JP2002536123A - Anti-resorbable bone cement and allogeneic, autologous, and xenograft - Google Patents

Abstract

  (57) [Summary] An anti-absorbable bone cement comprising an anti-absorbable amount of one or more anti-absorbents. Preferably, the anti-absorbent is a bisphosphonate. Anti-resorbable bone cements are useful for reducing bone voids and bonding prostheses to bone. The invention also relates to anti-resorbable allogeneic, autologous, and xenograft bone grafts. Bone grafts contain an anti-resorbable amount of an anti-resorptive agent such as bisphosphonate. Anti-resorbable bone grafts are useful for bone reconstruction surgery.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] This application claims the benefit of US Provisional Application No. 60 / 119,260, filed February 9, 1999. The application is hereby incorporated by reference in its entirety.

[0002] 1. FIELD OF THE INVENTION The present invention relates to anti-absorbable bone cement. The present invention also relates to anti-resorbable allogeneic bone grafts, anti-resorbable autogenous bone grafts, and anti-resorbable xenograft bone grafts. More specifically, the invention comprises a bone cement comprising an anti-absorbent, an allogeneic bone graft comprising an anti-absorbent, an autogenous bone graft comprising an anti-absorbent, and an anti-absorbent. The present invention relates to a heterogeneous bone graft comprising: Provided that the anti-absorbents include bisphosphonates and pharmaceutically acceptable salts or esters thereof, salts of Group IIIA elements, cholesterol-lowering agents, bisphosphonate-chemotherapeutic conjugates, estrogen-bisphosphonate conjugates, and estrogens, prostaglandins And protein or hormonal anti-absorbents such as cytokines.

[0003] 2. BACKGROUND OF THE INVENTION Bone loss and orthopedic implants Progressive bone loss and pathological fractures are a major cause of skeletal pain and poor prosthesis in cancer patients.

[0004] Bone cement is used to coalesce most orthopedic joint replacements. Problems with the durability of implant fixation are aseptic loosening.
). It is triggered by granular debris shedding from the implant and is mediated by osteoclastic bone resorbable cells.

[0005] Accordingly, post-operative bone loss associated with the use of bone cements, such as acrylic bone cement,
Often this is due to loose prosthetic implants. This osteolytic process is related to the activity of osteoclasts.

[0006] Cemented orthopedic implants cause time-dependent aseptic loosening (Martell, JM, Berdia, S., "Determination of polyethylene wear in total hip replacement using digital radiography"). polyethylene wea
r in total hip replacement with use of the digital radiographs), J. Bone
Joint Surg. Am., 79: 11, 1635-1642 (1997); Madey, SM, Callaghan, J.
J., Olejniczak, JP, Goetz, DD, Johnston, RC, "Charnley total hip arthroplasty using improved cementation techniques. Results obtained after a minimum of 15 years of follow-up" (Charnley total hip arthroplasty). with use of improved
techniques of cementing.The result after a minimum of fifteem years o
f follow-up), J. Bone Joint Surg Am., 79: 1,53-64, (1997); Neumann, L.,
Freund, KG, Surensen, KH, `` Results of total hip arthroplasty with t
he charnley prosthesis in patients fifty-five years old and less), J. Bo
ne Joint Surg. Am., 78: 1,73-79, (1996); Kobayashi, S., Takaoka, K., Sai.
to, N., Hisa, K., "Factors affecting aseptic failure of fixation aseptic loosening after primary Chernley total hip arthroplasty"
fixation after primary Charnley total hip arthroplasty), J. Bone Joint S
urg. Am., 79: 11,1618-1627 (1997)). When these prostheses occur, they cause pain, loss of patient function, require surgical correction in about 10% of all arthroplasty procedures, and considerable medical costs (Shanbhag, AS, Hasselman, CT , Rubas
h, HE, "Inhibition of wear debris-mediated osteolysis in a canine total hip arthroplasty model" (I
nhibition of wear debris mediated osteolysis in a canine total hip arthr
oplasty model), Clin. Orthop. Rel. Res., 344, 33-43, (1997)).

[0007] Debris-induced osteolytic loosening is the end of a series of events that begins with the production of metal, polymethylmethacrylate ("PMMA") cement, and polyethylene wear debris. This debris is formed by normal stresses at the bone-cement-prosthesis interface and is unavoidable as a result of normal patient movement.

In a recent review, Lewis considered the mechanism of bone cement-induced osteolysis (Lewis G., "Properties of Acrylic Bone Cement: Review of Advanced Technologies" (Properti
es of Acrylic Bone Cement: State of the Art Review), J. Biomed. Mater. R
es. (Appl. Biomater.), 38, 155-182, (1997)). Debris particles enter the small space between the bone and the cement mantle.

Rberson, JR, Spector, M., Baggett, MA, Kita, K., “Porous coated femor components for revision joint arthroplasty in dog models”
al components in a canine model for revision arthroplasty), J. Bone and
According to the report of Joint Surgery, 70A: 8,1201-1208, (1988), debris particle size and chemical properties contribute to adverse responses.

In the case of ultra-high molecular weight polyethylene debris, bone resorption is 20% higher than in the case of PMMA debris.
It was suggested that it would increase. In addition, regardless of chemical composition, debris with a particle size of less than 10 microns caused a loosening process. Debris elicits macrophage infiltration and a granulomatous response. The activity of macrophages in the presence of particles is linked to a biochemical environment that promotes membrane formation around the prosthesis, and membrane formation is associated with osteoclast-mediated bone resorption. Inhibition of this osteoclast activity by anti-resorptive agents may suppress the bone resorption stage that causes loosening of prostheses (Horowitz, SM, Algan, SA, Purdon, MA, Pharmacologic inhibition of particulate-induced bone
resorption), J. Biomed. Mat. Res., 31: 1, 91-96, (1996)). Similarly, Clohis
demonstrated that osteoclasts mediate tumor-induced local bone resorption (Clohisy, D. et al.
R., Ogilvie, CM, Carpenter, RJ, Ramnaraine, ML, `` Localized tumor-associated osteolysis involves recruitment and activity of osteoclasts '' (Localized, tumor-asso
ciated osteolysis involves the recruitment and activation of osteoclasts
), J. Orth. Res., 149: 1,2-6, (1996)).

Anti- Resorptives : Bisphosphonates Bisphosphonates are widely used FDA approved drugs and have been used to treat conditions characterized by excessive bone resorption. Bisphosphonates have been used experimentally to prevent pathological conditions due to bone metastasis and to delay bone loss around loose orthopedic materials where resorption of host bone is induced by accumulated particulate debris. Bisphosphonates are also used in dentistry to treat alveolar bone resorption.

[0012] Bisphosphonates are potent inhibitors of osteoclast activity (Mallmin et al.,
“Short-term effects of pamidronate disodium on biochemical markers of bone metabolism in osteoporosis-a placebo-controlled dose-finding study”
ronate disodium on biochemical markers of bone metabolism in osteoporosi
sa placebe-controlled dose-finding study), Upsala Journal of Medical Sc
iences, 96: 3,205-12, (1991); Fitton, A., McTavish, D., `` Pamidronate.
: Review of its pharmacological properties and therapeutic efficacy in resorbable bone disease "(P
amidronate: A review of its pharmacological properties and therapeutic e
fficacy in resorptive bond disease), Drugs, 41: 2,289-318, (1991)) and is used clinically to treat malignant hypercalcemia, Paget's disease of bone, and a high turnover form of osteoporosis Have been. In animal studies, bisphosphonates have the ability to inhibit bone metabolism (Orr, FW, Sanchez-Sweatman, OH et
al., `` Tumor-borne interactions of skeleta
l metastasis), Clin. Orthop. (US), 312, 19-33, (1995)), and a reduction in the number of bone-related events in a series of clinical cases of patients with breast cancer, multiple myeloma, or other cancers Have the ability to

Bisphosphonates have a dose-dependent effect of inhibiting the function of osteoclasts, delaying bone formation by osteoblasts, and preventing bone calcification. The relative importance of action will be different for each drug in each class. Second and third generation bisphosphonates preferentially increase the desired osteoclast inhibitory activity (100-fold) while minimizing or avoiding adverse effects.

In general, anti-absorbable bisphosphonates bind strongly to bone hydroxyapatite and retain the bond forever. The mechanism of inhibition involves blocking osteoclasts and their precursors from recognizing the bisphosphonate-hydroxyapatite matrix (Papapoulos, SE, Hoekman, K., Lowik, CWG
M., Vermeij, P., Bijvoet, OLM, "Application of in vitro models and clinical protocols in evaluating the efficacy of new bisphosphonates" (Application of an in vi
tro model and a clinical protocol in the assessment of the potency of a
new bisphosphonate), J. Bone Min. Res., 4: 5,775-782, (1989)). In addition, other mechanisms are still being elucidated.

[0015] Bisphosphonates are used systemically to block a generalized form of bone resorption. Experimental trials using this drug to address local issues such as monofibrous fibrous dysplasia and bone pain in alveolar bone resorption are ongoing, but these trials are indicated for systemic therapy It is rare to do so.

It has been reported that systemic administration of alendronate, a bisphosphonate, suppressed osteolysis associated with wear debris in a dog non-cemented hip arthroplasty model (Shanbhag et al., Supra).

(Yaffe, A., Iztkovich, M., Earon, Y., Alt, I., Lilov, R., Bind
erman, I., "Local delivery of aminobisphosphonate after mucoperiosteal flap surgery inhibits alveolar bone resorption in rats" (Local Delivery of an amino bilayer).
phosphonate prevents the resorptive phase of alveolar bone following muc
operiousteal flap surgery in rats), J. Periodontal, 68,884-889, (1997))
Used a rat mucoperiosteal flap surgery model to administer alendronate in the vicinity of the alveolar bone of an animal in the form of a drug-immersed pellet. The pellet was kept in contact with the bone for 2 hours and then removed. The effect of drug on the pellet application area was monitored after 21 days. This study demonstrated that topical administration significantly reduced bone resorption. According to a previous report by Yaffe et al., Contacting alendronate-soaked pellets with alveolar bone for 10 seconds had no effect on absorption, but systemic administration did.

Bisphosphonates do not interfere with the mechanisms underlying debris-induced osteolysis. Bisphosphonates inhibit the activity of osteoclasts.

For ceramic hydroxyapatite dental implants for releasing bisphosphonates, see Denissen, H., van Beek, E., Lowik, C., Papapoulos,
S., Van den Hooff, A., "Ceramic hydroxyapatite implants for the release of bisphosphonate"
bisphosphonate), Bone and Material, 25, 123-134 (1997) and Denissen, H.,
van Beek, E., Martinetti, R., Klein, C., van den Zer, E., RavaglioliA.,
"Net-shaped hydroxyapatite implants for release of age"
nts modulating periodontal-like tissue), J. Periodont Res., 32,40-46 (19
97). These publications state that the inorganic ceramic implant is impregnated with bisphosphonates to function as a local delivery system to prevent bone resorption. In each case, the ceramic was molded, machined and then immersed in a bisphosphonate solution.

Bisphosphonates inhibit bone resorption by osteoclasts. This bone resorption (1)
Occurs in response to granular wear debris, which is a major cause of aseptic loosening of joint replacements (Kobayashi et al., Supra; Hicks, DG, Judkins, AR, Sickel, J. et al.
Z., Rosier, RN, Puzas, JE, O'Keefe, RJ, `` Granular histiocytosis of pelvic lymph nodes after total hip arthroplasty, presence of wear debris, cytokine production, and immune-activating macrophages '' (Guranular histiocytosis of pelvic lym
ph nodes following total hip arthroplasty.The presence of wear debris,
cytokine production, and immunologically activated macrophages), J. Bone
Joint Surg. Am., 78: 4,482-496, (1996)), (2) occurs with local tumor progression and is a major cause of failure of pathological fracture treatment. Clinically, anti-absorbents have been used systemically to treat diseases that trigger osteolytic processes. The anti-absorbent is distributed to the bone in proportion to its blood flow through the bone capillary network. After performing the arthroplasty procedure, the amount of drug reaching the site adjacent to the bone cement is reduced compared to the site adjacent to normal bone. Bone marrow blood supply is suppressed by femoral reaming in hip replacement surgery and other arthroplasty procedures. Prosthetic cementing has other detrimental effects, such as exothermic PMMA polymerization, monomer release, and damage to the bone capillary network (Lewis, supra). As a net effect of the cemented prosthesis, the local bioavailability of any systemically administered drug will be relatively reduced. In the case of anti-resorptive drugs at the bone-cement interface may not be sufficient to properly inhibit osteoclasts. The persistence of response to systemic therapy is not known.

[0021] Regarding the duration of efficacy of the anti-absorbent, it may be necessary to repeat systemic administration over time. Local administration with a depot may (i) deliver high titer levels of anti-absorbent, and (ii) provide sustained efficacy without repeated administration There is.

The iontophoresis administration of bisphosphonates is disclosed in US Pat. Nos. 5,735,810, 5,730,715, and 5,668,120. The entire contents of all these patents are incorporated herein by reference.

Drug Filled PMMA Cement Polymethyl methacrylate (PMMA) cement is effective for securing prostheses to bone. However, a large biomechanical link between PMMA, prostheses, and bone
(biomechanical) differences exist. This difference, coupled with the trauma associated with surgery and normal post-operative physical activity, results in the generation of particulate debris, which results in an unavoidable series of events that cause implant damage.

[0024] The PMMA polymerization reaction causes some osteonecrosis and disrupts bone blood flow. Thus, systemically administered bisphosphonates may not reach the affected bone-cement interface at concentrations suitable to show significant therapeutic value. Mechanisms for local delivery of anti-resorptive drugs to bone around the cement may be a more effective means of overcoming hypoperfusion and inhibiting wear debris-induced osteoclast activity in the surrounding bone.

