deep yellow thick syrup (190 g). further purification in 650 ml of 9:1 toluene: heptane mixture The resulting compound was characterized by "H NMR (CDC1) & 0.88 (t, 3H, CH), 1.2-1.65 (m, 24H, 12xCH), under nitrogen and heated up to 85-90° C. (mass temp) with 2.12 (t, 2H, COCH), 3.5 (m, 1H, CH) 5.12 (m, 1H, CH), 5.45 thorough shaking and allow for settle the brown impurity (m. 1H, CH), 6.55 (m, 4H, Ar), 6.85 (m,2H, Ar), 7.75 (m,2H, 45 layer at bottom and decant the top clear layer and given Ar). charcoal & Sodium Sulphate treatment for the clear decanted Example 1E layer at 90-95° C. and filtered through hyflow and washed with toluene 100 ml, distilled up total solvent under reduced Synthesis of Ricinoleic Acid Diisocyanate 50 Compound pressure and kept for traces removal under vacuum for 1 hour at 90-95° C. to get Diisocyanate as syrup and the resulted syrup was taken for next purification as follows. This purifi O 55 cation procedure is repeated for one more time to get the pure diisocyanate (100g) as deep yellow syrup (98.8% NCO). The HN resulting compound was characterized by H NMR (CDC1) c-O- 80.84 (t,3H, CH), 1.21-1.43 (m, 24H, 12xCH), 2.12 (t, 2H, 60 COCH), 3.5 (m, 1H, CH) 5.12 (m, 1H, CH), 5.45 (m. 1H, O O CH), 7.12-7.32 (m, 4H, Ar)7.85-8.15 (m, 4H, Ar). The hydro lytic degradation of the urethane prepared from this isocyan Triphosgene ate was carried out in pH 9.0 buffer solution. The study 65 showed that 1% solution is 100% hydrolyzed in 14 hours at 500 C. US 9,328,192 B2 75 76 Example 2 Diisocyanate from Ricinoleic Acid, Mono Glycolate Extended 4-Nitro-Phenol, and 4-Nitro-Benzoic Acid

OH

O

21 OH ON

4-Nitro benzoyl chloride

O

R

ON R = BriC NO

21 O O O ON

O

O Reduction

NH2

21 O O O HN

O O Triphosgene 1,4-Dioxane

NCO

21 O O O

OCN

O O US 9,328,192 B2 77 78 Example 3 Diisocyanate from Di-Glycolic Acid Extended Ricinoleic Acid, 4-Nitro Benzoic Acid, and 4-Nitro-Phenol

O O

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

O

21 OH

O r O O ON ON O

O ---

O 21 or O O O NO r O O ON estin

O 21 r O O O NH2 r O HN Triphosgene 1,4-Dioxane US 9,328,192 B2 79 80 -continued

r cro O OCN

Example 4 15 -continued O NH2 Diisocyanate from 12-Hydroxy Stearic Acid, 4-Nitro-Benzoic Acid, and 4-Nitro-Phenol coO OH O O Triphosgene 25 1,4-Dioxane NCO

— - O 30 OCN

O O OH O2N O's 35 O Example 4A OH ON Synthesis of 12-Hydroxy Stearic Mono Nitro Acid 40 O

O O

45 OH |ocl: -e- O 4-Nitro benzoyl chloride, TEA, OH Acetone ON OH O O OH O Nin phenol ON O C NO O O ON 60 To a mixture of 12-Hydroxy stearic acid (450 grams, 1.5 O moles), Triethylamine (313 ml, 2.35 moles) in Acetone (1 L) at 10-15° C., was added 4-Nitro Benzoyl Chloride (332 grams, 1.78 moles) and later stirred at room temperature for 65 10 hours. 75% of the solvent was distilled off. The resulting chain Solution was cooled to room temperature and poured onto cold water. The pH of the solution was adjusted to 4-5 with US 9,328,192 B2 81 82 dilute HCl, and resulting solid was filtered off and washed 2.12 (t, 2H, COCH), 3.45 (m, 1H, CH), 7.52 (m,2H, Ar) 7.75 with chilled water. The solid was converted into slurry with (m. 1H, Ar) 8.3-8.52 (m, 5H, Ar). 500 ml diisopropyl ether. The DIPE was filtered off and the resulting solid was dried in vacuum oven at 70-75°C. to yield Example 4C 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 Synthesis of 12-Hydroxy Stearic Diamino (DMSO-d) & 0.85 (t, 3H, CH), 1.2-1.6 (m. 28H, 14xCH), Compound 1.8 (m, 2H, CH), 2.32 (t, 2H, COCH), 3.2 (m. 1H, CH) O 8.1-8.25 (m, 4H, Ar). 10 Example 4B o-()-No,

