PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(51) International Patent Classification 6 :
`(11) International Publication Number:
`WO 99/08627
`AG6OIF 2/44
`:
`sas
`(43) International Publication Date:
`
`
`25 February 1999 (25.02.99)
`
`N ber:
`1 Applicati
`ti
`21) Inte
`Application Number
`(21)
`International
`(22) International Filing Date:
`
`PCT/US98/ 16650
`
`11 August 1998 (11.08.98)
`
`(74) Agents: HEINE, Holliday, Cc. et aly Weingarten, Schurgin,
`Gagnebin & Hayes LLP, Ten Post Office Square, Boston,
`MA 02109 (US).
`
`
`
`(30) Priority Data:
`US
`13 August 1997 (13.08.97)
`60/055,291
`US
`9 February 1998 (09.02.98)
`60/074,076
`US
`10 February 1998 (10.02.98)
`60/074, 197
`Us
`15 April 1998 (15.04.98)
`60/08 1,803
`
`
`09/131,716 US|Published10 August 1998 (10.08.98)
`With international search report.
`
`(81) Designated States: CA, JP, European patent (AT, BE, CH, CY,
`DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT,
`SE).
`
`(71) Applicant; CAMBRIDGE SCIENTIFIC, INC. [US/US]; 195
`Common Street, Belmont, MA 02178 (US).
`
`40 Salisbury Road,
`Joseph, D.
`(72) Inventors: GRESSER,
`Brookline, MA 02146 (US). TRANTOLO,Debra, J.; 28
`Radford Road, Princeton, MA 01541 (US).
`LANGER,
`Robert, S.; 77 Lombard Street, Newton, MA 02159 (US).
`LEWANDROWSKI, Kai—Uwe; Apartment 6, 423 Wash-
`ington Street, Brookline, MA 02446 (US). KLIBANOV,
`Alexander, M.; 61 West Boulevard Road, Newton, MA
`02159 (US). WISE, Donald, L.;
`195 Common Street,
`Belmont, MA 02178 (US).
`
`
`
`(54) Title: RESORBABLE INTERBODY SPINAL FUSION DEVICES
`
`(57) Abstract
`
`A resorbing interbody fusion device (10) for use in spinal fixation is disclosed. The device (10) is composed of 25 % to 100 %
`bio_resorbing or resorbing material. A preferred resorbing spinal fusion device (10) is in the shape of a tapered wedge having a top face
`(11), a bottom face (12), side faces (13), a front end (14), and a back end (15). The surfaces of the top (11), and bottom (12) faces each have
`serration (16) to aid in anchoring the device (10) to the surrounding bone. The fusion device (10) preferably has holes (17) of convenient
`diameter to facilitate resorption of the polymer from which the device has been made.
`
`

`

`
`
`
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`Lesotho
`SI
`LS
`Slovenia
`ES
`LT
`sk
`Slovakia
`FI
`Lithuania
`FR
`SN
`LU
`Senegal
`Luxembourg
`Latvia
`SZ
`Swaziland
`LV
`GA
`TD
`Chad
`MC
`Monaco
`GB
`MD
`TG
`Togo
`Republic of Moldova
`MG
`TJ
`Tajikistan
`Madagascar
`T™
`MK
`Turkmenistan
`The former Yugoslav
`TR
`Republic of Macedonia
`Turkey
`TT
`Mali
`Trinidad and Tobago
`UA
`Ukraine
`Mongolia
`UG
`Mauritania
`Uganda
`US
`Malawi
`United States of America
`Mexico
`UZ
`Uzbekistan.
`VN
`Viet Nam
`Niger
`Netherlands
`YU
`Yugoslavia
`Zw
`Zimbabwe
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Céte d'Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Treland
`Israel
`Iceland
`taly
`Japan
`Kenya
`Kyrgyzstan
`Democratic People’s
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`KR
`KZ
`Lc
`LI
`LK
`LR
`
`ML
`MN
`MR
`
`
`
`

`

`WO 99/08627
`
`PCT/US98/1 6650
`
`TITLE OF THE INVENTION
`
`Resorbable Interbody Spinal Fusion Devices
`
`-
`
`CROSS REFERENCE TO RELATED APPLICATIONS
`
`This application claims priority from U.S. Provisional
`Patent Application Nos. 60/055,291, filed August 13, 1997;
`60/074,076,
`filed February 9,
`1998;
`60/074,197,
`filed
`February 10, 1998, and 60/081,803, filed April 15, 1998,
`the
`entire disclosures of which are incorporated herein by
`reference.
