throbber
United States Patent [19J
`Wallace et al.
`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US006066325A
`[11] Patent Number:
`[45] Date of Patent:
`
`6,066,325
`*May 23, 2000
`
`[54] FRAGMENTED POLYMERIC
`COMPOSITIONS AND METHODS FOR
`THEIR USE
`
`6/1995 WIPO .............................. A61K 9/16
`WO 95/15747
`3/1996 WIPO ................................ COSJ 3/28
`WO 96/06883
`WO 96/39159 12/1996 WIPO ............................ A61K 38/00
`
`[75]
`
`Inventors: Donald G. Wallace, Menlo Park; Cary
`J. Reich, Los Gatos; Narinder S.
`Shargill, Dublin; Felix Vega; A.
`Edward Osawa, both of San Francisco,
`all of Calif.
`
`[73] Assignee: Fusion Medical Technologies, Inc.,
`Mountain View, Calif.
`
`[ *] Notice:
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`[21] Appl. No.: 09/032,370
`
`[22] Filed:
`
`Feb. 27, 1998
`
`Related U.S. Application Data
`
`[63] Continuation-in-part of application No. 08/903,674, Jul. 31,
`1997, and a continuation-in-part of application No. 08/704,
`852, Aug. 27, 1996, abandoned.
`[60] Provisional application No. 60/050,437, Jun. 18, 1997.
`
`[51]
`
`Int. Cl? ............................. A61K 9/00; A61F 13/00;
`A61F 2/00
`[52] U.S. Cl. .......................... 424/400; 424/422; 424/423;
`424/426; 524/916
`[58] Field of Search ..................................... 524/916, 400;
`424/426, 423, 422
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,013,078
`4,291,013
`4,347,234
`
`3/1977 Feild ....................................... 128/303
`9/1981 Wahlig et a!. ............................ 424/16
`8/1982 Wahlig et a!. ............................ 424/15
`
`(List continued on next page.)
`
`FOREIGN PATENT DOCUMENTS
`
`376931
`wo 86/00912
`wo 92/21354
`wo 92/22252
`
`7/1990
`2/1986
`12/1992
`12/1992
`
`European Pat. Off ......... C08L 89/06
`WIPO ............................ C08B 37/00
`WIPO .......................... A61K 31!725
`WIPO ............................ A61B 17/00
`
`OTHER PUBLICATIONS
`
`Boyers et al., "Reduction of postoperative pelvic adhesions
`in the rabbit with Gore-Tex surgical membrane" F ert. Ster.
`(1988) 49(6):1066-1070.
`Heller et al., "Release of Norethindrone from Poly(Ortho
`Esters)" Polymer Engineering Sci. (1981) 21:727-731.
`Jeong et al., "Biodegradable block copolymers as injectable
`drug-delivery systems" Nature (1997) 388:860-862.
`Langer et al., "Chemical and physical structure of polymers
`as carriers for controlled release of bioactive agents: A
`review" Rev. Marco Chern. Phys. (1983) C23(1):61-126.
`Leong et al., "Polymeric controlled drug delivery" Adv.
`Drug Delivery Rev. (1987) 1:199-233.
`Leong et al., "Polyanhydrides for controlled release of
`bioactive agents" Biomaterials (1986) 7:364--371.
`Masar et al., "Synthesis of polyurethanes and investigation
`of their hydrolytic stability" J. Polymer Sci.
`(1979)
`66:259-268.
`Sidman et al., "Biodegradable, implantable sustained release
`systems based on glutamic acid copolymers" J. Membrane
`Science (1979) 7:227-291.
`
`Primary Examiner-Thurman K. Page
`Assistant Examiner-Todd D Ware
`Attorney, Agent, or Firm-Townsend and Townsend and
`Crew LLP
`
`[57]
`
`ABSTRACT
`
`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
`mechanically disrupted and used in implantable articles,
`such as breast implants. When used in vivo, the composi(cid:173)
`tions 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.