Synthesis of 12-Hydroxy Stearic Di-Nitro 15 O O Compound etc. Oil O O o-()-Nil, OH

ON 25 O O O To a solution of 4-Nitro-benzoic acid 1-hexyl-11-(4-nitro O phenoxycarbonyl)-undecyl ester (290 g) in a mixture of Ethyl 30 acetate (1.5 L) and DMF (300 mL) taken in a pressure vessel ON was added Raney Nickel (80 g). The reaction mixture was stirred under an atmosphere of Hydrogen (8-10 Kg) for 4 hours at a temperature of 60-65°C. The catalyst was removed OH by filtration. 75% of the solvent was distilled off and poured 35 into cold water (2 L). The resulting solid was filtered off and washed with chilled water (100 mL) and do the slurry with 1 lit diisopropylether and filtered off, then dried the material properly in vacuum oven at 60-80° C. to yield pure 4-amino O benzoic acid 11-(4-amino-phenoxycarbonyl)-1-hexyl-unde 40 cyl ester product as off white powder (190 g) with a melting o–K)-No, point of 156-159°C. The resulting compound was character ized by "H NMR (CDC1) & 0.83 (t, 3H, CH), 1.2-1.65 (m, 26H, 13xCH), 1.81 (m,2H, CH), 2.12 (t, 2H, COCH), 3.50 (m. 1H, CH), 5.5-6.1 (m, 4H, 2xNH)6.8-7.2 (m, 4H, Ar), O O 45 7.2-7.8 (m, 4H. Ar). The hydrolytic degradation of the com pound was carried out in pH 9.0 buffer solution. The study showed that 1% solution is 100% hydrolyzed in 15 hours at 500 C.

To a solution of 4-Nitro-benzoic acid 11-carboxy-1-hexyl 50 Example 4D undecyl ester (350 g) in dry THF (2 L), Di-azabicyclounde cane (DBU) (23 gr) at 5-10° C., was added a solution of N,N'Dicyclohexylcarbodiimide DCC (192g) in 600 ml THF Synthesis of 12-Hydroxy Stearic Diisocyanate under nitrogen atmosphere, and later stirred at room tempera ture for 16-18 hours. DCU salts were filtered off and washed 55 with tetrahydofuran. THF solvent was distilled off com pletely under reduced pressure at 60-65C. and the resulting mass was poured into ice water (2 L). The resulting solid was o–K)-Nil, filtered and washed with chilled water. The resulting crude 60 HN was turned into slurry with 500 ml diisopropyl ether. DIPE was filtered off and then the material was dried in vacuum oven at 80-90° C. to yield pure 4-Nitro-benzoic acid 1-hexyl 11-(4-nitro-phenoxy carbonyl)-undecyl ester product as white powder with a melting point of 142-145°C. The result 65 n phosgene ing compound was characterized by "H NMR (CDC1) & 0.88 (t,3H, CH), 1.3-1.6 (m, 26H, 13xCH), 1.78 (m, 2H, CH), US 9,328,192 B2 83 84 -continued under nitrogen and heated up to 85-90° C. with thorough O shaking. The resulting solution was allowed to sit to enable brown impurity layer to settle down at bottom. The top clear layer was decanted off and given charcoal & Sodium Sulphate OCN 5 treatment for the clear decanted layer at 90-95°C. and filtered and washed with toluene. The solvent was distilled off under reduced pressure and kept for removal of trace solvent under vacuum for 1 hour at 90-95°C. It was then allowed to cool to O 40-45° C. and added 200 ml of dry n-Hexane and cooled to 0-5°C. under nitrogen with proper stirring for 30 minutes 10 with glass rod in a beaker. The resulting solid was filtered off To a solution of 4-Amino-benzoic acid 11-(4-amino-phe to yield the pure diisocyanate as off white powder 85 grams noxycarbonyl)-1-hexyl-undecyl ester (180 g) in dry 1,4-di (99.25% NCO) with a melting point of 98-101° C. The prod oxane (1.4 L) was added tri-phosgene (201 g) by dissolving in uct was characterized by "H NMR (CDC1) & 0.82 (t, 3H, 360 ml of 1,4 dioxane. The solution was heated up to 60-65° CH), 1.21-143 (m, 26H, 13xCH), 1.83 (m, 2H, CH), 2.12 C. followed by cooling to room temperature. The solution 15 (t, 2H, COCH), 3.82 (m. 1H, CH), 7.12-7.32 (m, 4H, Ar) was again heated up to 100-105° C. and stirred for 3-4 hours. 7.75-8.15 (m, 4H. Ar). The hydrolytic degradation of the The solvent was distilled off completely under reduced pres urethane prepared from this isocyanate was carried out in pH sure at 85-90° C. The traces were completely removed by 9.0 buffer solution. The study showed that 1% solution is using 14 dioxane followed by toluene (300 mL) under 100% hydrolyzed in 16 hours at 50° C. reduced pressure at 85-90° C. The resulting residue was dis Solved in toluene and given charcoal and Sodium Sulphate treatment followed by distillation of the total solvent under Example 5 reduced pressure at 95-100° C. and kept for removal of trace solvent for 2 hours at 95-100° C. to get 130 grams of the crude Diisocyanate from 12-Hydroxy Stearic Acid, product as deep yellow thick syrup which was taken for 25 Mono-Glycolate Extended-4-Nitro Phenol, and further purification in 650 ml of 6:4 toluene: hexane mixture 4-Nitro-Benzoic Acid

