1 of 11
`
`MILLENIUM EXHIBIT 2014
`Baxter Healthcare Corp. et. al. v. Millenium Biologix, LLC
`IPR2013-00582,-00583,-00590,-00591
`
`

`

`US. Patent
`
`Aug. 29, 1989
`
`4,861,733
`
`LIQUID
`
`pt3)+(4)
`
`flame)
`
`1 l | | | l |
`
`[800
`
`£600
`
`I400
`
`I200
`
`[000
`
`800
`
`2.0
`1.0
`c
`1.5
`I
`|
`CI/P "—-'
`I
`I
`ea4pzogc4)
`l
`CazP207{2)
`Ca3P208(3)
`20a0- p205
`[Ca|0(PO4)5(OH}EEI(HA}
`
`3(00 +P205
`
`4cao+ P205
`
`20f11
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`1
`
`4,861,733
`
`CALCIUM PHOSPHATE BONE SUBSTITUTE
`MATERIALS
`
`BACKGROUND OF THE INVENTION
`
`Porous carbonate echinoderm or scleractinian skele-
`tal material of marine life has a unique structure. This
`material has a uniformly permeable microporous struc-
`ture characterized by a substantially uniform pore vol-
`tune in the range from about 10 to about 90% and by a
`pronounced three-dimensional fenestrate structure. The
`microstructure of this material is somewhat similar to
`the cancellous structure characteristic of honey tissue
`or bone. Because of this unique microstructure of the
`porous carbonate echinoderm or scleractinian coral
`skeletal material of marine life these materials would
`appear to be useful as bone substitute material. How-
`ever, the carbonate of this material, such as provided in
`echinoid spine calcite and Porites skeletal aragonite, do
`not have the desired durability for employment as bone
`substitutes. These materials, however, including their
`unique above-mentioned microporous structure, have
`been replicated in other materials, such as metals, which
`would appear to possess better physical properties from
`the point of strength and durability while at the same
`time providing the distinct unique microporous struc-
`ture of the original porous carbonate coral skeletal ma-
`terial U.S. Pat. No. 3,390,107 discloses techniques, and
`products resulting therefrom, for replicating the unique
`microporous structure of the above-mentioned coral
`material including derivatives thereof.
`It is also known that the aforementioned coral materi-
`als may be converted by chemical techniques employ-
`ing a hydrothermal exchange reaction so as to convert
`the carbonate or the calcium carbonate of the coral
`material to hydroxyapatite while at the same time re-
`taining the unique microstructure of the coral material.
`U.S. Pat. No. 3,929,971 discloses a hydrothermal ex—
`change reaction for converting the porous carbonate
`skeletal material of marine life into a phosphate or hy—
`droxyapatite skeletal material possessing the same mi-
`crostructure as the carbonate skeletal material. These
`synthetic hydroxyapatite materials have been produced
`commercially and are available from Interpore Interna-
`tional Inc., Irvine, Calif., under the tradenatne Inter-
`pore-ZUO, which is derived from certain coral of the
`genus Porites which have an average pore diameter of
`about 200 um and under the tradename Interpore-SOO
`derived from certain members of the family Cloni-
`Opora,, which have pore diameters of about 500 pm.
`These special
`Interpore hydroxyapatite materials
`have also been identified as replamineform hydrox-
`yapaptite and coralline hydroxyapatite.
`lnterpore-200
`and Interpore-SGO have been found to be useful as bone
`substitute materials. More information concerning these
`materials is to be found in the article by Eugene White
`and Edwin C. Shors entitled “Biomaterial Aspects of
`Interpore-200 Porous Hydroxyapatite", which ap-
`peared in Dental clinics ofNarth America, Vol. 30, No. 1,
`January 1986. Pp- 49-67.
`In addition to the above-described materials which
`have the unique microstructure of porous skeletal coral
`material. other materials have been proposed as bone
`substitute materials,
`see U.S. Pat. Nos. 4,097,935,
`4.191366, 4,303,064 and 4,314,380. For the most part,
`however, these other bone substitute materials which
`do not possess the unique structure of coral material
`
`10
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`65
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`2
`which is possessed by Interpore-ZOO and Interpore-SOD,
`have not been completely satisfactory.
`Despite the fact that calcium phosphates have been
`well investigated, see the publication entitled Br'ocercm-
`it's of Calcium Phosphate, particularly Chapter 1 of F. C.
`M. Driessens entitled "Formation and Stability of Cal-
`cium Phosphates in Relation to the Phase Composition
`of the Mineral in Calcified Tissues", and Chapter 5 by
`Klaus deGroot entitled “Ceramics of Calcium Phos-
`phates: Preparation and Properties”, other calcium
`phosphate materials which possess the advantages and
`the unique coral-derived microporous structure of In-
`terpore—ZOO anti Interpore-SOO have not yet been satis-
`factorily produced.
