WO1999008718A2

WO1999008718A2 - Bioresorbable compositions for implantable prostheses

Info

Publication number: WO1999008718A2
Application number: PCT/US1998/016933
Authority: WO
Inventors: Gary L. Loomis
Original assignee: Meadox Medicals, Inc.
Priority date: 1997-08-18
Filing date: 1998-08-14
Publication date: 1999-02-25
Also published as: EP1019096B1; EP1019096A2; US5854382A; DE69826882T2; JP2001514931A; US6028164A; DE69826882D1; CA2303807C; WO1999008718A3; US6005020A; ATE278423T1; US6403758B1; JP5227487B2; AU8700898A; CA2303807A1

Abstract

Cross-linked compositions formed from a water-insoluble copolymer are disclosed. These compositions are copolymers having a bioresorbable region, a hydrophilic region and at least two crosslinkable functional groups per polymer chain. These compositions are able to form hydrogels in aqueous environments when cross-linked. These hydrogels are good sealants for implantable prostheses when in contact with an aqueous environment. In addition, such hydrogels can be used as delivery vehicles for therapeutic agents.

Description

BIORESORBABLE COMPOSITIONS FOR IMPLANTABLE PROSTHESES

FIELD OF INVENTION

This invention relates generally to coating compositions for medical devices. More

particularly, the present invention relates to cross-linked compositions formed from a

water insoluble copolymer having a bioresorbable region, a hydrophilic region and at least

two cross-linkable functional groups per polymer chain. These compositions when placed

in contact with an aqueous environment form hydrogels which are useful as sealants for

porous materials and particularly for implantable prostheses. Furthermore, these

hydrogels can be used as delivery vehicles for therapeutic agents. Medical devices coated

and/or sealed with such hydrogels, processes for forming such devices and methods of

making the hydrogels are also disclosed.

BACKGROUND OF THE INVENTION

It is generally known to provide a porous substrate, such as an implantable

prosthesis, with a biocompatible, biodegradable sealant or coating composition which

initially renders the porous substrate fluid-tight. Over time, such a sealant composition is

resorbed and the healing process naturally takes over the sealing function of the sealant

composition as tissue ingrowth encapsulates the prosthesis. The art is replete with

examples of naturally derived, as well as chemically synthesized sealant compositions.

Natural materials, such as collagen and gelatin, have been widely used on textile

grafts. U.S. Patent Nos. 4,842,575 and 5,034,265 to Hoffman Jr., et al. disclose the use of collagen as a sealant composition for grafts. More recently, co-owned and co-pending

U.S. Serial No. 08/713,801 discloses the use of a hydrogel or sol-gel mixture of

polysaccharides for rendering fluid-tight porous implantable devices. Such sealant

compositions are beneficial in that they are able to seal an implantable device without the

need for chemical modification of the surface thereof and provide improved

bioresorbability as the healing process occurs. Furthermore, fibrin, an insoluble protein

formed during the blood clotting process, has also been used as a sealant for porous

implantable devices.

The use of such biologically derived sealant compositions, however, suffers from

several drawbacks. One such drawback is the difficulty in producing consistent coatings

due to variations inherent in natural materials. Another drawback is that the body may

identify such compositions as foreign and mount an immune response thereto. Thus,

biologically-based sealant compositions can cause inflammation, as well as infection at or

around the site of implantation, which can lead to life-threatening complications.

Accordingly, attempts have been made to design sealant systems from chemically

synthesized materials which are easier to manufacture and control the desired

characteristics and qualities and which have less potential for causing adverse biological

reactions. For example, U.S. Patent No. 4,826,945 to Cohn et al. discloses synthetically

produced resorbable block copolymers of poly(α-hydroxy-carboxylic

acid)/poly(oxyalkylene) which are used to make absorbable sutures, wound and burn

dressings and partially or totally biodegradable vascular grafts. These copolymers, however, are not crosslinked. The poly(alkylene) segments of such bio-absorbable

copolymers are disclosed to be water-soluble so that the body can excrete the degraded

block copolymer compositions. See also, Younes, H. and Cohn, D., J Biomed. Mater.

Res. 21, 1301-1316 (1987) and Cohn, D. and Younes, H., J Biomed. Mater. Res. 22, 993-

1009 (1988). As set forth above, these compositions are uncrosslinked and, as a

consequence, are relatively quickly bio-absorbed. Moreover, these uncrosslinked

compositions generally require the presence of crystalline segments to retain their

hydrogel-like consistency. As a result of such crystalline segments, these compositions

have limited utility as sealants for vascular grafts.

Furthermore, U.S. Patent No. 4,438,253 to Casey et al. discloses tri-block

copolymers produced from the transesterification of poly(glycolic acid) and an hydroxyl-

ended poly(alkylene glycol). Such compositions are disclosed for use as resorbable

monofilament sutures. The flexibility of such compositions is controlled by the

incorporation of an aromatic orthocarbonate, such as, tetra-p-tolyl orthocarbonate into the

copolymer structure. The strength and flexibility which makes such a composition useful

as a suture, however, does not necessarily make it appropriate for use as a sealant for a

porous implantable prosthesis. Moreover, these tri-block copolymers are substantially

uncross-linked. Thus, while compositions are somewhat hydrophilic, they do not form

hydrogels.

