CA1324082C

CA1324082C - Bioerodable implant composition

Info

Publication number: CA1324082C
Application number: CA000561225A
Authority: CA
Inventors: Tobin N . Gerhart; Wilson C. Hayes
Original assignee: Beth Israel Hospital Association
Current assignee: Beth Israel Deaconess Medical Center Inc
Priority date: 1987-03-12
Filing date: 1988-03-11
Publication date: 1993-11-09
Anticipated expiration: 2010-11-09
Also published as: US4843112A; AU1575488A; WO1988006873A1

Abstract

ABSTRACT OF THE DISCLOSURE
An improved bone cement is comprised of a particulate biocompatible calcium phosphate ceramic and particulate resorbable calcium salt dispersed in a cross-linked biodegradable polyester matrix. The polymer/salt-particle composite exhibits good biomechanical strength/modules characteristics with surgically acceptable cure times. When used for sustained release of biologically active agents in a physiological environment, controlled release of biological agents that are mixed into the composite can be achieved as the cement biodegrades. When used for bone/implant fixation, or as a filler or cement for bone repair, gradual biodegradation of the cement composite permits, under suitable circumstances, eventual replacement of the cement with developing bone tissue.

Description

~ ~ 32~0~
': BIOERODABLE IMPLANT COI~POSITION

~ackarouna and Summarv of the Invention - - This invention relates to an implantable bioerodable composition u~eful for the repair of living ~- bone and for the aaministration of biologically active substances. More particularly, this invention relates to a moldable, biocompatible, polye~ter~particulate composite that can be used for reinforcement of fracture~ and defects in bone, for fisation of implant~
- and prosthe~es ~n bone, and for controlled-release deli~ery of biologically active agents.
Applicant~ ha~e found that incorporation of i~ biocompatible calciu~ phosphate ceramic~ and resorbable calcium salt~ into a cros~-linked biodegradable ~ polyester matris produce~ a cement-like composition -~ having the combined feature~ of developing escellent biomechanical strength within a ~hort curo time and tho ~ capacity to degrade progre~sively, ~n Y~YQ, permitting, i~ 20 u~der suitable condition~, eventual replacement of the cement by body tissue. Thu~, for e~ample, where the present bioerodable compo~ition ia implante~ in contact g with bone or u~e to repalr skeletal deformitie~ and in~urie~, to treat infection~ an~ di~ease~, or to ~fis~
~ 25 prosthetis appllancea in bone, the composition i~
,~ gradually re~orbed ana may then be replaced wlth living ~; bone.
;~ Surg~cal cement~ are well known in the art.
Such cement~ are commonly u~ea for implant fisation in the ~urgical re~lacement of ~oint ana bone ti~ue with :;. -, :
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~324082 prosthetic appliance~. At the time of surgery the $ cement, in a fluid or semi-fluid pre-cured form, is ; injected or otherwise applied between the bone and implant, flowing around the contour~ of the bone and implant and into the interstices of cancellous bone.
,, Upon hardening ~curing), the cement mechanically-' interlocks the bone and implant.
~ Poly(methyl methacrylate) (PMMA) i5 the most .~' widely u~e~ bone c~ment. PMMA cement comprise~ two components, a powder of prepolymerlzed methyl methacrylate and a liquid monomer, methyl ~ethacrylate, $ that are mi~ed at the time of surqerr to form a pa~te-like cement material. PMMA cement is ~permanent~
in the ~enso that it is not degraded within the body.
~owever~ PMMA does not alway~ pro~ide ~permanent~
implant fisation. ~oosening of prosthetie appliances due to cement failure ha~ long been reeognized as the single most ~re~alont problem in eonventional yrosthetic arthroplastr, plaeing a seriouJ limitation on the suecessful ~uration of ~oint and bone replaeement surgery. PMMA eement ean sustain fatigue damage and has been ~nown to eraek ana fail auo to biomeehanieal over~tres~ing. Yet another problem eneountered with the eurront PMM~ bono eement il that of the resorption of bony ti~Jue immediately aa~eent to the bone eement as~oeiatea ~ith the formation of a biologieally aeti~e fibrou~ ti~àu~ membrane. Indueement of the formation of thi~ membrano, ~hich eontainJ bone re~orbing cells and onzymeJ, may bo a ~eeond msehani~m, in aaaition to ,.
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( ~, 132~082 biomechanical overstressing, whereby PMMA cement lose~
its purchase in the surrounding bone and thereby fails to provide secure implant fisation.
More recent research efforts con~erning fisation of bone prosthese~ ha~e been directed to development of bone cements that are more compatible s with bone tissue and to definition o~ implant surfaces ^'r capable of receiving direct bone ingrowth to enhance the rt bone-implant interlock. For esample, pro~thetie appliances have been construeted with a highly porou~
eoating on their bone-eontacting ~urface~, providi~
r;~ interstices into which bone tissue can grow to effeet direet bone fisation of the implant. For a bone to interloek with the porous surfaee strueture of the implant, however, the implant must be firmly fise~ at the time of ~urgery and load applieation mu~t be rh minimized during the ingrowth period. This fisation method is, therofore, not entirely ~atisfaetory beeause ~Y it is very difieult to provide adoguate immobilization and stabilization of the implants during the bone ~ Sngrowth proeess. Further it is impo~ible to aehieve r bone ingro~th if a ~uffieiently large gap esists between the patient'~ bone and the porous implant ~urfaee.
One ombodiment of the pre~ent invention relates r,: 25 to the u~e of n ero~s-lin~ed biodegradable polye~tor~partieulate eompo~ite for ~urgieal bone repair '~ and i~plant fisation. The invention i8 ba~ed on the diseovery that partiele~ of bioeompatible sintered ealeium phosphate eeramie~ and more porous and ;~ 30 ' ,~

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resorbable calcium salts can be incorporated into a cross-lin~ed biodegradable polymer matri~ to produce a surgical cement possessing physical and biological properties that are ~uperior to conventional fi~ation cement~. The poIymer matri~ is a biodegradable polyester solidiied, or cured, immediately following -~ placement in YiVo by reaction with a chemical cros~-linking agent. The polymer matris ~er~es as a supporting binder for particles of biocompatible inorganic salts and ceramics. The cured cement eshibits escellent biomechanical properties within ~hort cure times. A patient receiving an implant fi~ed using the present cross-linked polyester compo~ite a~ a cement could be ambulatory early after surgery, thereby facilitating rapid rehabilitation and minimizing costly hospitalization.
The polye~ter composite of thi~ in~ention is formulated to allo~ a unigue multi-stage proce~ in which the cement 1~ gradually re~orbed and could be replaced in vivo under ~uitable conaitions by growing natural bone. Thu~ an implant originally ~eeurea u~ing the present cement eould, ~ith time, be ~eeured by direet eontaet ~ith living bone. Initially, particulate ealeiw~ ~alta ln the cement are eluted from the polye~ter matri~ by body fluid~ ereating small ~oid~ or eavitie- in tho polymer matri~. O~er time, the more 810~1~ resorbable partieulate csramie eomponent i~
holly or partially re~orbed, and the polye~ter matri~
it~elf degrade~ ~ YiYQ into it~ component non-to~ic ~`~ 3~ as~imilable ~iearbo~ylie acid~, snd dihydrie or ,~; .