`The disclosures of the above-identified patents and
`publications are herein incorporated and made part of
`this disclosure.
`The physical properties of the apatite bone substitute
`materials which possess the unique microstructure of
`skeletal material, such as Interpore-ZOO and Interpore-
`500, although satisfactory, do not provide for all the
`needs of surgeons employing the same as bone replace-
`ments and bone implant materials. For example, some
`surgeons would prefer a similar material but made up of
`a more readily absorbable or resorbable material, such
`as a material which would be absorbed by the body or
`would disintegrate within about six months to two
`years. Other surgeons would prefer to employ a similar
`such material which is more refractory, lasts about ten
`years, more or less, or be substantially permanent. The
`presently available materials, such as Interpore-ZOO and
`Interpore-SOO, possess properties semewhat intermedi-
`ate and are rather fixed since these materials are com-
`prised substantially only of hydroxyapatite.
`It is an object of this invention to provide bone substi-
`tute materials and a method for their manufacture de-
`
`rived from hydrosyapatite or other calcium phosphate
`bone substitute material having the unique microstruc-
`ture of the porous carbonate eohinoderm scleractinian
`coral skeletal material of marine life.
`It is another object of this invention to provide bone
`substitute materials derived from hydroxyapatite mate-
`rial or other calcium phosphate bone substitute material
`which has the unique microstructure of the porous car-
`bonate echinoderm or scleractinian coral skeletal mate-
`rial of marine life or the cancellous structure character-
`istic of boney tissue or bone but which is chemically
`different from hydroxapatite or the material from which
`it is derived but yet possessing substantially the same
`microstructure of the material from which it is derived
`and which is relatively more or less readily absorbable
`by the body.
`How these and other objects of the invention are
`achieved will become apparent in the light of the ac-
`companying disclosure made with reference to the ac-
`companying drawing which illustrates a portion of the
`phase diagram of the system Ca0-P105.
`SUMMARY OF THE INVENTION
`
`Calcium phosphates chemically differing from hy-
`droxapatite and useful as bone substitute materials for
`the manufacture of prosthetic devices have been pre-
`pared from hydroxyapatite material. The hydroxyapa-
`tite material employed in one embodiment of this inven—
`tion for the manufacture of these calcium phosphates is
`desirably itself useful as a bone substitute material and
`has the cancellous structure characteristic of honey
`tissue or bone or a uniformly permeable microporous
`
`30f11
`3 of 11
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`

`3
`structure characterized by a substantially uniform pore
`volume in the range from about 10—90% and by a pro—
`nounced three-dimensional fenestrate material corre-
`sponding to the microstructure of the porous carbonate
`echinoderm scleractinian coral skeletal material of ma-
`rine life.
`The calcium phosphates of this invention in accor-
`dance with one embodiment are prepared by reacting
`hydroxyapatite Cam(P04)5(Ol-Dz material which has
`the above-described microporous structure and which
`has a calcium to phosphorus atomic to phosphorus
`atomic ratio of about 1.66 with one or more other mate-
`rials, calcium or phasphorus compounds. so as to pro-
`duce a reactiOn product wherein the Ca/P ratio is less
`than 1.66 or greater than 1.66.
`Suitable such hydroxyapatite material is the above-
`described Interpore-ZOO and Interpore-SDO. The hy—
`droxy-apatite material is reacted with a phoSphate-con-
`tributing or phosphorus-contributing moiety or with a
`calcium-contributing or calcium oxide-contributing
`moiety so as to alter the calcium to phosphorus Ca/P
`atomic ratio of the resulting reaction product to yield a
`calcium phosphate material which. while retaining the
`above-described microstructure of the porous carbon-
`ate echinodernt or scleractinian coral skeletal material,
`has an altered,
`increased or decreased, calcium to
`phosphours Ca/P atomic ratio greater than 1.6 or less
`than about 1.6. The resulting calcium phosphate has a
`Ca/P atomic ratio in the range 1.
`.5, or less than 1.66
`when hydroxyapatite material is reacted with a phos»
`phate-contributing or phosphorus-contributing moiety.
`This resulting calcium phosphate material would con-
`tain tricalcium phosphate or dicalcium phosphate or
`mixtures thereof, depending upon the extent of the addi-
`tion and the reaction of the phosphate-contaming or
`phosphorus-contributing moiety with the hydroxyapa-
`the material being treated. By employing, instead of
`phosphate-contributing or
`phosphorus-contributing
`moiety for reaction with the hydroxyapatite material, a
`calcium-contributing or calcium oxide-contributing
`moiety for reaction with the hydroxyapatite material,
`there would be produced a calcium phosphate material
`which would have a Ca/P atomic ratio greater than
`. 1.66 up to about 2.0 and which would comprise tetracal-
`cium phosphate Cainog, usually a mixture of terms]-
`cium phosphate and hydroxyapatite.