Accordingly, attempts have been made to engineer bio-compatible hydrogel

compositions whose integrity can be controlled through crosslinking. For example, U.S. Patent Nos. 5,410,016 and 5,529,914 to Hubbell et al. disclose water-soluble systems

which when crosslinked utilize block copolymers having a water-soluble central block

segment sandwiched between two hydrolytically labile extensions. Such copolymers are

further end-capped with photopolymerizable acrylate functionalities. When crosslinked,

these systems become hydrogels. The water soluble central block of such copolymers can

include poly(ethylene glycol); whereas, the hydrolytically labile extensions can be a

poly(α-hydroxy acid), such as, polygly colic acid or polylactic acid. See, Sawhney, A.S.,

Pathak, C.P., Hubbell, J. A., Macromolecules 1993, 26, 581-587.

Furthermore, U.S. Patent No. 5.202,413 to Spinu discloses biodegradable multi-

block copolymers having sequentially ordered blocks of polylactide and/or polyglycolide

produced by ring-opening polymerization of lactide and/or glycolide onto either an

oligomeric diol or a diamine residue followed by chain extension with a di-functional

compound, such as, a diisocyanate, diacylchloride or dichlorosilane. The general structure

of such a composition is R-(A-B-A-L)_λ-A-B-A-R, where A is a polyhydroxy acid, such as

polylactide, polyglycolide or a copolymer thereof, B is an oligomeric diol or diamine

residue, L is a diacyl residue derived from an aromatic diacyl halide or diisocyanate and R

is H or an end-capping group, such as an acyl radical. A major difference between the

compositions set forth in the Spinu '413 patent and those described by the Cohn references

supra is that Spinu uses lactide blocks whereas Cohn uses lactic acid blocks. Furthermore,

like the Cohn copolymers, the copolymers described in the Spinu '413 patent are not

crosslinkable. In general, all of the synthetic compositions set forth above describe copolymers

having one or more segments which are water-soluble. Accordingly, many of the

compositions described by these references are intended to be rapidly biodegraded by the

body.

Thus, there is a need for water-insoluble, fully crosslinkable polymeric materials

which are easily synthesized and provide controlled bioresorption in vivo . Moreover,

there is a need for improved, cost-efficient synthetic sealant compositions for porous

implantable prostheses which are characterized by their ability to self-emulsify and form

stable low viscosity emulsions. There is a further need for sealant compositions which are

quickly cured, exist as hydrogels in an aqueous environment and which remain flexible

while dehydrated without the need for an external plasticizer. The present invention is

directed to meeting these and other needs.

SUMMARY OF THE INVENTION

In one embodiment of the present invention, there is provided a covalently

crosslinkable composition. This composition includes a water-insoluble copolymer which

has a bioresorbable region, a hydrophilic region and a plurality of crosslinkable functional

groups per polymer chain.

In another embodiment of the present invention, there is provided a medical device

which has on at least one surface thereof a bioresorbable coating composition. This composition includes a hydrogel formed from the crosslinking of a polymer containing a

bioresorbable region, a hydrophilic region, a plurality of crosslinkable functional groups

and a crosslinking agent.

In a further embodiment of the present invention, there is provided a process for

forming a hydrogel. This process includes providing an aqueous emulsion of a water-

insoluble copolymer. This water-insoluble copolymer includes a bioresorbable region, a

hydrophilic region, a plurality of crosslinkable functional groups per polymer chain and a

crosslinking agent. Activation of the crosslinking agent crosslinks the copolymer

composition and forms the hydrogel.

In yet a further embodiment of the present invention, there is provided a process

for forming a medical device coated with a hydrogel. The hydrogel is formed from an

aqueous emulsion which includes a water-insoluble copolymer having a bioresorbable

region, a hydrophilic region, a plurality of crosslinkable functional groups per polymer

chain and a crosslinking agent. This process includes applying the hydrogel to the medical

device and then activating the crosslinking agent in a humid environment.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to covalently crosslinkable compositions formed

from water-insoluble copolymers. The copolymers of the present invention include a

bioresorbable region, a hydrophilic region and a plurality of crosslinkable functional groups per polymer chain. When uncrosslinked, the copolymer compositions form stable

aqueous emulsions. Once crosslinked, however, such compositions form hydrogels in the

presence of water. Hydrogels formed from the compositions of the present invention can

serve as coatings for a medical device and/or as a therapeutic agent delivery vehicle.

The copolymers of the present invention are multi -block copolymers including, for

example, di-block copolymers, tri-block copolymers, star copolymers, and the like. For

purposes of illustration only, a typical tri-block copolymer of the present invention may

have the following general formula:

xABAx (I)

wherein A is the bioresorbable region, B is the hydrophilic region and x is the

crosslinkable functional group.

A more specific example of a copolymer useful in the present inventive

compositions has

the following chemical structure:

O CH₃ CH₃ O

CH₂=C-C[-0-CH-C]_x-[(OCH₂-CH₂ [C-CH-0] -C-C=CH₂ (II)

I II II I

CH₃ o o CH₃

wherein x is from about 10 to about 50 and y is from about 50 to about 300, so long as the

composition remains water-insoluble as a whole.