`
`8 Claims, 5 Drawing Sheets
`
`ETHICON EXHIBIT 1001
`
`

`
`6,066,325
`Page 2
`
`U.S. PATENT DOCUMENTS
`
`4,749,689
`4,803,075
`4,832,686
`4,925,677
`4,946,870
`5,007,916
`5,017,229
`5,041,292
`5,061,274
`5,061,492
`5,080,893
`5,108,421
`5,126,141
`5,129,882
`5,134,229
`5,135,751
`5,140,016
`5,192,300
`5,196,185
`5,204,382
`5,275,616
`5,300,494
`
`6/1988 Miyata eta!. ............................ 514/21
`2/1989 Wallace et a!. ......................... 424/423
`5/1989 Anderson .................................. 604/49
`5/1990 Feijen ...................................... 424/484
`8/1990 Partain, III et a!. .. ... ... .... ... ... .. 514/777
`4/1991 Linsky et a!. ........................... 606/151
`5/1991 Burns et a!.
`............................ 106/162
`8/1991 Feijen ...................................... 424/484
`10/1991 Kensey .................................... 606/213
`10/1991 Okada et a!.
`........................... 424/423
`1!1992 Goldberg eta!. ........................... 514/0
`4/1992 Fowler .................................... 606/213
`6/1992 Henry ...................................... 424/423
`7/1992 Weldon eta!. ........................... 604/96
`7/1992 Saferstein eta!. ........................ 536/56
`8/1992 Henry et a!. ............................ 424/426
`8/1992 Goldberg eta!. ......................... 514/57
`3/1993 Fowler .................................... 606/213
`3/1993 Silver et a!.
`.............................. 424/45
`4/1993 Wallace et a!. ......................... 523/115
`1!1994 Fowler .................................... 606/213
`4/1994 Brode, II eta!. ......................... 514/55
`
`5,304,377
`5,306,501
`5,330,446
`5,350,573
`5,352,715
`5,356,614
`5,384,333
`5,399,361
`5,418,222
`5,428,024
`5,437,672
`5,447,966
`5,478,352
`5,507,744
`5,512,301
`5,514,379
`5,516,532
`5,531,759
`5,540,715
`5,648,506
`5,672,336
`5,674,275
`5,698,213
`
`4/1994
`4/1994
`7/1994
`9/1994
`10/1994
`10/1994
`1!1995
`3/1995
`5/1995
`6/1995
`8/1995
`9/1995
`12/1995
`4/1996
`4/1996
`5/1996
`5/1996
`7/1996
`7/1996
`7/1997
`9/1997
`10/1997
`12/1997
`
`Yamada et a!. ......................... 424/426
`Viegas et a!. ........................... 424/423
`Weldon et a!.
`... .... ... ... ... ... ... ... 604/271
`Goldberg et a!. ......................... 424/78
`Wallace et a!. ......................... 523/115
`Sharma ..................................... 424/45
`Davis eta!. ......................... 514/772.3
`Song et a!. .............................. 424/486
`Song et a!. .. ... ... .... ... ... ... ... ... ..... 514/21
`Chu eta!. ................................. 514/21
`Allyne ....................................... 606/61
`Hermes et a!.
`......................... 523/113
`Fowler .................................... 606/213
`Tay et a!. .................................. 606!50
`Song et a!. .............................. 424/484
`Weissleder et a!.
`.................... 424/426
`Atala et a!. ............................. 424/548
`Kensey et a!. .......................... 606/213
`Katsaros et a!. ........................ 606/213
`Desai et a!. ............................. 549/510
`Sharma ..................................... 424/45
`Tang eta!. .............................. 607/152
`Jamiolkowski et a!. ................ 424/426
`
`

`
`U.S. Patent
`
`May 23,2000
`
`Sheet 1 of 5
`
`6,066,325
`
`VB
`
`FIG. 1
`
`

`
`U.S. Patent
`
`May 23,2000
`
`Sheet 2 of 5
`
`6,066,325
`
`G
`
`FIG.2A
`
`FIG.2B
`
`

`
`U.S. Patent
`
`May 23,2000
`
`Sheet 3 of 5
`
`6,066,325
`
`78
`
`FIG. 3A
`
`FIG. 3B
`
`

`
`U.S. Patent
`
`May 23,2000
`
`Sheet 4 of 5
`
`6,066,325
`
`96
`
`90
`
`I
`
`i
`
`I I I
`I I
`' ' '
`
`94
`
`FIG.4
`
`

`
`U.S. Patent
`
`May 23, 2000
`
`Sheet 5 of 5
`
`6,066,325
`
`~
`
`I
`
`~
`
`~
`
`~
`
`~
`
`~
`.
