PCT
`INTERNATIONAL APPLICATION PUBLISHED UNDER·THE PATENT COOPERATION TREATY (PCT)
`WO 98/08773
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`(51) International Patent Classification 6 :
`COlB 33124, A61L 27100, 25/00
`
`(II) International Publication Number:
`
`A1
`
`(43) International Publication Date:
`
`5 March 1998 (05.03.98)
`
`(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
`BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, Fl, GB, GE,
`GH, HU, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR,
`LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ,
`PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR,
`TI, UA, UG, US, UZ, VN, YU, ZW, ARIPO patent (GH,
`KE, LS, MW, SD, SZ, UG, ZW), Eurasian patent (AM, AZ,
`BY, KG, KZ, MD, RU, TJ, TM), European patent (AT, BE,
`CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL,
`PT, SE), OAPI patent (BF, BJ, CF, CG, Cl, CM, GA, GN,
`ML, MR, NE, SN, TD, TG).
`
`Published
`With international search report.
`
`(21) International Application Number:
`
`PCf/GB97/02325
`
`(22) International Filing Date:
`
`29 August 1997 (29.08.97)
`
`(30) l'riority Data:
`9618175.5
`
`30 August 1996 (30.08.96)
`
`GB
`
`(71) Applicants (for all designated States except US): ABONET(cid:173)
`ICS LIMITED [GB/GB]; Queen Mary and Westfield Col(cid:173)
`lege, University of London, Mile End Road, London El
`4NS (GB). INSTITUTO DE ENGENHARIA BIOMEDICA
`[PT/PT]; Pra~a do Coronel Pacheco, I, P-4050 Porto (PT).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): BEST, Serena, Michelle
`[GB/GB]; The Old Manse, 17 High Street, Ridgmont, Bed(cid:173)
`fordshire MK43 OTS (GB). BONFIELD, William [GB/GB];
`48 Harmer Green Lane, Digswell, Welwyn, Hertfordshire
`AL6 OAT (GB). GIBSON, lain, Ronald [GB/GB]; Ill
`Spring Garden, Aberdeen AB25 IDG (GB). JHA, Lakhan,
`Jee [IN/IN]; 14, Magistrate Colony, P.O. Ashiyana Nagar,
`Patna-800 025 (IN). SANTOS, Jose Domingos Da Silva
`[PT/PT]; Rua D., Fernando 83, P-4465 Leca Do Balio (PT).
`
`(74) Agent: BOULT WADE TENNANT; 27 Furnival Street,
`London EC4A lPQ (GB).
`
`(54) Title: SILICON-SUBSTITUTED APATITES AND PROCESS FOR THE PREPARATION THEREOF
`
`(57) Abstract
`
`The present invention provides a synthetic silicon-substituted apatite or hydroxyapatite which comprises from 0.1 % to 5 % by weight
`of silicon. The silicon-substituted apatite or hydroxyapatite material may be used as a synthetic bone material for use in bone substitution,
`implants, fillers and cements, coatings for metallic implants, and for making hydroxyapatite-polymer composites. The silicon-substituted
`apatite is prepared by reacting a calcium salt or calcium hydroxide with orthophosphoric acid or a salt of orthophosphoric acid in the
`presence of a silicon-containing compound, the molar ratio of calcium ions to phosphorous-containing ions being from l :0.5 to I :0.7 and
`the molar ratio of calcium ions to silicon-containing ions being at least I :0.2, whereby a precipitate of a silicon-substituted apatite is formed.
`On heating and/or sintering the silicon-substituted apatite at a temperature of from 500 •c to 1400 •c part or substantially all of the
`silicon-substituted apatite transforms to silicon-substituted hydroxyapatite.
`
`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 1
`
`

`

`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`Cll
`Cl
`CM
`CN
`cu
`cz
`DE
`DK
`EE
`
`Albania
`Annenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Cllte d'lvoire
`Cameroon
`China
`Cuba
`Czech Republic
`Gennany
`Denmark
`Estonia
`
`ES
`Fl
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`IIU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`Ll
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People's
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`Nt<:
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The fanner Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`Sl
`SK
`SN
`sz
`TD
`TG
`TJ
`TM
`TR
`'IT
`UA
`UG
`us
`UZ
`VN
`YU
`zw
`
`Slovenia
`Slovakia
`Senegal
`Swa1.iland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`VietNam
`Yugoslavia
`Zimbabwe
`
`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 2
`
`