The following categories of drugs were impregnated into PMMA cement: (a) antibiotics, (b) cytotoxic drugs, and (c) non-steroidal anti-inflammatory drugs. Drugs used in combination with inorganic cements include bone morphogenic proteins, and therapeutic peptides.

PMMA includes antibiotics (Duncan, CP, Masri, BA, "The role of antibiotic-load in the treatment of infections after hip replacement").
ed cement in the treatment of an infection after a hip replacement), Ins
tructional Course Lectures, 44: 305-313, (1996); Wininger, DA, Fass,
RJ, "Antibiotics-impregnated cements and beads for orthopedic infections" (Antibioti
c-impregnated cement and beads for orthopaedic infections), Antimicrobia
l Agents and Chemotherapy, 40: 12,2675-2679, (1996); Elson, RA, Jephc
ott, AE, McGechie, DB, Verettas, D., Antibiotic-loaded Acrylic Cement, J. Bone Joint Surg., 59-B: 2,200
-205, (1977); Baker, AS, Greenham, LW, Release of Gentamicin from Acrylic Bone Cement: Elution and Diffusion Studies.
acrylic bone cement: Elution and diffusion studies), J. Bone Surg., 70A:
10,1551-1557, (1988)) and chemotherapeutic drugs (Wasserlauf, SM, Warshawsky,
A., Arad-Yelin, R., Mazur, Y., Salama, R., Dekel, S., `` The release of cytotoxic drugs from acrylic b.
one cement), Bull.Hosp.For Joint Diseases, 53: 1,68-74, (1993); Wang,
HM Galasko, CSB, Crank, S., Oliver, G., Ward, CA, Methotrexate-loaded acrylic cement in the maintenance treatment of skeletal metastases: biomechanical, biological, and systemic effects. the manag
ement of skeletal Metastases: Biomechanical, Biological and Systemic Eff
ect), Clin. Orthoped. Rel. Res. 312,173-186, (1995); Boland, P., Sparkes.
, JMP, Healey, JH, "In vivo model for local delivery of chemotherapeutic drugs to bone using polymethyl methacrylate" (Meeting abstract), Fourth Comb
ined Meeting of the American and European Muscular Skeletal Tumor Societ
ies, Washington, DC, May 6-10,1998, page 58). In one or more of the above references, PMMA was used as a support grout for prostheses and as a depot for drugs to reduce infectious complications and tumor recurrence near the implant, respectively.

[0027] Antibiotics have been incorporated into cement to treat infections around the bone and prostheses. Antineoplastics (eg, methotrexate and cis-platinium)
Has been used experimentally and anecdotally for clinical indications. It has been reported that iontophoresis facilitates the incorporation of antibiotics into allografts (Megs
on, S., Day, R., Wood, DJ, `` Iontphoresis as a means of antibiotic delivery in alogr ''
aft bone), Int.Soc. of Limb Salvage, 9th Int.Symp., Sept. 10-12,1997,
page 35, Transactions, which is hereby incorporated by reference).

In vitro studies Characterization studies using drug-PMMA constructs (Lewis, G., Nyman,
JS, Trieu, HH, "The effect of centrifugation on the fracture properties of ac"
rylic bone cements), J. Biomed. Mater. Res. (Appl. Biomater.), 38,221-22.
8, (1997); Schreurs, BW, Spierlings, PTJ, Huiskes, R., Slooff, T
JJH, "Effect of Preparation Method on Porosity of Acrylic Cement", Acta. Orth
op. Scanc., 59: 4,403-409, (1988); Rimnac, CM, Wright, TM, McGill,
DL, "Effect of centrifugation on fracture properties of acrylic bone cement", J. Bone Jo
int Surg., 68-A: 2,281-287, (1986)) demonstrated that the construct could function as a delayed release drug delivery system.

Some commercially available PMMA cements, such as “SIMPLEX®” (Howmedica,
Allendale, NJ), and studies using "PALACOS®" (Smith and Nephew, Wilimington, DE) were performed to determine the following properties.

(1) Effect of drug incorporation level in cement on the final biomechanical properties of the polymerized matrix. For gentamicin (Duncan et al., Supra), 4.5
When added more than gm / 40gm PMMA cement, the resulting polymer matrix becomes Am
Vulnerable to levels below the minimum standard set by the erican Society of Testing and Materials (ASTM).

(2) Rate of drug release from the matrix. Drug dissolution studies identified a "biphasic" dissolution profile, for example, an initial high concentration short-term sustained elution phase followed by a low concentration long-term sustained elution phase. The dissolution test also found that most of the drug remained trapped in the PMMA matrix. Dissolution studies performed with radiolabeled antibiotic tracers have shown detectable levels of drug eluting from the matrix for over two years (
Elson, RA, et al., Supra). The initial dissolution rate was found to depend on the level of drug mixed with the PMMA cement and the porosity of the final matrix. The porosity of the matrix is directly related to the drug elution rate, but is inversely related to the material strength. In addition, porosity correlates with mixing method and cement formulation. PALACOS® cement was found to have a higher porosity and consequently a faster drug dissolution rate. When the drug-PMMA mixture was centrifuged, the "strongest" matrix with minimal porosity was obtained, but the elution rate was minimal.

(3) Influence of polymerization method on drug efficacy. The activity assay demonstrated that the polymerization method used to obtain PMMA did not adversely or alter the therapeutic potential of gentamicin, methotrexate, cisplatin, and other drugs.

In vivo studies Drug delivery studies in animals and humans have demonstrated that local drug levels in the peripheral area of drug-impregnated PMMA are significantly higher than those measured after systemic administration. In addition, increased local levels have provided significant therapeutic benefits (
Duncan et al., Supra, Wininger et al., Supra, Elson et al., Supra, and Ba.
ker et al., supra). Randomized clinical trials involving hip arthroplasty using gentamicin-filled PMMA reveal significantly lower infection rates in the filled cement group than in the control cement group at 2- and 5-year follow-up periods Was. These studies also showed that antibiotic-filled cement had significant advantages over systemic antibiotic administration.

[0034] To address the problem of osteolysis in the art, the lack of an in vivo local delivery system for anti-absorbents , systemic delivery of bisphosphonates has been attempted.
However, to date, there has been no in vivo local delivery system for bisphosphonates. Citation of a document herein shall not be construed as an indication that such document is prior art to the present invention.

[0035] 3. SUMMARY OF THE INVENTION It is an object of the present invention to provide an anti-absorbable bone cement. It is a further object of the present invention to provide an anti-resorbable bone cement that allows the prosthetic implant to be bonded to bone substantially over the life of the patient.

It is a further object of the present invention to inhibit debris-induced osteolysis, particularly debris-induced osteolysis associated with hip arthroplasty, and to have a positive effect on local bone formation (eg, promotion of bone growth). And prevention of resorption).

Another object of the present invention is to provide a bone cement useful as a topical drug delivery system for delivering an anti-absorbent (eg, an anti-absorbable drug) to the prosthetic bone, such as
The purpose is to provide polymethyl methacrylate (PMMA) bone cement.

It is also an object of the present invention to provide an anti-resorbable allogeneic bone graft.

Another object of the present invention is to provide an anti-resorbable autogenous bone graft or an anti-resorbable xenograft.

It is yet another object of the present invention to slow the rate of early resorption of the implanted bone and to slow the rate of resorption of adjacent host bone induced by the implanted allograft.

In one embodiment, the present invention provides (b) a bone cement material selected from the group consisting of organic bone cement dough, inorganic bone cement dough, and composite bone cement dough;
M) a moldable composition comprising an anti-absorbing amount of one or more anti-absorbing agents. The anti-absorbent is preferably selected from the group consisting of bisphosphonates, pharmaceutically acceptable salts or esters thereof, salts of Group IIIA elements, cholesterol-lowering agents, and estrogen-bisphosphonate conjugates. More preferably, the anti-absorbent is a bisphosphonate selected from the group consisting of pamidronate, etidronate, and alendronate, or a pharmaceutically acceptable salt or ester thereof. Preferably, the bone cement dough is an acrylic bone cement dough, more preferably a polymethyl methacrylate bone cement dough.

In another embodiment, the invention provides a bone cement dough selected from the group consisting of (a) an organic bone cement dough, an inorganic bone cement dough, and a composite bone cement dough; And at least one proteinaceous or hormonal anti-absorbent.

[0043] In yet another embodiment, the invention provides a bone cement dough selected from the group consisting of: (a) an organic bone cement dough, an inorganic bone cement dough, and a composite bone cement dough; And an effective amount of a bone forming agent.

In yet another embodiment, the invention is directed to an ex-vivo bone graft that is impregnated with an anti-resorbable amount of an anti-resorbent. Preferably, the anti-absorbent is selected from the group consisting of bisphosphonates, pharmaceutically acceptable salts or esters thereof, salts of Group IIIA elements, cholesterol-lowering agents, and estrogen-bisphosphonate conjugates.

In yet another embodiment, the invention includes a method of making a moldable anti-absorbable bone cement, wherein the method is selected from the group consisting of an inorganic bone cement dough, an organic bone cement dough, and a composite bone cement dough. Contacting the bone cement material to be treated with an anti-resorbable amount of an anti-resorbent. Preferably, the anti-absorbent is selected from the group consisting of bisphosphonates, pharmaceutically acceptable salts or esters thereof, salts of Group IIIA elements, cholesterol-lowering agents, chemotherapeutic agent-bisphosphonate conjugates, and estrogen-bisphosphonate conjugates. Is done.

In another embodiment, the present invention is a method of making a moldable, anti-absorbable bone cement dough, comprising the steps of: providing an organic, inorganic, or composite bone cement dough with an anti-absorbable bone cement dough. A method comprising contacting an amount of a proteinaceous or hormonal anti-absorbent or a pharmaceutically effective amount of an osteogenic agent.

In another embodiment, the invention includes a method of making an anti-resorbable bone graft, wherein the method is selected from the group consisting of an allogeneic bone graft, an autologous bone graft, and a xenogeneic bone graft. The method comprising contacting the bone graft with a fluid vehicle containing an anti-resorbable amount of one or more anti-resorptive agents. Preferably, the anti-absorbent is selected from the group consisting of bisphosphonates, pharmaceutically acceptable salts or esters thereof, salts of Group IIIA elements, cholesterol-lowering agents, chemotherapeutic agent-bisphosphonate conjugates, and estrogen-bisphosphonate conjugates. Is done.

In a further embodiment, the invention provides a bone cement material selected from the group consisting of (a) an organic bone cement dough, an inorganic bone cement dough, and a composite bone cement dough; The invention relates to a moldable composition comprising one or more anti-absorbents and (c) a chemotherapeutic agent. Preferably, the anti-absorbent is selected from the group consisting of bisphosphonates, pharmaceutically acceptable salts or esters thereof, salts of Group IIIA elements, cholesterol-lowering agents, and estrogen-bisphosphonate conjugates. More preferably, the anti-absorbent is a bisphosphonate, and the chemotherapeutic is preferably doxorubicin or methotrexate.

In yet another embodiment, the invention is a method of reducing bone void (eg, reducing or filling a cavity or defect in bone) in a patient in need of bone void reduction, A method comprising adding an anti-absorbable moldable bone cement dough composition to the voids in an amount sufficient to reduce voids. Preferably, the moldable bone cement dough composition comprises (a) an organic bone cement dough, an inorganic bone cement dough, and a bone cement material selected from the group consisting of a composite bone cement dough, and (b) preferably, One of the anti-absorption amounts selected from the group consisting of bisphosphonates, pharmaceutically acceptable salts or esters thereof, salts of Group IIIA elements, cholesterol lowering agents, chemotherapeutic agent-bisphosphonate conjugates, and estrogen-bisphosphonate conjugates The above anti-absorbents are included.

In another embodiment, the invention includes a bone cement kit comprising a polymer component and a liquid monomer component packaged with instructions for use. The instructions for use include instructions for preparing a bone cement dough containing an anti-absorbent. Preferably, the polymer component or liquid monomer component includes an anti-absorbent.

The invention can be better understood with reference to the detailed description, drawings, and example embodiments. These references are intended to specifically describe embodiments of the present invention and are not intended to limit the present invention.

[0052] 4. Brief Description of the Drawings "(see below for a description of the drawings)" 5. DETAILED DESCRIPTION OF THE INVENTION The bone cement of the present invention can be used to attach a prosthesis, joint, or bone graft to skeletal tissue to reduce bone voids. Preferably, the bone cement of the invention is used for surgery, more preferably for dental or orthopedic surgery. The bone graft of the present invention may be used in place of conventional bone grafts in all known procedures requiring bone grafts or in any surgery involving skeletal tissue reconstruction requiring bone grafts Can be. For example, the bone cements and bone grafts of the present invention are used for surgery, including reconstruction of the hip, iliac, jaw, shoulder, wrist, head, neck, face, nasal cavity, oral cavity, breast, prostate, and knee can do. The bone cements of the present invention are particularly useful for fixing prostheses and bone grafts to living bone tissue in animals, especially mammals, and more particularly humans. The bone cement of the present invention is suitable for use with any prosthesis, such as a prosthesis comprising stainless steel, titanium, cobalt, chromium, ceramic, rubber, plastic, or silicone. is there.

As used herein, the term “ex-vivo” means ex vivo.
For example, an ex-vivo bone graft refers to a bone graft that is external to the patient prior to implanting the bone graft into the patient by implanting the bone graft into the patient's bone. For example, bone grafts (eg, allogeneic bone grafts, autologous bone grafts,
Alternatively, the bone graft may be implanted in the patient by transplanting a xenograft).