`
`1400
`1300
`1200
`1100
`=; 1000
`~ 900
`~ aoo
`700
`600
`500
`.
`r--...
`400
`6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
`ro sot ids
`
`~ 1\
`'
`\
`\
`1\
`
`'
`
`i' ~
`' ~
`"' ~ looo... -r--...
`
`FIG.S
`
`

`
`6,066,325
`
`1
`FRAGMENTED POLYMERIC
`COMPOSITIONS AND METHODS FOR
`THEIR USE
`
`The present application 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, abandoned. The full disclosures of
`each of these applications are incorporated herein by refer(cid:173)
`ence.
`
`BACKGROUND OF THE INVENTION
`
`Field of the Invention
`
`2
`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-esterification to lactic acid, a normal product of muscle
`5 metabolism. PGA is chemically related to PLA and is
`commonly used for absorbable surgical sutures, as in the
`PLA/PGA copolymer. However, the use of PGA in
`controlled-release implants has been limited due to its low
`solubility in common solvents and subsequent difficulty in
`10 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
`include: 1) the ability to control release rate through varia-
`15 tion 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 particular importance in light of the advances in
`molecular biology and genetic engineering which have lead
`20 to the commercial availability of many potent biological
`macromolecules. Such macromolecules usually have short
`in vivo half-lives and low GI tract absorption which often
`render them unsuitable 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 biode-
`grades into soluble products which are excreted from the
`body. Unfortunately, the ability to design ideal biodegrad(cid:173)
`able delivery systems is limited by many characteristics of
`the polymers, including weak mechanical strength, unfavor(cid:173)
`able degradation characteristics, toxicity, inflexibility, fab-
`rication difficulty, and the like. Although known biodegrad(cid:173)
`able polymers 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 continues to be need to develop new
`biodegradable polymers.
`U.S. Patent Nos. 5,672,336 and 5,196,185 describe a
`wound dressing comprising a micro-particulate fibrillar col(cid:173)
`lagen having a particle size of 0.5-2.0 ,urn. This composition
`generally comprises an aqueous phase and does not form a
`45 hydrogel as described in the present invention. U.S. Pat. No.
`5,698,213 describes a cross-linked aliphatic poly-ester
`hydrogel 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.
`50 No. 5,306,501 describes a polyoxyalkylene based thermor(cid:173)
`eversible hydrogel useful as a drug delivery vehicle.
`U.S. Pat. No. 4,925,677 and U.S. Pat. No. 5,041,292
`describe a hydrogel comprising a protein component cross(cid:173)
`linked with a polysaccharide or mucopolysaccharide and
`55 useful as a drug delivery vehicle.
`For these reasons, it would be desirable to provide
`improved compositions, methods, and kits for delivering
`biological macromolecule and other drugs to target body
`sites. In particular, it would be desirable to provide compo-
`60 sitions 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 of hydro gels which are biocompatible
`and which permit substantial control or "programming" of
`65 the release characteristics, including release rate, composi(cid:173)
`tion persistence, drug carrying capacity, product delivery
`characteristics (such as injectability), and the like. In addi-
`
`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 25
`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 30
`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
`polymeric carrier is one effective means to deliver the
`therapeutic agent locally and in a controlled fashion. In 35
`addition to controlled levels, such systems often require less
`total drug and minimize systemic side effects.
`Polymeric carriers may be biodegradable or non(cid:173)
`biodegradable. 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-biodegradable 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 significant chance that the therapeutic
`agent may be decomposed or inactivated inside the non(cid:173)
`biodegradable matrix before it can be released. The risk is
`particularly significant for many biological macromolecules
`and smaller polypeptides, since these molecules are gener(cid:173)
`ally unstable in buffer and have low permeability through
`polymers. In fact, in a non-biodegradable matrix, many
`bio-macromolecules will aggregate and precipitate, clog(cid:173)
`ging the channels necessary for diffusion out of the carrier
`matrix.