One required feature of the present invention is that the crosslinkable copolymer

composition be water-insoluble. For purposes of the present invention, "water-insoluble"

is intended to mean that the copolymers of the present invention are substantially insoluble

in water or water-containing environments. Thus, although certain regions or segments of

the copolymer may be hydrophilic or even water-soluble, however, the copolymer

molecule, as a whole, does not by any substantial measure dissolve in water or water-

containing environments.

As set forth above, the water-insoluble copolymer includes a bioresorbable region.

For purposes of the present invention, the term "bioresorbable" means that this region is

capable of being metabolized or broken down and resorbed and/or eliminated through

normal excretory routes by the body. Such metabolites or break-down products should be

substantially non-toxic to the body.

The bioresorbable region is preferably hydrophobic. In another preferred

embodiment, however, the bioresorbable region may be designed to be hydrophilic so long

as the copolymer composition as a whole is not rendered water-soluble. Thus, the

bioresorbable region is designed based on the requirement that the copolymer, as a whole,

must remain water-insoluble. Accordingly, the relative properties, i.e., the kinds of

functional groups contained by, and the relative proportions of the bioresorbable region, and the hydrophilic region are selected to ensure that the present compositions remain

water-insoluble.

The copolymers of the present invention form a stable aqueous emulsion. For

purposes of the present invention, the terms "emulsion", "emulsifiable" and "self-

emulsifying" refer to the ability of the copolymers of the present composition to form an

emulsion, i.e., a colloidal suspension of one liquid in another, without the requirement of

an emulsifying agent to stabilize the emulsion. Although emulsifying agents are not

required by the present invention, their use is not excluded in appropriate circumstances is

so desired by the skilled artisan. The relative proportions or ratios of the bioresorbable

and hydrophilic regions, respectively are specifically selected to render the block

copolymer composition water-insoluble. Furthermore these compositions are sufficiently

hydrophilic to form a hydrogel in aqueous environments when crosslinked. Such

hydrogels, as set forth in more detail below, can form a fluid-tight barrier when applied to

a medical device. The specific ratio of the two regions of the block copolymer

composition of the present invention will of course vary depending upon the intended

application and will be affected by the desired physical properties of the porous

implantable prosthesis, the site of implantation, as well as other factors. For example, the

composition of the present invention remains substantially water-insoluble when the ratio

of the water- insoluble region to the hydrophilic region is from about 10:1 to about 1 :1, on

a percent by weight basis. The bioresorbable region of the present invention can be designed to be

hydrolytically and/or enzymatically cleavable. For purposes of the present invention,

"hydrolytically cleavable" refers to the susceptibility of the copolymer, especially the

bioresorbable region, to hydrolysis in water or a water-containing environment. Similarly,

"enzymatically cleavable" as used herein refers to the susceptibility of the copolymer,

especially the bioresorbable region, to cleavage by endogenous or exogenous enzymes.

Based on the characteristics set forth above, a number of different compositions

can be utilized as the bioresorbable region. Thus, the bioresorbable region includes

without limitation, for example, poly(esters), poly(hydroxy acids), poly(lactones),

poly(amides), poly(ester-amides), poly(amino acids), poly(anhydrides), poly(ortho-esters),

poly(carbonates), poly(phosphazines), poly(thioesters), polysaccharides and mixtures

thereof. Furthermore, the bioresorbable region can also be, for example, a poly(hydroxy)

acid including poly (α-hydroxy) acids and poly (β-hydroxy) acids. Such poly(hydroxy)

acids include, for example, polylactic acid, polyglycolic acid, polycaproic acid,

polybutyric acid, polyvaleric acid and copolymers and mixtures thereof.

As set forth above, the present composition also includes a hydrophilic region. For

purposes of the present invention, "hydrophilic" is used in the classical sense of a material

or substance having an affinity for water. Although the present composition contains an

hydrophilic region, this region is designed and/or selected so that the composition as a

whole, remains water-insoluble at all times. When placed within the body, the hydrophilic region can be processed into

excretable and/or metabolizable fragments. Thus, the hydrophilic region can include

without limitation, for example polyethers, polyalkylene oxides, polyols, poly(vinyl

pyrrolidine), poly(vinyl alcohol), poly(alkyl oxazolines), polysaccharides, carbohydrates,

peptides, proteins and copolymers and mixtures thereof. Furthermore, the hydrophilic

region can also be, for example, a poly(alkylene) oxide. Such poly(alkylene) oxides can

include, for example, poly(ethylene) oxide, poly(propylene) oxide and mixtures and

copolymers thereof.

As set forth above, the composition of the present invention also includes a

plurality of crosslinkable functional groups. Any crosslinkable functional group can be

incorporated into the present compositions so long as it permits or facilitates the formation

of a hydrogel. Preferably, the crosslinkable functional groups of the present invention are

olefinically unsaturated groups. Suitable olefmically unsaturated functional groups

include without limitation, for example, acrylates, methacrylates, butenates, maleates, allyl

ethers, allyl thioesters and N-allyl carbamates. Preferably, the crosslinking agent is a free

radical initiator, such as for example, 2,2'-Azobis (N,N'dimethyleneisobutyramidine)

dihydrochloride.