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polyhydric alcohols A~ the matri~ of the cement slowly degrades void~ are formed which can be f~lled in by new bone Eventually the extent of the new bone ingrowth could contact and secure the pro~thetic appliance The estent o new bone ingrowth will vary depending upon local condition~ affecting the implant For in~tance new bone ingrowth can be e~pected only if the bone cement i~ implanted intrao~eou~ly a~ oppoJed to ~ubcutaneously or intramuscularly Furthermore ~` 10 cancellous bone with it~ greater blood supply iB r8 likely to f~cilitats bone ingrowth than cortical bone The presence of an infecting organism would have an adver~e affQct on ingrowth. Proportionally le~
ingrowth will occur with a large amount of implanted cement Mixing ho~t bone into the cement before u~e coula facilit~te bul~ regrowth and ne~ bone ingrowth In contra~t to the aituation mentioned above where a PMMA-fi~ed yrosthe~ia can wor~ loo~e ~ith formation of Jurrounding fibrou~ ti~uo li~ing bone able to heal and to remodel it~elf in re~ponse to ~tre~aS it ia, thorefore resiatant to tbe problem of failure with repeatod loading. ~his in~ontion repre~enta a dgnificant improvement in bone implant methodoloqy.
It i~ ~nown in the bon~ e~moAt art to eombine a ~; bior-aorbablo partieulato eompound ~ueh aa tricaleium phoaphato with a non-biodogra~abl- polymorie r~in.
i See, for example, U.S. Patent No. 4,373,217; J. Vanio, $`~ Arch. Orthop. Traumat. Surg., 92, 169-174 (1978).
However, such compositions ;t :x ,. ~, .
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,, 132~082 do not function in YiYQ as doe~ the cement of thi3 invention. ~ecause polymer resin~ of prior art composites are not biodegradable, prior art composite cements cannot be replaced by growing bone tissus.
~he use of biodegradable polymer~ ~n iYo is also known in the art. ~iodegradable polymer~ have been described for a v~r~ety of applications, ineluding controlled release dosage form~ and biore~orbable suture~. S~ U.S. Patents 3,463,158; 4,080,969;
3,997,512; 4,181,983; 4,481,353; and 4,452,973. Ibay et al. describe the preparation and use of moldable implant ~; appliances from Yinylpyrrolidone eross-linked poly(propylene glyeol fumarate) (PPF) for use as temporary replacement~ for ~oft tissue and~or bone following trauma. A.C. Ibaj et al., l~ 9~
~Ci~ n~_ln~ , 505-509 ~1985). Absorbable polyglyeolie aeid suture has been used sueees~fully for internal fisation of fraetures. 8. Roed-Peterson, Int.
J. Oral. Suro., 3, pp. 133-136 (197~). There i~
nothing, however, to suggo~t u~e of erosa-linked bioaegradable polymer eompo~ite~ for implant fi~ation.
-Nor is thore any ~ugge~tion to eombine bioaegradable ~` ero~-linkable polye~ter~ ~ith bioeompatible partieulate ;~ eal~ium ~alt~ an~ eeramie~ to form the present -~ 25 partieulato~polrmer eompo~ite~ finding use a~ bone `~` e _ nt~ and a~ effeeti~e deli~err sy3tem~ for the su~tained-reloa~o of biologieally aetive ~ub~taneo~.
It i~ tberefore, an ob~eet of thi~ in~ention to ~ pro~i~e a bioeom~atiblo re~orbable ~urgieal eement for `~ 30 repairing li~ing bone.
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1324~82 .
It is another ob~ect of thi~ in~ention to provide a method for permitting bone ingrowth and bone adhesion to implanted pro~theses.
Another ob~ect of this invention is to provide a biodegradable implantable composite comprising a cros~-lin~ed biodegradable organic polymer in combination with particulate, biocompatible calcium phosphate ceramics snd a resorbable calcium salt~.
Still a further object of thi~ invention i~ the use of particulate~cross-linked polyester compooites a~
;- means for sustained-release delivery o drug~ for - treatment of disease in warm-blooded vertebrates, and drug depot de~ices utilizing ~aid composites.

Brief DescriDtion of the Drawina~
FIG. 1 illustrate~ compressive ~trength values measured in Megapa~cal~ for various weight compositions of PPF~MMA cement prepared in accordanco with thi~
invention, implantea a~ 6 s 12 mm cylindrical ~pecimen~ -~` 20 subcutaneou~ly in rabbita, and measure~ at time intervals ranging from ono day to three ~ee~a after ~ implantation.
;~ FIG. 2 illustrate~ ela~tic moduli value~
~`~ moa~urd in Megapascal~ for variou~ weight compo~itions `~ 25 of PPF~MMA c~ment prepared in accoraance ~it~ thi~
-.~ inv~ntlon.
~`'!, FIa. 3 i~ a graphic comparison of vancomycin level~ in ~oun~ flui~ following implantation of PMMA and ` 4` ' PPF matricea.
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^` 132~082 FIG. 4 ls slmllar to FIG. 3 lllustratlng gentamlcln levels.
FIG. 5 ls slmllar to FIG 3 lllustratlng vancomycln levels ln serum.
FIG. 6 ls slmllar to FIG 3 lllustrating gentamicln - levels ln serum.
Detalled Descrl~tlon of the Inventlon The present lnventlon ls dlrected to a blodegradable cement composltlon adapted for use ln the surglcal repalr of llvlng bone and for the controlled-release of pharmaceutlcal agents. A composltlon comprlslng a partlculate, blocompatlble .~, resorbable calclum salt and a partlculate calclum phosphate ceramlc dlspersed ln a cross-llnked blodegradable polyester matrlx ~` whereln the welght ratlo of partlcular calclum phosphate ceramlc ~" ,., ~
~ to partlcular resorbable calclum salt ranges from about 1:4 to .. , ~ about 4-1.

