111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US008512729B2
`
`c12) United States Patent
`Wallace et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,512, 729 B2
`*Aug. 20, 2013
`
`(72)
`
`( *) Notice:
`
`(54) FRAGMENTED POLYMERIC
`COMPOSITIONS AND METHODS FOR
`THEIR USE
`(71) Applicants: Baxter International Inc., Deerfield, IL
`(US); Baxter Healthcare S.A., Glattpark
`(Opfikon) (CH)
`Inventors: Donald G. Wallace, Menlo Park, CA
`(US); Cary J. Reich, Los Gatos, CA
`(US); Narinder S. Shargill, Dublin, CA
`(US); Felix Vega, San Francisco, CA
`(US); A. Edward Osawa, San Francisco,
`CA (US); Zhen Qian-Wallis, Fremont,
`CA (US)
`(73) Assignees: Baxter International Inc., Deerfield, IL
`(US); Baxter Healthcare S.A., Glattpark
`(Opfikon) (CH)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`This patent is subject to a terminal dis(cid:173)
`claimer.
`(21) Appl. No.: 13/665,475
`Oct. 31, 2012
`(22) Filed:
`Prior Publication Data
`(65)
`US 2013/0108611 Al
`May 2, 2013
`Related U.S. Application Data
`(63) Continuation of application No. 13/174,963, filed on
`Jul. 1, 2011, now Pat. No. 8,303,981, which is a
`continuation-in-part of application No. 09/553,969,
`filed on Apr. 21, 2000, now abandoned, which is a
`continuation-in-part of application No. 09/032,370,
`filed on Feb. 27, 1998, now Pat. No. 6,066,325, which
`is
`a
`continuation-in-part of application No.
`08/903,674, filed on Jul. 31, 1997, now Pat. No.
`6,063,061, which
`is a continuation-in-part of
`application No. 08/704,852, filed on Aug. 27, 1996,
`now abandoned, which is a continuation-in-part of
`application No. 12/176,945, filed on Jul. 21,2008, now
`Pat. No. 8,383,141, which is a continuation of
`application No. 09/908,464, filed on Jul. 17, 2001, now
`Pat. No. 7,435,425.
`
`(60) Provisional application No. 60/050,437, filed on Jun.
`18, 1997.
`Int. Cl.
`A61F 13100
`A61F 2100
`A61K 9/44
`(52) U.S. Cl.
`USPC ............ 424/422; 424/443; 424/445; 424/489
`(58) Field of Classification Search
`None
`See application file for complete search history.
`References Cited
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`(51)
`
`(56)
`
`U.S. PATENT DOCUMENTS
`2,507,244 A
`5119 50 Correll
`2,558,395 A
`6/1951 Studer
`(Continued)
`
`CN
`EP
`
`FOREIGN PATENT DOCUMENTS
`1270240 A
`10/2000
`0282316 A2
`9/1988
`(Continued)
`OTHER PUBLICATIONS
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`Ansell, J., eta!., "Gelfoam and Autologous Clot Embolization: Effect
`on Coagulation," Investigative Radiology, 1978, vol. 13, pp. ll5 -120.
`
`(Continued)
`Primary Examiner- Lakshmi Channavajjala
`(74) Attorney, Agent, or Firm- Kikpatrick Townsend &
`Stockton LLP
`ABSTRACT
`(57)
`Cross-linked hydrogels comprise a variety of biologic and
`non-biologic polymers, such as proteins, polysaccharides,
`and synthetic polymers. Such hydrogels preferably have no
`free aqueous phase and may be applied to target sites in a
`patient's body by extruding the hydrogel through an orifice at
`the target site. Alternatively, the hydrogels may be mechani(cid:173)
`cally disrupted and used in implantable articles, such as breast
`implants. When used in vivo, the compositions are useful for
`controlled release drug delivery, for inhibiting post-surgical
`spinal and other tissue adhesions, for filling tissue divots,
`tissue tracts, body cavities, surgical defects, and the like.
`18 Claims, 6 Drawing Sheets
`
`ETHICON EXHIBIT 1001
`
`

`
`(56)
`
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`1
`FRAGMENTED POLYMERIC
`COMPOSITIONS AND METHODS FOR
`THEIR USE
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation of U.S. Ser. No. 13/174,
`963 filed Jul. 1, 2011, which is a continuation-in-part of U.S.
`Ser. No. 09/553,969 filed Apr. 21, 2000, which is a continu(cid:173)
`ation of U.S. Ser. No. 09/032,370 filed Feb. 27, 1998 (now
`U.S. Pat. No. 6,066,325), which is a continuation-in-part of
`U.S. Ser. No. 08/903,674, filed on Jul. 31, 1997 (now U.S. Pat.
