US 2005O281.883A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0281883 A1 Daniloff et al. (43) Pub. Date: Dec. 22, 2005 (54) COMPOSITIONS AND SYSTEMS FOR Publication Classification FORMING CROSSLINKED BOMATERLALS AND ASSOCATED METHODS OF (51) Int. Cl. ................................................... A61K 9/14 PREPARATION AND USE (52) U.S. Cl. .............................................................. 424/489 (76) Inventors: George Y. Daniloff, Mountain View, CA (US); Louis C. Sehl, Redwood (57) ABSTRACT City, CA (US); Olof Mikael Trollsas, San Jose, CA (US); Jacqueline Schroeder, Boulder Creek, CA (US); David M. Gravett, Vancouver (CA); Crosslinkable compositions are provided that readily Philip M. Toleikis, Vancouver (CA) crosslink in Situ to provide crosslinked biomaterials. The Correspondence Address: composition contains at least two biocompatible, non-im REED INTELLECTUAL PROPERTY LAW munogenic components having reactive groups thereon, GROUP with the functional groups Selected So as to enable inter 1400 PAGE MILL ROAD reaction between the components, i.e., crosslinking. In one PALO ALTO, CA 94304-1124 (US) embodiment, a first component has nucleophilic groups and a Second component has electrophilic groups. Additional (21) Appl. No.: 11/118,088 components may have nucleophilic or electrophilic groups. Methods for preparing and using the compositions are also (22) Filed: Apr. 28, 2005 provided as are kits for delivery of the compositions. Exem Related U.S. Application Data plary uses for the crosslinked compositions include tissue augmentation, biologically active agent delivery, bioadhe (60) Provisional application No. 60/566,569, filed on Apr. Sion, and prevention of adhesions following Surgery or 28, 2004. injury. Patent Application Publication Dec. 22, 2005 Sheet 1 of 2 US 2005/0281883 A1 FIG ... 1 Patent Application Publication Dec. 22, 2005 Sheet 2 of 2 US 2005/0281883 A1 16 FIG. 3 US 2005/0281883 A1 Dec. 22, 2005 COMPOSITIONS AND SYSTEMS FOR FORMING by the instant invention, which is a mixture of two compo CROSSLINKED BOMATERIALS AND nents, each component having a core Substituted with reac ASSOCATED METHODS OF PREPARATION AND tive groups, where the reactive groups on one component are USE capable of reacting with the reactive groups on the other component. The components are essentially non-reactive in TECHNICAL FIELD a dry environment, and upon reaction form a three-dimen 0001. This invention relates generally to compositions Sional matrix. and Systems for forming crosslinked biomaterials, to the crosslinked biomaterials prepared thereby, and to methods SUMMARY OF THE INVENTION of using Such compositions as, for example, bioadhesives for 0008 One aspect of the invention relates to a homoge tissue augmentation, for prevention of Surgical adhesions, neous dry powder composition comprised of a first com for coating Surfaces of Synthetic implants, as drug delivery ponent having a core Substituted with m nucleophilic matrices, for ophthalmic applications, for Orthopedic appli groups, where me2; and a Second component having a core cations, as Sealants, as hemostats, and in other applications, Substituted with n electrophilic groups, where ne2 and as discussed herein and/or as appreciated by one of ordinary m+n>4, wherein the nucleophilic and electrophilic groups skill in the art. are non-reactive in a dry environment but are rendered reactive upon exposure to an aqueous environment Such that BACKGROUND OF THE INVENTION the components inter-react in the aqueous environment to 0002 Much work has been done in developing bioadhe form a three-dimensional matrix. A pharmaceutically sive materials. U.S. Pat. No. 5,162,430 to Rhee et al. acceptable carrier may also be included. describes the use of collagen-Synthetic polymer conjugates 0009. In one embodiment of the homogeneous dry pow prepared by covalently binding collagen to Synthetic hydro der composition, the nucleophilic and electrophilic groups philic polymerS Such as various derivatives of polyethylene undergo a nucleophilic Substitution reaction, a nucleophilic glycol. In a related patent, U.S. Pat. No. 5,328,955 to Rhee addition reaction, or both. The nucleophilic groups may be et al., various activated forms of polyethylene glycol and selected from -NH, -NHR', -N(R'), -SH, -OH, various linkages are described, which can be used to produce COOH, -CH-OH, -H, -PH, -PHR', -P(R'), collagen-Synthetic polymer conjugates having a range of -NH-NH, -CO-NH-NH2, and -CHN, where R' physical and chemical properties. U.S. Pat. No. 5,324,775 to is a hydrocarbyl group, and each R' may be the same or Rhee et al. also describes Synthetic hydrophilic polyethylene different. The electrophilic groups may be Selected from glycol conjugates, but the conjugates involve naturally CO-Cl, -(CO)-O-(CO)-R (where R is an alkyl occurring polymerS Such as polysaccharides. group), -CH=CH-CH=O and -CH=CH 0003) EP 0732 109 A1 to Rhee discloses a crosslinked C(CH.)