~ ~ The composltlon can be applled to bone-contactlng ,~ surfaces of prosthetlc appllances (as a cement)r or lt can be ':.
: ~ lnserted lnto and around bone defects and cavltles (as a flller), ~`~ 20 thereby provldlng an effectlve means for treatlng or repalrlng llvlng bone. When a pharmaceutlcal agent 1~ lncorporated lnto the . cross-llnked blodegradable matrlx lt serves as a depot devlce for controlled-release of the pharmaceutlcal agent. Release of the . agent occurs over a prolonged perlod of tlme upon lmplantatlon.
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~: The present lnventlon also provldes a klt for preparlng ; a blodegradable surglcal cement comprlslng a partlculate calclum phosphate ceramlc and a resorbable calclum salt selected from the , , ~, group conslstlng of calclum carbonate, calclum sulfate and calclum .
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~ s 132~82 ~ a 71727-36 sulfate hemlhydrate, whereln the welght ratlo of partlculate . calclum phosphate ceramlc to partlculate resorbable calclum salt ranges from about 1:4 to about 4:1, a cross-llnkable blodegradable polyester, and chemlcal means for cross-llnking the polyester.
The present lnventlon further provides a use of a ~ blodegradable bone cement for flxatlon of bone or ~olnt prostheses ,.~, and for surglcal repalr of bone, whereln sald blodegradable bone ~il .~ cement comprlses methyl methacrylate cross-llnked poly(propylene glycol fumarate), a calclum phosphate ceramlc and a blocompatlble ~ 10 resorbable calclum salt and whereln the welght ratlo of cross-.; . linked polymer to ceramlc plus salt ls about 2 :1 to about 1:5, ~ respectlvely.
:- . The present lnventlon also provldes a method of ~ .
preparlng a polymerlc cement for use ln the surglcal repalr of a i:; ~ bone or ~olnt comprlslng;

: . formlng a dlsperslon of a partlculate blocompatlble calclum .~ phosphate ceramlc and a partlculate blocompatlble resorbable .. calclum salt ln a mlxture of a polymer matrlx-formlng fluld':~` ~:
'"'A~ . Comprlslng a chemlcally cross-llnkable blodegradable polyester and .,.
a cross-llnklng agent, and .,., , .~ lnltlatlng a chemlcal reactlon between the polyester and the ; i cross-llnklng agent prlor to uslng sald cement.
The present lnventlon yet also provldes an lmplantable : artlcle for use ln the sustalned release of effectlve amounts of a ~; blologlcally actlve agent lnto a physlologlcal envlronment, sald .
dellvery system comprlslng a partlculate, calclum phosphate . . ~;
. ceramlc, a partlculate resorbable calclum salt, and the `~ blologlcally actlve agent dlspersed ln a cross-llnked .

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., 8b 71727-36 blodegradable polyester matrlx whereln the welght ratlo of partlculate calclum phosphate ceramlc to partlculate resorbable calclum salt ranges from about 1:4 to about 4:1.
In general, the lnventlon features a blodegradable polyester ln comblnatlon wlth partlculate calclum phosphate ceramlcs and resorbable calclum salts. Polyesters useful ln thls lnventlon are non-toxlc, blodegradable, and bloresorbable, l.e., ; .~

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degradation products are used by or are otherwise eliminated rom the human body via e~ist~ng biochemical pathways. The polyesters should also be chemically eross-linkable, i.e., posgess functional groups which will allow the polyester polymer ehain~ to be reacted with cross-linking agents reactive with said functional groups. Suitable polyester materials inelude polyesters formed from biocompatible di- and tri-carbo~ylic aeid~
or their ester-forming der~ative~ (e.g., aeid chloride~
or anhydrides) and di- or polyhydric C2-C6 alcohol~. The functionsl group~ in the polyester allowing for polyester eross-linking ean derive from either the aleohol or the acid monomer components of the . .
polyester.
~ 15 Representati~o earbo~ylic acid~ for formation .~ of polyester~ useful in thi~ invention inelude Kreb's cycle intermediate~ sueh a~ eitrie, isocitrie, ~, eis-aeonitie, alpha-kotoglutarie, ~uecinie, malie, o~aloacetie and fumarie aeid. Many of sueh earbo~ylie -~; 20 aeids ha~e a~ditional funetionalitio~ which can allow J` eross-linking and therefore mean~ for euring the present - eement formulation from a paate-like moldablo ma~ to a hardenod eement ~tate. Fumarie aeid i~ a preferred aeid for forming the polye~ter of the present invention. It i~ a diearbo~rlie aeid ha~ing a free-radieal reaetive double bond ~ell ~uited for freo radieal induee~
ero~à-linking reaetion~.
lllu~trati~e of C2-C6 alkyl or aklylene alcohol~ useful to form polye~ter~ in aeeordaneo ~ith thia in~ention are ethylene glyeol, 2-buten-1,~-diol, ..
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: . 1324~82 ; 2-methyl-2-buten-1,4-diol, 1,3-propylene glycol, 1,2-propylene glyeol, glycerine, 1,3-butanediol, ` 1,2-butanediol, 4-methyl-1,2-butanediol, 2-methyl-1,3-propanediol, 4-methyl-1,2-pentanediol, cyclohesen-3,4-diol and the like. In a preferred embodiment, the polyester component of the iresent composite cement i~ poly~propylene glycol fumarate)(PPF) formed by the condensation (esteriication) reaction of ii~ propylene glycol and fumaric aeid.
PPF is advantageou~ in the pre~ent invention `~ because PPF possesse~ two ehemieal propertie~ that are ~ critical to the function of a biodegradable bone ;; cement. The fir~t is the ease by which PPP can be degraded ~n YiYQ into its original fumaric aeid and ~ lS propylene glyeol subunits. 80th fumarie aeid and -~ propylene glycol are non-to~ie and well-tolerated ~n vivo. As a Xreb'~ cycle intermediate, fumarie aeid play~ ~n essential role in the proee~ by whieh food i~
eon~erted into energy. Propylene glyeol i~ u~ea throughout the food industry a~ a food additive and ean be metabolized or o~ereted by the body. The ~eeond ; eritieal property i~ that eaeh aubunit of the PP~
prepolymsr eontaina ~n aetivated unaaturated site , through ~hleh the polye~ter ean be ero~-lin~ed with ? 25 varioua olofinie froe-radieal indueed cro~-linking gent~.
She polye~ter i~ ero~-lin~d during tho euring period for the Qre~ent eomyo~ite eement to form a ~olidified eement matri~. Whero the reaetive ehemieally funetional group- in tb- poly--t-r r- e-r:on-c-rbon .