[0054] The bone cement bone cement, three basic types, ie, organic bone cement, inorganic bone cement, and composite bone cement is present. Organic bone cements include acrylic resins such as polymethyl methacrylate (PMMA) compounds, such as "SIMPLEX®" (Howmedica, Allendale, NJ), "PALACOS®" (Smith and N
ephew, Wilminton, DE), `` Zimmer® '' (Zimmer Inc., Warsaw, IN),
And "CMW" (Wright Medical Technology, Arlington, TN). Other acrylic resins useful as bone cement polymers include C ₁ -C ₁₂
Alkyl acrylates (e.g., methyl acrylate, ethyl acrylate, propyl acrylate, iso-propyl acrylate, n-butyl acrylate, sec-
Butyl acrylate, iso-butyl acrylate, tert-butyl acrylate, hexyl acrylate, heptyl acrylate, 2-heptyl acrylate, 2-ethylhexyl acrylate, 2-ethyl butyl acrylate, dodecyl acrylate, hexadecyl acrylate, 2-ethoxyethyl acrylate, isovol sulfonyl acrylate, cyclohexyl acrylate); C ₁ ~C ₁₂ - alkyl methacrylate (
For example, methyl methacrylate, ethyl methacrylate, propyl methacrylate, iso-propyl methacrylate, n-butyl methacrylate, sec-butyl methacrylate, iso-butyl methacrylate, tert-butyl methacrylate, hexyl methacrylate, heptyl methacrylate, 2-heptyl methacrylate, 2-ethylhexyl Methacrylate, 2-ethylbutyl methacrylate, dodecyl methacrylate, hexadecyl methacrylate, 2-ethoxyethyl methacrylate, isobornyl methacrylate, cyclohexyl methacrylate); polyfunctional acrylates (e.g., t-butylaminoethyl methacrylate, dimethylaminoethyl methacrylate, 2 -Hydroxyethyl methacrylate, 2-hydroxyethyl acrylate, glycidyl methacrylate, 1,4 butylene dimethacrylate); C ₁ -C ₁₂ alkylene acrylate (eg, a polymer derived from allyl acrylate and allyl methacrylate); and and methyl acrylate or methyl methacrylate, acrylonitrile, butadiene, styrene, vinyl chloride, vinylidene chloride And copolymers with ethylenically unsaturated compounds such as vinyl acetate (see, for example, US Pat. Nos. 4,791,150 and 4,064,566, which are incorporated herein by reference).

As the inorganic cement, calcium hydroxyapatite (Hayek et al. Inor
ganic Synth. 7,63-69 (1963)), apatite-wollastonite glass ceramic (Nippon Electric Glass Co., Kawanabe et al. J. B.
one Joint Surg. 80-B: 3, 527-530), and hydraulic calcium phosphate (prepared as described in Bohner et al. J. Pharm.Sci. 86: 5,565-572 (1997)). No. Composite cements are mixtures of organic or inorganic substances or salts with organic or inorganic binders. Suitable organic and inorganic binders include the organic and inorganic bone cements described above. Suitable inorganic materials suitable for use in the composite bone cement include, but are not limited to, titanium fibers and glass fibers. Organic materials suitable for use in the composite bone cement include carbon fiber and graphite,
It is not limited to these. Examples of composite bone cements include graphite-containing acrylic bone cement (US Pat. No. 4,064,566, incorporated herein by reference) and alumina-polylactic-PMMA (Vallet-Regi et al., Incorporated herein by reference).
al. J. Biomed. Mater. Res. 139, 423-428 (1998)). Salts suitable for use in the composite cement include both organic and inorganic salts, for example, tricalcium phosphate particles or sodium salicylate.

Composite bone cements include, for example, poly (propylene glycol fumarate-methyl methacrylate) matrix mixed with particles of calcium carbonate and tricalcium phosphate; polymethyl methacrylate bone cement containing titanium fibers; tricalcium phosphate Crosslinked gelatin matrix containing particles; bis-phenol-
A suspension of glass fibers in a solution of A-glycidyl-methacrylate and triethylene-glycol-dimethacrylate; a confinement of granular tricalcium phosphate in a composite matrix of gelatin, water, and sodium salicylate; carbon fibers And polymethyl (methyl methacrylate) beads impregnated with alumina.

Bone cement is generally prepared by mixing the bone cement components to provide a bone cement dough that is particularly useful in reducing bone voids in a patient. After reducing the bone void, the bone cement dough can be solidified or hardened into a bone cement. As used herein, a "bone cement component" is a material that first forms a bone cement dough when mixed. The bone cement component is optionally mixed in the presence of additional chemicals, solvents, ingredients, or materials. Bone cement dough is a moldable, bendable, stretchable, or deformable composition that can be manually shaped into a desired shape by those skilled in the art. It is possible to provide a bone cement dough with a consistency that reduces the bone cavity and preferably presses the bone cavity to fill and conform to the shape of the cavity. For example, a bone cement dough can be used to reduce bone voids created by bone reconstruction surgery. It is also possible to provide the bone cement dough with a consistency that can be injected into the bone cavity via a syringe designed to inject the bone cement dough. For example, a bone cement dough can be used to connect the prosthesis to the bone. In this case, a hole can be drilled in the bone to provide a void that can be reduced with a bone cement dough. To bone with bone cement dough,
The connecting portion of the prosthesis can be inserted. When the bone cement dough is cured, the prosthesis is bonded to the bone.

[0058] Preferably, the bone cement comprises an organic material, preferably an acrylic polymer material. Typically, acrylic bone cement comprises two components: a dry polymer component (e.g., an acrylic powder component or an acrylic particulate component, such as a polyacrylate homopolymer component or the copolymer components listed above) and a liquid monomer component. Prepared from The ingredients are mixed together, preferably at room temperature, to form a bone cement dough, and the bone cement dough is then used as desired (e.g., filling or filling bone voids during bone reconstruction surgery). Fill the bone cavity before attaching the tool to the bone),
Then it is hardened into bone cement.

Suitable liquid acrylate monomers include, for example, C ₁ -C ₁₂ alkyl acrylates (eg, methyl acrylate, ethyl acrylate, propyl acrylate, iso-propyl acrylate, n-butyl acrylate, sec-butyl acrylate, iso-butyl (Acrylate, tert-butyl acrylate, hexyl acrylate, heptyl acrylate, 2-heptyl acrylate, 2-ethylhexyl acrylate, 2-ethylbutyl acrylate, dodecyl acrylate, hexadecyl acrylate, 2-ethoxyethyl acrylate, isobornyl acrylate, cyclohexyl acrylate) ; C ₁ ~C ₁₂ - alkyl methacrylates (e.g., methyl methacrylate, ethyl methacrylate, propyl methacrylate, iso- propyl methacrylate, n- Bed Methacrylate, sec- butyl methacrylate, iso-
Butyl methacrylate, tert-butyl methacrylate, hexyl methacrylate, heptyl methacrylate, 2-heptyl methacrylate, 2-ethylhexyl methacrylate, 2-ethylbutyl methacrylate, dodecyl methacrylate, hexadecyl methacrylate, 2-ethoxyethyl methacrylate, isobornyl methacrylate, cyclohexyl methacrylate ); Polyfunctional acrylates (e.g., t-
Butylaminoethyl methacrylate, dimethylaminoethyl methacrylate, 2-
Hydroxyethyl methacrylate, 2-hydroxyethyl acrylate, glycidyl methacrylate, 1,4-butylene dimethacrylate); C ₁ -C ₁₂ alkylene acrylate (e.g., allyl acrylate and allyl methacrylate); other ethylenically unsaturated compounds (e.g., acrylonitrile , Butadiene, styrene, vinyl chloride, vinylidene chloride, and vinyl acetate); or any mixtures thereof. Combinations of any polymer component and a liquid monomer, such as any of the materials described above, are suitable for the present invention. Preferably, polymethyl methacrylate (PMMA) is the polymer component and methyl methacrylate is the monomer component. When the polymer component is an acrylic resin such as PMMA, it is preferably in the form of small polymer beads or amorphous particles. When the polymer component is PMMA powder, it generally has the consistency of flour. For example, for a typical PMMA bone cement, the polymer component may include a mixture having several particle sizes, where about 65 to about 70 percent of the polymer particles have an average diameter of about 25 microns. And about 30 to about 35 percent of the polymer beads have a diameter of about 13 to about 17 microns. The desired particle size and distribution are readily obtained by passing through a suitable screen mesh (see, for example, US Pat. No. 4,341,691 incorporated herein by reference).

The composition of the liquid monomer component of a typical bone cement (eg, US Pat. No. 4,341,691)
No. 95) to about 98 percent (by volume) of acrylic monomers, preferably methyl methacrylate monomers, about 2.5 to about 3 percent (by volume).
, And N, N-dimethyl-p-toluidine, and about 75 ppm of a stabilizer such as hydroquinone. Accelerators are added to promote curing when the liquid monomer component and the polymer component are mixed at room temperature. Other examples of accelerators for use in the present invention include amines such as N, N-hydroxypropyl-p-toluidine, N, N-dimethyl-p-aminophenetanol, trihexylamine, and trihexylamine. Octylamine; polyamines, such as N, N, N ', N'-tetramethylethylenediamine; barbituric acids, such as dimethylbarbituric acid and diethylbarbituric acid; and dimethylamino-benzene-sulfonamide; or the like. Mixtures include, but are not limited to. The stabilizer is
Advantageously, it prevents premature polymerization that can occur when the liquid monomer component and the polymer component are mixed in the presence of heat, light, or other materials. Examples of other stabilizers suitable for use in the present invention include hydroquinones and alkylated hydroquinones such as tolhydroquinone, methyl-tert-butylhydroquinone, 2,5-diquinone.
-t-butylhydroquinone, 2,6-di-tert-butyl-4-methoxyphenol, 2,5-di-t
ert-butylhydroquinone, 2,5-di-tert-amylhydroquinone, 2,6-diphenyl-4
-Octadecyloxyphenol, 2,6-di-tert-butylhydroquinone, 2,5-di-te
rt-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxyphenylstearate, and bis (3,
5-di-tert-butyl-4-hydroxyphenyl) adipate; alkylated monophenols, for example, 2,6-di-tert-butyl-4-methylphenol, 2-tert-butyl-4,6-
Dimethylphenol, and 2,6-di-tert-butyl-4-ethylphenol; alkylthiomethylphenols, for example, 2,4-dioctylthiomethyl-6-tert-butylphenol and 2,4-dioctylmethyl-6-methyl Phenols; hydroxylated thiodiphenyl ethers such as 2,2′-thiobis (6-tert-butyl-4-methylphenol) and 2,2′-thiobis (4-octylphenol); alkylidene bisphenols such as 2,2 '-Methylenebis (6-tert-butyl-4-methylphenol) and 2,2'-methylenebis (6-tert-butyl-4-ethylphenol); O-, N-, and S
-Benzyl compounds, such as 3,5,3 ', 5'-tetra-tert-butyl-4,4'-dihydroxydibenzyl ether and octadecyl-4-hydroxy-3,5-dimethylbenzylmercaptoacetate; and triazines Compounds, for example, 2,4-bis (octylmercapto) -6- (3,5-di-tert-butyl-4-hydroxyanilino) -1,3,5-triazine and 2-octylmercapto-4, 6-bis (3,5-di-tert-butyl-4-hydroxyanilino) -1,3,5-triazine; or any mixture thereof,
It is not limited to these.

The composition of the preferred bone cement polymer component includes about 80 to about 100 percent (by weight), preferably about 90 percent polymethyl methacrylate, and optionally about 9 to about 11 percent (by weight), Preferably about 10 percent barium sulfate USP is included. The presence of barium sulfate renders it radiopaque, resulting in the appearance of a cement image when the X-ray film is developed.

In addition, the polymer component may optionally include a polymerization initiator, such as benzoyl peroxide, in an amount of from about 0.5 to about 1% by weight to initiate a free radical polymerization process upon mixing of the polymer component and the liquid monomer component. , Preferably in an amount of about 0.75% by weight. Preferably, a polymerization initiator of small particles (eg, particles of a size about the same as or smaller than the particle size of the polymer component particles) is mixed with the polymer component. Alternatively, where the polymer component is in the form of beads, an initiator can be incorporated into the beads during the bead preparation process. Other initiators suitable for use in the present invention include organic peroxides such as di-tert-butyl peroxide, dicumyl peroxide, di-tert-amyl peroxide, dibenzoyl peroxide, diacetyl peroxide, diacetyl peroxide, Lauroyl peroxide, succinic peroxide, diisononanoyl peroxide, tert-butylperoxybenzoate, tert-
Butylperoxyacetate, ethyl 3,3-di- (tert-amylperoxy) -butyrate; inorganic peroxides such as potassium peroxydisulfate; and azo compounds such as 2,2′-azobis [4-methoxy -2,4-dimethyl] pentanenitrile and 2,2'-azobis [2,4-dimethyl] -pentanenitrile; or mixtures thereof, but are not limited thereto. Further examples of useful initiators are
The Encyclopedia of Chemical Technology, 1 which is incorporated herein by reference.
4 Kirk-Othomer (4 ^th ed. At 431-482).

Typically, the ratio of liquid monomer component to polymer component is about 1 gram of liquid monomer component to about 2 grams of polymer component. Generally, the liquid monomer is added to the polymer component when the liquid monomer component and the polymer component are mixed at room temperature. The resulting mixture is stirred until a bone cement dough is formed, which preferably does not adhere to the rubber glove. The bone cement dough is then kneaded to a consistency that can be applied to the bone with finger pressure or injected into a bone cavity formed, for example, by drilling a hole in the bone. The connecting part of the prosthesis
It can be inserted into bone with bone cement dough. Upon curing the bone cement dough, the prosthesis is bonded to the bone.