`
`STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR
`
`DEVELOPMENT
`
`Not applicable
`
`BACKGROUND OF THE INVENTION
`
`The present invention relates to the field of interbody
`
`spinal fusion devices.
`
`In the structure of the spine of vertebrates including
`
`humans,
`
`the space between adjacent vertebrae is referred to
`
`as the interbody space.
`
`In normal spines,
`
`this space is
`
`occupied by the structure commonly referred to as a disc.
`
`intervertebral structure separates and cushions the
`This
`vertebrae.
`
`require
`Various pathologic and traumatic conditions
`excision of a spinal disc and stabilization of the superior
`
`In 1995,
`and inferior vertebrae while bony fusion develops.
`approximately 225,000 new spinal fusions were performed in
`the United States alone, and of
`these about one half were
`
`performed in the thoracic and cervical
`spine, with the
`remaining spinal
`fusions focused on the lumbar spine.
`To
`stabilize the spine where the surgery has occurred,
`an
`internal fixation device is frequently used.
`Such implants
`provide the ability to improve spinal alignment and maintain
`the developing alignment while fusion develops. Fixation of
`the spine can further correct deformity and provide immediate
`stability,
`thereby
`facilitating spinal
`fusion,
`early
`
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`
`-2-
`
`mobilization, and, when necessary, entry into rehabilitative
`
`programs.
`
`The use of fixation devices is beneficial
`
`in several
`
`ways. First,
`
`the avoidance of long-term bed rest,
`
`thought
`
`by many to decrease non-neurological morbidity, is achieved.
`
`Additionally,
`
`fixation devices
`
`are
`
`thought
`
`to promote
`
`fracture healing and therefore reduce the need for rigid and
`
`cumbersome post-operative bracing.
`
`While a number of commercially available implants for
`
`spinal
`
`stabilization are
`
`known,
`
`these devices
`
`are not
`
`resorbable and therefore,
`
`remain permanently at the implant
`
`site. Meticulous bone preparation and grafting is essential
`
`for successful
`
`long-term stability using current devices.
`
`Metallic and graphite implants have been known to fatigue and
`
`will eventually fail if the desired solid bony fusion is not
`
`achieved.
`
`Thus,
`
`it would
`
`be
`
`advantageous
`
`to obtain
`
`successful bony fusion and spinal development while avoiding
`
`the use of devices having the aforementioned drawbacks.
`
`SUMMARY OF THE INVENTION
`
`The present
`
`invention
`
`is directed to
`
`resorbable
`
`interbody fusion devices
`
`for use as
`
`spacers
`
`in spinal
`
`fixation, wherein
`
`the
`
`device
`
`is
`
`composed
`
`of
`
`25-100%
`
`bioresorbable or resorbable material.
`
`The devices can be in
`
`any convenient form, such as a wedge, screw or cage.
`
`In one
`
`embodiment,
`
`the interbody fusion device of
`
`the invention
`
`further desirably incorporates structural features such as
`
`serrations to better anchor
`
`the device in the adjoining
`
`vertebrae.
`
`In another embodiment,
`
`the device comprises a
`
`plurality of peripheral voids and more desirably a central
`
`void space therein, which may desirably be filled with a
`
`grafting material for facilitating bony development and/or
`Spinal fusion, such as an autologous grafting material.
`In
`
`addition, void spaces
`
`increase the surface area of
`
`the
`
`device,
`occur.
`
`thereby providing multiple sites for resorption to
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`
`In yet another embodiment,
`
`the interbody fusion device
`
`of
`
`the invention further
`
`includes
`
`reinforcing fibers to
`
`enhance the structural properties thereof. These fibers may
`
`be made of
`
`the same polymeric material as the resorbable
`
`material from which the interbody fusion device is made,
`
`from
`
`a neutralization compound or, alternatively,
`
`from another
`
`biocompatible polymer, which may be crosslinked with a
`
`to yield an interpenetrating
`Suitable crosslinking agent
`network for increased strength and stability.
`In another
`
`alternative
`
`embodiment,
`
`the
`
`reinforcing
`
`fibers
`
`are
`
`incorporated into the device, e.g., during the molding
`
`process, being placed in the mold under tension and released
`
`after the process of molding is complete.
`
`Bioerodible polymers that are useful
`
`in the invention
`
`include polydioxanone, poly(¢e-caprolactone) ; polyanhydride;
`
`poly (ortho
`ester) ;
`copoly (ether-ester) ;
`polyamide;
`polylactone; poly(propylene fumarate)
`(H[-O-CH(CH,) -CH,-O-CO-
`
`CH=CH-CO-],0OH); and combinations thereof.