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132~082 double ~onds (e.g., in the preferred PPF polyester eomponent) representati~e eros~-linking agents are methyl methacrylate (MMA), N-vinylpyrrolidone, and like olefinic cross-linking agent~. A preferred ~-i 5 cross-linking agent is MMA, which e~ist~ as a clear - liquid at room temperature. It i~ part~cularly suitable ; for free radical induced cross-linking of PPF in accordance with a preferred embodiment of this in~ention.
The preparation of the present compo~ite cement typically invol~es combining the polyestQr and the cross-linking agent into a substantially homogeneous mi~ture, and addinq the particulate calcium phosphate . ceramic and ealcium salt to form a moldable eompo~ite eement mass which hardens on curing, i.e., eompletion of the cros~-lin~ing reaction. The number average molecular weight lM~n)] and molecular weigbt distribution tMWDl of the polyester shoula be such that the polyester and eros~-linking agent can be combined to form a sub~tantiallr homogenou~ mistute. Preferably the ero~s-linking agent i~ a liquid and the polyester i~
~ubstantially soluble in, or miseible with, the r eross-linking agont. Alternati~ely, tho ero~s-linking agent ean be ~ ~olid ~oluble in a liquid low moleeular weight polye~ter, or a liquid miseible therewith. Under ideal elreun~tanees, the ero~-lin~ing reaetion will '~ re~lt ln a ho~ogenous (uniormly ero~-linked) polye~t-r~artieulate eompo~ite eement.
In a ~referred embodiment poly(propylene glyeol fumarate)(PPF) is eombined with an amount of methyl ~ 30 ',~

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methacrylate sufficient upon reaction initiation, to cross-lin~ the polyester to the level necessary to form a rigid cross-linked PPF polymer matri~ for ths admi~ed ~- particulate calcium salts. Preferred MWD for the PPF
r 5 ranges from about 500 to about 1200 M(n) ana from about 1500 to about 4200 M(w).
In a preerred embodiment of this invention, the liquid polymer phase of the cement formulation i8 about 80 to about 95 percent by weight PPF and about 5 to about 20 percent by weight MMA monomer. The optimal - weight percentage~ for mechanical ~trength are appro~imately 85 percent PPF and about lS percent MMA.
The MMA monomer i~ typically stabilized to prevent ~ premature polymerization, i.e., prior to mi~ing with `3 15 PP~, with a few part~ per million of hyaroguinone-It is im~ortant that the proportion~ of PPF and MMA are controlle~. If too much NMA monomer is added, the MMA molecùlel can polymerizo themselve~ ~ithout ;~i being interrupted by the PPP chains. Tho re~ult i~ a material that behaves li~e con~entional PMMA bone cement ana doe~ not biodegrade. I too little MMA o~nomer i~
ddd, the PP~ polymer chaina ~ill not bo effectlvely cro~-linke~ ana the cement ~ill not curo to form a ~ matri~ of ~ufficient rigiaity.
`~ 25 The MMA-PP~ croaa-linklng reaction proceed~ via a fr~e-raaical propag-tea polymerlzation roaction. The cro~a-lin~i~g reactlon therefore i~, in practice, acceleratd by aaaition of a free-raaical lnltiator.
,~` Ono ~uitablo frse-raaical initiator for thi~ proco~
~ 30 benzoyl pero~ide.
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~ 1324082 A catalytic amount (less than 1~ by weight) of . dimethyltoluidene (DMT) is typically aaded to accelerate the formation of free radicals at room temperature.
Thus, the rate o cross-linking (i.e. time for curing or hardening of the cement) can be adjusted by controlling the amount of DMT added to the PPF~MMA mi~ture. ~he cement-curing rate can be ad~usted so that the cement is substantially cured in a period ranging from less than a minute to over 24 hours. The preferred curing time -~ 10 dependæ, of course, upon what is the most practical period of time for surgical purposes. The curlng period shoula be sufficiently long to allow the surgeon time to work with the cement to mold it or apply it to the appropriate surface~. At the ~ame time, the cure rate should be high enough to effect, for e~ample, implant staW lization within a short time following the ~urgical procedure. The polymerization or solidification period for bone implant fi~ation typically ranges from about 5 to about 20 minute~, and preferably about 10 minute~. -The particulate phase of- the present cement is ~; comprisea of biocompatible particulate calcium phosphate ceramic~ and particulate bioresorbable calcium salt~.
Tho particulato phase initially wt~ as a strength-imp~rting filler, much like the aggregate componont of concrete. However, in vivo, the calcium sslt particle~ ~re slowly eluted from the cement matri~
`~ by body flui~, le~ving sites for bone ingrowth into the ~; polymer ma~ri~. E~emplarr resorbable calcium salts effectiYe in the composition of this invention include : i;, ~ , ~ .~

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` 1324082 ..:
calcium sulfate, calcium sulfate hemihydrate (plaster of Paris), calcium carbonate, calcium hydrogen phosphate, certain porous precipitated forms of calcium phosphate and the like.
Biocompatible calcium phosphate ceramics are selected particularly in the bone repair embodiment of this invention for their known properties vis a vis I growing~living bone; that i~, they are known to promote interfacial osteoconduction. O~teoconduction refers to the ability of a substance to induce bone to grow on it. A~ u~ed herein the term ~calcium phosphate ceramics~ i~ to be ~istinguished from the sscond particulate component ~bioresorbable calcium salts~, and refers to a number of ~intered (heat-consoliaated) ~-~ 15 materials appro~imately defined by the formula Ca3(P04)2 including not only tricalcium phosphate itself but also ayatit~s, such a~ hydre~yapatite, and phosporite~. The particulate calcium phosphate ceramic~
u~ed in accordance ~ith this invention are characteri~ed them~elves as ~resorbable~ but they are resorbable at a much lower rate than the more porous particulate ~calcium salt~ component of the present compo~ite~.
Calcium pho~phate ceramic~ are in general preparea by sintering more ~oluble calcium ~alts, for e~ample, Ca~OH)2, CaC03 and CaHP04 with P205 or with each other. Calcium phosphate ceramic~ and their use in ~ implant material~ are known in the art. See, for -¦~ e~ample, U.S. Patent~ 3,7~7,900; 4,195,366; 4,322,398;
4,373,217 ana 4,330,514.

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:' ,~, i r ; Bone particles, either autograft or allograft, can also be included in the particulate phase.
Including natural bone in the cement enhances the property of osteoinductlon or the ability to induce new bone formation.
- In a preferred embodiment of this invention, a misture of calcium salts and calcium phosphate ceramics i8 used to eorm the particulats phase. A coarse tricalcium phosphate ceramic having a porous surface and -~ 10 a particle diameter of about 300 to about 600 microns i~ mised with fine-particulate or powdered calcium carbonate or plaster of pari~ (calcium sulfate hemihydrate) having a masimum particle size of les~ than s:
p about 10 micron~ and preerably less than about 5 ~; 15 microns in diameter. Use of smaller diameter tricàlcium phosphate particulate louers the mechanical strength of . the c*ment but increase~ lt~ ability to penetrate into -~; small interstices. The particulate tricalcium phosphate is preferably combined with the calcium carbonate or calcium suleate in ratios ranging from about 1:4 to about 4:1 by weiqht, and preferably in a ratio of about ~ 1:1 to form the particulate component of the present -~ biodegradable polymer composite~.
,1 In the cement composition of this in~ention, tho ~eight ratio of calcium salt~ and calcium phosphate Geramics (the particulate phase) to the polye~ter matris phase (polyester plus cross-linking agent) can range : from about 5:1 to ~bout 1:2. Preferably, the cement -$~ compo~ition is prepared by mising about 2 part~ by ~ 30 weight of particulate phase with about 1 part by ueight ,~
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~, , polymer matri~ phase. The ratio of particulate phase to polymer phase can be adjusted to provide the functional characteristics warranted by any given surgical application of the-compos$te cement.
A kit for preparing the particulate cross-linked polyester composite of this invention can be conveniently packaged for surqical applications. For e~ample, the inorganic particulate calcium ~alt~, calcium phosphate ceramic~, and benzoyl pero~ide can be packaged as a particulate powder phase while the PPF and MMA can be packaged a~ a liguid phase.
In the eperating room, the surgeon mi~es the powder and liquid (polymer plu~ cross-linker) phases to form a paste-like mass. In a preferred composition, the ~} 15 re~ulting surgical cement i~ comprised of appro~imately one third by weight of the liquid phase and appro~imately two third~ by weight of the particulate P phase. At thi~ time, the ~urgeon may wish to add to the - cement misture bone that i~ taken from the patient and ground into particulate form in order to enhance o~teoinduction or the ability to induce new bone ~; formation to the cement. The cro~-linking~curing proce~ begin~ immediately at room temperature when the ,' DMT is added. Alternatively all ingredient~ can be 2S mi~-d tog-ther ~ce~t for tho benzoyl ~ero~ide which i~
;~ added when initiation of the curing proce~ de~ired.
. ~
The cro~-linking reaction can tran~form the bone cement from an in~ectable or moldable pa~te into a durable ~olid particulate compo~ite within about 10 minute~.

