Biodegradable polymers, compositions, articles and methods for making and using the same

Biodegradable polymer compositions that degrade in vivo into non-toxic residues are described. In part, the present invention is directed to such polymers containing phosphorus and desaminotyrosyl L-tyrosine linkages in the polymer backbone. Processes for preparing such polymers, compositions containing such polymers and biologically active substances, articles useful for implantation or injection into the body fabricated from the compositions, and methods for controllably releasing biologically active substances using the polymers, are also described.

BACKGROUND OF THE INVENTION
 1. Introduction
 The present invention relates in part to biodegradable polymer
 compositions, in particular those containing phosphorus and
 desaminotyrosyl L-tyrosine linkages in the polymer backbone and that
 degrade in vivo into non-toxic residues. In certain embodiments, the
 polymers of the invention are particularly useful as implantable medical
 devices and drug delivery systems.
 2. Description of the Prior Art
 Biocompatible polymeric materials have been used extensively in therapeutic
 drug delivery and medical implant device applications. Sometimes, it is
 also desirable for such polymers to be, not only biocompatible, but also
 biodegradable to obviate the need for removing the polymer once its
 therapeutic value has been exhausted.
 Conventional methods of drug delivery, such as frequent-periodic dosing,
 are not ideal in many cases. For example, with highly toxic drugs,
 frequent conventional dosing can result in high initial drug levels at the
 time of dosing, often at near-toxic levels, followed by low drug levels
 between doses that can be below the level of their therapeutic value.
 However, with controlled drug delivery, drug levels can be more nearly
 maintained at therapeutic, but non-toxic, levels by controlled release in
 a predictable manner over a longer term.
 If a biodegradable medical device is intended for use as a drug delivery or
 other controlled-release system, using a polymeric carrier is one
 effective means to deliver the therapeutic agent locally in a controlled
 fashion (see Langer et al., (1983) Rev. Macro. Chem. Phys. C23(1):61). As
 a result, less total drug is required, and toxic can be minimized.
 Polymers have been used as carriers of therapeutic agents to effect: a
 localized and sustained release (see Controlled Drug Delivery, Vols. I and
 II; Bruck et al., eds. (1982); and Chien et al., (1982) Novel Drug
 Delivery Systems). Such delivery systems offer the potential of enhanced
 therapeutic efficacy and reduced overall toxicity.
 For a non-biodegradable matrix, the steps leading to release of the
 therapeutic agent are water diffusion into the matrix, dissolution of the
 therapeutic agent, and diffusion of the therapeutic agent out through the
 channels of the matrix. As a consequence, the mean residence time of the
 therapeutic agent existing in the soluble state is longer for a
 non-biodegradable matrix than for a biodegradable matrix, for which
 passage through the channels of the matrix, while it may occur, is no
 longer required. Since many pharmaceuticals have short half-lives,
 therapeutic agents can decompose or become inactivated within the
 non-biodegradable matrix before they are released. This issue is
 particularly significant for many bio-macromolecules and smaller
 polypeptides, since these molecules are generally hydrolytically unstable
 and have low permeability through a polymer matrix. In fact, in a
 non-biodegradable matrix, many bio-macromolecules aggregate and
 precipitate, blocking the channels necessary for diffusion out of the
 carrier matrix.
 These problems are alleviated by using a biodegradable matrix that, in
 addition to some diffusional release, also allows controlled release of
 the therapeutic agent by degradation of the polymer matrix. Examples of
 classes of synthetic polymers that have been studied as possible
 biodegradable materials include polyesters (Pitt et al., (1980) Controlled
 Release of Bioactive Materials, Baker, ed.), polyamides (Sidman et al.,
 (1979) J. of Membrane Sci., 7:227), polyurethanes (Maser et al., (1979) J.
 of Polymer Sci., 66:259), polyorthoesters (Heller, et al. (1981) Polymer
 Engineering Sci., 21:7271), and polyanhydrides (Leong et al. (1986)
 Biomaterials, 7:364). Specific examples of biodegradable materials that
 are used as medical implant materials are polylactide, polyglycolide,
 polydioxanone, poly(lactide-co-glycolide),
 poly(glycolide-co-polydioxarone), polyanhydrides,
 poly(glycolide-co-trimethylene carbonate), and
 poly(glycolide-co-caprolactone).
 Polymers having phosphate linkages, called poly(phosphates),
 poly(phosphonates) and poly(phosphites), are known. (See Butler, (1967)
 Reviews in Macromolecular Chemistry, Dekker, ed., Vol.2, 91-177). The
 respective structures of these three classes of compounds, each having a
 different sidechain connected to the phosphorus atom, are as follows:
 ##STR1##
 The versatility of these polymers comes from the versatility of the
 phosphorus atom, which is known for a multiplicity of reactions. Its
 bonding can involve the 3p orbitals or various 3s-3p hybrids; spd hybrids
 are also possible because of the accessible d orbitals. Thus, the
 physico-chemical properties of the poly(phosphoesters) can be readily
 changed by varying either the R or R' group. The biodegradability of the
 polymer is due primarily to the physiologically labile phosphoester bond
 in the backbone of the polymer. By manipulating the backbone or the
 sidechain, a wide range of biodegradation rates are attainable.
 An additional feature of poly(phosphoesters) is the availability of
 functional side groups. Because phosphorus can be pentavalent, drug
 molecules or other biologically active substances can be chemically linked
 to the polymer, as shown by Leong, U.S. Pat. Nos. 5,194,581 and 5,256,765.
 For example, drugs with -0-carboxy groups may be coupled to the phosphorus
 via an ester bond, which is hydrolyzable. The P-O-C group backbone also
 lowers the glass transition temperature of the polymer and, importantly,
 confers solubility in common organic solvents, which is desirable for easy
 characterization and processing.
 Kohn et al., U.S. Pat. No. 4,638,045, discloses bioerodible polymers
 comprising monomer units of two or three amino acids polymerized via
 hydrolytically labile bonds at their respective sidechains, rather than at
 the amino- or carboxylic acid-terminals by amide bonds. Zalipsky et al.,
 U.S. Pat. No. 5,219,564, discloses copolymers of poly(alkylene oxides) and
 amino acids having pendent fuinctional groups capable of being conjugated
 with pharmaceutically active compounds for drug delivery systems.
 Kohn et al., U.S. Pat. No. 5,099,060, describes a particularly preferred
 monomer for making amino-acid derived poly(iminocarbonates) as:
 ##STR2##
 The resulting poly(iminocarbonate) type polymers are said to be
 hydrolytically unstable and yet exhibit improved thermal stability for
 convenient processing. Similar tyrosine-derived poly(carbonate) compounds
 have been reported as promising orthopedic implant materials. (Ertel et
 al., (1995) J. Biomedical Materials Res. 29:1337-1348; and Choueka et al.,
 (1996) J. Biomed. Materials Res., 31:35-41). However, there has been a
 need for materials to degrade at a significantly higher rate than
 desaminotyrosyl L-tyrosine based polv(iminocarbonates), and none of these
 documents suggests the use of phosphoester linkages in combination with
 amino acid-derived monomeric units for this purpose.
 SUMMARY OF THE INVENTION
 The present invention is directed to a polymer system, methods for
 therapeutic and/or cosmetic treatment using the polymer system, and a
 precursor of the polymer system, a liquid composition.
 One aspect of the present invention relates to a polymeric composition
 comprising one or more recurring monomeric elements in the polymer
 represented in the general formula (I):
 ##STR3##
 wherein,
 Ar, independently for each occurrence, represents an aryl moiety;
 X, for each occurrence, represents O or S (preferably O);
 Y represents a phosphate, or derivative thereof;
 R represents H, an alkyl, an alkenyl, an alkynyl, an aryl or a heterocycle,
 preferably a branched or straight chain aliphatic group having from 1-20
 carbon atoms;
 R1 represents H or a lower alkyl; and
 n and m, independently, are 0, 1, 2 or 3 (preferably 1 or 2).
 In the above formula, and others used herein, "*" represents another
 monomeric unit of the polymer, which can be the same or different from I,
 or a chain terminating group, e.g., a hydrogen or hydroxyl-protecting
 group, as appropriate.
 In preferred embodiments, the biodegradable polymers of the invention
 comprise the recurring monomeric units shown in formula III:
 ##STR4##
 wherein:
 R is selected from the group consisting of H, alkyl, aryl or heterocyclic;
 and
 R' is selected from the group consisting of H, alkyl, alkoxy, aryl,
 aryloxy, heterocyclic or heterocycloxy; and
 n is 5 to 500,
 wherein the biodegradable polymer is biocompatible before and upon
 biodegradation.
 In another embodiment, the invention comprises polymer compositions
 comprising:
 (a) at least one biologically active substance and
 (b) a polymer having the recurring monomeric units shown in formula
 In yet another embodiment of the invention, an article useful for
 implantation, injection, or otherwise placed totally or partially within
 the body, comprises the biodegradable polymer of formula I or the
 above-described polymer composition.
 In a further embodiment, the invention contemplates a process for preparing
 a biodegradable polymer, comprising the step of reacting an amino acid
 derivative having fomula IV:
 ##STR5##
 wherein R is as defined above, with a phosphodihalidate of formula V:
 ##STR6##
 where "halo" is Br, Cl or I, and R' is as defined above, to form the
 polymer of formula III.
 In a still further embodiment of the invention, a method is provided for
 the controlled release of a biologically active substance comprising the
 steps of:
 (a) combining the biologically active substance with a biodegradable
 polymer having the recurring monomeric units shown in formula I to form an
 admixture;
 (b) forming the admixture into a shaped, solid article; and
 (c) implanting or injecting the solid article in vivo at a preselected
 site, such that the solid implanted or injected article is in at least
 partial contact with a biological fluid.
 In yet another embodiment of the present invention, the polymers and blends
 can be used as a pharmaceutical carrier in a drug delivery matrix. To form
 this matrix the polymers and blends can be mixed with a therapeutic agent
 to form the matrix. The variety of different therapeutic agents which can
 be used in conjunction with the aliphatic polyoxaesters of the invention
 is vast. In general, therapeutic agents which may be administered via the
 pharmaceutical compositions of the invention include, without limitation:
 antiinfectives such as antibiotics and antiviral agents; analgesics and
 analgesic combinations; anorexics; antihelmintics; antiarthritics;
 antiasthmatic agents; anticonvulsants; antidepressants; antidiuretic
 agents; antidiarrleals; antihistamines; antiinflammatory agents;
 antimigraine preparations; antinauseants; antineoplastics;
 antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics,
 antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives;
 cardiovascular preparations including calcium channel blockers and
 beta-blockers such as pindolol and antiarrhythmics; antihypertensives;
 diuretics; vasodilators including general coronary, peripheral and
 cerebral; central nervous system stimulants; cough and cold preparations,
 including decongestants; hormones such as estradiol and other steroids,
 including corticosteroids; hypnotics; immunosuppressives; muscle
 relaxants; parasympatholytics; psychostimulants; sedatives; and
 tranquilizers; and naturally derived or genetically engineered proteins,
 polysaccharides, glycoproteins, or lipoproteins.