`These concerns are largely alleviated by using a biode(cid:173)
`gradable controlled release matrix. Biodegradable polymers
`release contained drugs as the matrix is consumed or bio(cid:173)
`degraded 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
`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
`
`40
`
`

`
`6,066,325
`
`15
`
`3
`tion to drug delivery and release, the products, methods, and
`kits of the present invention should be adaptable for local(cid:173)
`izing 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 5
`by the embodiments of the invention described hereinafter.
`Biodegradable injectable drug delivery polymers are
`described in U.S. Pat. No. 5,384,333 and by Jeong et al.
`(1997) "Nature," 388:860-862. Biodegradable hydrogels for
`controlled released drug delivery are described in U.S. Pat. 10
`No. 4,925,677. Resorbable collagen-based drug delivery
`systems are described in U.S. Pat. Nos. 4,347,234 and
`4,291,013. 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
`to effect a localized and sustained release (Langer, et al.,
`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 et al., Adv. Drug Delivery 20
`Review, 1:199, 1987). These therapeutic agent delivery
`systems simulate infusion and offer the potential of
`enhanced therapeutic efficacy and reduced systemic toxicity.
`Other classes of synthetic polymers which have been
`proposed for controlled release drug delivery include poly- 25
`esters (Pitt, et al., in Controlled Release of Bioactive
`Materials, R. Baker, Ed., Academic Press, New York, 1980);
`polyamides (Sidman, et al., Journal of Membrane Science,
`7:227, 1979); polyurethanes (Maser, et al., Journal of Poly(cid:173)
`mer Science, Polymer Symposium, 66:259, 1979); poly- 30
`orthoesters (Heller, et al., Polymer Engineering Scient,
`21:727, 1981); and polyanhydrides (Leong, et al.,
`Biomaterials, 7:364, 1986).
`Collagen-containing compositions which have been
`mechanically disrupted to alter their physical properties are 35
`described in U.S. Pat. Nos. 5,428,024; 5,352,715; and 5,204,
`382. These patents generally relate to fibrillar and insoluble
`collagens. An injectable collagen composition is described
`in U.S. Pat. No. 4,803,075. An injectable bone/cartilage
`composition is described in U.S. Pat. No. 5,516,532. A 40
`collagen-based delivery matrix comprising dry particles in
`the size range from 5 ,urn to 850 ,urn which may be suspended
`in water and which has a particular surface charge density is
`described in WO 96/39159. A collagen preparation having a
`particle size from 1 ,urn to 50 ,urn useful as an aerosol spray 45
`to form a wound dressing is described in U.S. Pat. No.
`5,196,185. Other patents describing collagen compositions
`include U.S. Pat. Nos. 5,672,336 and 5,356,614.
`A polymeric, non-erodible hydrogel that may be cross(cid:173)
`linked and injected via a syringe is described in WO 50
`96/06883.
`The following pending applications, assigned to the
`assignee of the present application, contain related subject
`matter: U.S. Ser. No. 08/903,674, filed on Jul. 31, 1997; U.S.
`Ser. No. 60/050,437, filed on Jun. 18, 1997; U.S. Ser. No.
`08/704,852, filed on Aug. 27, 1996; U.S. Ser. No. 08/673,
`710, filed Jun. 19, 1996; U.S. Ser. No. 60/011,898, filed Feb.
`20, 1996; U.S. Ser. No. 60/006,321, filed on Nov. 7, 1996;
`U.S. Ser. No. 60/006,322, filed on Nov. 7, 1996; U.S. Ser.
`No. 60/006,324, filed on Nov. 7, 1996; and U.S. Ser. No.
`08/481,712, filed on Jun. 7, 1995. The full disclosures of
`each of these applications is incorporated herein by refer(cid:173)
`ence.