`The calcium phosphates produced in accordance
`with this invention, e.g. from hydroxyapatite material,
`are produced by adding to or incorporating in the hy-
`droxyapatite material
`the phosphate-contributing or
`phosphorus-contributing moiety in the instance when it
`is desired to produce a calcium phoSphate material hav-
`ing a lower Ca/P atomic ratio in the range 1.0—1.5, such
`as a calcium phosphate material containing dicalcium
`phosphate and tricalcium phosphate, or by adding to or
`incorporating in the hydroxyapatite material a calcium-
`contributing or calcium oxide—contributing moiety
`when it is desired to produce a calcium phosphate mate-
`rial having Ca/P atomic ratio above 1.6, such as greater
`than 1.66 up to 2.0, and to produce a calcium phosphate
`material which contains therein tetracalcium phos-
`phate.
`The above-mentioned moieties for reaction with the
`calcium phosphate or hydroxyapatite material whose
`Ca/P ratio is to be altered, are added to or incorporated
`therein, preferany in the form of an aqueous solution or
`finely divided suspension, by employing water-soluble
`moieties or by employing very finely divided moieties
`
`10
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`4,861,733
`
`4
`in suspension in a suitable carrier, such as an aqueous
`suspension. These moieties are added to the hydroxyap-
`atite material so as to substantially completely and uni-
`formly occupy and coat or cover the surfaces, internal
`and external, of the hydroxyapatite or calcium phos-
`phate material undergoing treatment. By alternately
`and successively wetting and drying the material to be
`treated, a substantial layer or amount of the desired
`moiety can be deposited onto and within the material.
`Thereupon, the treated calcium phosphate material.
`such as hydroxyapatite, is heated or fired to an elevated
`temperature without melting to carry out the solid state
`reaction to effect the alteration of the Cal? atOmic
`ratio. such as from a value of about 1.6 characteristic of
`hydroxyapatite up to 2.0 characteristic of tetracalcium
`phosphate or to a lower value of 1.0 characteristic of
`dicalcium phosphate. A firing temperature up to about
`1350°—l550' C.
`is employed for the production of a
`calcium phosphate product containing tetracaclium
`phosphate or a firing temperature up to about 1275' C..
`such as a temperature in the range NOW—1250" C. for a
`dicalciurn phosphate and/or a tricalcium phosphate
`product. At these relatively firing lower temperatures
`there would be produced upon the employment of
`phosphate-contributing
`or
`phosphorus-contributing
`moiety. a resulting treated calcium phosphate which, as
`indicated, would have a Ca/P atomic ratio less than 1.6.
`such as a ratio of less than 1.5 or in the range 1.0—1.5,
`and containing dicalcium phosphate or tricalciurn phos-
`phate or mixtures thereof.
`Suitable phosphate-contributing or phosphorus-con-
`tributing moieties for use in the practice of this inven-
`tion include phosphoric acid, H3P04 the ammonium
`phosphates,
`such
`as
`diammonium phosphate
`(NH4J2HP04 and other, preferably water-soluble and
`volatilizable phosphate compounds. Suitable calcium
`oxide-contributing or calcium-contributing moieties
`useful
`in the practice of this invention include the
`water-soluble, also preferably volatilizable calcium
`compounds. Particularly useful are solutions and/or
`finely divided suspensions of calcium oxide, calcium
`hydroxide, calcium nitrate and other calcium organic
`compounds, such as calcium acetate, calcium butyrate
`and calcium propionate.
`The firing operation during which the calcium phos-
`phate material, e.g. hydroxyapatite, undergoing alter-
`ation of its Ca/P ratio to a higher or lower value along
`with the added calcium-contributing or phosphorus-
`contributing moiety is carried out in an inert or, prefera-
`bly, in an oxidizing atomosphere, e.g. in the presence of
`air or oxygen, for a sufficient period of time to effect the
`desired alteration of the Cal? ratio of the calcium phos-
`phate being fired to a higher or lower value. The lowest
`Ca/P ratio sought or desired is 1.0, equivalent to dim]-
`cium phosphate, and the highest Ca/P ratio sought or
`desired is 2, equivalent to tetracalcium phosphate.
`The duration of firing varies with the firing tempera—
`ture employed, a higher firing temperature tending to
`increase the reaction rate with the result that shorter
`firing times are experienced. For example, for the pro-
`duction of a fired calcium phospphate material having a
`Ca/P ratio of 2.0, the firing and temeprature is desirably
`carried out at a temperature in the range BOW—1550‘ C.
`The firing time is longer, about 12—24 hours, more or
`less, when carried out at a firing temperature of about
`1300“ C. and shorter. about 6-16 hours, more or less.