The crosslinkable functional groups can be present at any point along the polymer

chain of the present composition so long as their location does not interfere with the

intended function thereof. Furthermore, the crosslinkable functional groups can be present in the polymer chain of the present invention in numbers greater than two, so long as the

intended function of the present composition is not compromised.

Preferably, however, at least two olefmically unsaturated functional groups are

present on the polymer chain of the present composition. As set forth above, the number

of olefmically unsaturated functional groups present on the polymer chain can be increased

beyond two, depending upon the particular application. Although the olefmically

unsaturated functional groups can be positioned anywhere within the polymer chain of the

present composition, it is preferred that at least one olefmically unsaturated functional

group be positioned at a terminus of the polymer chain. More preferably, an olefinically

unsaturated group is positioned at both terminal ends of the polymer chain. Furthermore,

as there are at least two functional groups present in the present composition, the

functional groups contained therein can be the same or different.

Crosslinking of compositions of the present invention is accomplished through the

crosslinkable functional groups. These functional groups are activated to crosslink the

copolymer composition by a variety of crosslinking initiators. These crosslinking

initiators can include, for example, high energy radiation, thermal radiation and/or visible

light. The composition of the present invention can also include free radical initiators.

Such free radical initiators can include, for example, a peroxide or an azo compound.

In the present invention, the composition is crosslinked in an aqueous medium.

Furthermore, when crosslinked, the copolymer composition is able to form a hydrogel. The hydrogels of the present invention are polymeric materials that swell in water without

dissolving and that retain a significant amount of water in their structures. Such

compositions have properties intermediate between liquid and solid states. Hydrogels also

deform elastically and recover, yet will often flow at higher stresses. Thus, for purposes of

this invention hydrogels are water-swollen, three-dimensional networks of hydrophilic

polymers. These hydrogel compositions are not as transient as, and are more controllable

than the prior art non-crosslinked sealant compositions described above. Thus, the present

compositions have distinct advantages over the prior art and are able to function as

superior sealants, for example, porous implantable prostheses, as well as, delivery devices

for certain therapeutic agents.

In one embodiment of the invention, a therapeutic agent, such as for example a

drug or bio-active agent, may be incorporated into the composition of the present

invention for controlled release as the composition is bioresorbed. Thus, the present

composition can be used to target therapeutic agents to specific sites in the body.

Furthermore, the present composition can be engineered to bioresorb at a certain rate by

controlling the ratio of the bioresorbable to the hydrophilic regions, as well as by

controlling the degree of crosslinking thereof. Thus, the present compositions are able to

delivery controlled quantities of a therapeutic agent to a specific site in the body as the

block copolymer is bioresorbed.

Any drug or bio-active agent may be incorporated into the composition of the

present invention provided that it does not interfere with the required characteristics and functions of the composition. Examples of suitable drugs or bio-active agents may

include, for example, without limitation, thrombo-resistant agents, antibiotic agents, anti-

tumor agents, antiviral agents, anti-angiogenic agents, angiogenic agents, anti-

inflammatory agents, cell cycle regulating agents, their homologs, derivatives, fragments,

pharmaceutical salts and combinations thereof.

Useful thrombo-resistant agents can include, for example, heparin, heparin sulfate,

hirudin, hyaluronic acid, chondroitin sulfate, dermatan sulfate, keratin sulfate, lytic agents,

including urokinase and streptokinase their homologs, analogs, fragments, derivatives and

pharmaceutical salts thereof.

Useful antibiotics can include, for example, penicillins, cephalosporins,

vancomycins, aminoglycosides, quinolones, polymyxins, erythromycins, tetracyclines,

chloramphenicols, clindamycins, lincomycins, sulfonamides their homologs, analogs,

fragments, derivatives, pharmaceutical salts and mixtures thereof.

Useful anti-tumor agents can include, for example, paclitaxel, docetaxel, alkylating

agents including mechlorethamine, chlorambucil, cyclophosphamide, melphalan and

ifosfamide; antimetabolites including methotrexate, 6-mercaptopurine, 5-fluorouracil and

cytarabne; plant alkaloids including vinblastine, vincristine and etoposide; antibiotics

including doxorubicin, daunomycin, bleomycin, and mitomycin; nitrosureas including

carmustine and lomustine; inorganic ions including cisplatin; biological response

modifiers including interferon; enzymes including asparaginase; and hormones including tamoxifen and flutamide their homologs, .analogs, fragments, derivatives, pharmaceutical

salts and mixtures thereof.

Useful .anti-viral agents can include, for example, amantadines, rimantadines,

ribavirins, idoxuridines, vidarabines, trifluridines, acyclovirs, ganciclovirs, zidovudines,

foscarnets, interferons their homologs, analogs, fragments, derivatives, pharmaceutical

salts and mixtures thereof.

having on at least one surface thereof a bioresorbable coating composition. This coating

composition includes a hydrogel which is formed from the crosslinking of a polymer

containing a bioresorbable region, a hydrophilic region, a plurality of crosslinked

functional groups and a crosslinking agent, as set forth previously.