`

`W098/08773
`
`PCT/GB97/02325
`
`SILICON-SUBSTITUTED APATITES AND
`PROCESS FOR THE PREPABATIQH TREBEOP
`
`The present invention relates to a silicon-
`substituted apatite and to a process for the
`preparation thereof.
`The apatite group of minerals are based on
`calcium phosphate, with naturally occurring apatite
`having a molar ratio of Ca/P of 1.67. Hydroxyapatite,
`which has the chemical formula Ca 10 (P0 4 ) dOH)z, and
`hydroxyapatite - glass composites have been used in
`the recent past as skeletal reconstitution materials
`and it has been observed that bonding of these
`bioactive materials to living tissues is achieved
`through a bone-like apatite layer formed on their
`surfaces in a body environment. Formation of a bone(cid:173)
`like apatite layer on implant material thus plays a
`vital role in osseointegration of the implant.
`K. Hata et al., J. Am. Ceram. Soc., 78, 1049-1053
`(1995) have shown that a bone-like apatite layer is
`formed on the surfaces of cao and Si02 glass-ceramics
`in simulated body fluid. It is suggested by the
`authors that the mechanism of formation of the apatite
`layer comprises the dissolution of calcium and
`silicate ions from the glass surface which helps the
`formation of an apatite layer with silicate ions
`providing nucleation sites. Another mechanism
`proposed by Hench et al., J. Biomed. Mater. Res., 2,
`117, 1971 is that the pH of the surface of the implant
`becomes alkaline due to dissolution of ions which in
`turn causes supersaturation resulting in the
`precipitation of a bone-like apatite layer. Other
`mechanisms have also been suggested, including the
`proposal by Li et al., J. Mater. Sci. Mater. Med.,
`3, 452, 1992, that dissolution of amorphous calcium
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`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 3
`
`

`

`W098/08773
`
`PCT/GB97/02325
`
`-
`
`2 -
`
`phosphate from the glass creates a negatively charged
`surface which attracts calcium ions to the implant
`surface and finally forms an apatite layer.
`Silicate sulphate apatite has been synthesised by
`a solid state method, K.S. Leshkivich et al., J.Mater.
`Sci. Mater. Med., 4, 86-94, 1993, and found excellent
`biocompatability in vivo tests and this material has
`been suggested for use as a low-load bearing bone
`graft material.
`Silicon has been shown, in small quantities, to
`have a significant effect on the development and
`growth of the hard tissue of living bodies.
`EP-A-0 540 819 relates to calcium phosphate and
`calcium carbonate materials with antibacterial
`properties, in which these materials are used as a
`carriers for silver and silicon.
`JP-A-7165518 relates
`to an antibacterial inorganic powder.
`JP-A-7008550
`relates to a hydroxyapatite material for use in
`surgical replacement which contains Ba, Bi, Zr, Sr or
`Si to improve X-ray contrast.
`JP-A-60024848 relates
`to a tooth or bone repair composition comprising a
`mixture of apatite derived from the bones of fish or
`mammals and an oxide of Zr, Al, Si and Zn.
`We have now developed a silicon-substituted
`apatite material which has a much higher bioactivity
`than that of pure hydroxyapatite and which may be used
`as a synthetic bone material.
`Accordingly, the present invention provides a
`synthetic silicon-substituted apatite or
`hydroxyapatite which comprises from 0.1 to 5% by
`weight of silicon. By the term silicon-substituted is
`meant that silicon is substituted into the apatite
`crystal lattice and is not merely added, in contrast
`to the prior art. It is believed that the silicon
`enters the lattice on the phosphate site. The silicon
`
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`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 4
`
`