`when the firing temperature employed is about
`BOT-1550' C. When it is desired to produce a fired
`
`40f11
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`4,861,733
`
`5
`calcium phosphate material having a lower Ca/P ratio
`down to 1.0, the firing temperature employed is desir-
`ably in the range from about 1000 to about 1250" 0,
`preferably in the range 1000°—1125° C. A lower f'u'ing
`temperature would require a longer tiring time, in the 5
`range about 3—20 hours and a. higher firing temperature
`would yield a shorter firing time in the range 1—3 hours.
`more or less. If desired, multiple firing operations. also
`including muitiple additions of a calcium-contributing
`moiety or a phosphoric-contributing moiety, may be 10
`employed.
`The firing time required to produce the tired calcium
`phosphate product of desired quality, composition and
`Ca/P ratio, also depends upon the calcium-contributing
`or phosphorus-contributing moiety employed. Some 15
`such moieties are more effective reactive than others at
`a given firing temperature. The use of a firing adjuvant
`to improve or increase the eil'ectiveness or reactivity of
`the added calcium~contributing or phosphorus-con-
`tributing moiety to the calcium phosphate material un- 20
`dergoing firing is helpful, particularly in reducing the
`firing time required. The use of a scavenger when the
`calcium-contributing moiety or the phosphorus—con-
`tributing moiety includes one or more elements which
`would be undesirable to be present in the finished fired 25
`calcium phOSphate product, might also tend not only to
`decrease the firing time, but also increase the effective-
`ness of the calcium contributing or phosphorus-con-
`tributing moiety employed in the firing operation. In
`general, the firing operation is carried out for a sui'fi- 3t}
`cient period of time so that the finished fired calcium
`phosphate product has the desired Ca/P ratio with
`respect to the starting calcium phosphate material.
`
`BRIEF DESCRIPTION OF THE DRAWING
`The sole FIGURE of the Drawing is a binary phase
`diagram of the system CaO-ons, the phase boundaries
`for the phases of interest, Caszo-r, CaszOs and Cal’-
`209, being represented as sharp lines.
`
`35
`
`6
`tal material of marine life. said hydroxyapatite material
`having a Ca/P atomic ratio of 1.66 to a. lower Ca/P
`ratio. Specifically, experiments were carried out
`to
`convert the hydroxyapatite material to tricalcium phos-
`phate, more specifically, whitlockite beta-Castoa This
`work was carried out to produce from the hydroxyapa-
`tite material, tricalcium phosphate which is more re-
`sorbable than hydroxyapatite while at the same time
`retaining the microstructure of the starting hydroxyapa-
`tite material.
`In these tests blocks of hydroxyapatite material Inter-
`pore 500 or IP 500 measuring 15X 30X 30 mm were
`suspended from a stainless steel wire loop and iowered
`into
`a
`concentrate
`1:2
`aqueous
`solution ‘ of
`(NH4)2HP04:H20. After a two minute soaking in the
`solution,
`the blocks were removed and the treating
`solution removed by shaking the blocks. The blocks
`were placed on an alumina substrate and rotated in 90°
`increments every few minutes. After air drying for
`about 2 hours, the blocks on the alumina substrate were
`placed in a warm (50° C.) oven. The rotation was again
`continued every few minutes for an hour and the tem-
`perature increased to 80° C. and the blocks left in the
`oven overnight. The dry weight of the blocks increased
`by about 12.6%. Thereupon, the blocks were heated in
`an oven over a period of 2 i hours to about 1170‘ C. and
`maintained at about this temperature (heat soaked) for
`about 2 hours. Thereupon the blocks were reduced in
`temperature to about 100° C. or lower over a period of
`3 hours. It was observed that the final fired or heated
`weight of the blocks increased about 4.1% above the
`starting hydroxyapatite material.
`Upon examination, the fired hydroxyapatite blocks
`were found to have been converted to 60% whitlockite
`or beta-Caaons and 40% alpha-CaszO-p. Whitlockite,
`the familiar form of tricalcium phosphate, is absorbed in
`the body more readily than hydroxyapaptite and the
`tricalcium phosphate alpha-CangO-r, in turn,
`is more
`quickly absorbable than whitlocldte. From the various
`tests carried out following the above procedures and
`employing different hydroxyapatite starting material,
`the following results were obtained.
`
`BRIEF DESCRIPTION OF THE INVENTION
`Tests were carried out to alter hydroxyapatite mate-
`rial having the above-described microstructure of po-
`rous carbonate echinoderm or scleractinian coral skele-
`TABLE. NO. 1
`
`
`W
`9%:
`Added (dry)
`9'0
`Starting
`Hydroty-
`w % Phosphate
`CangOg
`%
`Hydroxy-
` apatite Run # (NMhHPOA {Whitlockite) n-Cazl'zoy apatite
`
`
`
`
`
`
`IPSOO
`HT-n
`12.6%
`50
`40
`—
`113500
`PIT-21A
`21%
`60
`40
`-—
`IPSDO
`I-lT-ZIB
`11.9
`To
`30
`—
`IPSDO
`PIT-21C
`36
`in
`it}
`—
`IP200
`l-lT-ZlD
`15
`85
`15
`—
`Bone HA HT-EB—
`29%
`85
`15
`-—
`BH-lS
`Bone HA HT-IQ-
`BH-13
`—
`40
`60
`32.8
`FIT-18A
`—
`40
`60
`32.3
`EFT-138
`15
`15
`70
`$.29}:
`HT-23A
`IPSDD
`20
`—
`70
`0.3%
`HT~23B
`IP500
`do
`—
`60
`3.0
`PIT-23C
`M00
`do
`-—
`60
`NA?