The bioresorbable coating composition of the present invention can be applied as

coatings to medical devices. In particular, the present bioresorbable coating compositions

are intended to coat medical devices made from implantable materials. These

bioresorbable coatings are capable of rendering fluid-tight porous medical devices such as

conduits, vascular grafts, textile materials, polymeric films and the like. For purposes of

the present invention, the term "fluid-tight" refers to the specific porosity of a material,

such as a porous vascular or endovascular graft. Porosity of textile materials is often

measured with a Wesolowski Porosity tester. With this apparatus, a graft is tied off at one

end and the free end is attached to a valve on a porometer so that the graft hangs freely in a vertical position. Then, water is run through the graft for one minute and the water that

escapes from the graft is collected .and measured. The specific porosity of the graft is then

calculated according to the following formula:

P= V A

where V is the volume of water collected in ml/min and A is the surface area of the graft

exposed to water in cm² A specific porosity of ≤ 1.0 ml/min/cm² is considered an

acceptable amount of leakage for an implantable vascular graft. Accordingly, for purposes

of this invention, a substantially fluid-tight graft means a graft with a specific porosity,

after impregnation with a sealant of the present invention, of < 1.0 ml/min/cm² . Porosities

meeting and exceeding the acceptable specific porosity criteria set forth above are

achieved through the use of certain block copolymers described herein having polyether-

polyester segments.

Implantable materials useful in the present invention can include, for example

polymeric compositions, non-polymeric compositions and combinations thereof. The

polymeric material can include, for example, olefin polymers including polyethylene,

polypropylene, polyvinyl chloride, polytetrafluoroethylene, fluorinated ethylene propylene

copolymer, polyvinyl acetate, polystyrene, poly(ethylene terephthalate), polyurethane,

polyurea, silicone rubbers, polyamides, polycarbonates, polyaldehydes, natural rubbers,

polyester copolymers, styrene-butadiene copolymers and combinations thereof. Non-

polymeric implantable materials can include, for example, ceramics, metals, inorganic

glasses, pyrolytic carbon and combinations thereof. The compositions set forth

hereinabove for the implantable substrate material of the present invention are intended to be exemplary only and should not be construed to limit in any way the types of materials

to which the present bioresorbable coatings can be applied.

As set forth above, these implantable materials are used to manufacture medical

devices, such as for example, endoprostheses. Grafts, stents .and combination graft-stent

devices are contemplated. Preferably these medical devices are vascular or endovascular

grafts. Useful vascular or endovascular grafts include those which are knitted, braided or

woven textiles, and may have velour or double velour surfaces. Alteratively, the medical

device can be manufactured from an extruded polymer, such as polytetrafluoroethylene

(PTFE), polyethylene terephthalate (PET), fluorinated ethylene propylene copolymer

(FEP), polyurethane, silicone and the like. Composite structures are also contemplated.

In another preferred embodiment, the medical device may be a catheter, a

guidewire, a trocar, an introducer sheath or the like. When coated onto such devices, the

composition of the present invention imparts increased bio-compatibility to one or more

surfaces thereof. Furthermore, when the present composition includes a drug or bio-active

agent, specific therapeutic effects can be imparted to the surfaces of such devices.

Moreover, the hydrophilic region of the present composition can impart increased

lubriciousness to the surfaces of, e.g., a guidewire or other similar device.

Thus, any medical device to which the bioresorbable coating composition can

adhere can be used in conjunction with the present invention. Accordingly, the examples

of implantable materials and medical devices set forth hereinabove are for purposes of illustration only and are not intended to limit the scope of the materials and devices to

which the present bioresorbable coatings can be applied or otherwise associated therewith.

In another embodiment of the present invention, there is provided a process for

forming a hydrogel. This process includes: (i) providing an aqueous emulsion of a water-

insoluble copolymer which contains a bioresorbable region, a hydrophilic region, a

plurality of crosslinkable functional groups per polymer chain and a crosslinking agent;

and (ii) activating the crosslinking agent, as set forth previously. In this process, the

crosslinkable functional groups can be, but are not limited to, olefinically unsaturated

groups. As set forth previously, the crosslinking agent can be a free radical initiator, an

azo or a peroxide composition. Still further, the crosslinking agent can be, for example,

thermally or photochemically activated.

In yet another embodiment of the present invention, there is provided a process for

forming a medical device coated with a hydrogel. As set forth previously, this hydrogel is

formed from an aqueous emulsion which includes a water-insoluble copolymer. This

copolymer includes a bioresorbable region, a hydrophilic region, a plurality of

crosslinkable functional groups per polymer chain and a crosslinking agent. Accordingly,

this process includes applying the hydrogel to the medical device and then activating the

crosslinking agent in a humid environment.

Although, the crosslinking agent can be activated in both humid and non-humid

environments, it is preferred that the activation take place in humid environments. Preferably, the humid environment contains from about 20% to about 100% water. More

preferably, the humid environment contains from about 60% to about 100% water.

The hydrogels formed by this process can be packaged and stored in a variety of

ways. For example, the hydrogel can be maintained in a hydrated state for an extended

period of time. Alternatively, the hydrogel can be dehydrated and stored in an essentially

desiccated state until use.

As set forth previously, a therapeutic agent, such as for example, a drug or bio-

active agent can be added to the emulsion for targeted, timed release of such agents in the

body. Examples of types of therapeutic agents which can be incorporated into the

emulsion have been set forth above.

