# US 2010/0167992 A1 · Phenyl Ester Side Chains to Increase Polymer Resorptivity

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- Number: US 2010/0167992 A1
- Document ID: US20100167992A1
- Status: Published application
- Kind: A1
- Application number: 12/641,996
- Filed: 2009-12-18
- Published: 2010-07-01
- Earliest claimed: 2007-06-21
- Assignees: TYRX, Inc.
- Inventors: Arthur Schwartz; Satish Pulapura; Sarita Nethula
- Web page: https://patentgrep.com/patent/US20100167992A1

## CPC

- A61L 31/10: Macromolecular materials
- A61L 31/041: {Mixtures of macromolecular compounds}
- A61L 31/148: {Materials at least partially resorbable by the body}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 17/00: Drugs for dermatological disorders
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C08G 63/6856: {Dicarboxylic acids and dihydroxy compounds}
- C08G 64/12: containing nitrogen
- A61L: METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS

## Abstract

The present invention relates to polymers modified to increase their resorbability. In particular, the polymers of the invention have phenyl ester side chains which are good leaving groups and which thereby increase the resorption rate of the polymer relative to the same polymer, for example, bearing a comparable amount of an alkyl ester side chain. Such polymers are generally water insoluble, but when modified are able to solublize drugs and upon degradation and resorption, release those in a physiological environment in a controlled and/or sustained manner.

## Claims

### Claim 1

A polymer comprising one or more monomer units represented by the formula:
wherein
“Monomer” is the repeating unit of a biocompatible, biodegradable polymer capable of resorption under physiological conditions;
R′ is phenyl-R , wherein from zero to five R substituents are present at any position on the phenyl ring, and each R is independently linear or branched, substituted or unsubstituted, saturated or unsaturated alkyl, aryl, alkylaryl, heteroatom-containing alkyl or aryl, alkylcycloalkyl, alkoxy, aryloxy or alkylether having from 1 to 20 carbon atoms; halide; nitro; —(R2)rO((CR3R4)aO)s—Rs; —O((CR3R4)aO)s—R5; —C(O)—R5; —(R2)bC(O)—YR6; a protected hydroxyl group; a protected amino group or a protected carboxylic acid group;
Y is —O— or —NH—;
each R2 is linear or branched, lower alkylene or lower alkenylene;
each R3 and R4 is independently hydrogen, or linear or branched lower alkyl;
each R5 is independently linear or branched, substituted or unsubstituted, saturated or unsaturated alkyl;
each R6 is hydrogen; saturated or unsaturated alkyl, aryl or alkylaryl having from 1 to 20 carbon atoms; or —(R2)rO((CR3R4)aO)s—R5;
each a is independently 1 to 4; each b is independently zero or one; each r is independently 1 to 4; and each s is independently 1 to 5000.

### Claim 2 (depends on 1)

The polymer of claim 1, wherein said polymer is a polyester, polycarbonate, polyarylate, polyurethane, polyphosphoester, polyiminocarbonate, polythiocarbonate, polyphosphate or polyanhydride.