 Specific examples of bioactive material that can be formulated in the
 subject polymers in accordance with the present invention include
 acebutolol, acetaminophen, acetohydoxamic acid, acetophenazine, acyclovir,
 adrenocorticoids, allopurinol, alprazolam, aluminum hydroxide, amantadine,
 ambenonium, amiloride, aminobenzoate potassium, amobarbital, amoxicillin,
 amphetamine, ampicillin, androgens, anesthetics, anticoagulants,
 anticonvulsants-dione type, antithyroid medicine, appetite suppressants,
 aspirin, atenolol, atropine, azatadine, bacampicillin, baclofen,
 beclomethasone, belladonna, bendroflumethiazide, benzoyl peroxide,
 benzthiazide, benztropine, betamethasone, betha nechol, biperiden,
 bisacodyl, bromocriptine, bromodiphenhydramine, brompheniramine,
 buclizine, bumetanide, busulfan, butabarbital, butaperazine, caffeine,
 calcium carbonate, captopril, carbamazepine, carbenicillin, carbidopa &
 levodopa, carbinoxamine inhibitors, carbonic anhydsase, carisoprodol,
 carphenazine, cascara, cefaclor, cefadroxil, cephalexin, cephradine,
 chlophedianol, chloral hydrate, chlorambucil, chloramphenicol,
 chlordiazepoxide, chloroquine, chlorothiazide, chlorotrianisene,
 chlorpheniramine, &lt;a&gt;6X chlorpromazine, chlorpropamide, chlorprothixene,
 chlorthalidone, chlorzoxazone, cholestyramine, cimetidine, cinoxacin,
 clemastine, clidinium, clindamycin, clofibrate, clomiphere, clonidine,
 clorazepate, cloxacillin, colochicine, coloestipol, conjugated estrogen,
 contraceptives, cortisone, cromolyn, cyclacillin, cyclandelate, cyclizine,
 cyclobenzaprine, cyclophosphamide, cyclothiazide, cycrimine,
 cyproheptadine, danazol, danthron, dantrolene, dapsone, dextroamphetamine,
 dexamethasone, dexchlorpheniramine, dextromethorphan, diazepan,
 dicloxacillin, dicyclomine, diethylstilbestrol, diflunisal, digitalis,
 diltiazen, dimenhydrinate, dimethindene, diphenhydramine, diphenidol,
 diphenoxylate & atrophive, diphenylopyraline, dipyradamole, disopyramide,
 disulfiram, divalporex, docusate calcium, docusate potassium, docusate
 sodium, doxyloamine, dronabinol ephedrine, epinephrine, ergoloidmesylates,
 ergonovine, ergotamine, erythromycins, esterified estrogens, estradiol,
 estrogen, estrone, estropipute, etharynic acid, ethchlorvynol, ethinyl
 estradiol, ethopropazine, ethosaximide, ethotoin, fenoprofen, ferrous
 fumarate, ferrous gluconate, ferrous sulfate, flavoxate, flecainide,
 fluphenazine, fluprednisolone, flurazepam, folic acid, furosemide,
 gemfibrozil, glipizide, glyburide, glycopyrrolate, gold compounds,
 griseofiwin, guaifenesin, guanabenz, guanadrel, guanethidine, halazepam,
 haloperidol, hetacillin, hexobarbital, hydralazine, hydrochlorothiazide,
 hydrocortisone (cortisol), hydroflunethiazide, hydroxychloroquine,
 hydroxyzine, hyoscyamine, ibuprofen, indapamide, indomethacin, insulin,
 iofoquinol, iron-polysaccharide, isoetharine, isoniazid, isopropamide
 isoproterenol, isotretinoin, isoxsuprine, kaolin & pectin, ketoconazole,
 lactulose, levodopa, lincomycin liothyronine, liotrix, lithium,
 loperamide, lorazepam, magnesium hydroxide, magnesium sulfate, magnesium
 trisilicate, maprotiline, meclizine, meclofenamate, medroxyproyesterone,
 melenamic acid, melphalan, mephenytoin, mephobarbital, meprobamate,
 mercaptopurine, mesoridazine, metaproterenol, metaxalone, methamphetamine,
 methaqualone, metharbital, methenamine, methicillin, methocarbamol,
 methotrexate, methsuximide, methyclothinzide, methylcellulos, methyldopa,
 methylergonovine, methylphenidate, methylprednisolone, methysergide,
 metoclopramide, metolazone, metoprolol, metronidazole, minoxidil,
 mitotane, monamine oxidase inhibitors, nadolol, nafcillin, nalidixic acid,
 naproxen, narcotic analgesics, neomycin, neostigmine, niacin, nicotine,
 nifedipine, nitrates, nitrofurantoin, nomifensine, norethindrone,
 norethindrone acetate, norgestrel, nylidrin, nystatin, orphenadrine,
 oxacillin, oxazepam, oxprenolol, oxymetazoline, oxyphenbutazone,
 pancrelipase, pantothenic acid, papaverine, para-aminosalicylic acid,
 paramethasone, paregoric, pemoline, penicillamine, penicillin, penicillin
 -v, pentobarbital, perphenazine, phenacetin, phenazopyridine, pheniramine,
 phenobarbital, phenolphthalein, phenprocoumon, phensuximide,
 phenylbutazone, phenylephrine, phenylpropanolamine, phenyl toloxamine,
 phenytoin, pilocarpine, pindolol, piper acetazine, piroxicam, poloxamer,
 polycarbophil calcium, polythiazide, potassium supplements, pruzepam,
 prazosin, prednisolone, prednisone, primidone, probenecid, probucol,
 procainamide, procarbazine, prochlorperazine, procyclidine, promazine,
 promethazine, propantheline, propranolol, pseudoephedrine, psoralens,
 syllium, pyridostigmine, pyrodoxine, pyrilamine, pyrvinium, quinestrol,
 quinethazone, uinidine, quinine, ranitidine, rauwolfia alkaloids,
 riboflavin, rifampin, ritodrine, alicylates, scopolamine, secobarbital,
 senna, sannosides a & b, simethicone, sodium bicarbonate, sodium
 phosphate, sodium fluoride, spironolactone, sucrulfate, sulfacytine,
 sulfamethoxazole, sulfasalazine, sulfinpyrazone, sulfisoxazole, sulindac,
 talbutal, tamazepam, terbutaline, terfenadine, terphinhydrate,
 teracyclines, thiabendazole, thiamine, thioridazine, thiothixene,
 thyroblobulin, thyroid, thyroxine, ticarcillin, timolol, tocainide,
 tolazamide, tolbutamide, tolmetin trozodone, tretinoin, triamcinolone,
 trianterene, triazolam, trichlormethiazide, tricyclic antidepressants,
 tridhexethyl, trifluoperazine, triflupromazine, trihexyphenidyl,
 trimeprazine, trimethobenzamine, trimethoprim, tripclennamine,
 triprolidine, valproic acid, verapamil, vitamin A, vitamin B-12, vitamin
 C, vitamin D, vitamin E, vitamin K, xanthine, and the like.

DETAILED DESCRIPTION OF THE INVENTION
 1. Overview
 We have discovered a new class of synthetic crosslinked polymeric materials
 and blends thereof that may be used to produce surgical devices such as
 molded devices, drug delivery matrices, coatings, lubricants and the like.
 The invention also contemplates a process for producing the crosslinked
 polymers and blends, and methods for utilizing the subject compositions in
 the pharmaceutical and/or cosemetic treatment of animals.
 One aspect of the present invention relates to a polymeric composition
 comprising one or more recurring monomeric elements in the polymer
 represented in the general formula (I):
 ##STR7##
 wherein,
 Ar, independently for each occurrence, represents an aryl moiety;
 X, for each occurrence, represents O or S (preferably O);
 Y represents a phosphate, or derivative thereof;
 R represents H, an alkyl, an alkenyl, an alkynyl, an aryl or a heterocycle,
 preferably a branched or straight chain aliphatic group having from 1-20
 carbon atoms;
 R1 represents H or a lower alkyl; and
 n and m, independently, are 0, 1, 2 or 3 (preferably 1 or 2).
 In the above formula, and others used herein, "*" represents another
 monomeric unit of the polymer, which can be the same or different from I,
 or a chain terminating group, e.g., a hydrogen or hydroxyl-protecting
 group, as appropriate.
 To further illustrate, Y can be a phosphonamidite, a phosphoramidite, a
 phosphorodiamidate, a phosphomonoester, a phosphodiester, phosphotriester,
 a phosphonate, a phosphonate ester, a phosphorothioate, a thiophosphate
 ester, phosphinate, or a phosphite. A criteria for the selection of Y, as
 described below, is the desired rate of hydrolysis of the resulting
 polymer.
 The aryl groups, Ar, can be monocyclic or polycyclic groups, which group
 may be further substituted beyond the backbone of the polymer chain. For
 instance, the aryl groups can be such groups benzene, pyrrole, furan,
 thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine,
 pyrazine, pyridazine and pyrimidine, and the like.
 The group R can essentially be any aliphatic moiety, substituted or
 unsubstituted, so long as it does not interfere undesirably with the
 polymerization or biodegradation reactions of the polymer. In preferred
 embodiments, R is a lower alkyl or an heterocycle.
 In other embodiments, R and/or R1 can be selected to permit additional
 inter-chain crosslinking by covalent or electrostatic (including
 hydrogen-binding or the formation of salt bridges), e.g., by the use of a
 sidechain appropriately substituted.
 In certain embodiments, it will be desirable for at least 25 percent of the
 polymer to be composed of monomeric elements shown in Formula I, and even
 more desirable for at least 50, 77, 85, 90, 95 or even 100 percent of the
 polymer to be composed of repetitive elements shown in Formula I. The
 inclusion of other monomeric elements in the polymer, along with the
 choice of phosphate group, etc., in Formula I, can be used to control the
 rate of biodegradation of the matrix.
