US 20020071822A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0071822 A1 Uhrich (43) Pub. Date: Jun. 13, 2002 (54) THERAPEUTIC POLYESTERS AND provisional application No. 60/261,337, filed on Jan. POLYAMIDES 12, 2001. (76) Inventor: Kathryn E. Uhrich, Hoboken, NJ (US) Publication Classification Correspondence Address: (51) Int. Cl." ..................... A61K 31/785; A61K 31/765; SCHWEGMAN, LUNDBERG, WOESSNER & C08G 63/685; CO8G 63/688 KLUTH, PA. (52) U.S. Cl. ....................... 424/78.37; 528/288; 528/293 P.O. BOX 2938 MINNEAPOLIS, MN 55402 (US) (57) ABSTRACT (21) Appl. No.: 09/917,194 Polymers (i.e. polyesters, polyamides, and polythioesters or (22) Filed: Jul. 27, 2001 a mixture thereof) which degrade hydrolytically into bio logically active compounds are provided. Methods of pro Related U.S. Application Data ducing these polymers, intermediates useful for preparing these polymers, and methods of using these polymers to (63) Non-provisional of provisional application No. deliver biologically active compounds to a host are also 60/220,707, filed on Jul. 27, 2000. Non-provisional of provided. US 2002/0071822 A1 Jun. 13, 2002 THERAPEUTIC POLYESTERS AND POLYAMDES 0012. The invention also provides processes and inter mediates disclosed herein that are useful for preparing a PRIORITY OF INVENTION polymer of the invention. 0001. This application claims priority from U.S. Provi DETAILED DESCRIPTION OF THE sional Application No. 60/220,707, filed Jul. 27, 2000 and INVENTION U.S. Provisional Application No. 60/261,337, filed Dec. 1, 2001, which are incorporated herein by reference. 0013 Definitions 0014. The following definitions are used, unless other BACKGROUND OF THE INVENTION wise described: halo is fluoro, chloro, bromo, or iodo. Alkyl, 0002 Polyesters are used routinely by those skilled in the alkoxy, etc. denote both Straight and branched groups, but art in various drug delivery Systems. reference to an individual radical Such as “propyl” embraces only the Straight chain radical, a branched chain isomer Such 0003) For example, U.S. Pat. No. 5,942,252 describes a as "isopropyl being Specifically referred to. Aryl denotes a microcapsule comprising as its biocompatible excipient a phenyl radical or an ortho-fused bicyclic carbocyclic radical poly(lactide-co-glycolide), poly(lactide), poly(glycolide), having about nine to ten ring atoms in which at least one ring copolyoxalate, polycaprolactone, poly(lactide-co-caprolac is aromatic. Heteroaryl encompasses a radical attached via a tone), poly(esteramide), polyorthoester, poly(p-hydroxybu ring carbon of a monocyclic aromatic ring containing five or tyric) acid and/or polyanhydride for use in delivering anti Six ring atoms consisting of carbon and one to four heteroa gens or vaccines into and through mucosally-associated toms each Selected from the group consisting of non lymphoid tissue. peroxide oxygen, Sulfur, and NCX) wherein X is absent or is 0004 WO 99/29885 describes a process for degrading H, O,(C-C)alkyl, phenyl or benzyl, as well as a radical of poly(ester-amides) and poly(ester-urethanes) encapsulating an Ortho-fused bicyclic heterocycle of about eight to ten ring chemicals, drugs, enzymes, microorganisms and Seeds by atoms derived therefrom, particularly a benz-derivative or introducing the polymer to an aqueous nutrient Solution and one derived by fusing a propylene, trimethylene, or tetram inoculating the Solution with a culture containing a Selected ethylene diradical thereto. bacteria. 0015 The term ester linkage means -OC(=O)- or 0005 WO 98/36013 describes aliphatic-aromatic dihy -C(=O)C)-; the term thioester linkage means droxy compounds for use as controlled drug delivery Sys -SC(=O)- or -C(=O)S-; and the term amide linkage temS. means-N(R)C(=O)- or-C(=O)N(R)-, wherein each R is a Suitable organic radical, Such as, for example, hydro 0006 WO 97/39738 describes preparation of micropar gen, (C-C)alkyl, (C-C)cycloalkyl, (C- ticles of a Sustained release ionic conjugate comprising a C.)cycloalkyl(C-C)alkyl, aryl, heteroaryl, aryl(C- free carboxyl group containing biodegradable polymers and C.)alkyl, or heteroaryl(C-C)alkyl. a free amino group-containing drug. 0016. The term “amino acid,” comprises the residues of SUMMARY OF THE INVENTION the natural amino acids (e.g. Ala, Arg, ASn, Asp, Cys, Glu, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, 0007 Polyesters, polythioesters, and polyamides which and Val) in D or L form, as well as unnatural amino acids degrade into useful biologically active compounds have now (e.g. phosphoSerine, phosphothreonine, phosphotyrosine, been developed. Accordingly, the invention provides a poly hydroxyproline, gamma-carboxyglutamate, hippuric acid, mer of the invention which is polymer comprising a back octahydroindole-2-carboxylic acid, Statine, 1,2,3,4-tetrahy bone, wherein the backbone comprises ester, thioester, or droisoquinoline-3-carboxylic acid, penicillamine, omithine, amide linkages, and wherein the backbone comprises one or citruline, a-methyl-alanine, para-benzoylphenylalanine, more groups that will yield a