`HT-I’AA
`1135(1)
`2t}
`—-
`so
`NA?
`sir-341s
`IP10!)
`10
`l0"I
`50
`NA?
`I-lTQd-C
`IPSOO
`—
`IO"
`90
`NA?
`HT—24D
`IP20!)
`10
`10"
`30
`8.3
`HT-24E
`IP50!)
`
`
`
`
`
`5.1 90 —Eff-14FIP200 10
`‘NA - Not Available
`"Mixture of a and .343ng0}
`
`NA'
`
`90
`
`10
`
`—
`
`IPSOO
`
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`4,861,133
`
`It)
`
`8
`7
`drying and firing at 111'5° (2., the hydroxyapatite was
`Referring now to the drawing which is a binary phase
`completely convened to 5 0% whitlockite and 30-50
`diagram of the system CaO-ons, the phase boundaries
`alpha-CaszOq. In with those hydroxyapatite materials
`for the phases of interest, CangO-i. Ca2P203 and Card’-
`which had been treated to produce beta-Caszoi. the
`109, are represented as sharp lines. In the interpretation
`of this binary diagram, if the Ca/P ratio is not almost
`alpha-CaszO-r materials were considerably stronger
`than the starting hydroxyapatite material. When hy-
`exactly 1.5. then traces of either Cango-l will appear or
`traces of hydroxyapatite will remain, depending upon
`droxyapatite material was immersed in a 1:3 HgPOM-
`which side of the Castoa boundary the bulk composi-
`H10 solution and dried and at III-’5“ C., there was pro-
`tion Occurs. It should be understood.
`therefOre. that
`duced a fired material comprising 70% hydroxyapatite
`and 30% whitlockite.
`pure tricalcium phosphate crystalline would be difficult
`In the treatment of hydroxyapatite with diammonium
`to obtain and the usual result is that a less pure product
`phosphate solutions, one sample of hydroxyapatite was
`is obtained i5-10%. It is pointed out that hydroxyapa-
`immersed in a hot saturated solution of diammonium
`tite which has a nominal Ca/P ratio of 1.6 does not
`phosphate, dried and fired at 1150' C. for 2.5 hours. The
`actually plot On the diagram because it contains some
`resulting fired sample was predominantly, about 70%,
`hydroxyl groups. It was observed that the hydroxyapa— 15
`tite material tested, the IP 200 and the IP 500, main-
`whitlockite with minor amounts of hydroxyapatite,
`about 10%, and alpha-Caszo-r, about 20%. Another
`tained its hydroxyapatite crystal structure even when
`heated for 2 hours at 1350‘ C. Thus, the resulting fired
`sample of hydroxyapatite material, when immersed in a
`1:13.75 solution of (NHahHPOttd-Izo solution, and dried
`products Cangos and Cangoy derived from the result-
`ing ammonium phosphate treated hydroxyapatite were 10
`and fired at 1175° C. for 2 hours yielded a material
`comprising 30% hydroxyapatite, 70% whitlocldte and a
`not just the result of heat treatment.
`trace of alpha-Gaff)”.
`Tests were also carried out involving the heat treat-
`Another sample, 10X15>< 82 mm of hydroxyapatite.
`ment of hydroxyapatite material, such as Interpore200,
`was dipped into a 1:3 (NH4)2HP04:H10 solution for 10
`at a temperature of1500° C. and these tests did not show
`any significant conversion of hydroxyapatite to whit- 25
`minutes and dried while suspending in air. When this
`lockite.
`material was fired for 2.25 hours at 1 175° C.. the top end
`of the fired material was converted to 10% hydroxyapa-
`Additional tests were carried out involving the treat-
`tite, 80% whitlockite and 10% alpha-Caszoi. The
`ment of hydroxyapatite material, such as lnterpore-ZOO,
`bottom end of this Vertically hung piece. however.
`with a phosphorus-centributing or phosphate-con-
`presumably having a high concentration of phosphate
`tributing moiety, such as phosphoric acid, and an am- 30
`therein, was converted to 80% whitlockite and 20%
`moniurn phosphate, such as diamrnonium phosPhate
`all he
`(NH-thHPOtt In these tests the hydroxyapaptite materi-
`li‘knother similarly treated hydrOxyapatite Caszo';
`als were also immersed in or soaked in solutions of
`phosphoric acid HgPOa or (NI-I4)1HP04, dried and then
`and produced a sample was fired for 2 hours at 1175‘ C.