The following examples are set forth to illustrate the copolymer compositions of

the present invention. These examples are provided for purposes of illustration only and

are not intended to be limiting in any sense.

EXAMPLE 1

A polymer (Polymer A) according to the present invention was synthesized as

follows: 125.0 gm poly(ethylene glycol-co-propylene glycol) (75 wt% ethylene glycol, M_n

= 12,000) was charged to a 4-necked reaction flask equipped with a Dean-Stark water trap,

a water-cooled condenser, a thermometer, and a gas inlet/a gas outlet system which

allowed for the controlled flow of nitrogen. While maintaining a nitrogen atmosphere, 660

ml anhydrous toluene was added to the flask and the mixture was heated and reflux was

maintained for 3-4 hours. During this period any water present was collected in the Dean-

Stark trap (approximately 10% of the original toluene was also removed during this

azeotropic water removal). The flask was allowed to cool to room temperature and 30.4

gm d,l -lactide was added to the flask followed by 50 mg of stannous 2-ethylhexanoate

catalyst (1% solution in anhydrous toluene). The reaction mixture was heated to reflux for

6 hours and was allowed to cool to room temperature.

5.28 gm of triethylamine was added to the mixture. After 5 minutes of stirring,

4.72 gm of acryloyl chloride was slowly added to the flask. The mixture was then heated

to reflux for 7 hours followed by cooling to room temperature. Unreacted acryloyl

chloride was quenched with 15 ml of methanol. Approximately 110 mg of 4-methoxy

phenol was added to the flask as a free-radical stabilizer.

The solution was filtered to remove triethylamine hydrochloride and the amount of

solvent was reduced in vacuo to approximately half of the original volume. This solution

was then precipitated into ether, filtered and the remaining solvent was removed in vacuo

to afford the polymer as a viscous oil which is substantially water-insoluble. EXAMPLE 2

Another polymer (Polymer B) according to the present invention was synthesized

as set forth in Example 1 with the following exceptions. 60.07 gm of 1-lactide was

substituted for the d,l-lactide of Example 1 and the amount of stannous 2-ethylhexanoate

was decreased to 40 mg. The resulting Polymer B was a waxy solid which was

substantially water-insoluble.

EXAMPLE 3

Polymer C according to the present invention was synthesized as set forth in

Example 1 with the following exceptions. The amount of d, 1-lactide was increased to 71.2

gm, the amount of stannous 2-ethylhexanoate was decreased to 40 gm, the amount of acryl

chloride was increased to 22.63 gm and the amount of triethylamine was increased to

25.63 gm. The resulting Polymer C was an oil which was substantially water-insoluble.

EXAMPLE 4

Polymer D according to the present invention was synthesized as set forth in

Example 1 with the following exceptions. The amount of d, 1-lactide was increased to 22.5

gm and the amount of stannous 2-ethylhexanoate was also decreased to 40 mg. The

resulting Polymer D was a viscous oil that was substantially water-insoluble. EXAMPLE 5

An aqueous emulsion (20% solids) was prepared by dispersing Polymer D and

Vazo™ 044 (13.4 mg Vazo/1.0 gm. polymer) in water with rapid stirring. The mixture

was transferred to a shallow Teflon™ mold (9cm X 9 cm X 1cm), which was sealed with a

glass cover plate and placed in an oven at 60 °C for approximately 60 minutes.

The resulting hydrogel was demolded and dehydrated in vacuo to afford a thick

elastic film with a hardness of Shore A = 28. Stress-strain (Instron testing with crosshead

speed = 200 mm/min.), tensile strength at break (T_b) = 50 psi (0.35 Mpa) and % elongation

at break

(%E_B) = 585. The water uptake of this dehydrated hydrogel was determined as follows:

EXAMPLE 6

A fabric suitable for use in medical procedures was coated with Polymer D of the

present invention. In particular, a 1 inch X 3 inch rectangle of a knitted polyester medical fabric was impregnated by immersing it for 5.0 minutes in a degassed aqueous emulsion

containing 1.0 gm of Polymer D and 13.4 mg. Vazo ™ 044 dispersed in 4.0 ml. de-ionized

water. The impregnated fabric was then passed twice through a soft rubber wringer to

remove excess emulsion. The impregnated fabric was then placed in an environmental

chamber maintained at about 60-65 °C and 100% relative humidity under nitrogen for 60

minutes. The sample was then cooled to room temperature, washed twice (each wash was

15 minutes) with distilled water, then dried to constant weight.

EXAMPLE 7

The water porosity of the coated medical fabric of Example 6 was determined in a

laboratory apparatus as described in AAMI Standards & Recommended Procedures, 1989,

Reference Book; and in "Evaluation of Tissue and Prosthetic Vascular Grafts", p. 62,

Charles Thomas, Publisher, Springfield, Illinois, 1962. In the water porosity test, the

coated medical fabric of Example 6 was placed over a hole, and a metal plate, containing a

concentric hole of the same size, was clamped over the sample. Water was permitted to

flow through the fabric, and the pressure was adjusted until the specific test pressure was

reached. Porosity was calculated as follows:

Porosity = Q/A

where,

Q = flow rate through the sample in cc/minute @ 120 mm Hg, and

A = the cross-sectional area in cm² of the hole. The following table sets forth the porosity data for the medical fabric coated with

Polymer D.