`
`4
`compositions at target sites in a patient's body. The methods
`and compositions will be particularly useful for delivering
`drugs and other active agents, such as biological
`macromolecules, polypeptides, oligopeptides, nucleic acids,
`small molecule drugs, and the like. The compositions will
`comprise biocompatible, cross-linked hydrogels, as
`described in more detail below, and the drug or other
`biologically active agent will typically be incorporated into
`the composition as an aqueous solution, suspension,
`dispersion, or the like. The drugs may be incorporated into
`the compositions prior to packaging, immediately prior to
`use, or even as the compositions are being applied to the
`target site. After introduction to the target site, the drug will
`usually be released over time as the composition degrades.
`In some instances, however, the drug or other biological
`agent may display activity while still incorporated or
`entrapped within the hydrogel. For example, the composi(cid:173)
`tions and methods may find specific use in stopping or
`inhibiting bleeding (hemostasis), particularly when com-
`bined with a suitable hemostatic agent, such as thrombin,
`fibrinogen, clotting factors, and the like.
`The compositions will have other uses as well, such as
`tissue supplementation, particularly for filling soft and hard
`tissue regions, including divots, tracts, body cavities, etc.,
`present in muscle, skin, epithelial tissue, connective or
`supporting tissue, nerve tissue, ophthalmic and other sense
`organ tissue, vascular and cardiac tissue, gastrointestinal
`organs and tissue, pleura and other pulmonary tissue, kidney,
`endocrine glands, male and female reproductive organs,
`adipose tissue, liver, pancreas, lymph, cartilage, bone, oral
`tissue, and mucosal tissue. The compositions of the present
`invention will be still further useful for filling soft implant(cid:173)
`able devices, such as breast implants, where the material will
`be protected from cellular or enzyme degradation by a
`protective barrier or cover. The compositions will addition(cid:173)
`ally be useful in other procedures where it is desirable to fill
`a confined space with a biocompatible and resorbable poly(cid:173)
`meric material. Additionally, the compositions may also find
`use for inhibiting the formation of tissue adhesions, such as
`spinal tissue adhesions, following surgery and traumatic
`injury.
`The compositions of the present invention comprise a
`biocompatible, molecular cross-linked hydrogel. Usually the
`compositions will have substantially no free aqueous phase
`as defined herein below. The hydrogel is resorbable and
`fragmented, i.e. comprises small subunits having a size and
`other physical properties which enhance the flowability of
`the hydrogel (e.g. the ability to be extruded through a
`syringe) and the ability of the hydrogel to otherwise be
`applied onto and conform to sites on or in tissue, including
`tissue surfaces and defined cavities, e.g. intravertebral
`spaces, tissue divots, holes, pockets, and the like. In
`particular, the fragmented subunits are sized to permit them
`to flow when the compositions are subjected to stresses
`55 above a threshold level, for example when extruded through
`an orifice or cannula, when packed into a delivery site using
`a spatula, when sprayed onto the delivery site, or the like.
`The threshold stresses are typically in the range from 3x104
`Pa to 5x105 Pa. The compositions, however, will remain
`60 generally immobile when subjected to stresses below the
`threshold level.
`By "biocompatible," it is meant that the compositions will
`be suitable for delivery to and implantation within a human
`patient. In particular, the compositions will be non-toxic,
`65 non-inflammatory (or will display a limited inflammatory
`effect which is not inconsistent with their implantation), and
`be free from other adverse biological effects.
`
`SUMMARY OF THE INVENTION
`The present invention provides improved biocompatible
`polymeric compositions and methods for applying such
`
`

`
`6,066,325
`
`5
`By "biodegradable," it is meant that the compositions will
`degrade and breakdown into smaller molecular subunits that
`will be resorbed and/or eliminated by the body over time,
`preferably within the time limits set forth below.
`By "substantially free of an aqueous phase" it is meant
`that the compositions will be fully or partially hydrated, but
`will not be hydrated above their capacity to absorb water. In
`particular, a test for determining whether a composition has
`a free aqueous phase is set forth in Example 8 below.
`Hydrogels which are substantially free of an aqueous phase
`should release less than 10% by weight aqueous phase when
`subjected to a 10 lb. force in the test, preferably releasing
`less than 5% by weight, and more preferably less than 1%
`by weight, and more preferably releasing no discernable
`aqueous phase and displaying no collapse.