When the liquid monomer component is first mixed with the polymer component, the liquid monomer wets the polymer component. As the polymer component generally dissolves at least partially in the liquid monomer, the solid polymer beads begin to partially dissolve or swell in the liquid monomer. The polymerization reaction is preferably started immediately after mixing the two components. After 2 to 4 minutes, the polymerization process proceeds, and the viscosity of the initial mixture changes from a syrup-like consistency (relatively low viscosity) to a dough-like consistency (relatively high viscosity).
Changes to

For example, PMMA is a matrix suitable both for supporting prosthetic implants and for minimizing osteolytic bone resorption by delivering anti-resorptive agents to adjacent bone osteoclasts. Can function as

In one embodiment, the bone cement dough can be impregnated with one or more anti-absorbents. Upon curing the bone cement dough, a bone cement impregnated with an anti-absorbent is obtained. This embodiment is suitable when using bone cement to secure the prosthesis to living bone. Add anti-absorbent before mixing bone cement
Bone cement dough can be impregnated with an anti-absorbent by mixing with one or more bone cement components. Preferably, such mixing is performed to obtain a homogeneous mixture. In this case, the components are mixed according to methods well known to those skilled in the art. The anti-absorbent can also be mixed with the freshly prepared bone cement dough by well-known mixing methods.
PMMA bone cement is prepared by known methods (e.g., U.S. Pat.Nos. 4,064,566 and 4,341,69).
No. 1, 4,554,686, 5,334,626, 5,795,922, and 4,791,
No. 150, both of which are incorporated herein by reference) or commercially available products such as SIMPLEX®, PALACOS®, Zimmer®, or CMW® Can be obtained according to the instructions for use or the package insert included in the PMMA bone cement kit. These bone cements can be impregnated with the anti-absorbent by adding the anti-absorbent to either the polymer component or the liquid monomer component and mixing at room temperature and then mixing the two components. It is preferred to add the anti-absorbent to the polymer component and mix it before mixing the polymer component with the liquid monomer component. In addition, the bone cement may be impregnated with the anti-absorbent by sufficiently mixing the acrylic bone cement dough immediately after preparation with the anti-absorbent. Similarly, for inorganic and composite bone cements, according to the manufacturer's instructions or by standard methods well known in the art (e.g., for calcium hydroxyapatite bone cement, Denissen et al. J. Periodont. Res. 32: 42-46 (1997) and U.S. Patent No. 4,064,566 for composite bone cement, both of which are incorporated herein by reference) prior to preparing the bone cement dough with one or more anti-absorbents. Add to ingredients. In addition, the bone cement dough immediately after the preparation may be sufficiently mixed with the anti-absorbent to impregnate the bone cement with the anti-absorbent.

In another embodiment, applying the anti-absorbent to the surface of the bone cement dough (organic, inorganic, or composite cement) by contacting the pre-mixed bone cement dough with the anti-absorbent. it can. This embodiment is suitable when using bone cement dough for bone reconstruction surgery or bone void reduction. Preferably, by forming the bone cement dough in the form of a sphere and rolling the dough sphere in an anti-absorbent, preferably in the form of particles, until the outer surface of the sphere is covered with an anti-absorbent, preferably a bisphosphonate Contact with an anti-absorbent. Preferably, the spheres are covered with an anti-absorbent so as to be substantially uniformly distributed on the surface of the spheres. Preferably, the sphere is covered to such an extent that no further absorption takes up the anti-absorbent after further rolling. For example, it is possible to prepare about 60 grams (about 50 cm ³ ) of bone cement dough from a standard PMMA bone cement kit according to the manufacturer's instructions. The resulting dough was divided into 10 balls (about 6g and about 5 cm ^3, respectively), and in anti-resorptive agent is uniformly distributed over the surface of the sphere until the sphere is covered, antiresorptive which is preferably a bisphosphonate It can be rolled in the agent. The spheres can then be attached to living skeletal tissue, such as teeth, during bone reconstruction surgery, which can function as a drug delivery device.

In a preferred embodiment, when impregnating the bone cement dough with the anti-absorbent or applying the anti-absorbent to the surface of the bone cement dough, the particle size of the anti-absorbent is approximately the same as the particle size of the bone cement. Is less than or equal to. For commercial products, bisphosphonates are generally in crystalline form and must be reduced to the proper particle size. Appropriate particle size of the anti-absorbent is easily achieved by grinding or passing through an appropriately sized mesh screen.

The antiresorptive is impregnated into the bone cement dough or applied to the surface of the bone cement dough in an antiresorbable amount. As used herein, an "anti-absorbed amount" refers to an optimal amount for an extended period of time, preferably about 2 to about 4 years, more preferably about 5 to about 10 years, and most preferably about 11 to about 50 years. Means an amount of anti-resorptive sufficient to prevent loosening of the bond between the bone cement and the living bone to which the bone cement is anchored over the life of the patient. Detection of loosening of the bond between bone cement and living bone can be easily performed by a well-known method. For example, a radiologist or other skilled
By performing a Gruen zone analysis of the bone cement / osseointegration and then measuring the thickness of the radiolucent line between the bone cement and the bone, loosening of the bone cement can be detected.

[0070] The amount of anti-absorbent to be impregnated in the bone cement depends on the type of bone cement and anti-absorbent. Preferably, the anti-resorptive comprises about 1 microgram to about 11 grams per 60 grams of bone cement dough, preferably about 0.1 grams to about 10 grams per 60 grams of cement dough, more preferably about 0.5 grams per 60 grams of bone cement dough. Present in the amount. To the extent that the chemical or mechanical properties of the cement are not worse than the control cement without anti-absorbent, or the local eluting drug level is not at a level that inhibits the bone remodeling process, Higher anti-absorbent levels may also be used.

When using bone cement to secure the prosthesis to living bone, it is possible to impregnate the bone cement dough with an anti-absorbent, preferably a bisphosphonate, the amount of About 1 microgram to about 5 milligrams of the anti-absorbent per 60 grams of bone cement dough, preferably about 2 micrograms to about 0.3 milligrams of the anti-absorbent per 60 grams of bone cement dough.

In yet another embodiment, the amount of anti-resorptive impregnated in bone cement dough is the amount used for antibiotics impregnated in bone cement (eg, Duncan et al., Instructional Course Lectures, 44,305-313, (1996); Wini
nger et al., Antimicrobial Agents and Chemotherapy, 40: 12,2675-2679, (1
996); Elson et al., J. Bone Joint Surg., 59-B: 2,200-205, (1977); Baker
et al., J. Bone Surg., 70-A: 10,1551-1557, (1988), both incorporated herein by reference).

The final level of anti-absorbent to impregnate into the bone cement dough will be determined by one skilled in the art. This final level also depends on the nature and efficacy of the anti-absorbent, the type of bone cement dough, in particular, the relationship between the mechanical strength of the bone cement dough and the amount of anti-absorbent,
And the physical conditions (eg, time, temperature, etc.) required to make the bone cement dough.

When applying an anti-absorbent to the surface of a bone cement dough (organic, inorganic or composite cement) by contacting the bone cement dough with the anti-absorbent, preferably the dough surface no longer incorporates the anti-absorbent The anti-absorbent is contacted with the bone cement dough until no more.

When filling any of these anti-absorbents into these cements, the temperature stability of the anti-absorbent must be taken into consideration. For example, PMMA reaches a temperature of 70 ° C. during its polymerization. At this high level, many organic molecules, such as proteins, are inactivated. Another consideration is the hydration state of the anti-absorbent and its effect on the polymerization and hardening of the cement. For example, the PMMA polymerization reaction is adversely affected by water entrapped within the anti-absorbing salt molecule. Also, during polymerization or hardening of the cement, the anti-absorbent may chemically inhibit the chemical reactivity of the cement or may be inactivated by the chemical reactivity of the cement.

The bone cement containing the anti-absorbent according to the present invention can be produced by adding a catalyst after pre-mixing an anti-absorbent such as bisphosphonate with, for example, methyl methacrylate powder. it can.

[0077] Bone cement can be made by impregnating or mixing with an anti-absorbent, such as a bisphosphonate, but may be prepared by a surgeon (or other person skilled in the art) at the time of use. It is also possible to prepare a bone cement dough, for example in an operating room or a treatment room. The formation of a bone cement dough in this manner overcomes the existing difficulties of reducing the life of the joint replacement.

After subjecting the two components to thorough mixing, the syringe can be filled with the bone cement dough while still in a completely liquid state for injection into the area of interest. In addition, by kneading the bone cement dough for about a few more minutes, it is possible to have an appropriate consistency so as to obtain a shape suitable for placement at the fixation site.

As is well known in the art, bone cement dough, especially polymethyl methacrylate bone cement dough, cures very quickly, and if not used within a short period of time, may have irregular structures and irregularities in the bone tissue of interest. It will not effectively flow into the protruding cavity.

[0080] Preferably, the bone cement dough is added to the bone void within about 3 minutes or about 4 minutes after preparation. Even so, if the cement and prosthesis are placed at the target site early rather than later in this time, the resulting bone cement for osteosynthesis will generally be stronger. However, bleeding may occur until late in the stiffening of the cement and there is sufficient counter pressure to withstand the bleeding. One skilled in the art may need to balance competing factors that maximize cement interdigitation with factors that minimize bleeding at the cement-bone interface. If the bone cement dough is applied immediately after preparation, the bone cement dough will have a correspondingly lower viscosity and will be more likely to flow into the irregular structures of the surface and the protruding cavities. The prosthesis is then advantageously held in place for a few more minutes while the bone cement dough continues to harden.

Impregnation of Anti-Resorptive Agent in Allograft, Autograft and Xenograft The types of graft used in the present invention include allograft, autograft and xenograft. Pieces are included.

The types of allogeneic bone grafts used in the present invention include: (1) allogeneic bone grafts from another living human, (2) obtainable, for example, from a bone bank, Includes allogeneic bone grafts from corpses, or (3) freeze-dried or freeze-dried grafts.

[0083] The corpse allograft can be frozen and stored to reduce bone immunogenicity. This step may involve the use of a cryopreservative such as ethylene glycol or DMSO to maintain chondrocyte viability.

[0084] Allogeneic bone grafts may also be treated prior to implantation by any of the following methods: (1) freeze drying, (2) contact with radioactivity (eg 2 million rad) (3) desalting, e.g., using 6N HCl, to leave only the protein portion of the bone, (4) desalting allogeneic bone grafts to best treat surfaces or cavities that require bone reducing agents Formulated in a temperature sensitive putty or combined with a vehicle such as glycerin.

The freeze-drying method for storing bone grafts most effectively reduces the immunogenicity of the graft material and allows for convenient storage at room temperature in small vacuum sealed bottles.

[0086] Fresh grafts from other living humans or frozen grafts from the corpse may contain attached soft tissue ligaments and tendons.

According to the present invention, the autograft or xenograft can also be impregnated with an anti-resorptive agent. Autologous bone grafts are bone tissue that is taken from one part of the individual's skeleton and implanted into another part of the individual's skeleton. For example, bone tissue taken from a patient's iliac bone and implanted in the patient's spine. A xenogeneic bone graft is bone tissue taken from one species and implanted in a different species.

The anti-allogeneic, autologous, or xenograft is attached to the allograft, autograft, or xenograft such that the anti-absorbent is permanently and chemically bound to the allograft, autogenous, or xenograft. Methods that can be used to effectively impregnate the absorbent include the following.

(1) Iontophoresis of Bone Fragments The iontophoresis method involves placing an anti-absorbent in a fluid vehicle, preferably an aqueous vehicle, in contact with or in close proximity to the implant so that the ions are implanted in the implant. Is a useful way to deliver The fluid vehicle solution is typically carried on a first electrode pouch or receptacle. A second or dispersive electrode is placed on the implant, some proximity to the first electrode. Ions move from the medium carrying the ions through the implant by applying a suitable polar potential or voltage to the two electrodes. Control of the current is achieved by providing a sufficient voltage difference between the first and second electrodes and placing a limited resistor or other current limiting device elsewhere in the circuit.

In the present invention, iontophoresis is used to optimize the efficiency and effectiveness of anti-absorbent delivery. By increasing the current level and duration of iontophoresis, larger amounts of anti-resorptives can be attempted to migrate into the bone graft matrix. Iontophoresis enhances simple diffusion of anti-absorbents by using an electric field gradient across the bone. This increases the local concentration of the anti-absorbent and prevents premature absorption of the implant before the intended fusion can occur. Procedures and equipment for performing iontophoresis are described in U.S. Patent Nos. 5,668,120, 5,730,715 and 5,735,810, all three of which are incorporated herein by reference and used in the present invention. To be able to adapt. The implant is then removed from the vehicle and washed with water.