Water Porosity of Hydrogel Coated Knitted Polyester Fabric

The invention being thus described, it will be obvious that the same may be varied

in many ways. Such variations are not to be regarded as a departure from the spirit and

scope of the invention and all such modifications are intended to be included within the

scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A covalently crosslinkable composition comprising a water-insoluble

copolymer having (i) a bioresorbable region; (ii) a hydrophilic region; and (iii) a plurality

of crosslinkable functional groups per polymer chain.

2. The composition of claim 1 , wherein said copolymer forms a stable

aqueous emulsion.

3. The composition of claim 1 , wherein the ratio of said bioresorbable region

to said hydrophilic region is from about 10:1 to about 1 :1 on a percent by weight basis.

4. The composition of claim 1, wherein the relative properties and proportions

of said bioresorbable region and said hydrophilic region are selected to render said

composition insoluble in water.

5. The composition of claim 1 , wherein said bioresorbable region is

hydrophobic.

6. The composition of claim 1, wherein said bioresorbable region has

hydrophilic character without rendering the polymer water-soluble.

7. The composition of claim 1 , wherein said bioresorbable region is

hydrolytically and/or enzymatically cleavable.

8. The composition of claim 1, wherein said bioresorbable region is selected

from the group consisting of poly(esters), poly(hydroxy acids), poly (lactones), poly

(amides), poly(ester-amides), poly (amino acids), poly(anhydrides), poly(orthoesters),

poly(carbonates), poly(phosphazines), poly(phosphoesters), poly(thioesters),

polysaccharides and mixtures thereof.

9. The composition of claim 1 , wherein said bioresorbable region is a

poly(hydroxy) acid.

10. The composition of claim 9, wherein said poly(hydroxy) acid is formed

from material selected from the group consisting of polylactic acid, polyglycolic acid,

polycaproic acid, polybutyric acid, polyvaleric acid and copolymers and mixtures thereof.

11. The composition of claim 1 , wherein said hydrophilic region is selected

from the group consisting of poly ethers, polyalkylene oxides, polyols,

poly(vinylpyrrolidine), poly(vinyl alcohol), poly(alkyl oxazolines), polysaccharides,

carbohydrates, peptides, proteins and copolymers and mixtures thereof.

12. The composition of claim 1, wherein said hydrophilic region forms an

excretable and or metabolizable fragment.

13. The composition of claim 1 , wherein said hydrophilic region is a

poly(alkylene) oxide.

14. The composition of claim 13, wherein said poly(alkylene) oxide is selected

from the group consisting of poly(ethylene) oxide, poly(propylene) oxide and mixtures

and copolymers thereof.

15. The composition of claim 1 , wherein said plurality of crosslinkable

functional groups are olefinically unsaturated groups.

16. The composition of claim 15, wherein at least one of said olefinically

unsaturated functional groups is positioned at a terminus of said polymer chain.

17. The composition of claim 15, wherein said olefinically unsaturated

functional groups are selected from the group consisting of acrylates, methacrylates,

butenoates, maleates, allyl ethers, allyl thioesters and N-allyl carbamates.

18. The composition of claim 1 being crosslinked by high energy or thermal

radiation.

19. The composition of claim 1 being crosslinked by visible light.

20. The composition of claim 1 further including a free radical initiator.

21. The composition of claim 20, wherein said free radical initiator is a

peroxide.

22. The composition of claim 20, wherein said free radical initiator is an azo

compound.

23. The composition of claim 1, wherein said copolymer is crosslinked in an

aqueous medium.

24. The composition of claim 23, wherein a crosslinked polymer forms a

hydrogel.

25. The composition of claim 23, wherein said hydrophilic region is water-

swellable.

26. The composition of claim 24, wherein said hydrogel is useful as a coating

for a medical device.

27. The composition of claim 24, wherein said hydrogel is useful as a drug or

bio-active agent delivery vehicle.

28. The composition of claim 27, wherein said drug or bio-active agent is

selected from the group consisting of thrombo-resistant agents, antibiotic agents, anti- tumor agents, antiviral agents, anti-angiogenic agents, angiogenic agents, anti-

pharmaceutical salts and combinations thereof.

29. The composition of claim 28, wherein said drug or bio-active agent is

selected from the group of thrombo-resistant agents consisting of heparin, heparin sulfate,

hirudin, hyaluronic acid, chondroitin sulfate, dermatan sulfate, keratan sulfate, lytic agents,

urokinase, streptokinase, their homologs, analogs, fragments, derivatives and

pharmaceutical salts thereof.

30. The composition of claim 28, wherein said drug or bio-active agent is

selected from the group of antibiotic agents consisting of penicillins, cephalosporins,

fragments, derivatives, pharmaceutical salts and mixtures thereof.