OH Her 4-Nitro benzoyl chloride, TEA, Acetone

OH

OH ON

ON O

O ---

O r O ON O NO O

O chain US 9,328,192 B2 85 86 -continued O r O HN O

O O 1,4-Dioxane5. O r O OCN O NCO

O

Example 5A and pH was adjusted to 4-5 with dilute HC1. The resulting solid was filtered off and washed with chilled water (100 mL). The slurry was prepared with 1 lit Di Isopropyl Ether and Synthesis of Dinitro 12-Hydroxy Stearic 30 filtered off. The resulting solid was then dried in vacuum oven Monoglycolate at 60-80°C. to yield pure (R)-18-(2-(4-nitrophenoxy)-2-oxo

OH ON

O

O

ON O

O --- Br O r O ON O NO O

To a solution of 4-Nitro-benzoic acid 11-carboxy-1-hexyl ethoxy)-18-oxooctadecan-7-yl 4-nitrobenzoate product as undecyl ester (500g) in dry Acetone, triethylamine (232 mL) off white powder with a melting point of 130-133° C. The at 10-15°C. was added Bromoacetic acid 4-nitro-phenyl ester resulting compound was characterized by H NMR (CDC1) (347 g). The solution was stirred at room temperature for 8 65 & 0.86 (t, 3H, CH), 1.2-1.5 (m. 28H, 14xCH), 1.68 (m. 2H, hours. 75% of the solvent was distilled off and cooled to room CH), 2.42 (t, 2H, COCH), 3.52 (m, 1H, CH), 5.2 (s. 2H, temperature. The resulting solid was poured onto cold water CH) 7.42 (m, 2H, Ar) 8.4–8.52 (m, 6H, Ar). US 9,328,192 B2 87 88 Example 5B Synthesis of 12-Hydroxy Stearic Monoglycolate Diamine

O r O ON O NO O

O r O HN O NH2 O

To a solution of (R)-18-(2-(4-nitrophenoxy)-2-oxoet compound was characterized by "H NMR (CDC1) & 0.83 (t, hoxy)-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 40 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 45 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 Example 14 pure (R)-18-(2-(4-amino phenoxy)-2-oxoethoxy)-18-oxooc tadecan-7-yl 4-amino benzoate product as off white powder Synthesis of 12-Hydroxy Stearic Monoglycolate (190 g) with a melting point of 124-127°C. The resulting Diisocyanate

O r O HN O NH2 O US 9,328,192 B2 89 90 -continued O r O HN O NCO

O

To a solution of (R)-18-(2-(4-amino phenoxy)-2-oxoet clear layer at 90-95°C. and filtered and washed with toluene hoxy)-18-oxooctadecan-7-yl 4-amino benzoate (180 g) in 15 100 ml. The solvent was distilled off under reduced pressure dry 1,4-dioxane (1.4 lit) Triphosgene (160 g) was added by and kept for removal of trace solvent under vacuum for 1-2 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 25 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 the crude product as deep yellow syrup that was taken for Example 6 further purification in 750 ml of 6:4 toluene: hexane mixture 30 under nitrogen and heated up to 85-90° C. and allow for settle Diisocyanate from 12-Hydroxy Stearic Acid, the brown impurity layer at bottom and decant the top clear Di-Glycolic Acid Extented, 4-Nitro Benzoic Acid, layer and given charcoal & Sodium Sulphate treatment for the and 4-Nitro Phenol