 In preferred embodiments, the polymeric chains of the subject compositions,
 e.g., which include repetitive elements shown in Formula I, have molecular
 weights of at least 10,000 daltons, more preferably at least 100,000
 daltons, and even more preferably at least 250,000 daltons, 500,000
 daltons or even at least 1,000,000 daltons.
 In preferred embodiments, the polymeric compositions of the present
 invention include polymeric chains represented in the general formula (Ia)
 ##STR8##
 wherein Ar, R, R1, X, Y, n and m are as defined above, and p represents an
 integer greater than 100, more preferably greater than 1000, and even more
 preferably greater than 10,000.
 In certain examples of the present invention, the polymers and blends can
 be used as a pharmaceutical carrier in a drug delivery matrix. To form
 this matrix the polymers and blends would be mixed with a therapeutic
 agent to form the matrix.
 The polymers and blends of the present invention, upon contact with body
 fluids including blood, spinal fluid, lymph or the like, undergoes gradual
 degradation (mainly through hydrolysis) with, if so formulated,
 concomitant release of the dispersed drug for a sustained or extended
 period (as compared to the release from an isotonic saline solution). This
 can result in prolonged delivery (over, say 1 to 2,000 hours, preferably 2
 to 800 hours) of effective amounts (say, 0.0001 mg/kg/hour to 10
 mg/kg/hour) of the drug. This dosage form can be administered as is
 necessary depending on the subject being treated, the severity of the
 affliction, the judgment of the prescribing physician, and the like.
 2. Definitions
 For convenience, certain terms employed in the specification, examples, and
 appended claims are collected here.
 As used herein, the term "aliphatic" refers to a linear, branched, cyclic
 alkane, alkene, or alkyne. Preferred aliphatic groups in the
 poly(phosphoester-co-amide) polymer of the invention are linear or
 branched and have from 1 to 20 carbon atoms.
 The term "alkyl" refers to the radical of saturated aliphatic groups,
 including straight-chain alkyl groups, branched-chain alkyl groups,
 cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and
 cycloalkyl substituted alkyl groups. In preferred embodiments, a straight
 chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone
 (e.g., C.sub.1 -C.sub.30 for straight chain, C.sub.3 -C.sub.30 for
 branched chain), and more preferably 20 or fewer. Likewise, preferred
 cycloalkyls have from 3-10 carbon atoms in their ring structure, and more
 preferably have 5, 6 or 7 carbons in the ring structure.
 Moreover, the term "alkyl" (or "lower alkyl") as used throughout the
 specification, examples, and claims is intended to include both
 "unsubstituted alkyls" and "substituted alkyls", the latter of which
 refers to alkyl moieties having substituents replacing a hydrogen on one
 or more carbons of the hydrocarbon backbone. Such substituents can
 include, for example, a halogen, a hydroxyl, a carbonyl (such as a
 carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such
 as a thioester, a thioacetate, or a thioformate), an alkoxyl, a
 phosphoryl, a phosphonate, a phosphinate, an amino, an amido, an amidine,
 an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a
 sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a
 heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will
 be understood by those skilled in the art that the moieties substituted on
 the hydrocarbon chain can themselves be substituted, if appropriate. For
 instance, the substituents of a substituted alkyl may include substituted
 and unsubstituted forms of amino, azido, imino, amido, phosphoryl
 (including phosphonate and phosphinate), sulfonyl (including sulfate,
 sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as
 ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates,
 and esters), --CF.sub.3, --CN and the like. Exemplary substituted alkyls
 are described below. Cycloalkyls can be further substituted with alkyls,
 alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls,
 --CF.sub.3, --CN, and the like.
 The term "aralkyl", as used herein, refers to an alkyl group substituted
 with an aryl group (e.g., an aromatic or heteroaromatic group).
 The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups
 analogous in length and possible substitution to the alkyls described
 above, but that contain at least one double or triple bond respectively.
 Unless the number of carbons is otherwise specified, "lower alkyl" as used
 herein means an alkyl group, as defined above, but having from one to ten
 carbons, more preferably from one to six carbon atoms in its backbone
 structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar
 chain lengths. Throughout the application, preferred alkyl groups are
 lower alkyls. In preferred embodiments, a substituent designated herein as
 alkyl is a lower alkyl.
 The term "heteroatom" as used herein means an atom of any element other
 than carbon or hydrogen. Preferred heteroatoms are boron, nitrogen,
 oxygen, phosphorus, sulfur and selenium, and more preferably oxygen,
 nitrogen or sulfur.
 As used herein, the term "aryl" refers to an unsaturated cyclic carbon
 compound with 4n+2 .pi. electrons, and includes, e.g., 5-, 6- and
 7-membered single-ring aromatic groups that may include from zero to four
 heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole,
 oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and
 pyrimidine, and the like. Those aryl groups having heteroatoms in the ring
 structure, as for example, nitrogen, oxygen, or sulfur, may also be
 referred to as "aryl heterocycles" or "heteroaromatics." The term "aryl"
 refers to both substituted and unsubstitited aromatic rings. The aromatic
 ring can be substituted at one or more ring positions with such
 substituents as described above, for example, halogen, azide, alkyl,
 aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro,
 sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl,
 silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester,
 heterocyclyl, aromatic or heteroaromatic moieties, --CF.sub.3, --CN, or
 the like. The term "aryl" also includes polycyclic ring systems having two
 or more cyclic rings in which two or more carbons are common to two
 adjoining rings (the rings are "fused rings") wherein at least one of the
 rings is aromatic, e.g., the other cyclic rings can be cycloalkyls,
 cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
 The terms ortho, meta and para apply to 1,2-, 1,3- and 1,4-disubstituted
 benzenes, respectively. For example, the names 1,2-dimethylbenzene and
 ortho-dimethylbenzene are synonymous.
 The terms "heterocyclyl" or "heterocycle" refer to 4- to 10-membered ring
 structures, more preferably 3- to 7-membered rings, whose ring structures
 include one to four heteroatoms. Heterocycles can also be polycycles.
 Heterocyclyl groups include, for example, thiophene, thianthrene, furan,
 pyran, isobenzofuran, chromene, xanthene, phenoxathlin, pyrrole,
 imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine,
 pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,
 quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine,
 quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,
 phenanthridine, acridine, pyrimidine, phenanthroline, phenazine,
 phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane,
 thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams
 such as azetidinones and pyrrolidinones, sultams, sultones, and the like.
 The heterocyclic ring can be substituted at one or more positions with
 such substituents as described above, as for example, halogen, alkyl,
 aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulthydryl,
 imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether,
 alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic
 or heteroaromatic moiety, --CF.sub.3, --CN, or the like.
 The terms "polycyclyl" or "polycyclic group" refer to two or more rings
 (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or
 heterocyclyls) in which two or more carbons are common to two adjoining
 rings, e.g., the rings are "fused rings". Rings that are joined through
 non-adjacent atoms are termed "bridged" rings. Each of the rings of the
 polycycle can be substituted with such substituents as described above, as
 for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl,
 hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate,
 phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl,
 ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic
 moiety, --CF.sub.3, --CN, or the like.
 The term "carbocycle", as used herein, refers to an aromatic or
 non-aromatic ring in which each atom of the ring is carbon.
 As used herein, the term "nitro" means --NO.sub.2 ; the term "halogen"
 designates --F, --Cl, --Br or --I; the term "sulfhydryl" means --SH; the
 term "hydroxyl" means --OH; and the term "sulfonyl" means --SO.sub.2 --.
 The terms "amine" and "amino" are art-recognized and refer to both
 unsubstituted and substituted amines, e.g., a moiety that can be
 represented by the general formula:
 ##STR9##
 wherein R.sub.9, R.sub.10 and R'.sub.10 each independently represent a
 hydrogen, an alkyl, an alkenyl, --(CH.sub.2).sub.m -R80, or R.sub.9 and
 R.sub.10 taken together with the N atom to which they are attached
 complete a heterocycle having from 4 to 8 atoms in the ring structure; R80
 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a
 polycycle; and m is zero or an integer in the range of 1 to 8. In
 preferred embodiments, only one of R.sub.9 or R.sub.10 can be a carbonyl,
 e.g., R.sub.9, R.sub.10 and the nitrogen together do not form an imide. In
 even more preferred embodiments, R.sub.9 and R.sub.10 (and optionally
 R'.sub.10) each independently represent a hydrogen, an alkyl, an alkenyl,
 or --(CH.sub.2).sub.m -R80. Thus, the term "alkylamine" as used herein
 means an amine group, as defined above, having a substituted or
 unsubstituted alkyl attached thereto, i.e., at least one of R.sub.9 and
 R.sub.10 is an alkyl group.
 The term "acylamino" is art-recognized and refers to a moiety that can be
 represented by the general formula:
 ##STR10##
 wherein R.sub.9 is as defined above, and R'.sub.11 represents a hydrogen,
 an alkyl, an alkenyl or --(CH.sub.2).sub.m -R80, where m and R80 are as
 defined above.
 The term "amido" is art recognized as an amino-substituted carbonyl and
 includes a moiety that can be represented by the general formula:
 ##STR11##
 wherein R.sub.9, R.sub.10 are as defined above. Preferred embodiments of
 the amide will not include imides which may be unstable.
 The term "alkylthio" refers to an alkyl group, as defined above, having a
 sulfur radical attached thereto. In preferred embodiments, the "alkylthio"
 moiety is represented by one of --S-alkyl, --S-alkenyl, --S-alkynyl, and
 --S--(CH.sub.2).sub.m -R80, wherein m and R80 are defined above.
 Representative alkylthio groups include methylthio, ethyl thio, and the
 like.
 The term "carbonyl" is art recognized and includes such moieties as can be
 represented by the general formula:
 ##STR12##
 wherein X is a bond or represents an oxygen or a sulfur, and R.sub.11
 represents a hydrogen, an alky, an alkenyl, --(CH.sub.2).sub.m -R80 or a
 pharmaceutically acceptable salt, R'.sub.11 represents a hydrogen, an
 alkyl, an alkenyl or --(CH.sub.2).sub.m -R80, where m and R80 are as
 defined above. Where X is an oxygen and R.sub.11 or R'.sub.11 is not
 hydrogen, the formula represents an "ester". Where X is an oxygen, and
 R.sub.11 is as defined above, the moiety is referred to herein as a
 carboxyl group, and particularly when R.sub.11 is a hydrogen, the formula
 represents a "carboxylic acid". Where X is an oxygen, and R'.sub.11 is
 hydrogen, the formula represents a "formate". In general, where the oxygen
 atom of the above formula is replaced by sulfur, the formula represents a
 "thiolcarbonyl" group. Where X is a sulfur and R.sub.11 or R'.sub.11 is
 not hydrogen, the formula represents a "thiolester." Where X is a sulfur
 and R.sub.11 is hydrogen, the formula represents a "thiolcarboxylic acid."