`
`In a preferred
`
`embodiment, the polymerpoly (lactide-co-glycolide) (PLGA: H[-
`
`OCHR-CO-],OH, R=H, CH,), with a lactide to glycolide ratio in
`
`the range of 0:100% to 100:0% inclusive,
`
`is used.
`
`As many of the preferred biocerodible polymers from which
`
`the resorbable interbody fusion device is manufactured are
`
`polymers that can produce acidic products upon hydrolytic
`degradation,
`the device preferably further
`includes
`a
`
`neutralization compound, or buffer.
`
`The neutralization
`
`compound is included in sufficiently high concentration to
`
`decrease the rate of pH change as the device degrades,
`
`in
`
`order
`
`to prevent sterile abscess formation caused by the
`
`accumulation of unbuffered acidic products in the area of the
`
`implant. Most preferably,
`
`the buffering or neutralizing
`
`agent is selected from a group of compounds wherein the pKa
`of the conjugate acids of
`the buffering or neutralization
`
`the acids produced by
`compound is greater than the pKa of
`hydrolysis of the polymers from which the device is prepared.
`The neutralization compound, or buffer,
`included in the
`bioerodible material of the invention may be any base, base-
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`
`~4-
`
`containing material or base-generating material
`
`that
`
`is
`
`capable of reacting with the acidic products generated upon
`
`hydrolysis of
`
`the bioerodible polymer.
`
`Polymeric buffers
`
`which preferably include basic groups which neutralize the
`
`acidic degradation products may also be used as buffering
`
`compounds. Another class of useful buffering compounds are
`
`those which, on exposure to water, hydrolyze to form a base
`
`as one reaction product.
`
`In another alternative embodiment,
`
`the
`
`resorbable
`
`interbody fusion device of the invention preferably includes
`
`a biological growth factor, e.g., bone morphogenic protein,
`
`to enhance bone cell growth.
`
`To protect
`
`the growth factor
`
`and to provide for controlled delivery,
`
`the biological growth
`
`factor may itself be compounded with a resorbable polymer in
`
`the many techniques available and prepared as a
`some of
`growth factor/polymer composite in pellet
`form,
`in small
`particle form or within the interstices or pores of
`a
`polymeric foam or low-density polymer and this polymer/growth
`
`factor composite
`
`is deposited into void spaces of
`
`the
`
`resorbable spinal fusion device. Alternatively,
`
`the growth
`
`factor, or protected growth factor, may simply be directly
`
`incorporated into the component formulation of the resorbable
`
`spinal fusion device.
`
`Active periosteum cells may also be incorporated into
`
`a foam, e.g., deposited into void spaces of the resorbable
`
`spinal
`
`fusion device,
`
`in order
`
`to facilitate bone cell
`
`Eusion. Further,
`
`the resorbable spinal fusion device of the
`
`invention may be prepared in such a manner as to exhibit a
`piezoelectric effect,
`to enhance bone wound healing.
`
`As
`
`used
`
`herein,
`
`the
`
`terms
`
`"resorbable"
`
`and
`
`"bioresorbable" are defined as the biologic elimination of
`
`the products of degradation by metabolism and/or excretion
`and the term "bioerodible" is defined as the susceptibility
`of a biomaterial
`to degradation over time, usually months.
`The terms "neutralization compound" or "buffer" are defined
`as any material that limits or moderates the rate of change
`of
`the pH in the implant
`and its near environment upon
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`
`-5-
`
`exposure to acid or base.
`The term "acidic products" is
`defined herein as any product
`that generates an aqueous
`solution with a pH less than 7.
`
`DESCRIPTION OF THE DRAWINGS
`
`The invention will be more fully understood from the
`
`Following detailed description taken in conjunction with the
`
`accompanying drawings in which:
`
`1B and 1C are perspective top, side and front
`Figs. 1A,
`views,
`respectively,
`of an interbody spinal fusion device
`
`according to the present
`
`invention;
`
`Figs. 2A, 2B and 2C are top, side and perspective views,
`
`respectively, of another embodiment of an interbody spinal
`fusion device of the invention;
`
`Figs. 3A, 3B and 3C are top, side and perspective views,
`
`respectively, of another embodiment of an interbody spinal
`fusion device of the invention;
`
`4A and 4B are side and top views, respectively,
`Figs.