`finished material comprising 30% hydroxyapatite and
`fired in air at a temperature of 1115‘ C. for about 2 35
`hours. It was observed that dipping or immersing the
`70% whitlocltite with traces of alpha-CaszO-i. The
`results of these tests are set forth in accompanying
`hydroxyapaptite material in concentrated phosphoric
`Table No. 2.
`acid H3P04. followed by drying and firing at 1175“ C.
`TABLE NO. 2
`
`Time
`%
`at
`Sample
`Temp Temp % White
`% a.-
`‘1’5 B
`9% o.-
`“it: Arno
`96' Ca]-
`
`SAMPLE TREATMENT
`code
`(Hrs)
`'C. HA.
`lockite CaszCl'l
`012902): Ca{P04}1
`gonite
`cite
`HJPOs Soak
`it
`2.5
`1175 —
`15
`—
`70
`IS
`—
`—
`1:1 Hams/mo Dip
`y
`2.5
`1175 —
`so
`40
`—
`—
`—
`—
`1:1 H3P04JH10 Dip 8: Rinse
`z
`2.5
`”75
`—-—
`50
`50
`—
`—
`—
`—
`Ill WHOIHGC'MVCONI
`AT—Oi
`T2
`I” la)
`—
`--
`—
`—
`—-
`—
`l:l (Nils); + (PDQ/Coral + 1% Mg.
`AT-02
`12
`217
`90
`10
`—
`—
`—
`—
`-—
`l:l (Nile) SOLNfCoral + 1% Mg.
`«AT-D4
`T2
`21?
`90
`ID
`—-
`—
`-—
`-
`--
`0.5:5 SOLNKCOtfl-l + 1% Mg.
`«AT-05
`T2
`2!?
`50
`10
`-—
`-~
`~—-
`20
`20
`1:3 (NI-L1)H(PO.1):H10
`HT-lflB
`2.5
`“75 —
`80
`20
`~—
`—
`—
`—
`2 min. Dip a Dry
`HT-IOT
`10
`so
`11:-
`—
`—
`+
`—
`[5 min.
`1:3 HJPOJIhO
`HT~11
`10
`30
`—
`—
`—
`—
`—
`T min.
`Hams
`HT-ll
`—
`20
`—
`80
`—
`—
`—
`10 min.
`1:1 Hallow-[go
`r-rr-rs
`1115 _
`so
`40
`-
`_
`—
`—
`5 min.
`1:3 £53130sz
`HT-H-
`70
`30
`—
`—
`—
`—
`—
`6 min.
`l:l HjPOa/Hzo
`PIT-15
`—
`70
`30
`«-
`—
`—
`—
`113.75 (tonnHmon/Hzo Dip
`HT-lfi
`30
`re
`5?
`—
`--
`—
`—
`
`HA #144 Hot Sat. (thHPQ, — HT-lr as use 10 re 20 _ — —
`
`
`
`
`
`
`
`
`2.0
`
`
`
`
`
`resulted in substantially complete conversion of the
`hydroxyapatite to produce a material containing about
`15—20% whitlocitite and a major amount of the remain-
`der comprising dicalcium phosphate, particularly beta-
`Cangor. It was observed that one sample of hydroxy-
`apatite so treated contained a small amount of delta-Ca(-
`P0432. This material delta-C3004); would be unstable
`in contact with water or body fluids.
`In the above tests, when the hydroxyapatite material
`was immersed in 1:1 H3POa/I-I20 solution followed by
`
`60
`
`The above-described tests which involved the addi-
`tion of a phosphate-contributing or phosphorus-con-
`tributing moiety, such as phosphoric acid H3P04 or an
`ammonium phosphate, such as (NH4)2HP04,
`to ‘hy-
`droxyapatite material, such as Interpore-SOO and Inter-
`65 pore-200, followed by subsequent heat
`treatment or
`firing in the presence of air at an elevated temperature
`of about 1125°—1175” C. for a number of hours, such as
`1.5-2 hours, produced a material which contained tri-
`
`60f11
`6 of 11
`
`

`

`4,861,733
`
`5
`
`10
`9
`and weighed in the range 10.1—16.05 grams. The phase
`calcium phosphate. In these tests, as indicated herein-
`compositions reported in Table No. 3 were obtained by
`above, when larger amounts of the phOSphate—con-
`x-ray powder diffraction analysis
`tributing or phosphoms-contributing moiety were in-
`In the samples designated HT-25, HT-26 and PIT-27
`corporated in the hydroxyapatite undergoing treatment
`reported in Table No. 3 the blocks were handled by
`there were produced materials which contained trical-
`dipping and soaking. The pipette/wick method em-
`cium phosphate and dicalcium phOSphate. In these tests,
`ployed for the test series lit-28 and I-IT—29 controlled
`however, where the hydroxyapatite materials were
`phosphate addition at a predetermined level. It should
`immersed in a solution of phosphoric acid or diammo-
`be noted, as reported in Table No. 3, that the fired
`nium phosphate and then drained, dried and fired, it was
`not always possible to obtain reproducible results. Fur- 10 weights of the hydroxyapatite blocks were only slightly
`ther. it has been noted that when the firing of the phos-
`greater than the starting hydroxyapatite material. This
`photo-treated hydroxyapatite material was carried out
`was due not only to loss of NH4 but also to the loss
`at 1175' C. for conversion of the hydroryapatite to
`during firing of some structural hydroxyl 0H and car-
`dicalcium phosphate CaszO-g, the produced dicalcium
`bon dioxide C01.