 Where X is a sulfur and R.sub.11 ' is hydrogen, the formula represents a
 "thiolformate." On the other hand, where X is a bond, and R.sub.11 is not
 hydrogen, the above formula represents a "ketone" group. Where X is a
 bond, and R.sub.11 is hydrogen, the above formula represents an "aldehyde"
 group.
 The terms "alkoxyl" or "alkoxy" as used herein refers to an alkyl group, as
 defined above, having an oxygen radical attached thereto. Representative
 alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the
 like. An "ether" is two hydrocarbons covalently linked by an oxygen.
 Accordingly, the substituent of an alkyl that renders that alkyl an ether
 is or resembles an alkoxyl, such as can be represented by one of
 --O-alkyl, --O--alkenyl, --O--alkynyl, --O--(CH.sub.2).sub.m -R.sub.80,
 where m and R80 are described above.
 The terms "sulfoxido", as used herein, refers to a moiety that can be
 represented by the general formula:
 ##STR13##
 in which R'.sub.11 is as defined above.
 A "sulfone", as used herein, refers to a moiety that can be represented by
 the general formula:
 ##STR14##
 in which R'.sub.11 is as defined above.
 The term "sulfonate" is art recognized and includes a moiety that can be
 represented by the general formula:
 ##STR15##
 in which R.sub.41 is an electron pair, hydrogen, alkyl, cycloalkyl, or
 aryl.
 The term "sulfate" is art recognized and includes a moiety that can be
 represented by the general formula:
 ##STR16##
 in which R.sub.41 is as defined above.
 The term "sulfonamido" is art recognized and includes a moiety that can be
 represented by the general formula:
 ##STR17##
 in which R.sub.9 and R'.sub.11 are as defined above.
 The term "sulfamoyl" is art-recognized and includes a moiety that can be
 represented by the general formula:
 ##STR18##
 in which R.sub.9 and R.sub.10 are as defined above.
 A "phosphoryl" can in general be represented by the formula:
 ##STR19##
 wherein Q.sub.1 represented S or O, and R.sub.46 represents hydrogen, a
 lower alkyl or an aryl. When used to substitute, e.g., an alkyl, the
 phosphoryl group of the phosphorylalkyl can be represented by the general
 formula:
 ##STR20##
 wherein Q.sub.1 represented S or O, and each R.sub.46 independently
 represents hydrogen, a lower alkyl or an aryl, Q.sub.2 represents O, S or
 N. When Q.sub.1 is an S, the phosphoryl moiety is a "phosphorothioate".
 A "phosphoramidite" can be represented in the general formula:
 ##STR21##
 wherein R.sub.9 and R.sub.11 are as defined above, and Q.sub.2 represents
 O, S or N.
 A "phosphonarnidite" can be represented in the general formula:
 ##STR22##
 wherein R.sub.9 and R.sub.10 are as defined above, Q.sub.2 represents O, S
 or N, and R.sub.48 represents a lower alkyl or an aryl, Q.sub.2 represents
 O, S or N.
 A "selenoalkyl" refers to an alkyl group having a substituted seleno group
 attached thereto. Exemplary "selenoethers" which may be substituted on the
 alkyl are selected from one of --Se-alkyl, --Se-alkenyl, --Se-alkynyl, and
 --Se--(CH.sub.2).sub.m -R80, m and R80 being defined above.
 Analogous substitutions can be made to alkenyl and alkynyl groups to
 produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls,
 amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls,
 carbonyl-substituted alkenyls or alkynyls.
 As used herein, the definition of each expression, e.g. alkyl, m, n, etc.,
 when it occurs more than once in any structure, is intended to be
 independent of its definition elsewhere in the same structure.
 Certain monomeric subunits of the present invention may exist in particular
 geometric or stereoisomeric forms. The present invention contemplates all
 such compounds, including cis- and trans-isomers, R- and S-enantiomers,
 diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and
 other mixtures thereof, as falling within the scope of the invention.
 Additional asymmetric carbon atoms may be present in a substituent such as
 an alkyl group. All such isomers, as well as mixtures thereof, are
 intended to be included in this invention.
 For the purposes of this application, unless expressly noted to the
 contrary, a named amino acid shall be construed to include both the D or L
 stereoisomers, preferably the L stereoisomer.
 If, for instance, a particular enantiomer of a compound of the present
 invention is desired, it may be prepared by asymmetric synthesis, or by
 derivation with a chiral auxiliary, where the resulting diastereomeric
 mixture is separated and the auxiliary group cleaved to provide the pure
 desired enantiomers. Alternatively, where the molecule contains a basic
 functional group, such as amino, or an acidic functional group, such as
 carboxyl, diastereomeric salts are formed with an appropriate
 optically-active acid or base, followed by resolution of the diastereomers
 thus formed by fractional crystallization or chromatographic means well
 known in the art, and subsequent recovery of the pure enantiomers.
 It will be understood that "substitution" or "substituted with" includes
 the implicit proviso that such substitution is in accordance with
 permitted valence of the substituted atom and the substituent, and that
 the substitution results in a stable compound, e.g., which does not
 spontaneously undergo transformation such as by rearrangement,
 cyclization, elimination, etc.
 As used herein, the term "substituted" is also contemplated to include all
 permissible substituents of organic compounds. In a broad aspect, the
 permissible substituents include acyclic and cyclic, branched and
 unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic
 substituents of organic compounds. Illustrative substituents include, for
 example, those described herein above. The permissible substituents can be
 one or more and the same or different for appropriate organic compounds.
 For purposes of this invention, the heteroatoms such as nitrogen may have
 hydrogen substituents and/or any permissible substituents of organic
 compounds described herein which satisfy the valences of the heteroatoms.
 This invention is not intended to be limited in any manner by the
 permissible substituents of organic compounds.
 For purposes of this invention, the chemical elements are identified in
 accordance with the Periodic Table of the Elements, CAS version, Handbook
 of Chemistry and Physics, 67th Ed., 1986-87, inside cover. Also for
 purposes of this invention, the term "hydrocarbon" is contemplated to
 include all permissible compounds having at least one hydrogen and one
 carbon atom. In a broad aspect, the permissible hydrocarbons include
 acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic,
 aromatic and nonaromatic organic compounds which can be substituted or
 unsubstituted.
 The phrase "protecting group" as used herein means temporary substituents
 which protect a potentially reactive functional group from undesired
 chemical transformations. Examples of such protecting groups include
 esters of carboxylic acids, silyl ethers of alcohols, and acetals and
 ketals of aldehydes and ketones, respectively. The field of protecting
 group chemistry has been reviewed (Greene, T. W.; Wuts, P. G. M.
 Protective Groups in Organic Synthesis, 2.sup.nd ed.; Wiley: New York,
 1991).
 The phrase "hydroxyl-protecting group" as used herein refers to those
 groups intended to protect a hydrozyl group against undesirable reactions
 during synthetic procedures and includes, inter alia, benzyl or other
 suitable esters or ethers groups known in the art.
 As used herein, the definition of each expression, e.g. lower alkyl, m, n,
 p, etc., when it occurs more than once in any structure, is intended to be
 independent of its definition elsewhere in the same structure.
 3. Exemplary Compositions and Methods
 In preferred embodiments, the polymeric composition of the present
 invention include one or more recurring monomeric elements in the polymer
 represented in the ageneral formula (II):
 ##STR23##
 wherein,
 Ar, independently for each occurrence, represents an aryl moiety;
 X, for each occurrence, represents O or S (preferably O);
 Q, represents O or S;
 Q.sub.2 represents O, S or NH;
 R represents H, an alkyl, an alkenyl, an alkynyl, an aryl or a heterocycle,
 preferably a branched or straight chain aliphatic group having from 1-20
 carbon atoms;
 R' represents hydrogen, alkyl, --O-alkyl, aryl, --O-aryl, heterocycle,
 --O-heterocycle, or --N(R.sub.9)R.sub.10 ;
 R.sub.9 and R.sub.10, each independently, represent a hydrogen, an alkyl,
 an alkenyl, --(CH.sub.2).sub.i -R.sub.80, or R.sub.9 and R.sub.10 taken
 together with the N atom to which they are attached complete a heterocycle
 having from 4 to 8 atoms in the ring structure;
 R.sub.80 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or
 a polycycle;
 R.sub.1 represents H or a lower alkyl; and
 i, n and m, independently for each occurrence, are 0, 1, 2 or 3 (preferably
 1 or 2).
 Thus, in certain preferred embodiments, the compositions of the present
 invention include polymeric chains represented in the general formula
 (IIa)
 ##STR24##
 wherein p is in the range of 100-10,000, though it may be greater than
 10,000.
 In even more preferred embodiments, the biodegradable polymer of the
 invention comprises the recurring monomeric units shown in formula III:
 ##STR25##
 wherein R is selected from the group consisting of H, alkyl, aryl or
 heterocyclic, preferably a branched or straight chain aliphatic group
 having from 1-20 carbon atoms. R can be any aliphatic moiety so long as it
 does not interfere undesirably with the polymerization or biodegradation
 reactions of the polymer. Specifically, R can be an alkyl group, such as
 methyl, ethyl, 1,2-dimethylethyl, n-propyl, isopropyl, 2,2-dimethylpropyl
 or tert-butyl, n-pentyl, tert-pentyl, n-hexyl, n-heptyl and the like; an
 alkyl group substituent, for example, halogen-substituted alkyl; or a
 cycloaliphatic group such as cyclopentyl, 2-methylcyclopentyl, cyclohexyl,
 cyclohexenyl and the like. Preferably, however, R is a branched or
 straight chain alkyl group and, even more preferably, an alkyl group
 having from 2 to 18 carbon atoms. Most preferably, R is an n-hexyl group.
 R' in the polymer of the invention is an alkyl, alkoxy, aryl, aryloxy,
 heterocyclic or heterocycl-loxy residue. Examples of useful alkyl R'
 groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl,
 --C.sub.8 H.sub.17, and the like groups; alkyl substituted with a
 non-interfering substituent, such as a halogen group; corresponding alkoxy
 groups, and alkyl that is conjugated with a biologically active substance
 to form a pendant drug delivery system.