=O, halo, -N=C=O, -N=C=S, biomaterial composition that is prepared using a hydropho -SOCH=CH, -O(CO)-C=CH, -O(CO)- bic crosslinking agent, or a mixture of hydrophilic and C(CH)=CH, -S-S-(CHN), -O(CO)- hydrophobic crosslinking agents, where the preferred hydro C(CHCH)=CH, -CH=CH-C=NH, -COOH, phobic crosslinking agents include hydrophobic polymers -(CO)O-N(COCH), -CHO, -(CO)O- that contain, or can be chemically derivatized to contain, two N(COCH)-S(O), OH, and -NCCOCH). or more Succinimidyl groups. 0010. In another embodiment of the homogeneous dry 0004 U.S. Pat. No. 5,580,923 to Yeung et al. discloses powder composition, the nucleophilic groups are amino Surgical adhesive material that comprises a Substrate mate groupS and the electrophilic groups are amine-reactive rial and an anti-adhesion binding agent. The Substrate mate groups. The amine-reactive groups may contain an electro rial is preferably collagen and the binding agent preferably philically reactive carbonyl group Susceptible to nucleo comprises at least one tissue-reactive functional group and at philic attack by a primary or Secondary amine. The amine least one Substrate-reactive functional group. reactive groups may be Selected from carboxylic acid esters, acid chloride groups, anhydrides, ketones, aldehydes, halo, 0005 U.S. Pat. No. 5,614.587 to Rhee et al. describes isocyanato, thioisocyanato, epoxides, activated hydroxyl bioadhesives that comprise collagen that is crosslinked using groups, olefins, carboxyl, Succinimidyl ester, SulfoSuccinim a multifunctionally activated Synthetic hydrophilic polymer. idyl ester, maleimido, epoxy, and etheneSulfonyl. 0006 U.S. Pat. No. 5,874,500 to Rhee et al. describes a crosslinked polymer composition that comprises one com 0011. In yet another embodiment of the homogeneous dry ponent having multiple nucleophilic groups and another powder composition, the nucleophilic groups are Sulfhydryl component having multiple electrophilic groups. Covalent groupS and the electrophilic groups are Sulfhydryl-reactive bonding of the nucleophilic and electrophilic groups forms groups. The Sulflhydryl-reactive groups may be Selected So as to form a thioester, imido-thioester, thioether, or disulfide a three dimensional matrix that has a variety of medical uses linkage upon reaction with the Sulfhydryl groups. Where the including tissue adhesion, Surface coatings for Synthetic Sulflhydryl-reactive groups form a disulfide linkage, they implants, and drug delivery. More recent developments may have the structure -S-S-Ar where Ar is a substi include the addition of a third component having either tuted or urisubstituted nitrogen-containing heteroaromatic nucleophilic or electrophilic groups, as is described in U.S. moiety or a non-heterocyclic aromatic group Substituted Pat. No. 6,458,889 to Trollsas et al. with an electron-withdrawing moiety. Where the sulfhydryl 0007. However, in spite of the advances in the art, there reactive groups form a thioether linkage, they may be remains a need for improved crosslinked biomaterials that Selected from maleimido, Substituted maleimido, haloalkyl, are easy to use and Store. This need, as well as others, is met epoxy, imino, aziridino, olefins, and C.B-unsaturated alde US 2005/0281883 A1 Dec. 22, 2005 hydes and ketones. The Sulfhydryl-reactive groups may be hydrophilic polymer may be selected from poly(methylox Selected from mixed anhydrides, ester derivatives of phos azoline) and poly(ethyloxazoline). phorus, ester derivatives of p-nitrophenol, p-nitrothiophenol and pentafluorophenol; esters of Substituted hydroxy 0016. Where the core is a hydrophobic polymer selected, lamines, including N-hydroxyphthalimide esters, N-hydrox the core may be selected from polylactic acid and polygly ySuccinimide esters, N-hydroxySulfoSuccinimide esters, and colic acid. N-hydroxyglutarimide esters, esters of 1-hydroxybenzotria 0017 Where the core is a C- hydrocarbyl, the core may zole, 3-hydroxy-3,4-dihydro-benzotriazin-4-one; 3-hy be selected from alkanes, diols, polyols, and polyacids. droxy-3,4-dihydro-quinazoline-4-One, carbonylimidazole 0018 Where the core is a heteroatom-containing C derivatives, acid chlorides, ketenes, and isocyanates. hydrocarbyl, the core may be selected from di- and poly 0012. In still another embodiment of the homogeneous electrophiles. dry powder composition, the number of nucleophilic groups 0019. In another embodiment of the homogeneous dry in the mixture is approximately equal to the number of powder composition, the first component has the Structure of electrophilic