.,~.~.
~, f ' ~.
'., 1324~82 Although cement solidification can proceed sufficiently within a 10 minute period to form a solid material, the reaction continues to proceed at a slower rate for a period of several hours to several days.
The particulate calc~um salts and organic polymers employed in the composition of the present invention are available commercially or are readily prepared through procedures which are known in the art.
The present particulate~polymer composites ha~e been found to provide an e~cellent matris for the sustained release in vivo of biologically active substances incorporated into the composite prioe to or - during the cross-linking (curing) step for preparing the present composites. Thu~ a drug ~ubstance~pharmaceutical agent incorporated into the pre-crosslinked polymer~particulate mi~ture to form about .1 to about 33~ by weight, more p~eferably about 2% to about 5% by weight, of the drug-composite misture will be released in vivo ~upon implantation of the cured composite) ov0r a perioa ranging from about two days to s~ about 30 days and longsr depending on the nature of the composite formulation.
: Release rate from a deli~ery system based on the pre8ent compo~ites is a function of the degree of cross-lin~ing, the nature and concentration of the drug 8ubstanco in tho matri~, particulate size~solubility, nature~bioaegradability of polyester component and the ~in vi~o environment~ of the implanted composite. ~hus u~e of the present composite~ as a drug delivery system allow~ for a significant degree of control over drug r61ease.

~ .

132~082 The cross-linking reaction employed to ~cure~
the present composites is only mildly e~othermic compared to, for e~ample, PMMA polymerization. This allows for formulation of sustained release deli.~ery systems for more thermally labile drugs.
The drug delivery systems in accordance with.
this invention can be formulated and implanted, or injected, either before or after curing (the cross-linking reaction) i~ complete. The drug/cross-linkea polymer~particulate composites are typically implanted surqically at a site in the body where high druq concentrations are desired. Thus, for esample, in the treatment of osteom~elitis, antibiotic-containing composites can be molded to conform to naturally occurring bone defect~ or they can be inserted into cavities formed by the surgeon specifically for receivinq the composition. Similarly, : the composites can be implanted or in~ected into soft ti~sue for sustained drug release. An important advantage of the present composite delivery systems is that a ~econd surgical procedure to remove the ~spent~
~ drug delivery d~vice is not reguired. The device is with time degraded and its degradation product~ are absorbed by the body.
The pre~ent invention is further illustrated by the following e~ample~, none of which are to be : construed a~ limiting ~he invention in any respect:

-.~ .

1324~82 A poly(propylene glycol fumarate) (PPF) based particulate composite surgical cement was prepared as follows: 3.0 moles of fumaric acid (348 grams) and 3.3 moles of propylene glycol (251 grams) were placed in a triple-ne~ked 1000 cc flask with overhead mechanical stirrer, thermometer, and 8arret trap beneath a condenser. The reaotion was initiated by heating at 145 C with continuous stirring. After about 2 hours, water 10 began to oollect in the Barret trap. The mi~ture wa~
heated for 5 hours by which time about 40 ml of water had been collected. The temperature was then increased to 180C in order to drive off the propylene glycol.
Ths progres~ of the reaction was monitored by removing samples and measuring their qiscosity at 100C. The viscosity initially measured about 2 poise at 100C and gradually rose to 15 poise, at which time the reaction was terminated. Terminating the polymerization at the proper time is critical. The proper endpoint occurs 20 when the PPF raaches a viscosity of about 10 to about 15 poise measured at lOO-C. This yislds PPF with a number average molecular weight of about 500 to about 1000, preferred for use in accordance with this invention.
The misturs wa~ cooled to room temperature to prevent further polymerization. In order to remove the esce3~ fumaric acid precipitate, 85 part~ by weight of the misture ~ere diluted with 15 parts by weight methylmethacrylate ~MMA) monomer, placed on a rotary stirring rac~ for 12 hour~ a~ 37 C to a~sure thorough âO

1~24~82 mi~ing, and centrifuged at 6000 RPM for 30 minutes. The PPF poiymer formed the supernatant.
Si~ grams of the liquid 85% PPF/15% MMA misture were mi~ed with the following particulate components:
.4 grams of benzoyl peroside powder, 7.5 grams of particulate tricalcium phosphate (30-45 mesh), and 7.5 grams of powdered calcium carbonate. These ingredients were warmed to 40-50C to facilitate the mi~ing process. This mi~ture e~hibited no signs of solidifying. At time of use, 2 drops o dimethyl-p-toluidine (DMT) wa3 added and thoroughly mi~ed. The resulting cement was immediately molded into specimens and allowed to cure at 37 C and 100~ relative humidity. ~he fresh cement was also implanted into e~perimental animals. Approsimately 5 minutes working time was available befors the cement began to harden.
Unconfined mechanical testing of the cured molded specimens, according to ASTM standards for acrylic cement~, gave a compres~i~e strength of 19 MPa and an elastic modulu~ of 200 MPa.
` EXAMPLS 2 In itro tests of biodsgradable cement materials prepared in accordance with E~ample 1 were conducted in Yariou~ liquid~. PPF~MMA ~pecimens were placed in water buffered at neutral pR. Initially, the water caused slight ~welling of the matris and the s2ecimens decreased in mechanical strength and stiffnes~. After a few day~, with the on3et of the secondary calcium ion reactions, the specimens returned to their original material prop~rties. No e~idence of degradation occurred.
Samples were also placed in an alkaline solution of pH 10. The specimens lost strength quickly because of the swelling of the polymer. Because of the polymer degradation due to the high pH, the samples did not regain strength. Within a few days, the specimens could be easily crushed with the end of a pencil.
These results were obtained for PPF/MMA
specimens prepared having a weight ratio of PPF to MMA
of about 85:lS. When higher amounts of MMA were used, - e.g., 30 weight percent, degradation of the PPF/MMA
specimens did not occur. The specimens regained their material properties and maintained them indefinitely.
When the specimens were placed in an acidic solution, the plaster of Paris was quickly leached out of the specimens. The specimen~ lost their stiffness but retained their shape due to the strength of the ; 20 POlymer.
These ~n vtro result~ demonstrated that the PPF/MMA bone cement pos~essed appropriate mechanical propertie~ and chemical properties for use as a biodegradable cement for orthope~ic applications.