`The compositions may be dry, partially hydrated or fully 15
`hydrated depending on the extent of hydration. The fully
`hydrated material will hold from about 400% to about
`5000% water or aqueous buffer by weight, corresponding to
`a nominal increase in diameter or width of an individual
`particle of subunit in the range from approximately 50% to 20
`approximately 500%, usually from approximately 50% to
`approximately 250%. Thus, the size of particles in the dry
`powder starting material (prior to hydration) will determine
`the partially or fully hydrated size of the subunit (depending
`on the factors described below). Exemplary and preferred 25
`size ranges for the dry particles and fully hydrated subunits
`are as follows:
`
`Particle/Subunit Size
`
`Exemplary Range
`
`Preferred Range
`
`0.01 mm-1.5 mm
`0.02 mm-3 mm
`
`0.05 mm-1 mm
`0.1 mm-1.5 mm
`
`Dry Particle
`Fully Hydrated
`Hydrogel Subunit
`
`6
`Mechanical disruption of the polymer material in the dry
`state is preferred in cases where it is desired to control the
`particle size and/or particle size distribution. It is easier to
`control comminution of the dry particles than the hydrated
`5 hydrogel materials, and the size of the resulting reduced
`particles is thus easier to adjust. Conversely, mechanical
`disruption of the hydrated, cross-linked hydrogels is gener(cid:173)
`ally simpler and involves fewer steps than does comminu(cid:173)
`tion of a dry polymer starting material. Thus, the disruption
`10 of hydrated hydrogels may be preferred when the ultimate
`hydrogel subunit size and/or size distribution is less critical.
`In a first exemplary production process, a dry, non-cross(cid:173)
`linked polymer starting material, e.g. dry gelatin powder, is
`mechanically disrupted by a conventional unit operation,
`such as homogenization, grinding, coacervation, milling, jet
`milling, and the like. The powder will be disrupted suffi(cid:173)
`ciently to achieve dry particle sizes which produce hydrogel
`subunit sizes in the desired ranges when the product is
`partially or fully hydrated. The relationship between the dry
`particle size and the fully hydrated subunit size will depend
`on the swellability of the polymeric material, as defined
`further below.
`Alternatively, a particulate polymeric starting material
`may be formed by spray drying. Spray drying processes rely
`on flowing a solution through a small orifice, such as a
`nozzle, to form droplets which are released into a counter(cid:173)
`current or co-current gas stream, typically a heated gas
`stream. The gas evaporates solvent from the liquid starting
`material, which may be a solution, dispersion, or the like.
`30 Use of spray drying to form a dry powder starting material
`is an alternative to mechanical disruption of the starting
`material. The spray drying operation will usually produce a
`non-cross-linked dry powder product which is spherical in
`shape with a generally uniform particle size. The particles
`35 may then be cross-linked, as described below.
`In many instances, the mechanical disruption operation
`can be controlled sufficiently to obtain both the particle size
`and particle size distribution within a desired range. In other
`cases, however, where more precise particle size distribu(cid:173)
`tions are required, the disrupted material can be further
`treated or selected to provide the desired particle size
`distribution, e.g. by sieving, aggregation, or the like. The
`mechanically disrupted polymeric starting material is then
`cross-linked as described in more detail below, and dried.
`The dried material may be the desired final product, where
`it may be rehydrated and swollen immediately prior to use.
`Alternatively, the mechanically disrupted, cross-linked
`material may be rehydrated, and the rehydrated material
`packaged for storage and subsequent use. Particular methods
`for packaging and using these materials are described below.
`Where the subunit size of the fragmented hydrogel is less
`important, the dried polymeric starting material may be
`hydrated, dissolved, or suspended in a suitable buffer and
`cross-linked prior to mechanical disruption. Mechanical
`disruption of the pre-formed hydrogel will typically be
`achieved by passing the hydrogel through an orifice, where
`the size of the orifice and force of extrusion together
`determine the particle size and particle size distribution.
`While this method is often operationally simpler than the
`mechanical disruption of dry polymeric particles prior to
`hydration and cross-linking, the ability to control the hydro(cid:173)
`gel particle size is much less precise.