(2) Rapid convective diffusion of anti-absorbent solution in fluid vehicle through bone fragments into high - pressure flow anti-absorbent (such as bisphosphonate) solution into graft matrix (such as allogeneic bone graft) High pressure pumping is an effective method for delivering anti-resorptive agents (such as bisphosphonates) to bone internal regions. This method is an alternative that delivers the drug primarily to the surface of the bone. High pressure pumping involves pumping an aqueous solution of a filtered anti-absorbent (such as a bisphosphonate) at a pH of about 7.3 and a temperature of about 37 ° C. Such solutions may contain polymeric substances and / or surfactants to reduce the surface tension of the solution. In such methods, it may be necessary to use a retaining structure that is attached to the implant and serves as a point of delivery of fluid to the implant. The anti-absorbent solution is pumped through a positive pressure pump, such as a gear, piston, etc., at a pressure sufficient to move the fluid through the implant. The output pressure of the pump is above about 50 psi. A steady flow system is preferred in which the pump provides the necessary pressure to create a flow in the matrix. This pressure will be directly affected by the resistance associated with the implant matrix. The flow is
A low speed (eg, 5-10 ml / min) is preferred to promote the binding reaction of the anti-absorbent (such as bisphosphonate) to the graft matrix. The flow is advantageously continued for about one hour or until the concentration of the anti-absorbent (such as a bisphosphonate) in the incoming and outgoing streams is equal, ie, until bone saturation is indicated. Subsequently, the implant is removed from the vehicle and washed with water.

(3) Immersion of Allograft in Anti-Absorbent Solution The allograft can be immersed in the anti-absorbent solution, preferably with gentle agitation. The implant is then removed from the vehicle and washed with water.

When the allograft is impregnated using any of the three methods described above, the concentration of the anti-absorbent solution may be such that the bone graft is impregnated with the anti-absorbent within about 1 to about 5 days. Or should preferably be such that it is saturated. Bone grafts can be measured by methods known in the art (eg, concentration measurement, titration of anti-absorbent, etc.)
It is saturated if the anti-absorbent concentration in the impregnation solution is kept constant. Preferably, the concentration of the anti-absorbent solution is from about 0.1 g to about 10 g of the anti-absorbent per liter of fluid vehicle,
More preferably, the concentration is from about 1 g to about 5 g. One skilled in the art can readily adjust the concentration with anti-absorbents and fluid vehicles. The vehicle can be any fluid vehicle so long as it is soluble in water and the anti-absorbent is soluble or partially soluble in the vehicle. One of skill in the art can readily select a fluid vehicle depending on the type and size of the anti-resorptive agent and bone graft.
Preferred vehicles include water, saline or buffer solutions, glycols such as ethylene glycol and propylene glycol, aqueous glycol solutions, solutions of dimethyl sulfoxide and water, and mixtures thereof. The most preferred vehicle is water. The surface tension and viscosity of the fluid vehicle may be adjusted by including one or more polymeric substances, salts or surfactants. Suitable polymeric materials, salts and surfactants are widely available, and those skilled in the art will readily be able to select such materials depending on the anti-absorbent, fluid vehicle and impregnation method.

The implant of the present invention is effectively impregnated with an anti-resorptive agent as described above and inhibits the site of degradation of osteoclasts, thereby preventing destruction of the implant.

Accordingly, embodiments of the present invention include pretreating a graft in vitro before using the graft in vivo in a bone grafting procedure.

Reconstruction of damaged bone tissue Bone grafting is a common procedure in skeletal reconstruction and trauma surgery to re-establish skeletal integrity. Bone grafting provides (1) structural support of the skeleton primarily through cortical grafts, and (2) assistance in bone fusion to the skeleton through osteoinduction, osteoconduction and cellular mechanisms. Various methods are used to bridge the gap between bones and reduce bone cavities. A variety of materials are selected to provide the best clinical combination of fusion, biocompatibility and convenience.

As noted above, graft options include autologous bone grafts, allogeneic bone grafts, xenograft bone grafts, or of other origin. Other options for grafts include natural or foreign material, such as coral. Examples of inorganic materials include, but are not limited to, hydroxyapatite and tricalcium phosphate synthetic implants, which are readily available raw materials. These can be mixed with a protein component of bone, such as collagen, to reduce the defect and to heal the bone. Such materials are easily scraped to fit the defect or to fill the cavity.

Alternatively, materials that readily adapt to the defect in vivo, such as cement and ceramics, are used. Hydroxyapatite cement contains various concentrations of calcium and phosphorus and hardens at body temperature in an aqueous environment. Examples include dicalcium phosphate and tetracalcium phosphate.

The most commonly used method for reconstructing damaged bone tissue is to first cut and pierce the bone tissue to match the shape of the securement site of the prosthesis Preparing the bone tissue. Subsequently, a number of shallow holes are generally drilled or cut into the bone tissue surface adjacent to the prosthesis, forming a protruding cavity into which the bone-cement dough will flow, Form a strong mechanical interlock between bone cement and bone tissue.

Subsequently, blood, fatty bone marrow tissue, bone fragments, etc. are completely removed from the prepared bone surface so that the bone-cement dough is compatible with all the irregularities on the prepared bone tissue surface. Finally, especially in the case of acrylic polymer cement, the two-component unpolymerized bone cement is mixed.

Anti- Resorptive As used herein, the term “anti-resorptive” is intended to prevent or delay bone resorption in a patient when administered systemically or locally to the patient. Any known, discoverable, or discoverable substance, compound or drug. Preferably, the anti-resorptive agent, when administered to a patient, functions to inhibit osteoclast activity. Examples of classes of anti-absorbents include, but are not limited to, bisphosphonates and pharmaceutically acceptable salts or esters thereof, salts of Group IIIA elements, cholesterol-lowering agents, bisphosphonate-chemotherapeutic conjugates, estrogen- Bisphosphonate conjugates and proteinaceous or hormonal anti-absorbents such as estrogens, prostaglandins and cytokines.

As used herein, the term “cholesterol-lowering agent” means any compound, substance or drug that partially or completely inhibits the mevalonate metabolic pathway. Suitable cholesterol-lowering agents for use in the present invention include, but are not limited to, mevastatin, lovastatin, simvastatin, pravastatin and fluvastatin.

As used herein, the term “bisphosphonate-conjugate” refers to
Any compound, complex, substance or drug that includes an anti-absorbent bisphosphonate linked to another substance, compound or drug via a covalent or ionic bond. For example, a "bisphosphonate-chemotherapeutic agent conjugate" comprises an anti-absorbable bisphosphonate linked to a chemotherapeutic agent via a covalent or ionic bond, and a "bisphosphonate-estrogen conjugate" comprises a covalent or ionic bond. And anti-absorbable bisphosphonates that are linked to estrogens through Examples of bisphosphonate-estrogen conjugates are described in Bauss et al.
Calcif. Tissue. Int. 59: 3,168-73 (1996) and th of September 10-14, 1997.
e Nineteenth Annual Meeting of the American Society for Bone and Mineral
Research, abstracts S478 and S479, both of which are incorporated herein by reference. Suitable bisphosphonate-estrogen conjugates for use in the present invention include 17β-estradiol-bisphosphonate conjugates (E2-BP), such as 17β-estradiol conjugated with pamidronate, etidronate or alendronate.

As used herein, the term “estrogen” refers to any female hormone,
For example, estrone, estradiol, diethylethylbestrol (diethy
letilbestrol), diethylstilbestrol diphosphonate, progesterone, norethynodrel, norethindrone and ethinylestradiol. The term “estrogen” also includes estrogen-like compounds, such as selective estrogen receptor modulators (SERMs). Examples of estrogenic compounds suitable for use in the present invention include, but are not limited to, triphenylethylene, such as tamoxifen and its derivatives, toremifene.
, Droloxifene and idoxifene, benzothiophenes such as raloxifene and LY353381, chromans such as levormeloxifene, naphthalenes such as CP336,156, and dihydronaphthylene; An example is nafoxidine.

As used herein, the term “prostaglandin” means a C ₂₀ carboxylic acid containing a five-membered ring and has the following general formula:

[0106]

[Formula 1] And has two or more oxygen-containing functional groups (such as hydroxyl) and one or more double bonds in one of the exocyclic carbon chains. Examples of prostaglandins include, but are not limited to, misoprostol, prostaglandin E ₂ , prostaglandin F _1α and prostaglandin F _2α .

As used herein, the term “cytokine” refers to a low molecular weight, hormone-like protein secreted from cells that control the intensity and duration of an immune response. Examples of cytokines include, but are not limited to, interleukins (eg, IL-1 to IL-10), tumor necrosis factor-α, tumor necrosis factor-β, and transforming growth factor-β.

Addition of a drug such as estrogen (to provide specificity of action) to a matrix protein such as osteocalcin or a small peptide (as a vehicle providing regiospecificity) that accumulates on hydroxyapatite to confer specificity on bone It is also possible. The prototype is a (Asp) ₆ conjugate with estrogen (The Second Joint Meeting of The Americ on December 16, 1998).
an Society for Bone and Mineral Research and The International Bone and
See Mineral Society Abstract SA 231, which is hereby incorporated by reference).

[0109] Any anti-absorbent may be used in combination with one or more of any other anti-absorbents. For example, risedronate and prostaglandin E ₂ (PGE ₂ )
It is a combination with For example, "Simultaneous treatment with prostaglandin E ₂ (PGE ₂ ) and risedronate (Ris) is equally anabolic as PGE ₂ alone (Co-treatment
of prostaglandin E ₂ (PGE ₂ ) and Risedronate (Ris) is equally Anabolic as
PGE ₂ Alone) "The Nineteenth Annual Meeting of the September 10-14, 1997
See American Society for Bone and Mineral Research, abstract S472, which is incorporated herein by reference.

The anti-absorbents to be mixed with the inorganic, organic and composite bone cement doughs of the present invention include bisphosphonates, bisphosphonate analogs and Group IIIA elements (B, Al, G
a, In and Tl) salts, preferably gallium salts, such as gallium nitrate, gallium chloride, gallium fluoride, gallium sulfate and gallium citrate, preferably gallium fluoride. Bisphosphonate analogs include pharmaceutically acceptable salts thereof and phosphate esters containing one or more substitutions of phosphoric acid. The inorganic or composite bone cement contains an anti-absorbed amount of a proteinaceous or hormonal anti-absorbent, such as an estrogen, prostaglandin or cytokine. Additionally or alternatively, a pharmaceutically effective amount of an osteogenic agent, such as OP-1 (BMP-7), LIM Mineralizaton Protein 1 (LMP-1), preferably OP-1,
Or a pharmaceutically effective amount of a bone morphogenetic protein (BMP), eg, BMP-2, BMP-3, B
MP-4 or BMP-1, preferably BMP-2, BMP-3 or BMP-4 may be used. Any combination of proteinaceous or hormonal anti-absorbents and osteogenic agents may be used. As used herein, a "pharmaceutically effective amount" of an osteogenic agent or bone morphogenetic protein refers to a bone cement that does not compromise mechanical integrity, is non-toxic,
It means the amount that promotes bone formation.

BMPs were synthesized using the gene cloning method using Wozney J. et al. (Science 242: 1528-34 (
1988), incorporated herein by reference), whose biological activity in desalted bone extracts has been previously characterized and described (Urist M. Science 150 : 893-99 (1965), which is incorporated herein by reference). Recombinant BMP-2 and BMP-4 can induce new bone formation upon local injection into rat subcutaneous tissue (Wozney J. Molec Reprod Dev. 32: 160-67,
(1992), incorporated herein by reference). OP-1 (also known as BP-7) can also induce new bone growth. These factors are expressed by normal osteoblasts during their differentiation and have been shown to stimulate osteoblast differentiation and bone nodule formation in vitro and bone formation in vivo (Harris
S. et al., J. Bone Miner. Res. 9: 855-63 (1994), incorporated herein by reference). In studies of primary cultures of rat fetal calvarial osteoblasts, BMPs 1, 2, 3, 4, and 6 are expressed by cultured cells before desalted bone nodules form (Harris S. et al.
(1994), supra). Like alkaline phosphatase, osteocalcin and osteopontin, BMP is expressed by cultured osteoblasts as they proliferate and differentiate. The preparation of BMP is known in the art, see for example the procedure described in US Pat. No. 5,948,428. The patent is hereby incorporated by reference. BMP is based on Genetics Institute, Inc (Cambridge,
MA).

Anti-absorbents useful for impregnating allogeneic bone grafts, autografts or xenografts include the bisphosphonates or analogs thereof described above, or the gallium salts described above.

The anti-absorbents can be used in combination. For example, a combination of a bisphosphonate or an analog thereof, or a combination of a bisphosphonate or an analog thereof and a gallium salt is used.

Bisphosphonates can be used with inorganic, organic or composite cements. No.
Salts of Group IIIA elements, such as gallium salts, may be used with inorganic or organic cements.

The bisphosphonate may be in an acid form or a salt form. Preferably,
Bisphosphonates are the clinically most appropriate form, for example, the commercial form that is sold and used by physicians. A non-limiting example for use in the present invention is Formula I below:

Embedded image Wherein R ¹ and R ² are independently hydrogen, an alkali metal, an alkaline earth metal, a C ₁ -C ₄ quaternary ammonium cation, a C ₁ -C ₁₀ alkyl, a C ₁ -C ₁₀ unsaturated alkyl, Aryl, 2-
R ³ is hydrogen, chloro, amino, or hydroxy; chloroethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, benzyl, or p-nitrophenyl; R ⁴ and R ⁵ Is independently hydrogen, C ₁ -C ₄ alkyl, or C ₂ -C ₄ unsaturated alkyl; n is an integer from 1 to 7; X is —NH—, —O—, or —S— And y is 0 or 1; and R ⁶ is hydrogen, —NH ₂ , —N (R ⁷ ) (R ⁷ ), —N ⁺ (R ⁷ ) (R ⁷ ) (R ⁷ ), 5-7 Membered aryl or cycloalkyl group, or 5-7 membered heteroaryl or heterocyclo having 1-3 heteroatoms (one or more of which may be quaternized if the heteroatom is nitrogen) R ⁷ is each independently hydrogen or a C ₁ -C ₄ alkyl group; and R ₆ is —N ⁺ (R ⁷ ) (R ⁷ ) (R ⁷ ) or 1-3 heteroatoms. Atoms (one or more of which are quaternized If the nitrogen) is a 5-7 membered heteroaryl or heterocycloalkyl group containing, R ⁶ is chloride, bromide, ^{iodide, - - OC (O) C} 1 -C 3 alkyl R ¹ and R ² are independently sodium, potassium or ammonium cations; R ³ is hydroxy; R ⁴ and R ⁵ are independently hydrogen, C ₁ -C ₄ alkyl, or C ₂ -C ₄ unsaturated alkyl; n is an integer from 1 to 3; y is 0 or 1; ⁶ is a 5- or 6-membered heteroaryl group having 1 or 2 nitrogen atoms;
And R ⁷ is a C ₁ -C ₄ alkyl group; more preferably: n is 1; the 5- or 6-membered heteroaryl group having 1 or 2 nitrogen atoms is imidazolyl or pyridyl, Preferably, it is 1-imidazolyl or 3-pyridyl.]