Additional esperiment~ were conducted to evaluate the mechanical properties of the PPF/MMA cement in animal implantation applications. Specimens wer2 prepared in accordance w~th the procedur~ set orth in Esample 1.

132~82 Threa group~ of standard 6 ~ 12 mm cylindrical specimens were implanted subcutaneously into a rabbit's back. At least sis (6) rabbits were sacrificed for mechanical testing of implanted specimens at intervals of one day to three weeks. Results of the biomechanical evaluation are set forth in FI~S. 1 and 2. The compressive strengths of the PPF cement implant measured at one day, four days, one week, and three weeks are set forth in FIG. 1. FIG. 2 depicts the elastic moduli values measured at the same intervals.
- Four different composition3 of cement were tested in each rabbit. Crosslinked PPF specimens - cross-linked with 10~, 15%, 20%, and 30% MMA e~hibited proportionately increasing mechanical strength and modulus values. The one-day values for material propertie~ for all concentrations were approsima~ely one-half that of the control~. This i8 believed to have been caused by swelling of the polymer in a wet environment. By four day~, all specimens had significantly increased their material properties. The lS% MMA specimens e~hibited compressive strength of 10 MPa. This is believed to be aue tu the secondary calcium ion effect.
At one, two, and three week intervals, differences in material properties were observed, depending upon the MMA concentration. For 20% and 30~
MMA ~pecimen~, only a slight drop in mechanical strength was noted. This is believed to have been due to the leaching out of the plaster of Pari~. For the 10~ and 132~082 15~ MMA specimens, a more significant drop in mechanical strenqth was noted. This is believed to have been due not only to the plaster of Paris leaching out but also to the initial stages of polymer deqradation. --Subsequent e~periments using 15/85 MMA/PPF cement showed that, after seven weeks of subcutaneous implantation, the compression strength of specimens had fallen below 1.0 MPa and many had crumbled and fragmented.

In vitrQ implantation of the biodegradable cement materials, prepared in accordance with E~ample 1, were conducted to test their effectiveness as carriers for sustained release of antibiotics. Prior to the addition of DM~, either gentamicin or vancomycin were mi~ed into the cement at a ratio of 1 gram of antibiotic to 30 grams of cement. The cement wa~ then activated with DMT and molded into 6X12 mm cylindrical specimens as described above. Similar specimens ~ere prepared with con~entional PMMA cement loaded with antibiotics in the sama manner. All specimens were implanted subcu~aneously in rats. Wound fluids aspirated from around the implants and blood sample~ were measured for concentrations of antibiotic~ by immunoassay from 1 to 14 days post-operatively as shown in Figures 3, 4, 5, and 6. She PPF~MMA cement produced significantly higher local antibiotic level~ in the wound fluid for both gentamicin and vancomycin, for a longer duration than did PMMA. Blood concentrations o~ both antibiotics remained well below to~c concentrations for both cement~.

:
.

1324~82 ~amvle ~
Treatment of E~perimental Osteomyelitis in a Rat Model:
Seven Sprague-Dawley retired male breeder albino rats were divided into 4 groups as noted below.
All rats underwent sterile surqical procedures under sodium pentobarbitol general anesthesia. Three successive surgical procedures were performed on each rat.
The first procedure was identical for all rats. The flat surface of the anteromedial tibial metaphysis was surgically e~posed via a 1.5 cm linear incision just distal to the knee joint and 2mm medial to the anterior tibial crest. The perio~teum was split and gently moved a~ide using a periosteal elevator. Using a high ~peed arill, ~Hall Air Surgery Instruments micro drill, 5053-01, Zimmer, USA) and a 2mm ~urr bit, a hole was made through the anteromedial metaphyseal corte~ and underlying. Care was taken not to violate the ar corte~ whilQ drilling. Immediatel~ following drilling, a suspensio~ of S,_~gL~g~ (1.0 ~ 10 CFU~l ul) wa~
prepared using the Prompt Inoculation System (3M, No.
6306). Ten ul were injected into the wound site. This represented an inoculum of appro~imately 1.0 ~ 106 CFU. Care wa~ taken to deliver all of the inoculum to the drill hole and avoid overflow. Immediately ; following inoculation, a 2 ~ 3 mm performed PMMA
cylinder with a central 4mm wire (to aid radiographic detection and facilitate la~er removal) was placed as a :

132~82 foreign body in the burr hole o~er the inoculum. A
synthetic resorbable suture (6.0 VICRYL suture, Ethioon, rnc.) was used to partially close the periosteum over the drill hole to securo the implant. She distal 2/3 of the skin incision wa~ then closed using 4.0 VICRYL, leaving the prosimal 1/3 of the incision open as a potential site for drainage. Only 3 interrupted sutures were used. Postoperative lateral radiographs were obtained of all rat tibiae. Rat~ wers then returned to cage activity for 3 week~.
At 3 weeks, all rat3 eYcept on~ (LONG) had their implants removed surgically using ~terile technique. The appearance of the infection site was recorded. The LONG rat was left at cage activity with hi8 original implant for the duration of the e~periment. ~mplants were inoculated on blood agar pla~es and into thioglycollate broth and incubated for 24 hours at 35C in 5% C)2. Subculture~ of the broth were made a~ necessary to identify all infecting organisms. A sterile gauze 4 ~ 4 was used to manually wipe away pu~ from the drill hole and surrounding soft tissue of the left hindlimb but no formal debridement was performed. The right hindlimb underwent formula debridement of infected and necrotic bone and soft ti~8U9 bone and 30ft t~ssue and the original drill hole was reamed to 4mm and the edges undermine~ using the Hlal micro air drill and 2mm burr. Two animal3 were treated bilaterally with gentamicin and ~ancomycin and PPF~MMA pac~ed into, ana allowed to polymerize ln the ~324~82 drill hole osteomyelitic site. Two animals were treated similarly but with gentamicin and vancomycin in PMMA.
Gentamicin and vancomycin were added at a ratio of 2 gm to 60 gm of either PPF/MMA or PMMA to prepare treatment samples-Antibiotic impregnated PPFrMMA specimens were prepared in the following manner: PPF 96gm, of as yet unpurified fumaric acid) and MMA (1 gm) were thoroughly mised at 37 degrees C until the PPF was completely dissolved in the MMA. The resultant matri~ material (~5% PP~ and 15S MMA) was centrifuged at 6000 rpm for 45 minutes to remove th~ suspended fumaric acid. The 'purified' PPF~MMA matric was then mi~ed with benzoyl pero~ide ~0.25 gm, a crosslinking catalyst) and the particulate phaso which consisted of TCP (7.5 qm, 30-45 mesh, 35~-6C0 micron diameter) and medical grade calcium carbonate powder (7.5 gm.). After thorough mi~ing of the particulate compo~ite, gentamicin sulfate powder tSigma Chemical Co.) or vancomycin hydrochloride lypholized powder ~Lederle Par~nterals Inc.) was added and mi~ed well. Finally, dimethyl-p-toluidine (DMT)(2 drops) ~as added to initiate cross-linkage of the cement. ~A 22.ZS gm batch of the particulate composite was preparea and 15 gms of this wa~ mised with 0.5 ~m of antibiotic to give a 2 gm~60 gm ratio or 3.3~
antibiotic. Two control animals had their initial foreign body implants removed and were not treated. All wound~ were closed ~oosely using 2 to 3 interrupted 4.0 VICRYL suture~ in the distal 2~3 of the wound only.