`In a particular aspect of the mechanical disruption of
`pre-formed hydrogels, the hydrogels may be packed in a
`syringe or other applicator prior to mechanical disruption.
`The materials will then be mechanically disrupted as they
`
`40
`
`45
`
`Compositions of the present invention will usually be in
`the form of a dry powder, a partially hydrated hydrogel, or
`a fully hydrated hydrogel. The dry powder (having a mois(cid:173)
`ture content below 20% by weight) will be useful as a
`starting material for preparation of the hydrogels, as
`described below. The partially hydrated hydro gels are useful
`for applications where it is desired that the material further
`swell upon application to a moist target site, e.g. a tissue
`divot. The fully hydrated forms will be useful for applica(cid:173)
`tions where in situ swelling is not desired, such as in the
`spinal column and other areas where nerves and other
`sensitive structures are present.
`The dimensions of the subunits may be achieved in a 50
`variety of ways. For example, a cross-linked hydrogel
`having dimensions larger than the target range (as defined
`below) may be mechanically disrupted at a variety of points
`during the production process. In particular, the composition
`may be disrupted (1) before or after cross-linking of a 55
`polymer starting material and (2) before or after hydration of
`the cross-linked or non-cross-linked polymer starting
`material, e.g. as a fully or partially hydrated material or as
`a dry particulate powder. The term "dry" will mean that the
`moisture content is sufficiently low, typically below 20% by 60
`weight water, so that the powder will be free-flowing and
`that the individual particles will not aggregate. The term
`"hydrated" will mean that the moisture content is sufficiently
`high, typically above 50% of the equilibrium hydration
`level, usually in the range from 70% to 95% of the equilib- 65
`rium hydration level, so that the material will act as a
`hydrogel.
`
`

`
`6,066,325
`
`7
`are applied through the syringe to the tissue target site, as
`discussed in more detail below. Alternatively, a non(cid:173)
`disrupted, cross-linked polymeric material may be stored in
`a dry form prior to use. The dry material may then be loaded
`into a syringe or other suitable applicator, hydrated within
`the applicator, and mechanically disrupted as the material is
`delivered to the target site, again typically being through an
`orifice or small tubular lumen.
`The polymer will be capable of being cross-linked and of
`being hydrated to form a hydrogel, as described in more
`detail below. Exemplary polymers include proteins selected
`from gelatin, collagen (e.g. soluble collagen), albumin,
`hemoglobin, fibrinogen, fibrin, fibronectin, elastin, keratin,
`laminin casein and derivatives and combinations thereof.
`Alterna~ively, the polymer may comprise a polysaccharide,
`such as a glycosaminoglycan (e.g., hyaluronic acid or chon(cid:173)
`droitin sulfate), a starch derivative, a cellulose derivative, a
`hemicellulose derivative, xylan, agarose, alginate, chitosan,
`and combinations thereof. As a further alternative, the
`polymer may comprise a non-biologic hydrogel-forming
`polymer, such as polyacrylates, polymethacrylates,
`polyacrylamides, polyvinyl polymers, polylactide(cid:173)
`glycolides, polycaprolactones, polyoxyethylenes, and
`derivatives and combinations thereof.
`Cross-linking of the polymer may be achieved in any
`conventional manner. For example, in the case of proteins,
`cross-linking may be achieved using a suitable cross-linking
`agent, such as an aldehyde, sodium periodate, epoxy
`compounds, and the like. Alternatively, cross-linking may be
`induced by exposure to radiation, such as y-radiation or
`electron beam radiation. Polysaccharides and non-biologic
`polymers may also be cross-linked using suitable cross(cid:173)
`linking agents and radiation. Additionally, non-biologic
`polymers may be synthesized as cross-linked polymers and
`copolymers. For example, reactions between mono- and
`poly-unsaturated monomers can result in synthetic polymers
`having controlled degrees of cross-linking. Typically, the
`polymer molecules will each have a molecular weight in the
`range from 20 kD to 200 kD, and will have at least one link
`to another polymer molecule in the network, often having
`from 1 to 5 links, where the actual leve

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