`

`W098/08773
`
`PCT/GB97/02325
`
`-
`
`3 .-
`
`is though to exist and/or substitute as a silicon ion
`or as a silicate ion.
`The silicon-substituted apatite or hydroxyapatite
`material according to the present invention may be an
`essentially single phase pure material.
`Preferably, the synthetic silicon-substituted
`apatite or hydroxyapatite comprises from about 0.1 to
`about 1.6%, more preferably from about 0.5 to about
`1.0% by weight of silicon.
`The present invention also provides for the
`preparation of a stoichiometric silicon-substituted
`apatite which, when heated and optionally sintered at
`a temperature of from about 500°C to 1400°C, for
`example at about 1200°C, produces an essentially
`single phase material with a crystal structure
`comparable to pure hydroxyapatite. The present
`invention therefore allows for the production of an
`essentially phase pure material of silicon-substituted
`hydroxyapatite, which contains substantially no
`impurity phases, such as calcium oxide or tricalcium
`phosphate (TCP).
`The silicon-substituted apatite or hydroxyapatite
`material may be used as a synthetic bone material,
`including dental materials, for example for use in
`bone substitution, implants, fillers and cements,
`coatings for metallic implants, and for making
`hydroxyapatite-polymer composites.
`In another aspect the present invention provides
`a process for the preparation of a silicon-substituted
`apatite, which process comprises reacting a calcium
`salt or calcium hydroxide with orthophosphoric acid or
`a salt of orthophosphoric acid in the presence of a
`silicon-containing compound, the molar ratio of
`calcium ions to phosphorous-containing ions being from
`about 1:0.5 to about 1:0.7 and the molar ratio of
`
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`
`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 5
`
`

`

`W098/08773
`
`PCT/GB97/02325
`
`- 4.-
`
`calcium ions to silicon-containing ions being at least
`about 1:0.2, whereby a precipitate of a silicon(cid:173)
`substituted apatite is formed. Under these conditions
`it is believed that the silicon-containing compound
`yields silicon-containing ions, such as silicon ions
`and/or silicate ions for example, which substitute in
`the apatite lattice.
`The molar ratio of calcium ions to phosphorous
`ions is preferably from about 1:0.55 to about 1:0.65
`and the molar ratio of calcium ions to silicon ions is
`preferably at least about 1:0.16.
`The process of the present invention is
`advantageously carried out by reacting an aqueous
`solution comprising a calcium salt or calcium
`hydroxide and a silicon-containing compound at a pH of
`from about 9 to about 13 with an aqueous solution
`comprising a salt of orthophosphoric acid at a pH of
`from about 9 to about 13. The calcium salt is
`preferably calcium nitrate and, in particular, calcium
`nitrate 4-hydrate. The salt of orthophosphoric is
`preferably diammonium orthophosphate or triammonium
`orthophosphate. The pH of the aqueous solution of the
`calcium salt and/or the pH of the aqueous solution of
`the salt of orthophosphoric acid is preferably
`adjusted using ammonia, for example concentrated
`aqueous ammonia. The preferred pH of each solution is
`about pH 11.
`An alternative way of carrying out the process of
`the present invention comprises reacting an aqueous
`solution of calcium hydroxide and a silicon-containing
`compound with an aqueous solution of orthophosphoric
`acid. The pH of the aqueous solution of calcium
`hydroxide is preferably from about 10 to about 14,
`more preferably about 12.3. The pH of the aqueous
`solution of orthophosphoric acid is preferably from
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`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 6
`
`

`

`W098/08773
`
`PCT/GB97/02325
`
`-
`
`5
`
`l""
`
`about 1 to about 3, more preferably from about 1 to
`about 1.5.
`In each of the embodiments of the process of the
`invention the silicon-containing compound preferably
`comprises a silicon salt, such as a silicon
`carboxylate. Advantageously the silicon-containing
`compound comprises silicon acetate and, in particular,
`silicon acetate 4-hydrate.
`The precipitated silicon-substituted apatite may
`be separated from the reaction mixture by, for
`example, filtration, and then washed and dried to
`result in a silicon-substituted apatite material. The
`dried filter cake material may then be powdered using
`conventional techniques.
`The dried silicon-substituted apatite material
`may then be heated and optionally sintered using
`conventional techniques, for example at a temperature
`of about 1200°C. Upon heating, the silicon(cid:173)
`substituted apatite material transforms to a silicon-
`substituted hydroxyapatite material, although some of
`the material may decompose to a mixture of
`hydroxyapatite and calcium oxide or hydroxyapatite and
`tricalcium phosphate (TCP), depending on the chemical
`composition of the material. If formed, then
`preferably substantially all of the TCP is a TCP.
`Ideally, little or no decomposition of the silicon(cid:173)
`substituted apatite material occurs upon heating,
`thereby resulting in an essentially phase pure
`material of silicon-substituted hydroxyapatite. A
`phase purity, as measured by x-ray diffraction, of at
`least 98% can be achieved, preferably at least 99%,
`more preferably approximately 100%. Because certain
`phases, for example TCP, are soluble in body fluids, a
`high phase purity is beneficial to the long-term
`stability of the material. It will be appreciated,
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`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 7
`
`