3~

132~082 Again the prosimal l/3 of each wound was left open. Pre and postoperative radiographs were obtained to document osteomyelitic changes~
Three weeks later (6 weeks post infection) all animals were sacrificed by intraperitoneal sodium pentobarbitol followed with an intracardiac injection of sodium pentobarbitol. In the operating room under sterile condition~, the hindlimb~ were dismembered and partially surface sterilized by immer~ion in 95% alcohol followed by spraying with povidine-iodine solution which was allowed to air dry. Using a new set of sterile instruments the tibial infection site was e~posed and its appearance recorded. The cement plugs and adjacent bone were then esamined bacteriologically. Standardized 4mm thick ~wafer-shaped~ tibia segments, which included, the infection site and cement-antibiotic pluq, were cultured guantitatively. Bone segments were inoculated into 2 ml of trypticase soy broth (TS~). The misture was vorte~ed, and serial 10-fold diulations in ~SB were made. A 10 ul inoculu~ wa3 subcultured to 5~ sheep blood agar plate~ that were incubated for 24 hours at 35- in 5% Co2. Colonie~ wsre counted on plates with approsimatsly 30-100 colonies only.
Result~: Three week~ post administration of the 5 ~ eU~ inoculum all animals demon~trated clinical and radiographic ~igns con~i~tent with establi~hed chronic osteomyeliti~. Thes~ included ab~cesses, draininq sinu~es, radiographic osteolysis and ~e~uestration, periosteal new bone formation and . i - 2~ -- 132~82 pathologic fractures. Sis weeks following infection, i.e., following three weeks of treatment or control protocols, all control animals demonstrated clinical signs of infection whereas both treated groups appeared more normal cl;nically. Radiographs were essentially unchanged. All tibia sites from all animals grew mi~ed bacterial ~lora including S. aureus, consistent with chronic osteomyelitis. In all cases there were dramatic differences between treated animals (PPF/MMA and PMMA
with antibiotics~ and control animals. In one PPF/MMA
treated case, there was complete sterili~ation o the infected site. In all cases, where debridement was performed, there was at least 2 to 3 orders of magnitude fewer organisms cultured from PPF~MMA animals than from treated animal~. Control animals demonstrated 1 to 6 orders of magnitude more bacteria by quantitative culture than did treated animals.
While the composition of the present invention has been described for use as a medication-bearing composition for the controlled delivery of medication ~n YLYQ as well as for U59 a~ a surgical cement for prosthetic appliances, such descriptions are illustrative only and are not intended to be limiting in any way. There are many other applications for the biodegradabla composites of the present invention. For esample, the ~urgical cement of the present lnve~tion could be used for the repair of osteoporotic fractures.
Such fractures are difficult and often not possible to treat by conventional internal fisation methods using 132~82 bone plates and screws because the bone screws are prone to loosen or to cut through th~ weaker osteoporotic bone. Although some surgeons use conventional PMMA bone cement to secure the bone screws, there is a risk that P~MA will actually impair the healing process. ~ny such impairment is detrimental because if the bone fragments do not heal, the fisation eventually will ~ail.
Moreover, osteoporosis-induced fractures frequently involve a crushing~type injury by which porous hone collapses into itself typically causing a large void or bony defect at the site of the fracture.
In order to achieve secure stabilization of the fracture, this bony defect must be illed in.
Conventional surqical techniques employ the use o~ a bone graft from another site in the body to pack and fill the cavity. The bone graft consolidates as living bone slowly grows into the graft. Patients with such fractures in the lower estremities must remain non-wRight-bearing for periods of up to three months because the bone grafts ar~ too weak to provide sufficient structural support. Hospitalization, nursing home care, traction, and medical complications associated with immobilization are, of course, very e~pen~ive and problematic for the patient. The use of a biodegradable ~one cement would alleviate the problems caused by prolonged, non-weight-bearing immobilization.
A bone cavity could simply be filled with the biodegradablo cement of the present invention, which would quickly set-up to form a ~trong solid mass.

132~

Patients could begin full weight-bearing actlvities within several days after the operation. The adYantages are obvious in that the patient would e~perience a much shorter hospitalization period. Over time, the biodegradable bone cement would slowly resorb as the fracture healed and th~ cement could be replaced by living bone.
In addition, the surgical cement of the present invention can also be employed advantageously in the treatment of bone tumors. Such treatment typically involves e~cision of the tumor as well as portion~ of the surrounding bone, leaving a large cavity in ths bone. An autogenou~ bone graft, or bona harvested from another site in the patient's body, i~ th~ conventional lS and accepted techniqu~ for filling such bony defects.
While esperimental clin~cal te~ts show that autogenous bone provides the most rapid incorporation of new bony ingrowth into a bon~ cavity, a disadvantage i5 that associated with the morbidity caused by the re~uired surgical e~pogure for har~esting of the patient's bone.
Moreo~er, some pat~ents, particularly o~teoporotic individual3, ha~e very limited amounts of bone that are appropriate for use as a graft. Alternatively, allographs, i.e., bones taken from other indi~iduals, may be used as bone-grafting material. There are certain risks a~sociated with such allographs, however, including the transfsr of infection~ and even unrecognized malignant cells rom the har~ested patient to the grafte~ ~atient as well as the problem of - 31 ~

1324~8~
immunologic barriers ~etween all individuals.
Furthermore, such processes are complicated and labor-intensive.
For these reasons, some surgeons have begun to employ synthetic bone substitutes. The two most common types of substitutes are hydro~yappatite (HA) and - tricalcium phosphate (TCP). HA and TCP haYe bioacti~e surfaces that promote osteoconduction when implanted in a bone cavity. In addition, TCP has the property of being slowly resorbed by the host tissues. A
biodegradable surgical cement would have important advantages over conventional bone substitutes such as TCP and HA particulates because the cement could be injected and molded to fill a cavity of any shape and would harden sufficlently tG immediatsly allow weight-bearing acti~ities. Moreover, unlike man-made materials, the problems with procurement, infection, and storage would be obviatsd.
While we have described the invention with respect to Ypecific materials, operating condition~, and procedures, such ~ra illustrative only. Numerous modifications and equivalents will be apparent to those of ordinary skill in thi8 art without departing from the spirit of the invention.