### Claim 3 (depends on 1)

The polymer of claim 1 comprising one or more diphenol monomer units, and represented by the formula
wherein
A is —C(O—, —C(O)—R1—C(O)—, —C(═NH)—, —C(O)—NH—R1—NH—C(O)— or —C(S)—;
B is a trivalent, linear or branched, substituted or unsubstituted alkyl, alkenyl, aryl or alkylaryl moiety having 1-20 carbon atoms, or is
each backbone aromatic ring has from zero to four Z1 or Z2 substituents, each of which is independently selected from the group consisting of halide, lower alkyl, alkoxy, nitro, alkylether, a protected hydroxyl group, a protected amino group and a protected carboxylic acid group;
the pendant phenyl ring has from zero to five R substituents at any position on the phenyl ring, and each R is independently linear or branched, substituted or unsubstituted, saturated or unsaturated alkyl, aryl, alkylaryl, heteroatom-containing alkyl or aryl, alkylcycloalkyl, alkoxy, aryloxy or alkylether having from 1 to 20 carbon atoms; halide; nitro; —(R2)rO((CR3R4)aO)S—R5; —O((CR3R4)aO)s—R5; —C(O)—R5; —(R2)bC(O)—YR6; a protected hydroxyl group; a protected amino group or a protected carboxylic acid group;
R1 is, independently, a divalent, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkylene oxide or arylene oxide moiety having from 1 to 30 carbon atoms; —(R2)rO((CR3R4)aO)s(R2)r; or —(R2)rCO2((CR3R4)aO)sCO(R2)r;
each R2 is linear or branched, lower alkylene or lower alkenylene;
each R3 and R4 is independently hydrogen, or linear or branched lower alkyl;
R5 is independently linear or branched, substituted or unsubstituted, saturated or unsaturated alkyl;
R6 is hydrogen; saturated or unsaturated alkyl, aryl or alkylaryl having from 1 to 20 carbon atoms; or —(R2)rO((CR3R4)aO)s—R5;
R7 is independently a bond, or linear or branched, substituted or unsubstituted alkyl, alkenyl or alkynyl having from 1 to 20 carbon atoms, and when substituted, the substituent is selected from the group consisting of a X, —CX3, —CHX2, —CH2X, —NHR9, —NHC(O)R10;
R8 is independently a bond or linear or branched, substituted or unsubstituted alkyl, alkenyl or alkynyl having from 1 to 20 carbon atoms, and when substituted, the substituent is selected from the group consisting of a X, —CX3, —CHX2, —CH2X, —NHR9, —NHC(O)R10;
R9 is a linear or branched, substituted or unsubstituted, saturated or unsaturated alkyl, aryl or alkylaryl group or an amino protecting group;
R10 is a linear or branched alkyl, aryl or alkylaryl group;
X is a halogen;
Y is —O— or —NH—;
each a is independently 1 to 4;
each b is independently zero or one;
each r is independently 1 to 4;
and each s is independently 1 to 5000.

### Claim 4 (depends on 3)

The polymer of claim 3, wherein R is a substituted alkyl group selected from the group consisting of —CX3, —CHX2, —CH2X, —R2CX3, —R2CHX2 and —R2CH2X.

### Claim 5 (depends on 4)

The polymer of claim 4, wherein R is —R2CX3, —R2CHX2 and —R2CH2X, R2 is CH2 or CH2CH2 and X is F or Cl.

### Claim 6 (depends on 3)

The polymer of claim 3, wherein R is selected from the group consisting of an alkylaryl group, alkoxy, and —(R2)bC(O)—YR6.

### Claim 7 (depends on 6)

The polymer of claim 6, wherein R is —(R2)bC(O)—YR6 and Y is —O—.

### Claim 8 (depends on 7)

The polymer of claim 7, wherein b is zero, and R6 is hydrogen, methyl, ethyl, propyl, butyl or benzyl.

### Claim 9 (depends on 8)

The polymer of claim 8, wherein R6 is methyl or propyl.

### Claim 10 (depends on 7)

The polymer of claim 7, wherein b is one, R2 is methylene or ethylene, and R6 is hydrogen, methyl, ethyl, propyl, butyl or benzyl.

### Claim 11 (depends on 10)

The polymer of claim 10, wherein R2 is ethylene, and R6 is ethyl.

### Claim 12 (depends on 6)

The polymer of claim 6, wherein R is —(R2)bC(O)—YR6 and Y is —NH—.

### Claim 13 (depends on 12)

The polymer of claim 12, wherein b is zero, and R6 is hydrogen, methyl, ethyl, propyl, butyl or benzyl.

### Claim 14 (depends on 12)

The polymer of claim 12, wherein R2 is methylene or ethylene, and R6 is hydrogen, methyl, ethyl, propyl, butyl or benzyl.

### Claim 15 (depends on 3)

The polymer of claim 3 having zero, one, or two R substituents.

### Claim 16 (depends on 15)

The polymer of claim 15, wherein said polymer has one R substituent, wherein the R substituent is at the 2 or 4 position on the aromatic ring.

### Claim 17 (depends on 15)

The polymer of claim 15, wherein said polymer has two R substituents, wherein one R substituent is at the 2 position, and the other R substituent is at the 4 position on the aromatic ring.

### Claim 18 (depends on 3)

The polymer of claim 3, wherein A is —C(O)—R1—C(O)—.

### Claim 19 (depends on 18)

The polymer of claim 18, wherein R1 is methylene, ethylene, n-propylene, —CH2OCH2— or —(R2)rCO2((CR3R4)aO)SCO(R2)r.