 When R' is aryl or the corresponding aryloxy group, it typically contains
 from about 5 to about 14 carbon atoms, preferably about 5 to 12 carbon
 atoms and, optionally, can contain one or more rings that are fused to
 each other. Examples of particularly suitable aromatic groups include
 phenyl, phenoxy, naphthyl, anthracenyl, phenanthrenyl and the like.
 When R' is heterocyclic or heterocycloxy, it typically contains from about
 5 to 14 ring atoms, preferably from about 5 to 12 ring atoms, and one or
 more heteroatoms. Examples of suitable heterocyclic groups include furan,
 thiophene, pyrrole, isopyrrole, 3-isopyrrole, pyrazole, 2-isoimidazole,
 1,2,3-triazole, 1,2,4-triazole, oxazole, thiazole, isothiazole,
 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole,
 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-dioxazole,
 1,2,4-dioxazole, 1,3,2-dioxazole, 1,3,4-dioxazole, 1,2,5-oxatriazole,
 1,3-oxathiole, 1,2-pyran, 1,4-pyran, 1,2-pyrone, 1,4-pyrone, 1,2-dioxin,
 1,3-dioxin, pyridine, N-alkyl pyridinium, pyridazine, pyrimidine,
 pyrazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine, 1,2,4-oxazine,
 1,3,2-oxazine, 1,3,5-oxazine, 1,4-oxazine, o-isoxazine, p-isoxazine,
 1,2,5-oxathiazine, 1,2,6-oxathiazine, 1,4,2-oxadiazine,
 1,3,5,2-oxadiazine, azepine, oxepin, thiepin, 1,2,4-diazepine, indene,
 isoindene, benzofuran, isobenzofuran, thionaphthene, isothionaphthene,
 indole, indolenine, 2-isobenzazole, 1,4-pyrindine, pyrando[3,4-b]-pyrrole,
 isoindazole, indoxazine, benzoxazole, anthranil, 1,2-benzopyran,
 1,2-benzopyrone, 1,4-benzopyrone, 2,1-benzopyrone, 2,3-benzopyrone,
 quinoline, isoquinoline, 12,-benzodiazine, 1,3-benzodiazine,
 naphthpyridine, pyrido[3,4-b]-pyridine, pyrido[3,2-b]-pyridine,
 pyrido[4,3-b]-pyridine, 1,3,2-benzoxazine, 1,4,2-benzoxazine,
 2,3,1-benzoxazine, 3,1,4-benzoxazine, 1,2-benzisoxazine,
 1,4-benzisoxazine, carbazole, xanthrene, acridine, purine, and the like.
 Preferably, when R' is heterocyclic or heterocycloxy, it is selected from
 the group consisting of furan, pyridine, N-alkylpyridine, 1,2,3- and
 1,2,4-triazoles, indene, anthracene and purine rings.
 In a particularly preferred embodiment, R' is an alkyl group, an alkoxy
 group, a phenyl group, a phenoxy group, or a heterocycloxy group and, even
 more preferably, an alkoxy group having from 1 to 7 carbon atoms. Most
 preferably, R' is an ethoxy group.
 The number n can vary greatly depending on the biodegradability and the
 release characteristics desired in the polymer, but typically varies
 between about 2 and 500. Preferably, n is from about 5 to about 300 and,
 most preferably, from about 5 to about 200.
 Biodegradable polymers differ from non-biodegradable polymers in that they
 can be degraded during in vivo therapy. This generally involves breaking
 down the polymer into its monomeric subunits. In certain embodiments, the
 ultimate hydrolytic breakdown products of a polymer of the invention are
 desaminotyrosyl tyrosine (which is derived from the naturally occurring
 amino acid L-tyrosine and its analog, desaminotyrosine, which occurs
 naturally in plants), an aliphatic alcohol, and phosphate. All of these
 degradation products are potentially non-toxic. However, the intermediate
 oligomeric products of the hydrolysis may have different properties. Thus,
 toxicology of a biodegradable polymer intended for implantation or
 injection, even one synthesized from apparently innocuous monomeric
 structures, is typically determined after one or more toxicity analyses.
 A typical in vitro toxicity assay would be performed with live carcinoma
 cells, such as GT3TKB tumor cells, in the following manner:
 200 .mu.L of various concentrations of suspensions of the test monomer or
 polymers are placed in 96-well tissue culture plates seeded with human
 gastric carcinoma cells (GT3TKB) at 10.sup.4 /well density. The degraded
 polymer products are incubated with the GT3TKB cells for 48 hours. The
 results of the assay can be plotted as % relative growth vs. concentration
 of degraded polymer in the tissue-culture well.
 Polymers for use in medical applications such as implants and prostheses
 can also be evaluated by well-known in vivo tests, such as subcutaneous
 implantations in rats to confirm that they hydrolyze without significant
 levels of irritation or inflammation at the subcutaneous implantation
 sites.
 The biodegradable polymer of the invention is preferably sufficiently pure
 to be biocompatible itself and remains biocompatible upon biodegradation.
 By "biocompatible" is meant that the biodegradation products or the
 polymer itself are non-toxic and result in only minimal tissue irritation
 when implanted or injected into vasculated tissue.
 The in vitro cytotoxicity profile for desaminotyrosyl L-tyrosine hexyl
 ester ("DTTH"), a monomer used to make a particularly preferred polymer of
 the invention, and the corresponding polymer P(DTTH-EOP), in microsphere
 form, as compared with those of a comparison monomer commonly used in
 biodegradable materials, L-lactide and poly(L-lactide), also in solid and
 microsphere form, is shown in FIG. 2.
 The polymer of the invention is preferably soluble in one or more common
 organic solvents for ease of fabrication and processing. Common organic
 solvents include such solvents as ethanol, chloroform, dichloromethane,
 acetone, ethyl acetate, DMAC, N-methyl pyrrolidone, dimethylformamide, and
 dimethylsulfoxide. The polymer is preferably soluble in at least one of
 the above solvents.
 The polymer of the invention can also comprise additional biocompatible
 monomeric units so long as they do not interfere with the biodegradable
 characteristics desired. Such additional monomeric units may offer even
 greater flexibility in designing the precise release profile desired for
 targeted drug delivery or the precise rate of biodegradability desired for
 structural implants such as for orthopedic applications. Examples of such
 additional biocompatible monomers include the recurring units found in
 polycarbonates; polyorthoesters; polyamides; polyurethanes;
 poly(iminocarbonates); and polyanhydrides.
 Synthesis of Poly(phosphoester-co-amide) Polymers
 The most common general reaction in preparing poly-(phosphates) is a
 dehydrochlorination between a phosphodichloridate and a diol according to
 the following equation:
 ##STR26##
 Most poly (phosphonates) are also obtained by condensation between
 appropriately substituted dichlorides and diols.
 Poly (phosphites) have been prepared from glycols in a two-step
 condensation. A 20% molar excess of a dimethylphosphite is used to react
 with the glycol, followed by the removal of the methoxyphosphonyl end
 groups in the oligomers by high temperature.
 An advantage of melt polycondensation is that it avoids the use of solvents
 and large amounts of other additives, thus making purification more
 straightforward. It can also provide polymers of reasonably high molecular
 weight. Somewhat rigorous conditions, however, are often required and can
 lead to chain acidolysis (or hydrolysis if water is present). Unwanted,
 thermally-induced side reactions, such as crosslinking reactions, can also
 occur if the polymer backbone is susceptible to hydrogen atom abstraction
 or oxidation with subsequent macroradical recombination.
 To minimize these side reactions, the polymerization can also be carried
 out in solution. Solution polycondensation requires that both the
 prepolymer and the phosphorus component be soluble in a common solvent.
 Typically, a chlorinated organic solvent is used, such as chloroform,
 dichloromethane, or dichloroethane. The solution polymerization must be
 run in the presence of equimolar amounts of the reactants and, preferably,
 a stoichiometric amount of an acid acceptor or a Lewis acid-type catalyst.
 Useful acid acceptors include tertiary amines as pyridine or
 triethylamine. Examples of useful Lewis acid-type catalysts include
 magnesium chloride and calcium chloride. The product is then typically
 isolated from the solution by precipitation in a non-solvent and purified
 to remove the hydrochloride salt by conventional techniques known to those
 of ordinary skill in the art, such as by washing with an aqueous acidic
 solution, e.g., dilute HCl.
 Reaction times tend to be longer with solution polymerization than with
 melt polymerization. However, because overall milder reaction conditions
 can be used, side reactions are minimized, and more sensitive functional
 groups can be incorporated into the polymer. The disadvantages of solution
 polymerization are that the attainment of high molecular weights, such as
 a Mw greater than 20,000, is less likely.
 Interfacial polycondensation can be used when high molecular-weight
 polymers are desired at high reaction rates. Mild conditions minimize side
 reactions. Also the dependence of high molecular weight on stoichiometric
 equivalence between diol and dichloridate inherent in solution methods is
 removed. However, hydrolysis of the acid chloride may occur in the
 alkaline aqueous phase. Sensitive dichloridates that have some solubility
 in water are generally subject to hydrolysis rather than polymerization.
 Phase transfer catalysts, such as crown ethers or tertiary ammonium
 chloride, can be used to bring the ionized diol to the interface to
 facilitate the polycondensation reaction. The yield and molecular weight
 of the resulting polymer after interfacial polycondensation are affected
 by reaction time, molar ratio of the monomers, volume ratio of the
 immiscible solvents, the type of acid acceptor, and the type and
 concentration of the chase transfer catalyst.
 In a preferred embodiment of the invention, the biodegradable polymer of
 formula III is made by a process comprising the step of reacting an amino
 acid derivative known as a desaminotyrosyl L-tyrosine ester, which has the
 formula IV:
 ##STR27##
 wherein R is as defined above, with a phosphodihalidate of formula V:
 ##STR28##
 where "halo" is Br, Cl or I, and R' is as defined above, to form the
 polymer of formula III.