`No. 6,063,061), which claims the benefitofpriorityfrom U.S.
`60/050,437 filed Jun. 18, 1997, and which is a continuation(cid:173)
`in-part ofU.S. Ser. No. 08/704,852 filed Aug. 27, 1996, U.S.
`Ser. No. 13/174,963 is also a continuation-in-part ofU.S. Ser.
`No. 12/176,945 filed Jul. 21, 2008, which is a continuation of
`U.S. Ser. No. 09/908,464 filed Jul. 17, 2001. The full disclo(cid:173)
`sures of each of these applications are incorporated herein by
`reference.
`
`BACKGROUND OF THE INVENTION
`
`Field of the Invention
`
`The present invention relates generally to biocompatible
`cross-linked polymeric compositions and to the use of such
`compositions for the controlled delivery of aqueous agents to
`target sites.
`It has long been recognized that tablets, capsules, and
`injections are not the optimum route of drug delivery for all
`purposes. These conventional routes often require frequent
`and repeated doses, resulting in a "peak and valley" pattern of
`therapeutic, agent concentration. Since each therapeutic
`agent has a therapeutic range above which it is toxic and
`below which it is ineffective, a fluctuating therapeutic agent
`concentration may cause alternating periods of ineffective(cid:173)
`ness and toxicity. For this reason, a variety of "controlled
`release" drug formulations and devices have, been proposed
`for maintaining the therapeutic agent level within the desired
`therapeutic range for the duration of treatment. Using a poly(cid:173)
`meric carrier is one effective means to deliver the therapeutic
`agent locally and in a controlled fashion. In addition to con(cid:173)
`trolled levels such systems often require less total drug and
`minimize systemic side effects.
`Polymeric carriers may be biodegradable or non-biode(cid:173)
`gradable. 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 out-diffusion
`of the therapeutic agent 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-biode(cid:173)
`gradable matrix than for a biodegradable matrix where a long
`passage through the channels is no longer required. Since
`many pharmaceuticals have short half-lives, there is a signifi(cid:173)
`cant chance that the therapeutic agent may be decomposed or
`inactivated inside the non-biodegradable matrix before it can
`be released. The risk is particularly significant for many bio(cid:173)
`logical macromolecules and smaller polypeptides, since 60
`these molecules are generally unstable in buffer and have low
`permeability through polymers. In fact, in a non-biodegrad(cid:173)
`able matrix, many bio-macromolecules will aggregate and
`precipitate, clogging the channels necessary for diffusion out
`of the carrier matrix.
`These concerns are largely alleviated by using a biodegrad(cid:173)
`able controlled release matrix. Biodegradable polymers
`
`2
`release contained drugs as the matrix is consumed or biode(cid:173)
`graded during therapy. The polymer is usually selected to
`breakdown into subunits which are biocompatible with the
`surrounding tissue. The persistence of a biodegradable poly-
`5 mer in vivo depends on its molecular weight and degree of
`cross-linking, the higher the molecular weights and degrees
`of cross-linking resulting in a longer life. Common biode(cid:173)
`gradable polymers include polylactic acid (PLA, also
`referred to as polylactide), polyglycolic acid (PGA), copoly-
`10 mers of PLA and PGA, polyamides, and copolymers of
`polyamides and polyesters. PLA undergoes hydrolytic de(cid:173)
`esterification to lactic acid, to normal product of muscle
`metabolism. PGA is chemically related to PLA and is com(cid:173)
`monly used for absorbable surgical sutures, as in the PLA/
`15 PGA copolymer. However, the use of PGA in controlled(cid:173)
`release implants has been limited due to its low solubility in
`common solvents and subsequent difficulty in fabrication of
`devices.
`An additional advantage of biodegradable drug delivery
`20 carriers is the elimination of the need for surgical removal
`after it has fulfilled its mission. Additional advantages
`include: 1) the ability to control release rate through variation
`of the matrix composition: 2) the ability to implant at sites
`difficult or impossible for retrieval; 3) an improved ability to
`25 deliver unstable therapeutic agents. This last point is of par(cid:173)
`ticular importance in light of the advances in molecular biol(cid:173)
`ogy and genetic engineering which have lead to the commer(cid:173)
`cial availability of many potent biological macromolecules.
`Such macromolecules usually have short in vivo half-lives
`30 and low GI tract absorption which often render them unsuit(cid:173)
`able tbr conventional oral or intravenous administration.
`Ideally, a biodegradable therapeutic agent delivery system
`would simply consist of a solution, suspension, or dispersion
`of the drug in a polymer matrix. The therapeutic agent is
`35 released as the polymeric matrix decomposes, or biodegrades
`into soluble products wh