### Claim 20 (depends on 3)

The polymer of claim 3, wherein B is

### Claim 21 (depends on 20)

The polymer of claim 20, wherein R7 is a bond, a methylene or an ethylene group, and wherein R8 is a bond, a methylene or an ethylene group.

### Claim 22 (depends on 1)

A composition comprising the polymer of claim 1 and one or more drugs.

### Claim 23 (depends on 3)

A composition comprising the polymer of claim 3 and one or more drugs.

### Claim 24 (depends on 22)

The composition of claim 22, wherein said one or more drugs are selected from the group consisting of antimicrobial agents, anesthetics, anti-inflammatory agents, anti- scarring agents, anti-fibrotic agents and leukotriene inhibitors.

### Claim 25 (depends on 24)

The composition of claim 24, wherein said one or more drugs is one or more antimicrobial agents.

### Claim 26 (depends on 25)

The composition of claim 25, wherein said one or more antimicrobial agents are selected from the group consisting of rifampin, minocycline, gentamicin, vancomycin, triclosan, and combinations thereof.

### Claim 27 (depends on 26)

The composition of claim 26, wherein said one or more antimicrobial agents are rifampin and minocyline.

### Claim 28 (depends on 1)

A medical device comprising one or more of the polymers of claim 1.

### Claim 29 (depends on 28)

The medical device of claim 28, wherein said one or more polymers are fully or partially resorbable.

### Claim 30 (depends on 28)

The medical device of claim 28, further comprising one or more drugs.

### Claim 31 (depends on 28)

The medical device of claim 28, wherein said device is a stent, a surgical mesh, a device covering or a catheter.

### Claim 32 (depends on 30)

The medical device of claim 30, wherein said one or more drugs are selected from the group consisting of antimicrobial agents, anesthetics, antiinflammatory agents, anti-scarring agents, anti-fibrotic agents and leukotriene inhibitors.

### Claim 33 (depends on 32)

The medical device of claim 32, wherein said one or more drugs are one or more antimicrobial agents selected from the group consisting of rifampin, minocycline, gentamicin, vancomycin, triclosan, and combinations thereof.

### Claim 34 (depends on 33)

The medical device of claim 33, wherein said one or more antimicrobial agents are rifampin and minocyline.

### Claim 35 (depends on 1)

A medical device comprising a coating on or adhered to a surface of said device, wherein the coating comprises one or more layers of the polymer of claim 1.

### Claim 36

A monomeric compound represented by Formula III or IV
wherein
B is a trivalent, linear or branched, substituted or unsubstituted alkyl, alkenyl, aryl or alkylaryl moiety having 1-20 carbon atoms, or is
each of Z1 and Z2 represent from zero to four substituents, each of which is independently selected from the group consisting of halide, lower alkyl, alkoxy, nitro, alkylether, a protected hydroxyl group, a protected amino group and a protected carboxylic acid group;
R represents from zero to five substituents at any position on the phenyl ring, and each R is independently linear or branched, substituted or unsubstituted, saturated or unsaturated alkyl, aryl, alkylaryl, heteroatom-containing alkyl or aryl, alkylcycloalkyl, alkoxy, aryloxy or alkylether having from 1 to 20 carbon atoms; halide; nitro; —(R2)rO((CR3R4)aO)s—R5; —O((CR3R4)al O)S—R5; —C(O)—R5; —(R2)bC(O)O—YR6; a protected hydroxyl group; a protected amino group or a protected carboxylic acid group;
each R2 is independently linear or branched, lower alkylene or lower alkenylene;
each R3 and R4 is independently hydrogen, or linear or branched lower alkyl;
R5 is independently linear or branched, substituted or unsubstituted, saturated or unsaturated alkyl;
R6 is hydrogen; saturated or unsaturated alkyl, aryl or alkylaryl having from 1 to 20 carbon atoms; or —(R2)rO((CR3R4)aO)s—R5;
R7 is independently a bond, or linear or branched, substituted or unsubstituted alkyl, alkenyl or alkynyl having from 1 to 20 carbon atoms, and when substituted, the substituent can be, but is not limited to, —X, —CX3, —CHX2, —CH2X, —NHR9, or —NHC(O)R10;
R8 is independently a bond or linear or branched, substituted or unsubstituted alkyl, alkenyl or alkynyl having from 1 to 20 carbon atoms, and when substituted, the substituent can be, but is not limited to, —X, —CX3, —CHX2, —CH2X, —NHR9, or —NHC(O)R10;
R9 is a linear or branched, substituted or unsubstituted, saturated or unsaturated alkyl, aryl or alkylaryl group or an amino protecting group;
R10 is a linear or branched alkyl, aryl or alkylaryl group;
P is an —OH protecting group;
X is a halogen;
Y is —)— or —NH—;
each a is independently 1 to 4;
each b is independently zero or one;
each r is independently 1 to 4;
and each s is independently 1 to 5000.