`of another embodiment of an interbody spinal fusion device
`
`of the invention;
`
`5A and 5B are side and top views, respectively,
`Figs.
`o£ another embodiment of an interbody spinal fusion device
`
`of the invention;
`
`Fig. 6A is a perspective view of a mold and ram assembly
`for preparing an interbody spinal
`fusion device of
`the
`
`invention;
`
`Figs. 6B and 6C are edge and plan views, respectively,
`of the front face plate of the mold of Fig. 6A;
`
`Fig.
`
`6D shows a disc with serrated slots for use in the
`
`mold of Fig. 6A;
`
`Figs. 6E and 6F are front and side views, respectively,
`of a threaded tension tube used with the mold of Fig. 6A;
`Fig. 6G is a section through a mold assembly fitted with
`reinforcing fibers and associated holder assemblies;
`
`Fig.
`
`7
`
`is a plot of displacement versus load for an
`
`interbody spinal fusion device of the invention; and
`
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`WO 99/08627
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`
`-6-
`
`strength with load. for
`compression
`shows
`8
`Fig.
`interbody spinal
`fusion devices of
`the invention with and
`
`the incorporation of
`without
`compound .
`
`a buffering or neutralizing
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`The present
`invention provides,
`in one embodiment, an
`interbody spinal fusion device (IFD) comprising a resorbable
`spinal wedge for vertebral spacing as an adjunct
`to spinal
`fusion. Made from a biodegradable, biocompatible polymer,
`preferably poly (lactic-co-glycolic) acid (PLGA), discussed
`
`further below, this resorbable spacer incorporates peripheral
`voids and central voids, which can be filled with autologous
`grafting material to facilitate bony development and spinal
`fusion, and serrated or threaded faces to stabilize and align
`vertebral bodies. The spinal fusion device of the invention
`is used as an adjunct
`to fusions of the cervical,
`thoracic
`
`or lumbar vertebrae,
`
`the configuration and dimensions of the
`
`device depending on the site of use.
`
`A preferred embodiment of a spinal implant, fabricated
`
`from a biocompatible and biodegradable polyester and intended
`
`is shown in Figs.
`to replace a cervical disc, C4, 5, or 6,
`1A,
`1B and 1c.
`A rod molded from a suitable material, as
`
`described below, is machined to the desired configuration and
`dimensions. Relatively complex geometries can be
`readily
`fabricated in this manner. Suitable biocompatible extraneous
`
`materials such as plasticizers or other machining aids, can
`be included in the material if desired.
`
`a preferred resorbable interbody
`1A,
`As shown in Fig.
`spinal fusion device of the invention 10 is in the shape of
`a tapered wedge, having a top face 11, a bottom face 12, side
`
`faces 13, a front end 14 and a back end 15.
`
`The surfaces of
`
`top and bottom faces 11 and 12 each have serrations 16 to aid
`in anchoring the device to the surrounding bone. Wedge 10
`preferably contains holes 17 of convenient diameter, which
`may be drilled through the wedge to facilitate resorption of
`the polymer from which the device has been made. A plurality
`
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`WO 99/08627
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`
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`
`of channels or ports 18 through the wedge or a larger center
`hole 19
`in the wedge are useful
`for the introduction of
`
`the
`1B and 1C,
`illustrated in Figs.
`As
`autologous bone.
`spinal wedge is preferably machined to have a taper from back
`end 15
`to front
`end 14,
`such that
`the front end 14
`is
`
`narrower than the back end 15.
`
`2A-2C
`in Figs.
`shown
`as
`embodiment,
`another
`In
`resorbable spinal fusion device 20 is shaped like a tapered
`rod having ridges 22 with threads 21. Device 20 functions
`
`as a screw and contains a cylindrical axially extending hole
`23 and slots 24 to facilitate screwing the device into the
`spine of the patient.
`The device also contains recesses 26
`between ridges 22 to facilitate ingrowth of tissue that would
`aid in anchoring the device in place.
`the
`As shown in Figs. 3A-3C,
`in a further embodiment,
`device 30 is of cruciform shape having arms 33. Threads 31
`extend the length of
`the outer surfaces of arms 33.
`In
`another embodiment,
`shown in Figs.
`4A-4B,
`the device is
`shaped like a threaded screw having a continuous thread 41
`provided around the surface of the tapered body. Cylindrical
`holes 43 and 44 are provided through the body,
`the holes
`being orthogonal
`to each other and to screw axis 42.
`A
`cylindrical hole 45
`is provided coaxially with axis 42.