In the present invention, “substituted” refers to —CN, —OH, oxo, —OC ₁ -C ₄ -alkyl, —
OC ₆ - _{aryl, -CO 2 H, -NH 2,} -NH (C 1 -C 4 - _{alkyl), - N (C 1 -C} 4 - alkyl) _2, -N
H (C ₆ - aryl), - N (C ₆ - _{aryl) 2, CO (C 1 -C} 4 - _{alkyl), - CO 2 (C 1} -C 4 - alkyl), - CO (C ₆ - aryl) , Or —CO ₂ (C ₆ -aryl) group.

As used herein, “alkyl group” means a straight-chain or branched monovalent group having no unsaturated bond containing a hydrogen atom and a carbon atom. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, hexyl, heptyl, octyl, and the like, wherein the ring structure is unsubstituted or substituted by one or more suitable substituents described above. Is also good.

As used herein, “unsaturated alkyl group” refers to a straight-chain or branched monovalent monovalent containing a hydrogen atom and a carbon atom and having at least one conjugated or non-conjugated double bond. Means a group. For example, allyl, butenyl, pentenyl, hexenyl, heptenyl, butadienyl, pentadienyl, hexadienyl and the like, the ring structure of which may or may not be substituted by one or more suitable substituents mentioned above.

As used herein, “aryl group” means a monocyclic or polycyclic aromatic group containing carbon atoms. The aromatic ring (or ring when the aryl group is polycyclic) may or may not be substituted with one or more suitable substituents described above. Examples of suitable aryl groups include phenyl, tolyl, indanyl, fluorenyl, indenyl, azulenyl and naphthyl.

As used herein, “heteroaryl group” refers to a carbon atom, preferably
Means a monocyclic aromatic ring containing 3, 4 or 5 ring-forming carbon atoms and one or more heteroatoms selected from nitrogen, oxygen and sulfur, wherein the ring comprises one or more suitable substituents May or may not be substituted. Examples of unsubstituted heteroaryl groups include, but are not limited to, furyl, pyrrolyl, imidazolyl, pyridyl, pyrazyl, pyrazolyl, pyrimidyl, thiophenyl and fienyl.

As used herein, “cycloalkyl group” refers to a carbon atom, preferably
A monocyclic group containing 5 or 6 ring-forming carbon atoms and having no unsaturated bond,
This group may or may not be substituted with one or more suitable substituents. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

As used herein, “heterocycloalkyl group” refers to a carbon atom, preferably 4 to 6 ring-forming carbon atoms, and one or more heteroatoms selected from nitrogen, oxygen and sulfur. And a monocyclic group having no unsaturated bond, wherein this ring has 1
It may or may not be substituted with more than one suitable substituent. Examples of unsubstituted heterocycloalkyl groups include pyrrolidenyl, piperidinyl, piperazinyl, morpholinyl and pyranyl.

Other preferred bisphosphonates useful in the present invention are those of formula II:

Embedded image Wherein X and Y are independently of each other OH, CH ₃ , —CH ₂ CH ₂ NH ₂ ,

Embedded image -CH ₂ -NH-C ₁ -C ₆ alkyl].

[0124] Bisphosphonates for use in the present invention can be divided into two general categories. Aminobisphosphonates and non-aminobisphosphonates.

In Formula II above, the OH group may be modified to form an analog of a bisphosphonate, for example, a pharmaceutically acceptable ester of a bisphosphonate.

Non-limiting examples of bisphosphonates for use in the present invention include alendronate (aldronic acid), etidronate (etidronic acid), and pamidronate (pamidronic acid), which have the following formula:

Embedded image It is represented by

[0127] Pharmaceutically acceptable salts of alendronate, etidronate and pamidronate are also useful.

Non-limiting examples of bisphosphonate salts for use in the present invention include alendronate sodium, and disodium etidronate and disodium pamidronate, which have the formula: :

Embedded image As used herein, the term "bisphosphonate" includes both the acid and salt forms of the bisphosphonate.

Other bisphosphonates for use in the present invention include, but are not limited to,
Risedronate, ibandronate, zoledronate, olpadronate, icandronate, and nelidronate (6-amino-1-hydroxyexilidene-1,1-bisphosphonate); 1-hydroxyethane-1,1- Bisphosphonic acid; dichloromethane bisphosphonic acid; 3-amino-1-hydroxypropane-1,1-bisphosphonic acid; 6-amino-1-hydroxyhexane-1,1-bisphosphonic acid; 4-amino-1-hydroxybutane-1, 1-bisphosphonic acid; 2- (3-pyridyl) -1-hydroxyethane-1,1-bisphosphonic acid; 2- (N-imidazoyl) -1-hydroxyethane-1,1-bisphosphonic acid; 3- (N- Pentyl-N-methylamino) -1-hydroxypropane-1,1-bisphosphonic acid; 3- (N-pyrrolidino) -1-hydroxypropane-1,1-
Bisphosphonic acid; N-cycloheptylaminomethanebisphosphonic acid; S- (p-chlorophenyl) thiomethane-bisphosphonic acid; 4-amino-1-hydroxybutylidene-1,1-
Bisphosphonic acid; (7-dihydro-1-pyringin) methanebisphosphonic acid; (7-dihydro-1-pyringin) hydroxymethanebisphosphonic acid; (6-dihydro-2-pyringin
) Hydroxy-methanebisphosphonic acid; 2- (6-pyrrolopyridine)-1-hydroxyethane-1, 1-bisphosphonic acid; and pharmaceutically acceptable salts and esters thereof. Suitable esters include hydrogens of one or more hydroxyl groups of the above bisphosphonates, wherein C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ unsaturated alkyl, aryl, 2-chloroethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, benzyl,
and those substituted by p-nitrophenyl.

The bisphosphonates used in the present invention further include the bisphosphonates described in US Pat. Nos. 5,668,120, 5,730,715 and 5,735,810. All three of these patents are incorporated herein by reference.

Useful methods for the preparation of bisphosphonates are well known in the art and involve synthetic procedures. For example, other useful bisphosphonates and methods of manufacture are described in the following patents, both of which are incorporated herein by reference: U.S. Patent Nos. 3,553,314, 3,683,080, 3,846,420. No. 3,899,496,
No. 3,941,772, No. 3,957,160, No. 3,962,432, No. 3,979,385, No.
No. 3,988,443, No. 4,113,861, No. 4,117,090, No. 4,134,969, No. 4,26
No. 7,108, No. 4,304,734, No. 4,330,537, No. 4,407,761, No. 4,469,68
No. 6, No. 4,578,376, No. 4,608,368, No. 4,621,077, No. 4,687,767, No. 4,687,768, No. 4,711,880, No. 4,719,203, No. 4,927,814, No. 4,990,503 and No. 5,019,651.

[0132] Etidronate is one which has chemical properties typical of the general class of bisphosphonates. Etidronate has been used for many years to inhibit bone resorption. However, it has been questioned because of reports that its long-term use may impair calcification (Mallmin et al., `` Short-term effects of pamidronate on biochemical markers of bone metabolism in osteoporosis-placebo versus control Short-term effects of pamidronate on biochemical markers of bone me
tabolism in osteoporosis-a placebo-controlled dose-finding study), Up
sala Journal of Medical Sciences, 96: 3, 205-212, (1991)).

Pamidronate has been shown to inhibit osteoclast activity and its recruitment from progenitor cells (Mallmin et al., Supra). On a molar basis, pamidronate is also one of the more potent bisphosphonates. These properties suggest that its action may be longer-lasting than other bisphosphonates (Fit
ton and McTavish, supra, Mallmin et al., supra).

When impregnating bone cement dough, bisphosphonates must be used without the additional buffers and the like normally found in clinical packaging.

The amount of bisphosphonate used is such that the short-term strength or long-term durability of the bone cement or allograft bone is not impaired.

The biological action of bisphosphonates must be optimized to suppress osteoclasts and to prevent osteolysis from being induced by particulate debris. Since the problem with the formation of particulate debris is time dependent, it is believed that long-term delivery of the bisphosphonate is necessary to prevent osteolytic effects. The retention of bisphosphonates in the bone matrix makes these drugs excellent choices as anti-resorptive agents.

The effects of bisphosphonates on bone resorption can be measured by radioactive indicators, bone histomorphometry or bone density, biochemical indicators, ie, serum alkaline phosphatase (SAP) activity and levels, or urinary hydroxyproline (UHP) Can be obtained by using the excretion. S
AP activity and UHP levels indicate osteoblast and osteoclast activity, respectively. Another indicator of osteoclast activity is the urinary level of n-telopeptide (NTX), which is more sensitive than UHP.

Pamidronate disodium reduces the activity of osteoclasts, as evidenced by a rapid drop in UHP levels in the early stages. Osteogenesis (eg, osteoblast activity) then continues until osteoclast activity is corrected by being corrected downward. This suggests that pamidronate disodium interferes with bone formation. However, its effects are secondary to the control of osteoclast behavior (Fitton and McTavish, supra).

The key to successful local delivery of the bisphosphonate to the bone surrounding the prosthetic implant is the time that the reduction of bone resorption lasts after the bisphosphonate has eluted from the bone cement mantle into the nearby bone.

[0140] The duration of action of pamidronate disodium can be estimated from open clinical trials with drugs for chronic bone diseases or conditions (eg, Paget's disease, osteoporosis, or malignant hypercalcemia). Harnick et al. (Harnick, HIJ, Papaoulou
s, SE, Blanksma, HJ, Moolenar, AJ, Vermeij, P., Bijvoet, OLM,
Paget's disease of the bone: early and late responses to three different treatment modalities with aminohydroxypropylidenebisphosphonate (APD) (Paget's Disease of
Bone: Early and Late Responses to Three Different Modes of Treatment wi
th Amino Hydroxy Propylidene Bisphosphonate (APD)), British Media Journ
al, 295, 1301-1305, (1987)), in patients with mild to moderate Paget's disease, administration of pamidronate for 10 days (intravenous administration group) to 6 months (oral administration group). It was found that bone resorption was reduced biochemically on average for 2.7 years. In addition, the intravenous group responded the fastest. In this study, normal SAP activity and duration of UHP excretion were used as primary indicators. Fitton and McTavish (see above)
Summarizes the duration of therapeutic effects of intravenously and orally administered bisphosphonates. Harnick and colleagues reported that in chronic disease, pamidronate disodium can be given as a single or short-term oral or intravenous dose.
It points out that bone resorption can be reduced over weeks to years. These observations suggest that local delivery of bisphosphonates is effective for several years in suppressing debris-induced osteolysis after arthroplasty.

In another embodiment of the present invention, the bone cement or bone graft of the present invention further comprises
It may contain more than one chemotherapeutic agent. According to this embodiment, the term "chemotherapeutic agent" means any substance that can be used to treat cancer in animals, preferably in mammals, more preferably in humans. In this embodiment, the anti-resorptive agent and the chemotherapeutic agent may be associated via a chemical bond or as a complex salt and may be present separately in the bone cement or bone graft. If the chemotherapeutic agent and the bisphosphonate are associated via a chemical bond or as a complex salt, the resulting compound or substance is referred to herein as a "bisphosphonate-chemotherapeutic agent conjugate." Preferably, the chemotherapeutic agent and the bisphosphonate are in the form of such a bisphosphonate-chemotherapeutic conjugate. The bisphosphonate can be any bisphosphonate, for example, any of those described above. Examples of suitable chemotherapeutic agents include, but are not limited to, daunorubicin, dactinomycin, doxorubicin, bleomycin, mitomycin, nitrogen mustard, chlorambucil, melphalan, cyclophosphamide, 6-mercaptopurine, 6-mercaptopurine Thioguanine, cytarabine (CA), 5-fluorouracil (5-FU), floxuridine (5-FUdR), methotrexate (MTX), colchicine, vincristine,
Teniposide, diethylstilbestrol (DES), aldesleukin, altamine (allutamine), anastrozle, asparaginase (asparag)
inese), live bcg vaccine, bicalutamide, busulfan, capecitabine, carbopplain, carmustine, chlorambusil, cisplatin, cladribine, cylarabine, dacarbazine (dscarbazine)
, Docetaxol, doxorubicin (encapsulated liposomes), estramustine (estra
musine), etoposide, fludarabine, fluorouracil, gum silabin (gamci
labine), gosereline, hydroxyurea, idarubicin, ifosfamide, interferon alpha, irinotecan, leuprolide acetate,
Levamisole, lomusline, mechlorethamine, megestrol acetate, melphalan, mesna, mitolanc, mitoxantrone (mitoxanrone)
), Paclitaxel (paciliaxel), pegaspergase (pegaspergase), pentostatin (pentoslatin), plicamycin (picamycin), procarbazine, riuxumab (riuxlmab), straprozosin (straplozocin), tamoxifen, thiotepa, thioguanine, topotebuma, trastuzumab Tretinoin, vinblastine, vincristine, vinorelbine, and pharmaceutically acceptable salts thereof. For other suitable chemotherapeutics, see The Merck Manual of
Diagnosis and Therapy, 15th edition, Berkow et al., 1987, Rahway, NJ, 1206-1228
See page (any compound is incorporated herein by reference).
. Preferably, the chemotherapeutic agent is doxorubicin or methotrexate, and the anti-absorbent is pamidronate. Suitable bisphosphonate-chemotherapeutic conjugates are pamidronate / doxorubicin conjugates or pamidronate / methotrexate conjugates.