`phosphate was in both the alpha and beta crystal form 15
`From the data presented in Table No. 3, it should be
`or structure. As indicated in the accompanying CaO-
`noted that ammonium phosphate additions, as small as
`P105 phase diagram, beta-Caszo-r is the low tempera—
`2.5% by weight. resulted in approximately 50% trical-
`ture form of dicalcium phosphate.
`cium phosphate yields. A 10% ammonium phosphate
`In order to improve reproducibility of the test results,
`addition gave 85—95% conversion. Even the addition of
`the phosphate-contributing or phosphorus-centributing 20 18% ammonium p did not eliminate some residual hy-
`moiety, i.e. the aqueous solution of H3P04. or ammo-
`droxyapatite. Based on the results reported, it would
`niurn phosphate, e.g. 1:2 (NI-I4)2HP04:H20 was pipet-
`appear that conversion of hydroxyapatite to tricalcium
`ted directly onto the hydroxyapatite material, a block of
`phosphate is preferably carried out by the so-called
`Interpore-SDO. This technique eliminated the uncer-
`pipette/wick technique for
`the addition of 12%
`tainty introduced by dipping and soaking and draining 25 (NH4)3HP04 aqueous solution (1:2 aqueous solution)
`the hydroxyapatite material into the treating solution.
`with firing at 1125” C. for 2 hours. Further, satisfactory
`When pipette additions of the treating solutiOn are made
`results would also likely be obtained by employing
`to the hydroxyapatite material, the solution does not
`more concentrated ammonium phOSphate solutions and
`immediately completely wet the entire structure. A few
`to carry out the draining and drying operations under 3
`minutes are required for the treating solution to wick 30 reduced atmospheric pressure and at slow temperature,
`into all areas or surfaces of the block. This so-called
`below room temperature.
`pipette/wick method of addition of the treating solution
`Additional tests were carried out on hydroxyapatite
`to the hydroxyapatite material was found to be satisfac-
`material, Interpore-SOO and Interpore-ZOD, for the con»
`tory and yielded more or less reproducible results. The
`version of the hydroxyapatite therein to tricalcium
`results of these tests employing the pipette/wick tech- 35 phosphate. These tests were carried out using the pipet-
`nique are set forth in accompanying Table No. 3.
`te/wick technique of phosphate addition. The results of
`
`TABLE NO. 3
`BASIC WEIGHT DATA FOR TCP RUNS
`FIRED AT 1125' C.
`$500+ Va Phosphate
`Fired
`IP500
`Sample
`Designation Weight Solution
`Addition
`Weight % HA % TCP
`H'I'v25-I
`11.15
`13.3
`4.4
`12.2
`60
`4-0
`-II
`14.1
`15.2
`2.6
`13.9
`55
`45
`-111
`10.1
`11.1
`3.3
`10.1
`50
`50
`-Iv
`12.85
`14.4
`4.0
`12s
`40
`so
`HT-‘ZE-I
`10.3
`15.9
`13.1
`10.9
`15
`85
`-II
`10.6
`16.7
`19.2
`11.3
`10
`90
`-III
`13.2
`13.9
`14.4
`13.8
`5
`95
`-1V
`10.9
`14.9
`12.2
`11.3
`5
`95
`HT-ZT-I
`11.0
`14.4
`10.3
`1 1.3
`10
`90
`-1.1
`15.8
`13.2
`5.1
`15.8
`40
`50
`-11[
`14.2
`16.5
`5.4
`14.2
`20
`30
`HT-ZS-i
`10.5
`11.3
`2.5
`10.4
`60
`4-0
`-1.1
`12.9
`14.35
`5.0
`13.0
`30
`70
`J“ 12.2
`14.95
`7.5
`12.3
`20
`30
`JV 11.35
`14.76
`10.0
`11.55
`{7
`93
`HT-29-l
`13.5
`15.55
`5.0
`13.55
`30
`70
`l
`~11
`11.55
`15.4
`111.0
`12.15
`5
`95
`1
`411
`16.65
`22.89
`12.5
`11.15
`10
`90
`
`18.5612.831V 1 15.0 13.50 5 95
`
`
`
`
`
`
`
`Addition
`Method
`1‘
`T
`1
`i
`Dip/Soak
`
`l
`l
`J,
`1‘
`T
`Pipette}
`Wick
`
`In the reported Table No. 3 tests, the hydroxyapatite 50 these tests are set forth in accompanying Table No. 4.