biologically active compound phenylglycine, propargylglycine, Sarcosine, and tert-butylg upon hydrolysis of the polymer. lycine). The term also comprises natural and unnatural amino acids bearing a conventional amino protecting group 0008. The invention also provides a pharmaceutical com (e.g. acetyl or benzyloxycarbonyl), as well as natural and position comprising a polymer of the invention and a unnatural amino acids protected at the carboxy terminus pharmaceutically acceptable carrier. (e.g. as a (C-C)alkyl, phenyl or benzyl ester or amide; or 0009. The invention also provides a therapeutic method as an O-methylbenzyl amide). Other Suitable amino and for treating a disease in an animal comprising administering carboxy protecting groups are known to those skilled in the to an animal in need of Such therapy, an effective amount of art (See for example, Greene, T. W.; Wutz, P. G. M. a polymer of the invention. “Protecting Groups. In Organic Synthesis” second edition, 0.010 The invention also provides a method of delivering 1991, New York, John Wiley & Sons, Inc., and references a biologically active compound to a host comprising admin cited therein). istering to the host a biocompatible and biodegradable 0017. The term “host” includes animals and plants. polymer of the invention, which degrades into the biologi 0018. The term “peptide' describes a sequence of 2 to 35 cally active compound. amino acids (e.g. as defined hereinabove) or peptidyl resi 0.011 The invention provides a polymer of the invention dues. The Sequence may be linear or cyclic. For example, a for use in medical therapy, as well as the use of a polymer cyclic peptide can be prepared or may result from the of the invention for the manufacture of a medicament useful formation of disulfide bridges between two cysteine residues for the treatment of a disease in a mammal, Such as a human. in a Sequence. Preferably a peptide comprises 3 to 20, or 5 US 2002/0071822 A1 Jun. 13, 2002 to 15 amino acids. Peptide derivatives can be prepared as controlled release Source for a biologically active com disclosed in U.S. Pat. Nos. 4,612,302; 4.853,371; and 4,684, pound, or as a medium for the localized delivery of a 620, or as described in the Examples hereinbelow. Peptide biologically active compound to a Selected Site. For Sequences Specifically recited herein are written with the example, the polymers of the invention can be used for the amino terminus on the left and the carboxy terminus on the localized delivery of a therapeutic agent to a Selected Site right. within the body of a human patient (i.e. within or near a 0019 Polymers of the Invention tumor), where the degradation of the polymer provides localized, controlled, release of the therapeutic agent. 0020. The biocompatible, biodegradable polyesters, polythioesters, and polyamides of the invention are useful in 0027 Biologically Active Compounds a variety of applications where delivery of a biologically active compound is desired. Examples of Such applications 0028. The term “biologically active compound” includes include, but are not limited to, medical, dental and cosmetic therapeutic agents that provide a therapeutically desirable SCS. effect when administered to an animal (e.g. a mammal, Such as a human). Biologically active compounds that can be 0021. The polymers of the invention may be prepared in incorporated into the polymers of the invention possess at accordance with methods commonly employed in the field of Synthetic polymers to produce a variety of useful products least two functional groups that can each be incorporated with valuable physical and chemical properties. The poly into an ester, thioester, or amide linkage of a polymer (as mers can be readily processed into pastes or Solvent cast to discussed in detail below), Such that, upon hydrolysis of the yield films, coatings, microSpheres and fibers with different polymer, the therapeutic agent is obtained. These groups can geometric shapes for design of various medical implants, independently be a hydroxy group (-OH), a mercapto and may also be processed by compression molding and group (-SH), an amine group (-NHR), or a carboxylic extrusion. acid (-COOH). 0022 Polyesters and polyamides prepared in accordance 0029. The biologically active compounds can also com with the present invention have average molecular weights prise other functional groups (including hydroxy groups, of about 1500 Daltons up to about 100,000 Daltons, calcu mercapto groups, amine groups, and carboxylic acids, as lated by Gel Permeation Chromatography (GPC) relative to well as others) that can be used to modify the properties of narrow molecular weight polystyrene Standards. Preferred the polymer (e.g. for branching, for cross linking, for polyesters and polyamides have average molecular weights appending other molecules (e.g. another biologically active of about 1500 Daltons, up to about 50,000 Daltons calcu compound) to the polymer, for changing the solubility of the lated by Gel Permeation Chromatography (GPC) relative to polymer, or for effecting the biodistribution of the polymer).