Claims

1. A composition comprising a particulate, biocompatible resorbable calcium salt and a particulate calcium phosphate ceramic dispersed in a cross-linked biodegradable polyester matrix wherein the weight ratio of particular calcium phosphate ceramic to particular resorbable calcium salt ranges from about 1:4 to about 4:1.

2 The composition of claim 1 wherein the biodegradable polyester is a polyester of fumaric acid and a polyhydric C2-C6 alcohol.

3. The composition of claim 2 wherein the particulate calcium phosphate ceramic is selected from the group consisting of tricalcium phosphate, hydroxyapatite, and combinations thereof.

4. The composition of claim 3 wherein the particulate calcium phosphate ceramic is tricalcium phosphate.

5. The composition of claim 2 wherein the calcium salt is selected from the group consisting of calcium carbonate, calcium sulfate, precipitated calcium phosphate, calcium sulfate hemihydrate and combinations thereof.

6. The composition of claim 1 wherein the particulate calcium phosphate ceramic has an average particle diameter of about 75 microns to about 600 microns and the particulate resorbable calcium salt has a particle diameter of less than 10 microns.

7. The composition of claim 6 wherein the weight ratio of particulate calcium phosphate ceramic to particulate resorbable calcium salt is about 1:1.

8. The composition of claim 7 wherein the cross-linked biodegradable polyester matrix comprises poly(propylene glycol fumarate) cross-linked using about 5% to about 20% by weight of methyl methacrylate monomer.

9. The composition of claim 2 wherein the polyhydric C2-C6 alcohol is selected from the group consisting of ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol, glycerine, 1,3-butanediol, 1,2-butanediol, 4-methyl-1, 2-butanediol, 2-methyl-1,3-propanediol, and 4-methyl-1,2-pentanediol.

10. The composition of claim 9 wherein the polyester is poly(propylene glycol fumarate).

11. The composition of claim 10 wherein the biodegradable polyester is cross-linked with a cross-linking agent selected from the group consisting of N-vinylpyrrolidone and methyl methacrylate.

12. The composition of claim 11 wherein the cross-linking agent is methyl methacrylate.

13. The composition of claim 12 wherein the average molecular weight and molecular weight distribution of the polyester is such that the polyester is miscible with or soluble in methyl methacrylate.

14. The composition of claim 12 wherein the polyester has a number average molecular weight of about 500 to about 1200.

15. The composition of claim 10 wherein the polyester matrix is formed by cross-linking poly(propylene glycol fumarate) with about 5 to about 20 weight percent methyl methacrylate.

16. The composition of claim 15 wherein about 15 weight percent methyl methacrylate is used to cross-link the poly(propylene glycol fumarate).

17. The composition of claim 13 wherein the weight ratio of particulates to polyester matrix ranges from about 5:1 to about 1:2.

18. The composition of claim 17 wherein the weight ratio of particulates to polyester matrix is about 2:1.

19. The composition of claim 17 wherein the particulate, biocompatible resorbable calcium salts are selected from the group consisting of calcium carbonate, calcium sulfate, calcium sulfate hemihydrate, precipitated calcium phosphate, and combinations thereof.

20. The composition of claim 2 wherein the cross-linked biodegradable polyester matrix comprises a polyester of fumaric acid and a propylene glycol.

21. The composition of claim 20 wherein the particulate calcium phosphate ceramic comprises tricalcium phosphate.

22. The composition of claim 20 wherein the particulate calcium phosphate ceramic has an average particle diameter of about 75 microns to about 600 microns and the particulate resorbable calcium salt has a particle diameter of less than 10 microns.

23. The composition of claim 22 wherein the weight ratio of particulate calcium phosphate ceramic to particulate resorbable calcium salt is about 1:1.

24. The composition according to any one of claims 1 to 23 comprising a biologically active agent dispersed in said matrix.

25. The composition of claim 24 wherein said biologically active agent forms about 0.1 to 33 percent by weight of the matrix.

26. A kit for preparing a biodegradable surgical cement comprising a particulate calcium phosphate ceramic and a resorbable calcium salt selected from the group consisting of calcium carbonate, calcium sulfate and calcium sulfate hemihydrate, wherein the weight ratio of particulate calcium phosphate ceramic to particulate resorbable calcium salt ranges from about 1:4 to about 4:1, a cross-linkable biodegradable polyester, and chemical means for cross-linking the polyester.

27. The kit of claim 26 containing:
a tricalcium phosphate ceramic and a calcium salt selected from the group consisting of calcium carbonate and calcium sulfate hemihydrate, the weight ratio of tricalcium phosphate ceramic to the calcium salt being about 2:1 to about 1:2;
poly(propylene glycol fumarate) having a number average molecular weight of about 500 to about 1200; and a chemical cross-linking means comprising methyl methacrylate and a free-radical initiator, the weight ratio of the calcium salts and calcium phosphate ceramics to the total weight of polyester and chemical cross-linking means being about 2:1, said poly(propylene glycol fumarate) and said methyl methacylate being in a weight ratio of about 4:1 to about 9:1, respectively.

28. A use of a biodegradable bone cement for fixation of bone or joint prostheses and for surgical repair of bone, wherein said biodegradable bone cement comprises methyl methacrylate cross-linked poly(propylene glycol fumarate), a calcium phosphate ceramic and a biocompatible resorbable calcium salt and wherein the weight ratio of cross-linked polymer to ceramic plus salt is about 2:1 to about 1:5, respectively.

29. A method of preparing a polymeric cement for use in the surgical repair of a bone or joint comprising:
forming a dispersion of a particulate biocompatible calcium phosphate ceramic and a particulate biocompatible resorbable calcium salt in a mixture of a polymer matrix-forming fluid comprising a chemically cross-linkable biodegradable polyester and a cross-linking agent, and initiating a chemical reaction between the polyester and the cross-linking agent prior to using said cement.

30. The method of claim 29 wherein the biodegradable polyester is poly(propylene glycol fumarate).

31. The method of claim 30 wherein the number average molecular weight of the polyester is about 500 to about 1200 and the cross-linking agent is methyl methyacrylate.

32. An implantable article for use in the sustained release of effective amounts of a biologically active agent into a physiological environment, said delivery system comprising a particulate, calcium phosphate ceramic, a particulate resorbable calcium salt, and the biologically active agent dispersed in a cross-linked biodegradable polyester matrix wherein the weight ratio of particulate calcium phosphate ceramic to particulate resorbable calcium salt ranges from about 1:4 to about 4:1.

33. The article of claim 32 wherein the biologically active agent is an antibiotic.