`Slots 46 in the top 48 serve to position and retain a tool
`that can be used to screw the device into place.
`As shown in Figs. 5A and 5B, a further embodiment of a
`threaded screw contains flat side areas 52 alternating with
`threaded corner areas 51.
`Slots 53
`can be machined or
`otherwise provided in the flat areas,
`to facilitate ingrowth
`of tissue, and can be of a constant width or can be tapered.
`A slot 56 in top 58 of the device accommodates a suitable
`
`tool to facilitate insertion.
`
`For replacement of one of the cervical dises C4, C5, or
`the device shown in Figs. 1A-1C preferably measures 15
`Cé,
`mm laterally by 12 mm sagittally. The
`flattened side,
`positioned posterially,
`is 6-8 mm thick, enlarging to about
`7-9 mm at the anterior edge;
`thus the device has a taper of
`
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`
`approximately 4.8 degrees. Both surfaces are serrated,. the
`serrations directed laterally. The serrations may be either
`square cut or cut at an angle with one face vertical and the
`other sloping upward anteriorly.
`The thickness of the device of the invention will govern
`the rate at which it degrades and total degradation time.
`Thus,
`interbody spinal fusion devices can be prepared with
`multiple thicknesses, but all having the same approximately
`5°
`taper. For example,
`the anterior thickness could range
`from 7 to 9 mm and the posterior thickness from 6 to 8 mm.
`
`The taper provides the correct orientation to the vertebrae
`
`with which the device is in contact and can also serve to
`
`keep the device in place.
`
`The vertebral body is a fairly cylindrical mass
`consisting of cancellous bone surrounded by a thin layer of
`cortical bone. Thus,
`the mechanical properties of the device
`should preferably match those of the cancellous bone of the
`
`vertebrae in regard to proportional limit stress, compression
`at proportional limit, modulus of elasticity, failure stress
`
`and compression at failure (See, e.g., Lindahl, Acta Orthop.
`Scand. 47:11, 1976; Hansson et al., Spine 12:56, 1987).
`Bioerodible polymers
`that are useful
`in the spinal
`fusion device of the invention include polydioxanone, poly(e-
`caprolactone) ;
`polyanhydride;
`poly (ortho
`ester);
`copoly (ether-ester); polyamide; polylactone; poly(propylene
`fumarate) (H[-O-CH(CH,) -CH,-O-CO-CH=CH-CO-],0H); poly(lactic
`acid); poly(glycolyic acid); poly (lactide-co-glycolide); and
`combinations thereof. Selection of a particular polymer is
`based primarily on the known properties of the polymer, such
`as the potentiality for cross-linking, polymer strength and
`moduli, rate of hydrolytic degradation, etc. One of ordinary
`skill in the art may take these and/or other properties into
`account
`in selecting a particular polymer for a particular
`application. Thus,
`the selection of a particular polymer is
`within the skills of the ordinary skilled practitioner.
`In a preferred embodiment,
`the polymer poly (lactide-co-
`glycolide)
`(H[-OCHR-CO-],OH, R=H, CH,)
`(PLGA)
`is used.
`The
`
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`
`PLGA polymers used according to the invention desirably have
`a
`lactide to glycolide ratio in the range of 0:100% to
`
`100:0%,
`
`inclusive, i.e., the PLGA polymer can consist of 100%
`
`L- or D,l-lactide
`
`(PLA),
`
`100% glycolide
`
`(PGA),
`
`or
`
`any
`
`combination of
`
`lactide and glycolide residues.
`
`These
`
`polymers have the property of degrading hydrolytically in
`
`vivo to form organic acids (lactic acid and glycolic acid)
`
`which accumulate in the region surrounding the implant. These
`
`acids are metabolized and eventually excreted as carbon
`
`dioxide and water or enter the citric acid cycle.
`
`The process by which alpha polyesters such as PLA, PGA,
`
`and PLGA biodegrade is primarily by non-specific hydrolytic
`
`scission of
`
`the ester bonds. The L-lactic acid that
`
`is
`
`generated when PLA or PLGA degrades becomes incorporated into
`
`the tricarboxylic acid cycle and is excreted from the lungs
`
`as carbon dioxide and water. Glycolic acid, produced both by
`
`random hydrolytic scission and by enzymatically mediated
`
`hydrolysis, may be excreted in the urine and also can enter
`
`the TCA cycle and eventually be oxidized to carbon dioxide
`
`and water
`
`(Hollinger et al., Clin. Orthop. Rel. Res. 207:
`
`290-305, 1986).