O

OH CICHCOCI OH Her

OH cry O O 4-Nitrobenzoic Acid, TEA, Acetone

O

OH

O r O O ON ON O US 9,328,192 B2 91 92 -continued O r O O O NO r O O ON estin O r O O O NH2 r O O HN Triphosgene 1,4-Dioxane O r O O O NCO r O O OCN

40 Example 7 Diisocyanate from 12-Hydroxy Stearic-Succinate is Prepared Using the Following Scheme

OH Succinic anhydride -e-

OH

OH

HO | Nin Pheno DCCTHF US 9,328,192 B2 94 -continued O

NO

O

O ON O O elein O

NH2

O

O HN O O Triphosgene 1,4-Dioxane O

NCO

O

O OCN O

O

Example 8 Diisocyanate from Ricinoleic Acid-Succinate 40 Prepared According to the Following Scheme

O

21 OH Succinic anhydride -e-

OH

O

21 OH

O

O HO

O | Nin Pheno DCCTHF US 9,328,192 B2 95 96 -continued O

21 NO

O

O ON O O elein O

21 NH2

O

O HN O O Triphosgene 1,4-Dioxane O

21 NCO

O

O OCN O

O

Example 9 Diisocyanate from Ricinoleic Acid-Diglycolic 40 Anhydride Prepared According to the Following Scheme

O

21 OH Diglycolic anhydride -e-

OH

OH

HO r r O O O | Nin Pheno DCCTHF US 9,328,192 B2 97 98 -continued O 21 o–K)-so os-()- rsr O O O estin O 21 o–K)- is-()- ^r O O O 5.1,4-Dioxane 21 o–K)-sco os-()- ror O O O

Example 10 Diisocyanate from 12 Hydroxystearic 40 Acid-Diglycolic Anhydride Prepared According to the Following Scheme

OH Diglycolic anhydride -e-

OH

OH

HO r r O O O |Nir Pheno DCCTHF US 9,328,192 B2 99 100 -continued O O -()– NO ON O -> r O O O estin O o–K)- HN O ^r O O O Triphosgene 1,4-Dioxane O o–K)-sco OCN O ror O O O

Numerous modifications and variations of the present -continued invention are possible in light of the above teachings. It is 40 (II) 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)

| -- 1.al NCO US 9,328,192 B2 101 102 -continued each X independently is selected from: O N —CHCOO (glycolic acid moiety); - Rn —CH(CH)COO (lactic acid moiety); O1 S- (X). R e —CH2CH2OCHCOO— (dioxanone moiety); and, NCO 5 —CHCHCHCH-CHCOO (caprolactone moi ety); wherein:- . each X" independently is selected from:-f-rry . variable A, the dashed bond, is absent or is a double bond; —OCHCO— (glycolic acid moiety): each R is independently the diacyl residue of a diacid; 10 –OCH(CH)CO (lactic acid moiety); R" is absent or each R" is independently a C- alkylene —OCHCHOCH2CO— (dioxanone moiety); and, group; —OCHCHCHCH-CHCO— (caprolactone moi R" is the residue of a diol or polyol; ety); from 1-4 R, are present; each p is independently selected from 0, 1,2,3,4, 5, and 6: each R, is independently selected from H. C. alkyl, C. and, alkoxy, benzyloxy, halogen, —CHO. —COH, and each p' is independently selected from 0, 1,2,3,4, 5, and 6: —NO, and each R, is independently attached directly provided that p--p' total from 2-6. to aromatic ring or attached through a —(CH2) - 2. The diisocyanate of claim 1, wherein the diisocyanate is linker; selected from formulae (Ia)-(IIIa):

NCO (Ia) N R | 2 -

N RN OCN 21

NCO (IIa) n R 1. i: 21

RN N OCN 2

NCO (IIIa) N R R (X) 1. 1 No1''n. 21

N Ris 21 US 9,328,192 B2 103 104 3. The diisocyanate of claim 1, wherein the diisocyanate is selected from formulae (Ia)-(IIIa):

(Ia) NCO O N1. X - 21 O1. 'nr, 2

RN O OCN 2 (Ia) NCO O N R 1. 1's 2

RN O OCN 2 (IIa) NCO O N R (X) 1 21 o1 'NR 2

1s1 R N,Nx 11N OSR 1 O OCN 2 (IIa) NCO O N1. 1. i: 1'n 2

R N, 1N1O O RN N (X), R OCN 21 (IIIa) O N it 1. i: 21 -N-1 ns 21

1s1 R N,Nx, 1N1 O SR O US 9,328,192 B2 105 106 -continued

O R R - (X) | - 1 No1'n 21

R O O

OCN 21r

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

(IalA) NCO O

X

R r (x)'s O OCN

(Ia2A) NCO O

R r (x)'s O OCN

(IIa) NCO O

O O RN x 1 NR-1n

OCN US 9,328,192 B2 107 108 -continued (IIa2A) NCO O 1's

R N x1 O NR1 O

OCN (IIIa 14) NCO O R (X) 21 O1 No1 Psa R

R N x1 O NR-1 O

OCN (IIIa) NCO. O R (X) O1 No1 Psa R

R O O N (x).51 n R1

OCN

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

O (1) 21 -X)