 The desaminotyrosyl L-tyrosine ester of formula IV can be prepared by
 dicyclohexylcarbodiimide (DCC)-mediated coupling reactions in an inert
 solvent following standard procedures of peptide chemistry, such as
 disclosed in Bodanszky, (1984) Practice of Peptide Synthesis, 145, the
 disclosure of which is hereby incorporated by reference. As a specific
 example, the hexyl ester of desaminotyrosyl L-tyrosine ester ("DTTH") can
 be prepared by the DCC-mediated coupling of desaminotyrosine and
 L-tyrosine hexyl ester in tetrahydrofuran as the solvent. The crude alkyl
 ester is typically obtained as an oil, which can be purified by a number
 of methods, e.g., flash chromatography on silica gel with 70:30
 chloroforn:ethyl acetate or 98:2 methylene chloride:methanol.
 Crystallization of the pure DTTH can usually be accelerated by crystal
 seeding.
 Alkyl esters of tyrosine having up to eight carbon atoms in the ester group
 can be prepared by the procedure disclosed in Greenstein et al. (1961),
 Chemistry of the Amino Acids, 929, particularly Illustrative Procedure
 10-48, the disclosure of which is hereby incorporated by reference. Alkyl
 esters of tyrosine having more than eight carbon atoms in the ester group
 can be prepared according to the procedure disclosed in the examples of
 Overell, U.S. Pat. No. 4,428,932, which is hereby incorporated by
 reference.
 The purpose of the polymerization reaction of the invention is to form a
 copolymer comprising (i) desaminotyrosyl L-desaminotyrosine recurring
 units derived from the amino acid derivative of formula IV and (ii)
 phosphorylated ester recurring units. The result can be a copolymer having
 a microcrystalline structure that is particularly well-suited to use as a
 controlled release carrier.
 The process of the invention can take place at widely varying temperatures,
 depending upon whether a solvent is used and, if so, which one; the
 molecular weight desired; the susceptibility of the reactants to form side
 reactions; and the presence of a catalyst. Preferably, however, the
 process takes place at a temperature ranging from about 0 to about
 +235.degree. C. for melt conditions. Somewhat lower temperatures, e.g.,
 for example from about -50 to about 100.degree. C. may be possible with
 solution polymerization or with the use of either a cationic or anionic
 catalyst.
 The time required for the process also can vary widely, depending on the
 type of reaction being used, the molecular weight desired and, in general,
 the need to use more or less rigorous conditions for the reaction to
 proceed to the desired degree of completion. Typically, however, the
 process takes place during a time between about 30 minutes and 7 days.
 While the process may be in bulk, in solution, by interfacial
 polycondensation, or any other convenient method of polymerization,
 preferably, the process takes place under solution conditions.
 Particularly useful solvents include methylene chloride, chloroform,
 tetrahydrofuran, di-methyl formamide, dimethyl sulfoxide or any of a wide
 variety of inert organic solvents.
 Particularly when solution polymerization reaction is used, an acid
 acceptor is advantageously present during the polymerization step (a). A
 particularly suitable class of acid acceptor comprises tertiary amines,
 such as pyridine, trimethylamine, triethylamine, substituted anilines and
 substituted aminopyridines. The most preferred acid acceptor is the
 substituted aminopyridine 4-dimethylaminopyridine ("DMAP").
 The polymer of formula III is isolated from the reaction mixture by
 conventional techniques, such as by precipitating out, extraction with an
 immiscible solvent, evaporation, filtration, crystallization and the like.
 Typically, however, the polymer of formula III is both isolated and
 purified by quenching a solution of polymer with a non-solvent or a
 partial solvent, such as diethyl ether or petroleum ether.
 Biodegradability and Release Characteristics
 The polymers of the present invention can, in preferred embodiments, be
 characterized by a release rate of the biologically active substance in
 vivo that is controlled at least in part as a function of hydrolysis of
 the phosphoester bond of the polymer during biodegradation. Additionally,
 the biologically active substance to be released may be conjugated to the
 phosphorus sidechain R' to form a pendant drug delivery system. Further
 other factors are also important.
 The life of a biodegradable polymer in vivo also depends upon its molecular
 weight, crystallinity, biostability, and the degree of crosslinking. In
 general, the greater the molecular weight, the higher the degree of
 crystallinity, and the greater the biostability, the slower biodegradation
 will be.
 Accordingly, the structure of the sidechain can influence the release
 behavior of compositions comprising a biologically active substance. For
 example, it is expected that conversion of the phosphate sidechain to a
 more lipophilic, more hydrophobic or bulky group would slow down the
 degradation process. Thus, release is usually faster from polymer
 compositions with a small aliphatic group sidechain than with a bulky
 aromatic sidechain.
 The mechanical properties of the polymer are also important with respect to
 the processability in making molded or pressed articles for implantation.
 For example, the glass transition temperature can vary widely but must be
 sufficiently lower than the temperature of decomposition to accommodate
 conventional fabrication techniques, such as compression molding,
 extrusion or injection molding. The polymers of the invention typically
 have glass transition temperatures varying between about 25 to about
 75.degree. C. and, preferably, from about 45 to about 65.degree. C.
 Weight-average molecular weights (Mw) typically vary from about 2,000 to
 about 200,000 daltons, preferably from about 2,000 to about 100,000
 daltons and, most preferably, from about 2,000 to about 20,000 daltons.
 Number average molecular weights (Mn) can also vary widely, but generally
 fall in the range of about 1,000 to 100,000, preferably about 1,000 to
 50,000 and, most preferably, from about 1,000 to about 10,000. Intrinsic
 viscosities generally vary from about 0.01 to about 2.0 dL/g in chloroform
 at 40.degree. C., preferably from about 0.01 to about 1.0 dL/g and, most
 preferably, about 0.01 to about 0.5 dL/g.
 Polymer Compositions
 The polymers of the present invention can be used either alone or as a
 composition containing, in addition, a biologically active substance to
 form a variety of useful biodegradable materials. For example, the polymer
 of formula I can be used to produce a biosorbable suture, an orthopedic
 appliance or bone cement for repairing injuries to bone or connective
 tissue, a laminate for degradable or non-degradable fabrics, or a coating
 for an implantable device, even without the presence of a biologically
 active substance.
 Preferably, however, the biodegradable polymer composition comprises both:
 (a) at least one biologically active substance and
 (b) the polymer having the recurring monomeric units shown in formula I.
 The terms "drug," "medicament," or "bioactive substance" (i.e.,
 biologically active substance) as used herein include, biologically,
 physiologically, or pharmacologically active substances that act locally
 or systemically in the human or animal body. Various forms of the
 medicaments or biologically active materials can be used which are capable
 of being released from the polymer matrix into adjacent tissues or fluids.
 The medicaments are at least very slightly water-soluble, preferably
 moderately water-soluble, and are diffusible through the polymeric
 composition. They can be acidic, basic, or salts. They can be neutral
 molecules, polar molecules, or molecular complexes capable of hydrogen
 bonding. They can be in the form of ethers, esters, amides and the like,
 which are biologically activated when injected into the human or animal
 body.
 The biologically active substance of the invention can vary widely with the
 purpose for the composition. The active substance(s) may be described as a
 single entity or a combination of entities. The delivery system is
 designed to be used with biologically active substances having
 high-water-solubility as well as with those having low water-solubility to
 produce a delivery system that has controlled release rates. The term
 "biologically active substance" includes without limitation, medicaments;
 vitamins; mineral supplements; substances used for the treatment,
 prevention, diagnosis, cure or mitigation of disease or illness; or
 substances which affect the structure or function of the body; or
 pro-drugs, which become biologically active or more active after they have
 been placed in a predetermined physiological environment.
 Non-limiting examples of useful biologically active substances include the
 following expanded therapeutic categories: anabolic agents, antacids,
 anti-asthmatic agents, anti-cholesterolemic and anti-lipid agents,
 anti-coagulants, anti-convulsants, anti-diarrheals, anti-emetics,
 anti-infective agents, anti-inflammatory agents, anti-manic agents,
 anti-nauseants, anti-neoplastic agents, anti-obesity agents, anti-pyretic
 and analgesic agents, anti-spasmodic agents, anti-thrombotic agents,
 anti-uricemic agents, anti-anginal agents, antihistamines, anti-tussives,
 appetite suppressants, biologicals, cerebral dilators, coronary dilators,
 decongestants, diuretics, diagnostic agents, erythropoietic agents,
 expectorants, gastrointestinal sedatives hyperglycemic agents, hypnotics,
 hypoglycemic agents, ion exchange resins, laxatives, mineral supplements,
 mucolytic agents, neuromuscular drugs, peripheral vasodilators,
 psychotropics, sedatives, stimulants, thyroid and anti-thyroid agents,
 uterine relaxants, vitamins, antigenic materials, and prodrugs.
 Specific examples of useful biologically active substances from the above
 categories include: (a) anti-neoplastics such as androgen inhibitors,
 antimetabolites, cytotoxic agents, immunomodulators; (b) anti-tussives
 such as dextromethorphan, dextro-methorphan hydrobromide, noscapine,
 carbetapentane citrate, and chlophedianol hydrochloride; (c)
 antihistamines such as chlorpheniramine maleate, phenindamine tartrate,
 zyrilamine maleate, doxylamine succinate, and phenyltcloxamine citrate;
 (d) decongestants such as phenylephrine hydrochloride, chenylpropanolamine
 hydrochloride, pseudoephedrine hydrochloride, and ephedrine; (e) various
 alkaloids such as codeine phosphate, codeine sulfate and morphine- (f)
 mineral supplements such as potassium chloride, zinc chloride, calcium
 carbonates, magnesium oxide, and other alkali metal and alkaline earth
 metal salts; (g) ion exchange resins such as cholestryramine; (h)
 anti-arrhythmics such as N-acetylprocainamide; (i) antipyretics and
 analgesics such as acetaminophen, aspirin and ibuprofen; (j) appetite
 suppressants such as phenyl-propanolamine hydrochloride or caffeine; (k)
 expectorants such as guaifenesin; (1) antacids such as aluminum hydroxide
 and magnesium hydroxide; (m) biologicals such as peptides, polypeptides,
 proteins and amino acids, hormones, interferons or cytokines and other
 bioactive peptidic compounds, such as hGH, tPA, calcitonin, ANF, EPO and
 insulin; (n) anti-infective agents such as anti-fungals, anti-virals,
 antiseptics and antibiotics; and (o) antigenic materials, particularly
 those useful in vaccine applications.
 To further illustrate, antimetabolites which can be formulated in the
 subject polymers include, but are not limited to, methotrexate,
 5-fluorouracil, cytosine arabinoside (ara-C), 5-azacytidine,
 6-mercaptopurine, 6-thioguanine, and fludarabine phosphate. Antitumor
 antibiotics may include but are not limited to doxorubicin, daunorubicin,
 dactinomycin, bleomycin, mitomycin C, plicamycin, idarubicin, and
 mitoxantrone. Vinca alkaloids and epipodophyllotoxins may include, but are
 not limited to vincristine, vinblastine, vindesine, etoposide, and
 teniposide.
