111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US008357378B2
`
`c12) United States Patent
`Wallace et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,357,378 B2
`*Jan. 22,2013
`
`(54) FRAGMENTED POLYMERIC
`COMPOSITIONS AND METHODS FOR
`THEIR USE
`
`(75)
`
`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)
`
`(73) Assignees: Baxter International Inc., Deerfield, IL
`(US); Baxter Healthcare S.A., Glattpark
`(Opfikon) (CH)
`
`( *) Notice:
`
`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.: 13/114,784
`
`(22) Filed:
`
`May24, 2011
`
`(65)
`
`Prior Publication Data
`
`US 2011/0223231 Al
`
`Sep. 15,2011
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 09/553,969, filed on
`Apr. 21, 2000, which is a continuation of application
`No. 09/032,370, filed on Feb. 27, 1998, 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.
`(60) Provisional application No. 60/050,437, filed on Jun.
`18, 1997.
`
`(51)
`
`Int. Cl.
`A61K 9100
`(2006.01)
`A61K 9114
`(2006.01)
`(52) U.S. Cl. ........................................ 424/400; 424/489
`
`(58) Field of Classification Search ........................ None
`See application file for complete search history.
`
`(56)
`
`References Cited
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`
`Primary Examiner- Lakshmi Channavajjala
`(74) Attorney, Agent, or Firm- Kilpatrick 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.
`
`6 Claims, 5 Drawing Sheets
`
`ETHICON EXHIBIT 1001
`
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`* cited by examiner
`
`

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`U.S. Patent
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`Jan.22,2013
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`Sheet 1 of 5
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`US 8,357,378 B2
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`FIG. 1
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`U.S. Patent
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`Jan.22,2013
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`Sheet 2 of 5
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`US 8,357,378 B2
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`54
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`G
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`FIG.2A
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`FIG.2B
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`

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`U.S. Patent
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`Jan.22,2013
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`Sheet 3 ofS
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`US 8,357,378 B2
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`FIG. 3A
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`BV
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`FIG.3B
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`

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`U.S. Patent
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`Jan.22,2013
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`Sheet 4 of 5
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`US 8,357,378 B2
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`96
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`90
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`i .
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`II l
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`94
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`FIC.4
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`U.S. Patent
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`Jan. 22, 2013
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`Sheet 5 of 5
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`US 8,357,378 B2
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`1300
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`1100
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`6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
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`