O NCO

O

OCN cer O (2) 21 -X)

O NCO

(X) NO O

O OCN US 9,328,192 B2 109 110 -continued (3) O

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

OCN 21 rol NCO

O O Ol (X),1. N1 (5) NCO O

OCN

Clu (x)51 O (6) O 21 o1 (X) rC NCO (x),1 O OCN cr's (7) NCO O uC

OCN Outs O

(8) O 21 rol O NCO

O

OCN Crs US 9,328,192 B2 111 112 -continued (9) NCO O 21 -X)

(x),.1 O rr O O O OCN (10) O 21 -X)

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

(11) O o1 (X)

O NCO (X), O

OCN

(12) O O -(X)p

O NCO Xes, O

O OCN

(13) O o1 (X)

OCN NCO US 9,328,192 B2 113 114 -continued O (14) -X) OCN NCO x 1 O NR-1 O (15) NCO O -X) OCN O (X),1 O

O (16)

O NCO (x),1 O

OCN

(17) NCO O -X) OCN O Xes, O

O

(18) O

O NCO Xes, O

O OCN US 9,328,192 B2 115 116 -continued (19) NCO O

(x,y,1 O r r O O O OCN (20) O o1 (X)

OCN

O- O O NCO. (X)1 rr O O

6. The diisocyanate of claim 1, wherein: 16. The diisocyanate of claim 5, wherein the diisocyanate each p is independently selected from 0, 1, 2, 3, and 4; and, is of formulae (6). each p' is independently selected from 0, 1, 2, 3, and 4: 30 17. The diisocyanate of claim 5, wherein the diisocyanate provided that p+p' total from 2-4. is of formulae (7). 18. The diisocyanate of claim 5, wherein the diisocyanate 7. The diisocyanate of claim 2, wherein: is of formulae (8). each p is independently selected from 0, 1, 2, 3, and 4; and, 19. The diisocyanate of claim 5, wherein the diisocyanate each p' is independently selected from 0, 1, 2, 3, and 4: 35 is of formulae (9). provided that p-p' total from 2-4. 20. The diisocyanate of claim 5, wherein the diisocyanate 8. The diisocyanate of claim 3, wherein: is of formulae (10). each p is independently selected from 0, 1, 2, 3, and 4; and, 21. The diisocyanate of claim 5, wherein the diisocyanate each p' is independently selected from 0, 1, 2, 3, and 4: is of formulae (11). provided that p-p' total from 2-4. 40 22. The diisocyanate of claim 5, wherein the diisocyanate 9. The diisocyanate of claim 4, wherein: is of formulae (12). each p is independently selected from 0, 1, 2, 3, and 4; and, 23. The diisocyanate of claim 5, wherein the diisocyanate each p' is independently selected from 0, 1, 2, 3, and 4: is of formulae (13). provided that p-p' total from 2-4. 24. The diisocyanate of claim 5, wherein the diisocyanate 10. The diisocyanate of claim 5, wherein: 45 is of formulae (14). each p is independently selected from 0, 1, 2, 3, and 4; and, 25. The diisocyanate of claim 5, wherein the diisocyanate each p' is independently selected from 0, 1, 2, 3, and 4: is of formulae (15). provided that p-p' total from 2-4. 26. The diisocyanate of claim 5, wherein the diisocyanate 11. The diisocyanate of claim 5, wherein the diisocyanate is of formulae (16). is of formulae (1). 50 27. The diisocyanate of claim 5, wherein the diisocyanate 12. The diisocyanate of claim 5, wherein the diisocyanate is of formulae (17). is of formulae (2). 28. The diisocyanate of claim 5, wherein the diisocyanate 13. The diisocyanate of claim 5, wherein the diisocyanate is of formulae (18). is of formulae (3). 29. The diisocyanate of claim 5, wherein the diisocyanate 14. The diisocyanate of claim 5, wherein the diisocyanate 55 is of formulae (19). is of formulae (4). 30. The diisocyanate of claim 5, wherein the diisocyanate 15. The diisocyanate of claim 5, wherein the diisocyanate is of formulae (20). is of formulae (5).