 Nitrosoureas can also be provided in the subject matrizes, including
 carmustine, lomustine, semustine and streptozocin.
 Hormonal therapeutics can also be included in the polymeric matrices, such
 as corticosteriods (cortisone acetate, hydrocortisone, prednisone,
 prednisolone, methyl prednisolone and dexamethasone), estrogens,
 (diethylstibesterol, estradiol, esterified estrogens, conjugated estrogen,
 chlorotiasnene), progestins (medroxyprogesterone acetate, hydroxy
 progesterone caproate, megestrol acetate), antiestrogens (tamoxifen),
 aromastase inhibitors (aminoglutethimide), androgens (testosterone
 propionate, methyltestosterone, fluoxymesterone, testolactone),
 antiandrogens (flutamide), LHRH analogues (leuprolide acetate), and
 endocrines for prostate cancer (ketoconazole).
 Other compounds which can be disposed in the polymeric compositions of the
 present invention include those presently classified as investigational
 drugs, and can include, but are not limited to alkylating agents such as
 Nimustine AZQ, BZQ, cyclodisone, DADAG, CB10-227, CY233, DABIS maleate,
 EDMN, Fotemustine, Hepsulfam, Hexamethylmelamine, Mafosamide, MDMS, PCNU,
 Spiromustine, TA-077, TCNU and Temozolomide; antimetabolites, such as
 acivicin, Azacytidine, 5-aza-deoxycytidine, A-TDA, Benzylidene glucose,
 Carbetimer, CB3717, Deazaguanine mesylate, DODOX, Doxifluridine, DUP-785,
 10-EDAM, Fazarabine, Fludarabine, MZPES, MMPR, A, PLAC, TCAR, TMQ,
 TNC-P and Piritrexim; antitumor antibodies, such as AMPAS, BWA770U,
 BWA773U, BWA502U, Amonafide, m-AMSA, CI-921, Datelliptium, Mitonafide,
 Piroxantrone, Aclarubicin, Cytorhodin, Epirubicin, esorubicin, Idarubicin,
 Iodo-doxorubicin, Marcellomycin, Menaril, Morpholino anthracyclines,
 Pirarubicin, and SM-5887; microtubule spindle inhibitors, such as
 Amphethinile, Navelbine, and Taxol; the alkyl-lysophospholipids, such as
 BM41-440, ET-18-OCH3, and Hexacyclophosphocholine; metallic compounds,
 such as Gallium Nitrate, CL286558, CL287110, Cycloplatam, DWA2114R, NK121,
 Iproplatin, Oxaliplatin, Spiroplatin, Spirogermanium, and Titanium
 compounds; and novel compounds such as, for example, Aphidoicolin
 glycinate, Ambazone, BSO, Caracemide, DSG, Didemnin, B, DMFO, Elsamicin,
 Espertatrucin, Flavone acetic acid, HMBA, HHT, ICRF-187, Iododeoxyuridine,
 Ipomeanol, Liblomycin, Lonidamine, LY186641, MAP, MTQ, Merabarone
 SK&F104864, Suramin, Tallysomycin, Teniposide, THU and WR2721; a nd
 Toremifene, Trilosane, and zindoxifene.
 Antitumor drugs that are radiation enhancers can also be formulated in the
 subject polymers. Examples of such drugs include, for example, the
 chemotherapeutic agents 5'-fluorouracil, mitomycin, cisplatin and its
 derivatives, taxol, bleomycins, daunomycins, and methamycins.
 The pharmaceutical and matrix combinations of the invention may,
 additionally, be used for the treatment of infections. For such an
 application, antibiotics, either water soluble or water insoluble, may be
 immobilized/formulated in the subject polymers. Antibiotics are well known
 to those of skill in the art, and include, for example, penicillins,
 cephalosporins, tetracyclines, ampicillin, aureothicin, bacitracin,
 chloramphenicol, cycloserine, erythromycin, gentamicin, gramacidins,
 kanamycins, neomycins, streptomycins, tobramycin, and vancomycin
 The subject polymers can also be formulated with peptide, proteins or other
 biopolymers, e.g., such as interferons, interleukins, tumor necrosis
 factor, and other protein biological response modifiers.
 Preferably, the biologically active substance is selected from the group
 consisting of polysaccharides, growth factors, hormones, anti-angiogenesis
 factors, interferons or cytokines, and pro-drugs. In a particularly
 preferred embodiment, the biologically active substance is a therapeutic
 drug or pro-drug, most preferably a drug selected from the group
 consisting of chemotherapeutic agents and other anti-neoplastics,
 antibiotics, anti-virals, anti-fungals, anti-inflammatories,
 anticoagulants, an antigenic materials.
 Upon formation of the polymer system, the biologically active material
 becomes incorporated into the polymer matrix. After implantation of the
 externally formed polymer system or insertion of a liquid composition to
 form in situ the polymer system, the bioactive material will be released
 from the matrix into the adjacent tissues or fluids by diffusion and
 polymer degradation mechanisms. Manipulation of these mechanisms also can
 influence the release of the bioactive material into the surroundings at a
 controlled rate. For example, the polymer matrix can be formulated to
 degrade after an effective an/or substantial amount of the bioactive
 material is released from the matrix. Release of a material having a low
 solubility in water, as for example a peptide or protein, typically
 requires the degradation of a substantial part of the polymer matrix to
 expose the material directly to the surrounding tissue fluids. Thus, the
 release of the biologically active material from the matrix can be varied
 by, for example, the solubility of the bioactive material in water, the
 distribution of the bioactive material within the matrix, or the size,
 shape, porosity, solubility and biodegradability of the polymer matrix,
 among other factors. The release of the biologically active material from
 the matrix is controlled relative to its intrinsic rate by varying the
 polymer molecular weight and by adding a rate modifying agent to provide a
 desired duration and rate of release.
 The biologically active substances are used in amounts that are
 therapeutically effective. While the effective amount of a biologically
 active substance will depend on the particular material being used,
 amounts of the biologically active substance from about 1% to about 65%
 have been easily incorporated into the present delivery systems while
 achieving controlled release. Lesser amounts may be used to achieve
 efficacious levels of treatment for certain biologically active
 substances.
 Other additives can be used to advantage in further controlling the desired
 release rate of a bioactive material for a particular treatment protocol.
 For example, if the resulting polymer is too impervious to water, a
 pore-forming agent can be added to generate additional pores in the
 matrix. Any biocompatible water-soluble material can be used as the
 pore-forming agent. These agents can be either soluble in the liquid
 composition or simply dispersed within it. They are capable of dissolving,
 diffusing or dispersing out of both the coagulating polymer matrix and the
 formed polymer system whereupon pores and microporous channels are
 generated in the matrix and system. The amount of pore-forming agent (and
 size of dispersed particles of such pore-forming agent, if appropriate)
 within the composition will directly affect the size and number of the
 pores in the polymer system.
 Pore-formning agents include any pharmaceutically acceptable organic or
 inorganic substance that is substantially miscible in water and body
 fluids and will dissipate from the forming and formed matrix into aqueous
 medium or body fluids or water-immiscible substances that rapidly degrade
 to water-soluble substances. The pore-forming agent may be soluble or
 insoluble in the polymer liquid composition of the invention. In the
 liquid composition of the invention, it is further preferred that the
 pore-forming agent is miscible or dispersible in the organic solvent to
 form a uniform mixture. Suitable pore-forming agents include, for example,
 sugars such as sucrose and dextrose, salts such as sodium chloride and
 sodium carbonate, and polymers such as hydroxylpropylcellulose,
 carboxymethylcellulose, polyethylene glycol, and polyvinylpyrrolidone. The
 size and extent of the pores can be varied over a wide range by changing
 the molecular weight and percentage of pore-forming agent incorporated
 into the polymer system.
 In addition, the polymer composition of the invention can also comprise
 polymer blends of the polymer of the invention with other biocompatible
 polymers, so long as they do not interfere undesirably with the
 biodegradable characteristics of the composition. Blends of the polymer of
 the invention with such other polymers may offer even greater flexibility
 in designing the precise release profile desired for targeted drug
 delivery or the precise rate of biodegradability desired for structural
 implants such as for orthopedic applications. Examples of such additional
 biocompatible polymers include other polycarbonates; polyesters;
 polyorthoesters; polyamides; polyurethanes; poly(iminocarbonates); and
 polyanhydrides.
 Pharmaceutically acceptable carriers may be prepared from a wide range of
 materials. Without being limited thereto, such materials include diluents,
 binders and adhesives, lubricants, disintegrants, colorants, bulking
 agents, flavorings, sweeteners, and miscellaneous materials such as
 buffers and absorbents in order to prepare a particular medicated
 composition.
 Implants and Delivery Systems Designed for Injection
 In its simplest form, a biodegradable therapeutic agent delivery system
 consists of a dispersion of the therapeutic agent in a polymer matrix. The
 therapeutic agent is typically released as the polymeric matrix
 biodegrades in vivo into soluble products that can be excreted from the
 body.
 In a particularly preferred embodiment, an article is used for
 implantation, injection, or otherwise placed totally or partially within
 the body, the article comprising the biodegradable polymer composition of
 the invention. The biologically active substance of the composition and
 the polymer of the invention may form a homogeneous matrix, or the
 biologically active substance may be encapsulated in some way within the
 polymer. For example, the biologically active substance may be first
 encapsulated in a microsphere and then combined with the polymer in such a
 way that at least a portion of the microsphere structure is maintained.
 Alternatively, the biologically active substance may be sufficiently
 immiscible in the polymer of the invention that it is dispersed as small
 droplets, rather than being dissolved, in the polymer. Either form is
 acceptable, but it is preferred that, regardless of the homogeneity of the
 composition, the release rate of the biologically active substance in vivo
 remain controlled, at least partially as a function of hydrolysis of the
 phosphoester bond of the polymer upon biodegradation.
 In a preferred embodiment, the article of the invention is designed for
 implantation or injection into the body of an animal. It is particularly
 important that such an article result in minimal tissue irritation when
 implanted or injected into vasculated tissue.