If the chemotherapeutic agent has a basic moiety such as an amine, the bisphosphonate-chemotherapeutic conjugate will quench the acidic bisphosphonate with the amine to form the amine complex salt of the bisphosphonic acid / chemotherapeutic agent. Can be prepared by
For example, the amino function of doxorubicin can be quenched with the acidic function of pamidronate to obtain a bisphosphonate-chemotherapeutic conjugate of pamidronate / doxorubicin as a complex salt. Similarly, where the chemotherapeutic agent has an acidic moiety, it can be condensed by the basic group of a bisphosphonate, for example, the amino group of alendronate.

Where the chemotherapeutic agent and the bisphosphonate are associated by a chemical bond, the bisphosphonate may be chemically linked via any functional group suitable to form a chemical bond to the appropriate functional group on the chemotherapeutic agent. It may be chemically linked to the therapeutic agent. Such functional groups and their methods of attachment are within the knowledge of those skilled in the art. Preferably, when associated by chemical bonding, the bisphosphonate is chemically linked to the chemotherapeutic via one or more hydroxyl or amino groups. For example, a bisphosphonate-chemotherapeutic agent conjugate is prepared by coupling any of the alcohol, carboxylic acid, or amino moieties present on the chemotherapeutic agent to the acid functionality of the bisphosphonate by well-known chemical coupling. Yes (for example, Ma
rch, J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure,
See the procedures described in 4th Edition, 1992, 393-396; 401-402; and 419-421 (hereby incorporated by reference).

Some of the suitable bisphosphonate-chemotherapeutic conjugates for use in the present invention include AA Shtil; NS Padyukova; M. Ya. Karpeisky; and WS Dalton,
H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612 and VA Engelgardt Institute of Molecular Biology, Moscow, Russia 11798
Abstract No. 4 "Novel Bisphosphonate-Based Compounds for Circumve for Avoiding Drug Resistance in Human Tumor Cells Targeting Bone"
Drug Resistance in the Bone Targeting Human Tumor Cells), which is incorporated herein by reference.

When included in bone cement, such a chemotherapeutic agent-bisphosphonate combination uses the bone cement to reduce (preferably fill) the bone voids caused by removal of bone metastatic lesions. Particularly useful in such cases, the composite formulation functions as a therapeutic support structure, delivering chemotherapeutic agents to kill remaining tumor cells and delivering bisphosphonates to prevent bone resorption. Such bone cement is particularly useful for reducing and repairing bone voids in vertebrae after removal of tumors near the spine. Complete removal of metastatic lesions from the spine is difficult because of its location near the spinal cord, thus leaving a significant portion of the tumor behind.

As described above, as an alternative to bisphosphonates or salts of Group IIIA elements (such as gallium salts), drugs such as estrogens (which impart specificity of action) may be substituted with hydroxyapatite or osteocalcin which imparts specificity to bone. It is also possible to bind to a short-chain peptide (vehicle that imparts position specificity) that is localized on the substrate protein. The prototype is an (Asp) ₆ conjugate with estrogen.

[0147] The function of the anti-resorptive for the implant and bone cement is different. The function of the anti-absorbent in the implant is to chemically bond, preferably permanently, the anti-absorbent to the implant. In contrast, when an anti-resorptive is used in combination with bone cement, the anti-resorptive is physically encapsulated (eg, impregnated) in the bone cement rather than chemically bonded. The bone cement thus obtained releases the anti-resorptive by a leaching or passive diffusion process (generally "elution"), resulting in local delivery of the anti-resorptive to the bone in vivo.

In addition to the anti-resorptive, the bone cements and bone grafts of the present invention may further comprise one or more other biologically active substances. For example, other biologically active substances include teracosactrin, alsactide, cortisone, cortisone acetate, hydrocortisone, hydrocortisone alcohol, hydrocortisone acetate, hydrocortisone hemisuccinate, prednisolone, prednisolone terbutate, 9-α fluoroprednisolone,
Adrenal hormones and corticosteroids such as triamcinolone acetonide, dexamethasone phosphate, flunisolide, budesonide, and toxicorol pivalate; amino acids; appetite suppressants such as benzphetamine hydrochloride and chlorphentermine hydrochloride; Antibiotics such as aminoglycoside, streptomycin, gentamicin, leucomycin, penicillin and derivatives; erythromycin; antiallergic drugs; antibodies such as monoclonal or polyclonal antibodies against infectious diseases; anticholinergic drugs such as atropine base; metopimazin and metoclopramide (metoch
antipramines such as lopramide), antihistamines such as thienylperazine or antiemetic drugs having a regulating effect on small intestinal motility such as domperidone; antiepileptic drugs; anticonvulsants such as clonazepam, diazepam, nitrazepam, lorazepam; diphenhydramine hydrochloride; Antihistamines and histamines such as chloropheniramine maleate, clemastine, histamine, profenpyridamine maleate, chloroprofenpyridamine maleate, disodium cromoglycate and meclizine; antihypertensives such as clonidine hydrochloride; chymotrypsin, bromelain, Anti-inflammatory drugs (enzymes) such as serratiopeptidase; acetaminophen, aspirin, aminopyrine, phenylbutazone, mefenamic acid, ibuprofen, diclofenac sodium,
Anti-inflammatory drugs such as indomethacin, colchicine, probenecid (probenocid) and the like (non-steroidal); Disinfectants such as chlorhexidine hydrochloride, hexyl resorcinol, dequalinium chloride, ethacridine; antitussive expectorants such as cromolyn sodium, codeine phosphate, isoproterenol hydrochloride; phenyl-p-guanidinobenzoic acid, enviroxime ) antiviral agents such as, beta-adrenergic blockers, such as propranolol hydrochloride; factor VII, blood factors such as factor VIII; vitamin D ₃ such as bone metabolism controlling agents or 1 (OH), 24 (OH) and 25 ( OH) Vitamin D ₃ Other metabolites such as combinations of: bradykinin antagonists, atrial natriuretic peptides and derivatives, angiotensin II antagonists, nitroglycerin, nifedipine, isosorbide dinitrate, propranolol, clofilium tosylate (clofi
cardiovascular regulatory hormones such as liumtosylate); central nervous system stimulants such as lidocaine and cocaine; diagnostic agents such as phenolsulfonphthalein, dye T-1824, vital dye, potassium ferrocyanide, secretin, pentagastrin, cerulein; bromocriptine mesylate; Dopamine agonists; enzymes such as lysozyme chloride and dextranase; gastrointestinal hormones and derivatives such as secretin and substance P; hypothalamic hormones and derivatives such as nafarelin, buserelin, zolidex, methkephamid, leucine enkephalin , Enkephalins such as TRH (thyroid stimulating hormone releasing hormone); local anesthetics such as benzocaine, procaine, lidocaine, tetracaine; dihydroergotamine, ergomethrin, ergotamine, pizotidine migraine therapeutic substances such as pizotizin); anesthetics such as buprenorphine and naloxone; antagonists and analgesics; pancreatic hormones and derivatives such as insulin (hexamer / dimer / monomer) and glucagon; Parasympathomimetics; parasympathomimetics such as scopolamine, atropine, ipratropium; parkinsonian substances such as apomorphine; pituitary gland such as growth hormone (eg, human growth hormone), vasopressin and analogs, lippressin, oxytocin and analogs. Hormones and derivatives; protease inhibitors such as aprotinin citrate; alprazolam, bromazepam, brotizolam, camazepam, chlordiazepeoxide, clobazam,
Chlorazepic acid, clonazepam, clotiazepam, cloxazolam, delorazepam, diazepam, estazolam, ethyl loflazepate, fludiazepam, flunitrazepam, flurazepam, flutazolam, halazepam,
Haloxazolam, ketazolam, lorazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordiazepam, oxazepam, oxazolam, pinazepam, prazepam, temazepam, tetrafepane, tofezeprin, fezephemine, tofezane, tofezeprin Sympathomimetics such as xylometazoline, tramazoline, dopamine and dobutamine; thyroid hormones and derivatives such as calcitonin; vasoconstrictors such as phenylephrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline nitrate, oxymetazoline hydrochloride, tramazoline hydrochloride; It is selected from the group consisting of vasodilators such as substance P, VIP (vasoactive intestinal polypeptide).

According to another advantage of the present invention, the present invention provides a method for treating bone cement or allografts (granular large sections) with one or more anti-absorbents, such as bisphosphonates or gallium salts, before implantation. Osteolytic processes that occur frequently after implantation of a prosthetic device or allograft as part of a limb regeneration procedure. Accordingly, embodiments of the present invention provide anti-absorbents, such as bisphosphonates, at or after implantation in vivo.
It is delivered by. Anti-resorptive agents act to inhibit bone resorption and prevent osteolysis and damage to prosthetic devices.

When the anti-absorbents of the invention contained in bone cement are delivered locally, the concentration of anti-absorbents at the interface increases significantly, increasing the achievable therapeutic index. Bone cement impregnated with anti-absorbents can be used not only for implant fixation but also for local drug storage (depo
t) It can also be used as an agent and can deliver anti-absorbents at a significant level compared to systemic administration. The anti-absorbent elutes from the cement and binds to nearby bone matrix.
The combined anti-resorptive agent locally inhibits osteoclast activity, minimizing local osteolytic processes that cause prosthetic device failure.

[0151] Bisphosphonates or salts of Group IIIA elements (such as gallium salts) for incorporation into bone cement dough (eg, PMMA bone cement dough or hydroxyapatite bone cement dough) or implant (eg, allograft) Anti-absorbents provide the following advantages: (1) Anti-absorbents incorporated into organic, especially acrylic, bone cements or grafts (such as allogeneic bone grafts) can provide adequate biomedical Maintain the characteristic.

(2) Organic, especially acrylic bone cement impregnated with anti-absorbents can function as a sustained release reservoir of drugs (eg, bisphosphonates) to nearby bone areas.

(3) When an organic, especially acrylic, bone cement impregnated with an anti-absorbent is used for hip arthroplasty, (a) when the prosthetic device begins to loosen, and (b) bone biochemistry The period during which serum alkaline phosphatase, N-telopeptide (N-telopeptide) and calcium, which are the target markers, are maintained at normal levels is greatly extended.

(4) The anti-absorbent binds to local bone as it elutes from the matrix and inhibits osteoclast activity. This can reduce the need for revision surgery to correct problems associated with bone resorption.

The present invention provides an effective system for delaying or preventing rapid bone resorption, which leads to fracture of the granular allograft due to bone fusion or poor bone resorption and fracture of the large graft following repair. This can prevent the aforementioned bone resorption of the host induced by the transplantation of the allograft. In addition, local delivery of anti-resorptive agents will induce massive bone formation stimulated from the host bone bed.

In some cases, each of the 200,000 implants performed annually in the United States (each implant costs about $ 250-5,000) may be carried out by a commercial bone bank or bone product expert. It is possible to pretreat with an anti-absorbent.

The present invention also reduces resorption (prevents or reduces the gap between allograft bone and normal bone)
An orthopedic implant is provided that is improved by preventing loss of mechanical properties that often cause fracture.

The present invention also provides a relatively easy and inexpensive means to increase the effectiveness of allogeneic bone grafting for various orthopedic indications. The dosage of the anti-absorbent can be adjusted according to local requirements and is at the discretion of the skilled practitioner (eg a surgeon).
While maximizing local effects, the systemic toxicity of the anti-absorbent must be minimized. Anti-absorbents, such as bisphosphonates, are not delivered to the implant by oral or intravenous administration because the graft does not pass through blood vessels. In vitro adsorption of anti-absorbents overcomes this obstacle.

Anti-resorptives such as bisphosphonates can be permanently adsorbed to nearby bones, so that their effects can be exerted continuously.

[0160] EXAMPLES Example 1: was performed biological mechanical test for PMMA impregnated with each of the evaluation etidronate disodium and pamidronate disodium biological mechanical properties and drug delivery capabilities of the bisphosphonate impregnated PMMA. All of these exams are Howmedica's
Performed using Surgical SIMPLEX® PMMA cement.

Each test was performed 10 times as required by the US FDA. 1 and 2 summarize the tableting test of PMMA impregnated with disodium etidronate and disodium pamidronate, respectively.

For all tests, PMMA powder (basic 40 g) and the bisphosphonate drug were blended using a rotary vibrating mixer for 30 minutes. The drug levels selected for these studies (such as 0.5, 1.0, 1.5, 2.0 g / 40 g PMMA) are similar to published antibiotic drug levels (Duncan et al., Supra).

The determination of the final drug level will depend on the elution profile of the drug from the polymerized drug-cement matrix. Blending should be such that the average dissolved drug level during the first 1-2 weeks of dissolution is approximately equal to the plasma level following 10 days of intravenous administration of the drug. For pamidronate disodium, this level is 90 mg for patients weighing 70 kg (Fitton and McTavish
, Supra).