`

`W098/08773
`
`PCT/GB97/02325
`
`-
`
`6 -:
`
`however, that a range of materials containing silicon(cid:173)
`substituted hydroxyapatite in varying amounts may be
`prepared in accordance with the present invention
`depending on the concentrations of the various
`reactants. For example, two phase materials
`comprising silicon-substituted hydroxyapatite and TCP
`or calcium oxide can still usefully be used and are
`intended to fall within the scope of the present
`invention.
`The present invention will now be described
`further, by way of example, with reference to the
`following drawing, in which:-
`Figure 1 shows the distribution of x-ray
`intensity for the hydroxyapatite material of Example 6
`(discussed below).
`The present invention will be further described
`with reference to the following Examples.
`
`EXAMPLE 1
`
`141.69g of calcium nitrate 4-hydrate was
`dissolved in 600ml of double distilled water. The pH
`of solution was adjusted to about 11.0 using a
`concentrated ammonia solution. 1200ml of double
`distilled water was then added to the solution. The
`solution was filtered. 8.46g of silicon acetate 4-
`hydrate was added to the constantly stirred calcium
`nitrate solution. The solution was heated at about
`65°C for about one hour, with stirring. Most of the
`silicon acetate 4-hydrate dissolved in the solution
`and only a very little remained suspended in the
`solution. The solution was constantly stirred and
`cooled down to the pre-determined temperature of the
`experiment. The solution was named as Solution A.
`47.54g of diammonium hydrogen orthophosphate was
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`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 8
`
`

`

`W098/08773
`
`PCT/GB97/02325
`
`- 7 -:
`
`dissolved in 360ml of double distilled water. The pH
`of the solution was adjusted to about 11 using a
`concentrated ammonia solution. 480ml of double
`distilled water was then added to the constantly
`stirred solution. The solution was filtered. The
`solution was named as Solution B.
`Solution B was added dropwise to constantly
`stirred Solution A at the predetermined temperatures
`of 3°, 25°, 60° and 90°C over a period of about 2
`hours. The precipitates so formed (A,B,C and D,
`respectively) were each agitated at room temperature
`for one hour and left overnight. Each precipitate was
`filtered using a Buchner funnel and washed several
`times using double distilled water. The filter cakes
`were dried for about 20 hours in a drier at about 85°C
`in filtered air. The dried materials were powdered
`using a pestle and mortar.
`The microstructures of the precipitates were
`studied using a JEOL 100 ex transmission electron
`microscope (TEM). Carbon coated 200 mesh copper grids
`were dipped in a dilute suspension of the precipitate
`and examined in the bright field mode at a
`magnification of 50000x using an accelerating voltage
`of 100 kV. The TEM micrographs indicated that the
`precipitate had a spheroidal shape when precipitated
`at 3°C and an increasingly acicular shape when
`precipitated at 60° and 90°C.
`X-ray diffraction studies of powdered samples
`were performed using a Siemens 05000 diffractometer.
`cuKa radiation (Ka = 1. 5418 A) was used with a linear
`position sensitive detector and a nickel diffracted
`beam monochromator.
`Fourier transform infrared Nicolet 800
`spectrometer (FTIR) with a Mtech photoacoustic (PAS)
`cell was used to analyse the powered samples. Spectra
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`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 9
`
`

`

`W098/08773
`
`PCT/GB97/02325
`
`-
`
`8
`
`...
`
`were obtained at 4 cm- 1 resolution averaging 128 scans.
`The FTIR spectra of the samples precipitated at 3° and
`25°C showed phosphate bands at 1085, 1030, 961,600 and
`563 cm- 1
`, carbonate bands at 1455, 1418, 1327 and 883
`cm- 1 and a hydroxyl band at 3567 cm- 1 with a broad
`peak.
`A GBC Integra XM sequential inductively coupled
`plasma spectrometer (ICPS) was used to analyse for
`calcium, phosphorous, silicon and other trace elements
`in the prepared apatites. The carbonate content in
`the dry powder of silicon substituted apatite was
`determined as carbon using a Control Equipment
`corporation Model 240 XA CHN element analyser. The
`results are given in Table 1 below:
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`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 10
`
`