31. The composition of claim 28, wherein said drug or bio-active agent is

selected from the group of anti-tumor agents consisting of paclitaxel, mechlorethamine,

chlorambucil, cyclophosphamide, melphalan, ifosfamide, methotrexate, 6-mercaptopurine,

5-fluorouracil, cytarabine, vinblastine, vincristine, etoposide, doxorubicin, daunomycin,

bleomycin, mitomycin, carmustine, lomustine, cisplatin, interferon, asparaginase,

tamoxifen, flutamide, their homologs, analogs, fragments, derivatives, pharmaceutical

salts and mixtures thereof.

32. The composition of claim 28, wherein said drug or bio-active agent is

selected from the group of anti-viral agents consisting of amantadines, rimantadines,

salts and mixtures thereof.

33. A medical device having on at least one surface thereof a bioresorbable

coating composition, said composition comprising a hydrogel formed from the

crosslinking of a polymer comprising the reaction of (i) a bioresorbable region; (ii) a

hydrophilic region; (iii) a plurality of crosslinkable functional groups; and (iv) a

crosslinking agent.

34. The medical device of claim 33 formed from an implantable material.

35. The medical device of claim 34, wherein said implantable material is

selected from the group consisting of polymeric compositions, non-polymeric

compositions and combinations thereof.

36. The medical device of claim 35, wherein said implantable material is

further selected from the group of polymeric compositions consisting of olefin polymers

including polyethylene, polypropylene, polyvinyl chloride, polytetrafluoroethylene,

fluorinated ethylene propylene copolymer, polyvinyl acetate, polystyrene, poly(ethylene

terephthalate), polyurethane, polyurea, silicone rubbers, polyamides, polycarbonates, polyaldehydes, natural rubbers, polyether-ester copolymers, styrene-butadiene copolymers

and combinations thereof.

37. The medical device of claim 35, wherein said implantable material is

further selected from the group of non-polymeric compositions consisting of ceramics,

metals, inorganic glasses, pyrolytic carbon and combinations thereof.

38. The medical device of claim 33, wherein said device is an endoprosthesis.

39. The medical device of claim 38, wherein said endoprosthesis is selected

from the group consisting of grafts, stents and graft-stent devices.

40. The medical device of claim 34, selected from the group consisting of

catheters, guide wires, trocars and introducer sheaths.

41. The medical device of claim 36, wherein said implantable material is a

vascular or endovascular graft.

42. The medical device of claim 41 , wherein said vascular or endovascular

graft is a knitted, braided or woven textile.

43. The medical device of claim 34, wherein said implantable material is made

from an extruded polymer.

44. A process for forming a hydrogel comprising:

a. providing an aqueous emulsion of a water-insoluble copolymer comprising

(i) a bioresorbable region; (ii) a hydrophilic region; (iii) a plurality of crosslinkable

functional groups per polymer chain; and (iv) a crosslinking agent; and

b. activating said crosslinking agent.

45. The process of claim 44, wherein said crosslinkable functional groups are

olefmically unsaturated.

46. The process of claim 44, wherein said crosslinking agent is a free radical

initiator.

47. The process of claim 44, wherein said crosslinking agent is an azo or a

peroxide composition.

48. The process of claim 44, wherein said crosslinking agent is thermally or

photochemically activated.

49. A process for forming a medical device coated with a hydrogel comprising:

a. applying said hydrogel to said medical device, said hydrogel formed from

an aqueous emulsion comprising a water-insoluble copolymer having (i) a bioresorbable region; (ii) a hydrophilic region; (iii) a plurality of crosslinkable functional groups per polymer chain; and (iv) a crosslinking agent; .and

b. activating said crosslinking agent in a humid environment.

50. The process of claim 49, wherein said hydrogel is dehydrated.

51. The process of claim 49, wherein said hydrogel is maintained in a hydrated

state.

52. The process of claim 49 further including adding a drug or bio-active agent

to said emulsion.

53. The process of claim 52, wherein said drug or bio-active agent is thrombo-

resistant agents, antibiotic agents, anti-tumor agents, antiviral agents, anti-angiogenic

agents, angiogenic agents, anti-inflammatory agents, cell cycle regulating agents, their

homologs, derivatives, fragments, pharmaceutical salts and combinations thereof.

54. The composition of claim 52, wherein said drug or bio-active agent is

hirudin, hyaluronic acid, chondroitin sulfate, dermatan sulfate, keratan sulfate, urokinase,

streptokinase, their homologs, analogs, fragments, derivatives and pharmaceutical salts

thereof.

55. The composition of claim 52, wherein said drug or bio-active agent is

fragments, derivatives, pharmaceutical salts and mixtures thereof.

56. The composition of claim 52, wherein said drug or bio-active agent is

selected from the group of anti-rumor agents consisting of paclitaxel, mechlorethamine,

chlorambucil, cyclophosphamide, melphalan and ifosfamide, methotrexate, 6-

mercaptopurine, 5-fluorouracil, cytarabine, vinblastine, vincristine, etoposide,

doxorubicin, daunomycin, bleomycin, mitomycin, carmustine, lomustine, cisplatin,

interferon, asparaginase, tamoxifen, flutamide, their homologs, analogs, fragments,

derivatives, pharmaceutical salts and mixtures thereof.

57. The composition of claim 52, wherein said drug or bio-active agent is

foscarnets, interferons, their homologs, analogs, fragments, derivatives, pharmaceutical

salts and mixtures thereof.