`
`A particularly preferred polymer for use in the device
`
`of
`
`the invention is poly(d,i-lactide-co-glycolide)-85:15
`
`(Boehringer-Ingelheim: distributor, Henley Chemicals, Inc.,
`
`Montvale, NJ),
`the 85:15 designation referring to the lactide
`to glycolide mole ratio. The particularly preferred polymer
`is
`Resomer™ RG
`858, with
`an
`inherent viscosity of
`
`approximately 1.4
`
`corresponding to a weight
`
`average
`
`molecular weight of 232,000 as measured by gel permeation
`
`chromatography (GPC).
`
`The polymer can be used as received or purified by
`
`precipitation From tetrahydrofuran solution into isopropanol,
`
`air dried and then exhaustively vacuum dried. Polymer data
`
`can be confirmed by
`(composition and molecular weight)
`nuclear magnetic resonance and by GPC (Hsu et al., J. Biomed.
`
`Mater. Res. 35:107-116, 1997).
`
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`WO 99/08627
`
`PCT/US98/16650
`
`-10-
`
`fusions require interbody fusion devices that
`Spinal
`will maintain significant
`structural
`rigidity for
`6-12
`months. Strength requirements depend on the location of the
`disc to be replaced. When a person is standing,
`the forces
`to which a disc is subjected are much greater than the weight
`of the portion of the body above it. Nachemson et al.
`(Acta.
`Orthop. Scand. 37:177, 1966; J. Bone Joint Surgery 46:1077,
`1964; Clin. Orthop. 45:107, 1966) has determined that
`the
`force on a lumbar disc in a sitting position is more than
`three times the weight of
`the trunk. Daniels et al.
`(Jd.
`Appl. Biomater. 1:57-78,
`1990) have reviewed much of
`the
`mechanical data of PGA, PLA, and PLGA.
`As a bioerodible polymer undergoes hydrolysis in the
`any
`acidic
`degradation products
`formed may
`be
`body,
`implicated in irritation, inflammation, and swelling (sterile
`abscess formation)
`in the treated area.
`To counteract this
`effect, a neutralization compound, or buffer,
`is desirably
`included in the bioerodible material to neutralize the acidic
`degradation products and thereby reduce the sterile abscess
`reaction,
`as described in copending U.S. Application No.
`08/626,521, filed April 3, 1996, the whole of which is hereby
`incorporated by reference herein.
`The buffering compound included in the bioerodible
`material of the invention may be any base, base-containing
`or base-generating material that is capable of reacting with
`the
`acidic products generated upon hydrolysis
`of
`the
`bioerodible polymer. Exemplary buffering materials include
`salts of
`inorganic or organic acids, salts of polymeric
`organic
`acids or polymeric bases
`such
`as polyamines.
`Preferably calcium salts of weak acids
`such as, e.g.,
`tribasic calcium phosphate, dibasic calcium phosphate, or
`calcium carbonate are use. To be useful,
`the conjugate acids
`from which the buffering materials are derived must have a
`pKa greater than those of L-lactic acid (pKa = 3.79), D, L-
`lactic acid (pKa = 3.86), or glycolic acid (pKa = 3.83),
`if
`a PLGA is the polymer which is undergoing hydrolysis. Thus,
`
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`WO 99/08627
`
`PCT/US98/16650
`
`-11-
`
`for example, salts of acetic acid (pKa = 4.74), or succinic
`acid (pK, = 4.19, pK, = 5.64) may also be used.
`
`Buffer compositions of lower solubility are preferred
`
`because buffer loss from the polymer by diffusion will be
`
`slower
`
`(Gresser
`
`and Sanderson,
`
`"Basis
`
`for Design
`
`of
`
`biodegradable Polymers for Sustained Release of Biologically
`
`Active Agents" in Biopolymeric Controlled Release Systems,
`
`Ch. 8, D.L. Wise, Ed., CRC Press, 1984).
`
`Preferably,
`
`the
`
`buffering compound has an acid dissociation constant that is
`smaller than the acid dissociation constant of
`the acidic
`
`products generated upon hydrolysis of
`
`the biocerodible
`
`polymer.
`
`Ionic buffers will,
`
`in general, be the salts of
`
`weak acids. The acid, of which the buffer is a salt, should
`
`have an ionization constant
`
`(acid dissociation constant, K,)
`
`which is less than the K, for the acid products of polymer
`
`hydrolysis. Alternatively,
`
`the buffering compound has a
`
`hydrolysis constant
`
`that
`
`is greater
`
`than the hydrolysis
`
`constant of the acidic products.