All cement-drug blends were combined with monomeric catalysts and combined with Howmedica's A
The dough was formed using an rtisan vacuum mixer. Subsequently, the dough was filled into a cement gun and poured into various molds. A domed with minimal void was created by a Howmedica vacuum blender. Several polymerized drug-cement matrix samples were cut with a diamond blade and found to have few voids.

The tableting and tension data shown in FIGS. 1 and 2 show that impregnation with disodium etidronate and disodium pamidronate does not degrade the strength of the cement. These drugs elute at therapeutically effective levels. In addition, by locally delivering the anti-absorbent to the bone area surrounding the implant,
The occurrence of loosening is reduced and the life of the implant is extended.

Example 2 Analysis of Drug Level The analysis of drug level was performed using capillary electrophoresis, HPLC and fluorescence spectroscopy techniques.

For disodium pamidronate and disodium etidronate samples from cement, bone and fluid samples, an analytical method by capillary electrophoresis (“CE”) technology is used (Leveque, D., Gallion, C., Tarral, Monteil H.). ., J
ehl, F., "Measurement of fosfomycin in biological fluids by capillary electrophoresis" (
Determination of fosfomycin in biological fluids by capillary electropho
resis), J. of Chromatography B., 655, 320-324, (1994); Olmstead, ML,
"Canine cemented total hip repl"
acements: State of the art), J. Small Animal Practice, 36, 395-399, (19
95); Peng, SX, Takigiku, R., Burton, DE, Powell, LL, "Direct pharmaceutical analysis of bisphosphonates by capillary electrophoresis" (Direct Pharmaceu
tical Analysis of Bisphosphonates by Capillary Electrophoresis), J. Chr
omatogr. B. Biomed. Sci. Appl., 709: 1, 157-160, (1998)). The detection level for these bisphosphonates is 1.0 μg / ml.

[0168] Pamidronate disodium and etidronate disodium are problematic for conventional HPLC assays because they do not have chromaphores. Pamidronate disodium has a primary amine group that readily derivatizes for high pressure liquid chromatography ("HPLC") analysis (King, LE, Veith, R.,
Extraction and Measurement of Pamidronate Disodium from Bone Samples Using Automated Precolumn Delivery: HPLC and Fluorescence Detection "(Extraction and Measure
ment of Pamidronate disodium from Bone Samples Using Automated Pre-Colum
n Derivatization, High Performance Liquid Chromatography and Fluorescenc
e Detection), Journal of Chromatography B., 678, 325-330, (1996)), but does not have etidronate disodium.

The detection limit of the King and Veith method is 0.1 μg / ml. The HPLC technique is about 10 times more sensitive than microelectrophoresis and is used to measure pamidronate disodium levels after the microelectrophoresis detection limit has been reached (this method cannot be used for etidronate disodium). Analysis of CE bisphosphonates from biological samples such as plasma and bone requires pre-analytical preparation and the approach used for the HPLC method for disodium pamidronate (King and Veith
The water solubility of bisphosphonates can be very high and bisphosphonates can have two ionized phosphate groups. CE, a new analysis technique, separates molecules based on their electric charges.

This technique is suitable for the analysis of such compounds and provides the indirect detection approach required for quantification of drug levels.

Separation was performed using a Hewlett Pac with a sensitive flow cell.
Using kard microelectrophoresis, using a 75 μm × 50 cm bare silica capillary, performed at −10 kv and monitored at 254 nm. Buffer is 1.5 mM sodium dihydrogen phosphate, 15.4 mM sodium 4-hydroxybenzoate (for indirect detection), 1
It consists of .3 mM centrimide, 25 mM lithium hydroxide and 2.5% methanol. Retention times for etidronate disodium and pamidronate disodium are 4.7 minutes and 5.6 minutes, respectively, and each drug can function as an internal standard for each other. It was confirmed that there was no interference from the PBS or bone cement aqueous extract used in the dissolution studies. The detection limit of bisphosphonate using CE is about 1
μg / ml.

Differences in electron holograms and HPLC chromatograms of microelectrophoresis, for example, the presence of additional peaks and differences in retention times compared to the internal standard strongly indicate a chemical change.

[0173] Cement drug levels of etidronate disodium or pamidronate disodium were measured from representative samples of each drug-PMMA blend after dough was polymerized for 24 hours. The aim of this analysis is to determine whether a homogeneously blended powder has been formed by the drug blending technique and to determine whether the heat generated during polymerization has changed the chemical nature of the drug. That is.

Bisphosphonate / bone containing samples were first powdered using a SPEX Freezer Mill Model 6700. The bisphosphonate was subsequently extracted from the powder by aqueous extraction and analyzed. Analysis revealed that the polymerization did not change the structure of any of the bisphosphonates. The standard electronic hologram of this drug and the drug eluted from the powdered polymerized drug-cement sample were substantially the same. No changes were observed that strongly favored the chemical change, such as additional peaks or differences in retention times. In addition, analysis of several preparations of the drug-cement matrix showed that the expected concentration was achieved and the variability was low, indicating that the cement and drug were homogeneously blended. . FIG. 3 is an electronic hologram of an eluted sample of etidronate disodium impregnated PMMA; pamidronate disodium was used as an internal standard for quantification purposes.

Example 3 Determination of Dissolution Rate One elution study was performed at 370 ° C. using pellets of disodium pamidronate impregnated PMMA in phosphate buffered saline. Table 4 shows the results of this study. Liquid samples were collected and analyzed by fluorescence spectroscopy. This technique is a simple and rapid approach for pamidronate disodium determination. Sample fluora
It was mixed with ldehyde reagent (Fischer) and read in a fluorescence spectrophotometer with an excitation wavelength of 340 nm and a fluorescence wavelength of 460 nm. Concentrations were measured using a standard curve.

Use a Simple Mathematical Model Based on the “Fick” Diffusion Principle to Analyze Elution Data
(Law, HT, Fleming, RH, Gilmore, MFX, McCarthy, ID and Hug
hes, SPF, `` In Vitro Measurement and Computer Modeling of the Diffu
sion of Antibiotic in Bone Cement, J. Biomed.Eng., 8: 2, 149-155, (198
6)). The parameters of this model are used with a mathematical model of the subsequent diffusion-adsorption process that describes the elution of the drug from the cement and its adsorption to bone. These mathematical analyzes (e.g., parameter evaluation and simulation) were performed using Macsyma / PDEase
Execute using a software package.

The present invention is not to be limited in scope by the specific embodiments disclosed in the Examples, which are intended to illustrate a few aspects of the present invention. Also, functional equivalents are within the scope of the invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to be within the scope of the appended claims.

[Brief description of the drawings]

FIG. 1 is a graph showing compressive strength versus drug level for pamidronate disodium-filled PMMA cement.

FIG. 2 is a graph showing compressive strength versus drug level for etidronate disodium-filled PMMA cement.

FIG. 3 is an electrophoretogram of an eluted sample of etidronate disodium-impregnated PMMA.

FIG. 4 is a graph showing elution of disodium pamidronate from PMMA.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI Theme coat ゛ (Reference) A61K 45/00 A61L 25/00 A A61L 27/00 A61K 37/02 (81) Designated countries EP (AT, BE , CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA , GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR , CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, K Z, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZWF terms (reference) 4C081 AB02 AC04 BB08 CA08 CD34 CE02 EA02 4C084 AA17 DA01 MA67 ZA96 ZC41 4C086 AA01 DA01 DA09 HA05 NA10 NA14 ZA96 ZC41

Claims (37)

[Claims] 1. A bone cement material selected from the group consisting of (a) an organic bone cement dough, an inorganic bone cement dough, and a composite bone cement dough, and (b) an antiresorptive having an antiresorptive amount. Moldable composition. 2. The anti-absorbent agent is selected from the group consisting of a bisphosphonate, a pharmaceutically acceptable salt or ester thereof, a salt of a Group IIIA element, a cholesterol-lowering agent, and an estrogen-bisphosphonate conjugate. The composition of claim 1. 3. The composition of claim 1, wherein said bone cement dough is an acrylic bone cement dough or a hydroxyapatite bone cement dough. 4. The composition of claim 1, wherein said anti-absorbent is a gallium salt selected from the group consisting of gallium nitrate, gallium chloride, gallium fluoride, gallium sulfate, and gallium citrate. 5. The bone cement dough is an acrylic bone cement dough and the anti-absorbent is a bisphosphonate selected from the group consisting of pamidronate, etidronate, and alendronate, or a pharmaceutically acceptable salt or ester thereof. The composition of claim 1, wherein 6. The composition of claim 5, wherein said acrylic bone cement dough contains polymethyl methacrylate. 7. The composition of claim 1, wherein said anti-absorbent is on a surface of said bone cement dough. 8. The composition of claim 1, wherein said anti-absorbent is impregnated in said bone cement dough. 9. A bone cement dough selected from the group consisting of (a) an organic bone cement dough, an inorganic bone cement dough, and a composite bone cement dough, and (b) an anti-resorbable proteinaceous or hormonal anti-absorbent A moldable composition comprising: 10. The composition of claim 9, wherein said anti-absorbent is on a surface of said bone cement dough. 11. The anti-absorbent is impregnated in the bone cement dough,
A composition according to claim 9. 12. The composition of claim 9, wherein said protein or hormonal anti-absorbent is selected from the group consisting of estrogens, prostaglandins, and cytokines. 13. A bone cement dough selected from the group consisting of: organic bone cement dough, inorganic bone cement dough, and composite bone cement dough, and (b) a pharmaceutically effective amount of an osteogenic agent. A moldable composition comprising: 14. The composition of claim 13, wherein said osteogenic agent is on a surface of said bone cement dough. 15. The bone forming agent is impregnated in the bone cement dough.
A composition according to claim 13. 16. The composition of claim 13, wherein said osteogenic agent is selected from the group consisting of OP-1, BMP-2, BMP-3, BMP-4, LMP-1, and BMP-1. object. 17. An ex-vivo bone graft impregnated with an anti-resorbable amount of an anti-resorbent. 18. The anti-absorbent may be a bisphosphonate, a pharmaceutically acceptable salt or ester thereof, a salt of a Group IIIA element, a cholesterol-lowering agent, a chemotherapeutic agent.
18. The bone graft of claim 17, wherein the bone graft is selected from the group consisting of a bisphosphonate conjugate, and an estrogen-bisphosphonate conjugate. 19. The bone graft of claim 17, wherein the bone is selected from the group consisting of an allograft, an autograft, or a xenograft. 20. The bone graft of claim 17, wherein the bisphosphonate is selected from the group consisting of pamidronate, etidronate, and alendronate, or is a pharmaceutically acceptable salt or ester thereof. 21. The bone graft of claim 17, wherein the anti-resorptive is a gallium salt. 22. The gallium salt is selected from the group consisting of gallium nitrate, gallium chloride, gallium fluoride, gallium sulfate, and gallium citrate.
A bone graft according to claim 21. 23. A method of making a moldable anti-absorbable bone cement, comprising:
A method comprising contacting a bone cement material selected from the group consisting of an inorganic bone cement dough, an organic bone cement dough, and a composite bone cement dough with an anti-resorbable amount of an anti-resorbent. 24. The anti-absorbing agent may be a bisphosphonate, a pharmaceutically acceptable salt or ester thereof, a Group IIIA element salt, a cholesterol lowering agent, a chemotherapeutic agent.
24. The method of claim 23, wherein the method is selected from the group consisting of a bisphosphonate conjugate, and an estrogen-bisphosphonate conjugate. 25. The method of claim 23, wherein said bone cement dough is an organic bone cement dough and said anti-absorbent is a bisphosphonate. 26. A method of making a moldable, anti-absorbable bone cement dough, comprising: forming an organic bone cement dough, an inorganic bone cement dough, or a composite bone cement dough.
Contacting with an anti-absorbed amount of a protein or hormonal anti-absorbent or a pharmaceutically effective amount of an osteogenic agent. 27. A method of making a moldable anti-absorbable bone cement dough, comprising: (a) mixing a polymer component with an anti-absorbing amount of an anti-absorbent to form a mixture; and (b) the mixture. Adding a liquid monomer component to the mixture. 28. The polymer component comprises polymethyl methacrylate,
28. The method of claim 27, wherein said liquid monomer component contains methyl methacrylate. 29. A method of making an anti-resorptive bone graft, comprising the steps of: isolating a bone graft selected from the group consisting of an allogeneic bone graft, an autogenous bone graft, and a xenograft bone graft; Contacting with a fluid vehicle containing an anti-absorbent. 30. The anti-absorbing agent may be a bisphosphonate, a pharmaceutically acceptable salt or ester thereof, a Group IIIA element salt, a cholesterol-lowering agent, a chemotherapeutic agent.
30. The method of claim 29, wherein the method is selected from the group consisting of a bisphosphonate conjugate, and an estrogen-bisphosphonate conjugate. 31. The composition of claim 1, further comprising a chemotherapeutic agent. 32. The composition according to claim 31, wherein said anti-absorbent is a bisphosphonate. 33. The composition of claim 32, wherein said chemotherapeutic agent and said bisphosphonate are in the form of a bisphosphonate-chemotherapeutic conjugate. 34. The composition of claim 33, wherein said chemotherapeutic agent is doxorubicin or methotrexate. 35. The method according to claim 3, wherein the bisphosphonate is pamidronate.
5. The composition according to 4. 36. A method of reducing bone void in a patient in need of reducing bone void, comprising adding the composition of claim 1 to said void in an amount sufficient to reduce said void. A method comprising: 37. The method of claim 36, wherein said bone cement contains polymethyl methacrylate and said anti-resorptive is a bisphosphonate.