 As a structural medical device, the polymer compositions of the invention
 provide a physical form having specific chemical, physical, and mechanical
 properties sufficient for the application and a composition that degrades
 in vivo into non-toxic residues. Typical structural medical articles
 include such implants as orthopedic fixation devices, ventricular shunts,
 laminates for degradable fabric, drug-carriers, bioabsorbable sutures, bum
 dressings, coatings to be placed on other implant devices, and the like.
 In orthopedic articles, the composition of the invention may be useful for
 repairing bone and connective tissue injuries. For example, a
 biodegradable porous material can be loaded with bone morphogenetic
 proteins to form a bone graft useful for even large segmental defects. In
 vascular graft applications, a biodegradable material in the form of woven
 fabric can be used to promote tissue ingrowth. The polymer composition of
 the invention may be used as a temporary barrier for preventing tissue
 adhesion, e.g., following abdominal surgery.
 On the other hand, in nerve regeneration articles, the presence of a
 biodegradable supporting matrix can be used to facilitate cell adhesion
 and proliferation. when the polymer composition is fabricated as a tube
 for nerve generation, for example, the tubular article can also serve as a
 geometric guide for axonal elongation in the direction of functional
 recovery.
 As a drug delivery device, the polymer compositions of the invention
 provide a polymeric matrix capable of sequestering a biologically active
 substance and provide predictable, controlled delivery of the substance.
 The polymeric matrix then degrades to non-toxic residues.
 Biodegradable medical implant devices and drug delivery products can be
 prepared in several ways. The polymer can be melt processed using
 conventional extrusion or injection molding techniques, or these products
 can be prepared by dissolving in an appropriate solvent, followed by
 formation of the device, and subsequent removal of the solvent by
 evaporation or extraction.
 Once a medical implant article is in place, it should remain in at least
 partial contact with a biological fluid, such as blood, internal organ
 secretions, mucus membranes, cerebrospinal fluid, and the like.
 In more detail, the surgical and medical uses of the filaments, films, and
 molded articles of the present invention include, but are not necessarily
 limited to:
 a. burn dressings
 b. hernia patches
 c. medicated dressings
 d. fascial substitutes
 e. gauze, fabric, sheet, felt or sponge for liver hemostasis
 f. gauze bandages g. arterial graft or substitutes
 h. bandages for skin surfaces
 i. suture knot clip
 j. orthopedic pins, clamps, screws, and plates
 k. clips (e.g.,for vena cava)
 l. staples
 m. hooks, buttons, and snaps
 n. bone substitutes (e.g., mandible prosthesis)
 o. intrauterine devices (e.g., spermicidal devices)
 p. draining or testing tubes or capillaries
 q. surgical instruments .r. vascular implants or supports
 s. vertebral discs
 t. extracorporeal tubing for kidney and heart-lung machines
 u. artificial skin
 v. catheters (including, but not limited to, the catheters described in
 U.S. Pat. No. 4,883,699 which is hereby incorporated by reference)
 w. scaffoldings for tissue engineering applications.
 In another embodiment, the aliphatic polyoxaester (including prepolymers
 and suitable crosslinked polymers and blends) is used to coat a surface of
 a surgical article to enhance the lubricity of the coated surface. The
 polymers may be applied as a coating using conventional techniques. For
 example, the polymers may be solubilized in a dilute solution of a
 volatile organic solvent, e.g. acetone, methanol, ethyl acetate or
 toluene, and then the article can be immersed in the solution to coat its
 surface. Once the surface is coated, the surgical article can be removed
 from the solution where it can be dried at an elevated temperature until
 the solvent and any residual reactants are removed. For use in coating
 applications the polymers and blends should exhibit an inherent viscosity
 (initial IV in the case of crosslinkable polymers), as measured in a 0.1
 gram per deciliter (g/dl) of hexafluoroisopropanol (HFIP), between about
 0.05 to about 2.0 dl/g, preferably about 0.10 to about 0.80 dl/g. If the
 inherent viscosity were less than about 0.05 dl/g (final IV for
 crosslinked polymers), then the polymer blend may not have the integrity
 necessary for the preparation of films or coatings for the surfaces of
 various surgical and medical articles. On the other hand, although it is
 possible to use polymer blends with an inherent viscosity greater than
 about 2.0 dl/g, initial IV for crosslinkable polymers), it may be
 exceedingly difficult to do so.
 Although it is contemplated that numerous surgical articles (including but
 not limited to endoscopic instruments) can be coated with the polymers and
 blends of this invention to improve the surface properties of the article,
 the preferred surgical articles are surgical sutures and needles. The most
 preferred surgical article is a suture, most preferably attached to a
 needle. Preferably, the suture is a synthetic absorbable suture. These
 sutures are derived, for example, from homopolymers and copolymers of
 lactone monomers such as glycolide, lactide, epsilon -caprolactone,
 1,4-dioxanone, and trimethylene carbonate. The preferred suture is a
 braided multifilament suture composed of polyglycolide or
 poly(glycolide-co-lactide).
 The biodegradable polymer particles according to the invention can also
 advantageously be used for diagnostic purposes. Thus an X-ray contrast
 agent, such as a poly-iodo aromatic compound, may formulated in the
 biodegradable polymer of the present invention so that it is liberated and
 safely eliminated from the body on biodegradation. Such particles may be
 used for visualisation of the liver and spleen since they are trapped in
 the reticulo-endothelial systems of those organs. The X-ray contrast agent
 may also be simply held physically in the polymers by being incorporated
 during polymerisation.
 Polymer particles according to the invention may also contain paramagnetic,
 superparamagnetic or ferromagnetic substances which are of use in magnetic
 resonance imaging (MRI) diagnostics. Thus, submicron particles of iron or
 a magnetic iron oxide can be physically incorporated into the polymers
 during polymerisation to provide ferromagnetic or superparamagnetic
 particles. Paramagnetic MRI contrast agents principally comprise
 paramagnetic metal ions, such as gadolinium ions, held by a chelating
 agent which prevents their release (and thus substantially eliminates
 their toxicity). In general many such chelating agents are poly-amino
 poly-carboxylic acids such as diethylene triamine pentaacetic acid (R. B.
 Lauffer, Chem. Rev. 87 (1987), pp. 901-927).
 Polymer particles of the invention may also contain ultrasound contrast
 agents such as heavy materials, e.g. barium sulphate or iodinated
 compounds such as the X-ray contrast agents referred to above, to provide
 ultrasound contrast media.
 EXEMPLIFICATION
 The invention now being generally described, it will be more readily
 understood by reference to the following examples which are included
 merely for purposes of illustration of certain aspects and embodiments of
 the present invention, and are not intended to limit the invention.
 Example 1
 Preparation of the Monomer Desaminotyrosyl L-T-yrosine Hexyl Ester (DTTH)
 ##STR29##
 14.15g of desaminotyrosine, 22.6 g of L -tyrosine hexyl ester, and 11.51 g
 of N-hydroxybenzotriazole hydrate ("HOBt") were dissolved in 150 ml
 tetrahydroflran and cooled to -10.degree. C. Di-cyclohexylcarbodiimide
 (DCC, 19.33 g) was added with stirring.
 The reaction mixture was stirred continuously for four hours. Then 5 ml of
 glacial acetic acid was added to destroy the unreacted DCC, and the
 mixture was filtered. The filtrate was evaporated to dryness, and the
 residue was re-dissolved in 150 ml of ethyl acetate, washed with 0.5 N HCl
 solution (100 ml.times.3), 0.5 N Na2CO3 solution (100ml.times.3) , and
 saturated NaCl solution (100 ml.times.3), successively. The ethyl acetate
 solution was dried over anhydrous MgSO4 and evaporated to dryness again.
 The crude product was purified by flash column chromatography
 (CH2Cl2-methanol, 98:2, v/v) . The fractions containing DTTH were
 evaporated to dryness and redissolved in a small volume of a 95:5 v/v
 mixture of ethyl acetate-methanol. The DTTH product was gradually
 crystallized/solidified after an excess of hexane was added. The solid
 DTTH was removed by filtration and dried under a vacuum to yield about
 15-20 g of white powder (43-58% yield).
 Example 2
 Synthesis of the Corresponding PCH(phosphoester-co-amide) P(DTTH-EOP)
 ##STR30##
 Under an argon stream, 7.8 g of desaminotyrosyl tyrosine hexyl ester
 (DTTH), 5.07 g of 4-dimethylaminopyridine (DMAP), and 50 ml of methylene
 chloride were transferred to a 250 ml flask equipped with a funnel. A
 solution of 3.07 g of ethyl phosphodichloridate (EOP) in 30 ml of
 methylene chloride was added to the funnel. The solution in the flask was
 cooled down to -40.degree. C. with stirring, and the EOP solution was
 added dropwise through the funnel. When the addition was complete, the
 mixture was gradually brought up to a temperature of 45.degree. C. and was
 maintained at reflux temperature overnight.
 The solvent was then evaporated, and a vacuum (0-1 mm Hg) was applied for
 one hour while the temperature of the residue was maintained at
 120.degree. C. The residue was redissolved in 100 ml of chloroform, washed
 with a 0.1 M solution of HCl in distilled water, dried over anhydrous
 Na.sub.2 SO.sub.4, and quenched into 500 ml of ether. The resulting
 precipitate was collected and dried under vacuum, producing a slightly
 yellow powder.
 Example 3
 Properties of P(DTTH-EOP)
 A P(DTTH-EOP) polymer was prepared as described above in Example 2. The
 resulting poly(phosphoester-co-amide) polymer was analyzed by GPC using
 polystyrene as a standard, and the resulting graph established an Mw of
 5,450 and an Mn of 1,670. The polydispersity (Mw/Mn) was determined to be
 3.27.
 The polymer was very soluble in chloroform, dichloromethane,
 dimethylformamide, and dimethyl sulfoxide; soluble in N-methylpyrrolidone;
 and swelled in ethanol, methanol, acetone, acetonitrile and
 tetrahydrofuran. The intrinsic viscosity was measured in chloroform
 (CH.sub.3 Cl) at 40.degree. C. and determined to be 0.055 dL/g.
 The Tg of the polymer was determined by differential scanning calorimetry
 ("DSC") to be 55.6.degree. C., as shown in FIG. 1. No melting peak was
 observed in the DSC curve.
 The invention being thus described, it will be obvious that the same may be
 varied in many ways. Such variations are not to he 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.
 All of the above-cited references and publications are hereby incorporated
 by reference.
 Equivalents
 Those skilled in the art will recognize, or be able to ascertain using no
 more than routine experimentation, many equivalents to the specific
 embodiments of the invention described herein. Such equivalents are
 intended to be encompassed by the following claims.