`
`Hydroxyapatite (HA) and calcium carbonate (CC) were each
`
`investigated as buffering fillers. Results demonstrate that
`
`the inclusion of CC or HA in a, e.g.,
`
`PLGA fixture can
`
`effectively moderate the rate of pH decline as the fixture
`
`degrades. Further,
`
`the rapid decline in pH can be offset
`
`without considering 100% neutralization of
`
`the lactic and
`
`glycolic components. Thus,
`
`even given that
`
`the polymeric
`
`Fixture will
`
`be
`
`filled with an
`
`inorganic buffer,
`
`the
`
`mechanical characteristics of the fixture can be stabilized
`
`Since the loading requirements for the buffer will not be
`
`nearly as compromising as expected at the outset.
`
`While both CC and HA can ameliorate the rate of decline
`
`in pH in the region of polymer hydrolysis,
`
`the use of
`
`hydroxyapatite as a filler also supports osteoconductivity.
`
`Thus,
`
`HA not only promotes bony
`
`ingrowth and obviates
`
`loosening of the fixture, but aiso acts as a buffer thereby
`
`preventing the formation of sterile abscesses that have been
`
`PLGA
`of
`attributed to the acidic degradative products
`implants. The resulting resorbable fixture should be capable
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`WO 99/08627
`
`PCT/US98/16650
`
`-12-
`
`of a buffered hydrolytic degradation and induction of bony
`ingrowth
`as
`resorption of
`the
`implant progresses.
`A
`resorbable buffered bone fixture with such properties could
`provide structural support to stabilize and support a spinal
`repair over the period of time required for natural healing
`to occur.
`
`invention a preferred buffering
`According to the
`compound is hydroxyapatite.
`The formula Ca,,(OH),(PO,), may
`be written as Ca(OH),e3Ca,(PO,),. When written in this manner
`it is seen that the following neutralization reactions may
`be written:
`
`2RCO,H + Ca(OH),°3Ca,(PO,), > 2RCO, + Ca’?+2H,0 + 3Ca,(PO,),
`12RCO,H + 3Ca,(PO,), > 6H,PO,+9Cat? + 12RCO,”
`The dissociation constant of water (the conjugate acid
`of the hydroxyl
`ion)
`is K,=10".
`The basic phosphate ion,
`PO, °?, can neutralize two protons forming the following acids,
`for which dissociation constants are given:
`RCO,H + PO,*
`- RCO,
`+ HPO,?
`RCO.H + HPO, ? + RCO, + H,PO,
`K, of H,PO,* = 6.2 K 10°
`K, of HPO,?
`= 4.2 X 10°
`
`Buffers included in the polymer in solid form preferably
`
`have a relatively small particle size, for example, between
`
`Particle size reduction can be
`less than 1.0 and 250 um.
`accomplished by any standard means known in the art, such as
`ball milling, hammer milling, air milling, etc.
`If buffer
`
`and polymer are to be blended by the dry mixing method
`(described below),
`the polymer particle size must also be
`considered.
`Polymers such as the PLGAs have relatively low
`glass
`transition temperatures
`and melting temperatures.
`Thus, polymer particle size reduction must be accompanied by
`cooling,
`for
`example using a Tekmar A-10 mill with a
`cryogenic attachment.
`
`the desired particle size range of
`Following milling,
`the buffer and the polymer may be
`recovered by sieving
`through, for example, U.S. Standard sieves. Particles in the
`
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`WO 99/08627
`
`PCT/US98/16630
`
`-13-
`
`size ranges of <45, 45-90, 90-125, 125-180, 180-250 pm may
`be conveniently isolated.
`
`In selection of particle size range,
`
`it is sometimes
`
`desirable to combine two or more ranges, or to use a wide
`
`for instance all sizes less than 250 pm.
`range of sizes,
`Larger particles may be preferred in some applications of the
`
`invention because larger particles take longer to be eroded
`
`lifetime
`therefore extend the useful
`by the acids and will
`of the buffer.
`In some cases particle size reduction will
`mot
`be necessary,
`such as when
`commercially available
`precipitated calcium carbonate
`is
`used
`(e.g.,
`Fisher
`Scientific, Inc., Catalog No. C-63).