`blocks, Interpore-SOO blocks, measured 30X 30X 50 mm
`TABLE NO. 4
`
`% DRY
`(NHalePO4
`%
`OVEN
`91':
`WITH
`OWN
`DRY
`ADDED
`SDLN.
`DRY
`FIRED
`FIRED PHOSPHATE
`%
`‘11:
`‘16
`Sample 1‘!
`WT.
`PHOSPHATE GAIN TREATED
`WT.
`GAIN
`ADDED
`HA WI-HT fi-CAngos
`
`IP 500 Precursor
`HT-30A-1
`
`11.3
`
`13.0
`
`15
`
`11.8
`
`11.3
`
`0
`
`4.4
`
`15
`
`85
`
`—
`
`70f11
`7 of 11
`
`

`

`4,861,733
`
`12
`11
`TABLE NO. 4-continued
`% DRY
`(thnroi
`at
`oven
`a.
`WITH
`OVEN
`DRY
`ADDED
`SOLN.
`DRY
`FIRED
`FIRED PHOSPHATE
`n
`95
`%
`
`Sample ill
`WT.
`PHOSPHATE GAIN TREATED
`“'1'.
`GAIN
`ADDED
`HA WRIT B-CA2P201
`HT-EOA-II
`15.5
`20.5
`30
`16.9
`15.7
`1.3
`9.0
`5
`90
`5
`HT-SDAJII
`15.1
`21.9
`45
`17.2
`15.7
`4.0
`13.9
`1-5
`35
`10
`HT-30A-IV
`13.9
`22.2
`60
`16.5
`14.7
`5.8
`13.7
`—
`35
`15
`HT-SDA-V
`13.15
`23.8
`75
`16.6
`14.6
`7.4
`22.1
`——-
`ES
`15
`HT-30A-VI
`11.7
`[1.7
`(0.0)
`11.5
`11.3
`—3.4-
`-—-1.‘i‘
`80
`20
`—
`IP 200 Precursor
`Tr?
`90
`10
`5.0
`1.0
`10.2
`10.6
`17.4
`1 1.86
`10. l
`uT-toB-t
`—
`70
`30
`0.0
`— 1.0
`9.9
`10.0
`7.5
`10.75
`10.0
`HT‘SDB-II
`2-5
`90
`10
`5.2
`2.1
`9.9
`10.4
`30
`11.6
`9.7
`HT-303-1’II
`15
`85
`-
`12.4
`4.5
`9.3
`10.0
`45
`12.9
`8.9
`H'I'JDB-IV
`10
`90
`—
`17.6
`7.]
`9.1
`10.0
`6:}
`13.6
`8.5
`HT-loB-V
`5
`BS
`10
`5.0
`0.0
`9.9
`10.4
`21.5
`12.1
`9.9
`HT-SOB-VI
`
`HT-3DE-Vll — 9.8 9.8 (0.0) 9.8 9.6 —2.0 0.0 90 10
`
`
`
`
`
`
`
`
`
`
`.
`.
`.
`.
`1:2
`a
`4
`reported in Table No.
`In the tests
`0mm filtrate solution 10 the hydroxyapatltfi. blocks,.the
`(Nm)2HPO4:H20 Solution was employed and the
`“€3th hydroxyapatite samples were f-“,ed at 1125. C. 20 blocks were placed on a polyethylene plastic mesh in a
`for 23 hours. As indicated in Table No. 4‘ the hydroxy-
`drying oven at a temperature of 80" F. and 30% relative
`apatite sample materials readily coriverted to tricalcium
`humidity. The blue!“ were rotated at apprommately 20
`phosphate. The hydroxyapatite was substantially com-
`minute uttervals for 6 hours and left overnight in the
`.
`.
`.
`-
`-
`oven. Thereupon, the oven was heated to 75" C. and the
`ffigt‘gzisefi’efilgi‘e?$113:agilimfipgfiiflgfifisfiifiIm 25 blocks dried for about 4 hours. The resulting treated,
`In order to determine if firing temperature had an
`dried blocks were placed on an alumina. substrate and
`effect on dicalciurn phosphate yield for a given phos-
`placed In a LeMont sdxcon carbide reststance heated
`phate addition. three samples which had been fired at a
`laboratory furnace. The blocks were. heated in the pres-
`temperature of 1 125° C. were retired at a temperature of
`ence of air at a temperature of 1350 C. for a period of
`1250. C. Accompanying Table No. 5 summarizes the 30 about 7hours