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`US 8,357,378 B2
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`1
`FRAGMENTED POLYMERIC
`COMPOSITIONS AND METHODS FOR
`THEIR USE
`
`This application is a continuation U.S. application Ser. No.
`09/553,969 filed on Apr. 21,2000, which is a continuation of
`application Ser. No. 09/032,370, filed on Feb. 27, 1998, which
`is a continuation-in-part of application Ser. No. 08/903,674,
`filed on Jul. 31, 1997, which was a continuation-in-part of
`provisional Application No. 60/050,437, filed on Jun. 18,
`1997, and was a continuation-in-part of application Ser. No.
`08/704,852, filed on Aug. 27, 1996. The full disclosures of
`each of these applications are incorporated herein by refer(cid:173)
`ence.
`
`BACKGROUND OF THE INVENTION
`
`1. 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 25
`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 concen(cid:173)
`tration may cause alternating periods of ineffectiveness and
`toxicity. For this reason, a variety of"controlledrelease" 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 polymeric carrier
`is one effective means to deliver the therapeutic agent locally
`and in a controlled fashion. In addition to controlled levels,
`such systems often require less total drug and minimize sys(cid:173)
`temic 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
`these molecules are generally unstable in buffer and have low
`permeability through polymers. In fact, in a non-biodegrad- 55
`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 60
`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(cid:173)
`mer in vivo depends on its molecular weight and degree of 65
`cross-linking, the higher the molecular weights and degrees
`of cross-linking resulting in a longer life. Common biode-
`
`2
`gradable polymers include polylactic acid (PLA, also
`referred to as polylactide), polyglycolic acid (PGA), copoly(cid:173)
`mers of PLA and PGA, polyamides, and copolymers of
`polyamides and polyesters. PLA undergoes hydrolytic de(cid:173)
`esterification to lactic acid, a 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/
`PGA copolymer. However, the use of PGA in controlled(cid:173)
`release implants has been limited due to its low solubility in
`10 common solvents and subsequent difficulty in fabrication of
`devices.
`An additional advantage of biodegradable drug delivery
`carriers is the elimination of the need for surgical removal
`after it has fulfilled its mission. Additional advantages
`15 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
`deliver unstable therapeutic agents. This last point is of par(cid:173)
`ticular importance in light of the advances in molecular biol-
`20 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
`and low GI tract absorption which often render them unsuit(cid:173)
`able for 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
`released as the polymeric matrix decomposes, or biodegrades
`into soluble products which are excreted from the body.
`30 Unfortunately, the ability to design ideal biodegradable deliv(cid:173)
`ery systems is limited by many characteristics of the poly(cid:173)
`mers, including weak mechanical strength, unfavorable deg(cid:173)
`radation characteristics, toxicity, inflexibility, fabrication
`difficulty, and the like. Although known biodegradable poly-
`35 mers have a broad range of potential utility, there is no one
`single material available that could satisfY all requirements
`imposed by different applications. Accordingly, there contin(cid:173)
`ues to be need to develop new biodegradable polymers.
`U.S. Pat. Nos. 5,672,336 and 5,196,185 describe a wound
`40 dressing comprising a micro-particulate fibrillar collagen
`having a particle size of0.5-2.0 im. This composition gener(cid:173)
`ally comprises an aqueous phase and does not form a hydro(cid:173)
`gel as described in the present invention. U.S. Pat. No. 5,698,
`213 describes a cross-linked aliphatic poly-ester hydrogel
`45 useful as an absorbable surgical device and drug delivery
`vehicle. U.S. Pat. No. 5,674,275 describes an acrylate or
`methacrylate based hydrogel adhesive. U.S. Pat. No. 5,306,
`501 describes a polyoxyalkylene based thermoreversible
`hydrogel useful as a drug delivery vehicle. U.S. Pat. No.
`50 4,925,677 and U.S. Pat. No. 5,041,292 describe a hydrogel
`comprising a protein component cross-linked with a polysac(cid:173)
`charide or mucopolysaccharide and useful as a drug delivery
`vehicle.
`For these reasons, it would be desirable to provide
`improved compositions, methods, and kits for delivering bio(cid:173)
`logical macromolecule and other drugs to target body sites. In
`particular, it would be desirable to provide compositions
`which are compatible with a wide variety of drugs either in
`solution or in suspension, particularly drugs present in an
`aqueous carrier. Still more preferably, the compositions
`should be in the form ofhydrogels which are biocompatible
`and which permit substantial control or "programming" of
`the release characteristics, including release rate, composi(cid:173)
`tion persistence, drug carrying capacity, product delivery
`characteristics (such as injectability ), and the like. In addition
`to drug delivery and release, the products, methods, and kits
`of the present invention should be adaptable for localizing
`
`

`
`3
`active agents at a target site, where the active agents can
`provide biological activity even prior to release from the
`product matrix. At least some of these objectives will be met
`by the embodiments of the invention described hereinafter.
`Biodegradable injectable drug delivery polymers are 5
`described in U.S. Pat. No. 5,384,333 and by Jeong et a!.
`(1997) "Nature," 388:860-862. Biodegradable hydrogels for
`controlled released drug delivery are described in U.S. Pat.
`No. 4,925,677. Resorbable collagen-based drug delivery sys(cid:173)
`tems aredescribedin U.S. Pat. Nos. 4,347,234 and4,291,013. 10
`Aminopolysaccharide-based biocompatible films for drug
`delivery are described in U.S. Pat. Nos. 5,300,494 and 4,946,
`870. Water soluble carriers for the delivery of taxol are
`described in U.S. Pat. No. 5,648,506.
`Polymers have been used as carriers of therapeutic agents 15
`to effect a localized and sustained release (Langer, eta!., Rev.
`Macro. Chern. Phys., C23(1), 61, 1983; Controlled Drug
`Delivery, Vol. I and II, Bruck, S.D., (ed.), CRC Press, Boca
`Raton, Fla., 1983; Leong eta!., Adv. Drug Delivery Review,
`1:199, 1987). These therapeutic agent delivery systems simu- 20
`late infusion and offer the potential of enhanced therapeutic
`efficacy and reduced systemic toxicity.
`Other classes of synthetic polymers which have been pro(cid:173)
`posed for controlled release drug delivery include polyesters
`(Pitt, et a!., in Controlled Release of Bioactive Materials, R. 25
`Baker, Ed., Academic Press, New York, 1980); polyamides
`(Sidman, eta!., Journal of Membrane Science, 7:227, 1