`The
`effectiveness
`of
`substances
`
`calcium
`
`such
`
`as
`
`carbonate
`
`and hydroxyapatite
`
`in neutralizing the
`
`acid
`
`products of polymer hydrolysis depends not only on the
`quantity of the substance in the matrix, but also on particle
`Size and distribution, total surface area in contact with the
`
`polymer, and solubility.
`The presence of calcium ions in the buffered device has
`advantages with respect
`to the physical properties of the
`device as it undergoes erosion.
`It has been shown that
`
`calcium ions form ionic bridges between carboxylate terminal
`
`polymer chains
`
`(Domb et al., J. Polymer Sci. A28, 973-985
`
`(1990); U.S. Pat. No. 4,888,413 to Domb).
`
`Calcium ion
`
`bridges between carboxylate anions increase the strength of
`the composite in which the polymer chains are terminated by
`carboxylate anion end groups over similar chains terminated
`by the hydroxyl groups of, e-.g.,
`terminal glycol moieties or
`
`terminal a-hydroxy acids.
`
`In an analogous manner,
`
`the
`
`polyesters comprising the family of PLGA’s are expected to
`
`be strengthened by calcium bridges between carboxylate anion
`
`terminated chains.
`
`As
`
`shown in Fig.
`
`8 PLGA-85:15 wedges
`
`reinforced with 40% HA showed an increase in compressive
`
`strength of approximately 5% over the nonreinforced controls.
`
`Another class of useful buffering compounds are those
`
`which, on exposure to water, hydrolyze to form a base as one
`
`reaction product.
`
`The generated base is free to neutralize
`
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`WO 99/08627
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`PCT/US98/16650
`
`-14-
`
`of |. the
`upon hydrolysis
`produced
`products
`acidic
`the
`bioerodible polymer. Compounds of this type include aryl or
`
`These "base-generating
`alkyl carbamic acids and imines.
`compounds" offer the advantage that the rate of hydrolysis
`of the base generator may be selected to correlate to the
`
`rate of hydrolysis of the bioerodible polymer.
`
`Necessarily,
`
`the
`
`conjugate
`
`acid of
`
`the buffering
`
`compound has an acid dissociation constant that
`
`is smaller
`
`than the acid dissociation constant of the acidic products
`
`generated upon hydrolysis of
`
`the bioerodible
`
`polymer.
`
`Alternatively,
`
`the buffering compound preferably has
`
`a
`
`hydrolysis constant
`
`that
`
`is greater
`
`than the hydrolysis
`
`constant of the acidic products.
`
`the buffering compound preferably is only
`Furthermore,
`partially soluble in an aqueous medium.
`In general, buffers
`of lower solubility are preferred because buffer loss from
`
`the polymer by diffusion will be minimized (Gresser and
`
`Sanderson, supra). The quantity of buffer to include depends
`
`on the extent of neutralization desired.
`
`This may be
`
`calculated as shown below, using a PLGA of any composition
`
`buffered with calcium carbonate as an example.
`
`The average residue molecular weight, RMW,
`
`for a PLGA
`
`is given by
`RMW = 14.03x + 58.04
`
`where x = mole fraction of
`
`lactide in the PLGA.
`
`The term
`
`"residue" refers to the repeating lactide or glycolide moiety
`of the polymer.
`For example,
`if x = 0.85 (PLGA=85:15), RMW
`
`= 69.96. Thus, 1.0 gram of PLGA=85:15 contains 0.01429 moles
`of residues which, on hydrolysis of the polymer, will yield
`0.01429 moles of
`lactic and/or glycolic acid.
`If, e.g.,
`calcium carbonate is the buffering agent, and it is desired
`
`to neutralize, e.g., 50 mole % of the acids by the reaction
`
`CaCO, + 2HA ~ CaA, + H,O + CO,
`where A = lactate or glycolate,
`then the weight of calcium
`carbonate needed is (0.25) (0.01429) (100.09) = 0.358 gram, and
`the required loading is (0.358) (1 + 0.358) (100)
`= 26.3% by
`weight.
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`WO 99/08627
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`PCT/US98/16650
`
`-15-
`
`Several methods may be used to incorporate the buffer
`into the polymer.
`These methods
`include solution casting
`coupled with solvent evaporation, dry mixing,
`incorporating
`the buffer into a polymer foam, and the polymer melt method.
`Solution casting coupled with solvent evaporation may
`be used with buffers which are either soluble or insoluble
`
`in the solvent. The bioerodible polymer is dissolved in any
`suitable volatile solvent, such as acetone,
`tetrahydrofuran
`(THF), or methylene chloride.
`The buffer, which may be
`solub

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