### Claim 37 (depends on 1)

A blend of polymers comprising one or more of the polymers of claim 1, and one or more second polymers.

### Claim 38 (depends on 37)

The blend of claim 37, wherein said one or more second polymers are selected from the group consisting of polylactic acid, polyglycolic acid, copolymers and mixtures of polylactic acid or polyglycolic acid, poly(L-lactide) (PLLA), poly(D,L-lactide) (PLA), polyglycolic acid, polyglycolide (PGA), poly(L-lactide-co-D,L-lactide) (PLLA/PLA), poly(L-lactide-co-glycolide) (PLLA/PGA), poly(D,L-lactide-co-glycolide) (PLA/PGA), poly(glycolide-co-trimethylene carbonate) (PGA/PTMC), poly(D,L-lactide-co-caprolactone) (PLA/PCL), poly(glycolide-co-caprolactone) (PGA/PCL); poly(oxa)esters, polyethylene oxide (PEO), polydioxanone (PDS), polypropylene fumarate, poly(ethyl glutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethyl glutamate), polycaprolactone (PCL), polycaprolactone co-butylacrylate, polyhydroxybutyrate (PHBT), copolymers of polyhydroxybutyrate, poly(phosphazene), polyphosphate ester, poly(amino acid), polydepsipeptides, maleic anhydride copolymers, polyiminocarbonates, poly[(97.5% dimethyl-trimethylene carbonate)-co-(2.5% trimethylene carbonate)], poly(orthoesters), tyrosine-derived polyarylates, tyrosine-derived polycarbonates, tyrosine-derived polyiminocarbonates, tyrosine-derived polyphosphonates, polyethylene oxide, polyethylene glycol, polyalkylene oxides, hydroxypropylmethylcellulose, polysaccharides, hyaluronic acid, chitosan, regenerated cellulose, proteins, gelatin, collagen, mixtures and copolymers thereof, and PEG derivatives or blends of any of the foregoing.

### Claim 39 (depends on 38)

The blend of claim 38, wherein said second polymer is polyethylene glycol, PLA, PLG, PLGA or PCL.

### Claim 40 (depends on 1, 37)

The blend of claim 37, comprising two different polymers according to claim 1.

### Claim 41 (depends on 37)

The blend of claim 37, further comprising one or more drugs.

### Claim 42 (depends on 41)

The blend claim 41, wherein said one or more drugs are selected from the group consisting of antimicrobial agents, anesthetics, anti-inflammatory agents, anti-scarring agents, anti-fibrotic agents and leukotriene inhibitors.

### Claim 43 (depends on 42)

The blend of claim 42, wherein said one or more drugs are one or moreantimicrobial agents selected from the group consisting of rifampin, minocycline, gentamicin, vancomycin, triclosan, and combinations thereof

### Claim 44 (depends on 43)

The blend of claim 43, wherein said one or more drugs are rifampin and minocyline.

### Claim 45 (depends on 28)

A method of treating a disorder or condition in a patient comprising implanting the medical device of claim 28 in a patient, wherein said disorder is a cardiovascular disorder, a neurological disorder, a hernia or hernia related disorder, an ophthalmic condition, or anatomical repair, reconstruction, replacement or augmentation.

### Claim 46 (depends on 45)

The method of claim 45, wherein said device is a stent, a surgical mesh or a fully resorbable device covering.

### Claim 47 (depends on 46)

The method of claim 46, wherein when the device is a stent, the disorder is selected from the group consisting of atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof; when the device is a surgical mesh, the mesh is used to reconstruct, reinforce, bridge, replace, repair, support, stabilize, position or strengthen a soft tissue defect or a hernia.

### Claim 48 (depends on 45)

The method of claim 45, wherein said device is a fully resorbable device covering.

### Claim 49 (depends on 48)

The method of claim 48, wherein said covering is for a cardiac rhythm management device, a neurostimulator or a breast implant.