`

`~ ~
`~ !
`
`!A
`~
`
`("}
`"C
`
`\.0
`
`0 I -..1
`
`~
`
`(;!
`
`7000
`
`56.0
`
`1.4
`
`4.8
`
`---
`
`155.0 <1.0
`
`54.9
`
`17.8
`
`81.5
`
`344000 179000
`
`HA at 90°C
`
`10000
`
`66.2
`
`1.6
`
`3.2
`
`13.6 <1.0
`
`106
`
`18.2
`
`34.0
`
`181000
`
`35400
`
`HA at 3°C
`
`HA = hydroxyapatite
`
`9000
`
`68.1
`
`<0.2
`
`2.1
`
`26.7
`
`22.5
`
`18.7
`
`3.4
`
`463100 182100 10330
`
`7000
`
`66.3
`
`<0.2
`
`2.6
`
`23.5
`
`15.4
`
`10.6
`
`4.4
`
`8820
`
`417700 176200
`
`8000
`
`61.1
`
`2.2
`
`<1. 0
`
`22.2
`
`21.3
`
`24.0
`
`408800 181300 10748 67.5
`
`12500
`
`65.5
`
`<0.2
`
`1.1
`
`25.8
`
`27.8
`
`4.98
`
`450800 185200 10146 15.4
`
`D
`
`c
`
`B
`
`A
`
`mg/kg
`
`mgfkg mgfkg
`
`mgfkg mg/kg mg/kg
`
`mg/kg mgfkg mg/kg mg/kg mg/kg
`
`carbonate
`
`sr
`
`Ba
`
`cu
`
`Fe
`
`Al
`
`Na
`
`Mg
`
`Si
`
`p
`
`ca
`
`sample
`
`TJ\BLE 1
`
`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 11
`
`

`

`W098/08773
`
`PCT/GB97/02325
`
`- 10 ·-
`
`EXAMPLE 2
`
`The procedure of Example 1 was repeated, using an
`amount of 4.23g of silicon acetate 4-hydrate.
`Precipitation was again carried out at temperatures of
`30, 25°, 60° and 90°C to form precipitates A, B, C and
`D.
`
`The precipitates were subjected to ICPS analysis,
`and the results are given in Table 2 below:
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`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 12
`
`

`

`~ ~
`~ = ID
`
`Ul
`~
`
`~
`1":1
`~
`
`1-"'
`1-"'
`
`~
`....a
`~ QO
`ID
`0
`~
`
`7000
`
`6000
`
`6000
`
`9000
`
`65.3
`
`64.6
`
`64.5
`
`60.8
`
`<0.2
`
`<0.2
`
`<0.2
`
`0.3
`
`mgjkg
`
`mg/kg mg/kg
`
`Carbonate I
`
`Sr
`
`Ba
`
`Cu
`
`Fe
`
`Al
`
`Na
`
`Mg
`
`Si
`
`p
`
`Ca
`
`sample
`
`TABLE 2
`
`<1.0
`
`25.9
`
`28.6
`
`44.9
`
`44.9
`
`22.0
`
`30.3
`
`1.8
`
`3.1
`
`4820
`
`454700 185500
`
`4429
`
`433400 186600
`
`33.3
`
`20.2
`
`30.4
`
`<1.0
`
`4188
`
`469700 194200
`
`23.6
`<1.0
`mgfkg mgjkg mg/kg
`
`20.0
`
`191
`
`7.8
`
`4526
`
`458200 191400
`
`mgfkg mgfkg mg/kg mgfkg mgfkg
`
`2.0
`
`1.2
`
`D
`c
`B
`
`A
`
`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 13
`
`

`

`W098/08773
`
`PCT/GB97/02325
`
`- 12 .-
`
`EXAMPLE 3
`
`The procedure of Example 1 was repeated, using
`amounts of l.06g and 12.69g of silicon acetate 4-
`hydrate, respectively. The precipitations were
`carried out at 3°C to give precipitates A and B,
`respectively.
`The precipitates were subjected to ICPS analysis
`and the results are given in Table 3 below:
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 14
`
`

`

`~ u.
`= \C
`?5 g
`
`~
`~ QCI
`0
`~
`
`w
`.....
`
`16500
`
`11500
`mgfkg
`
`67.9
`
`3.6
`
`0.8
`
`24.6
`
`10.5
`
`64.9
`
`393000 268000 16101 10.3
`
`63.6
`<0.1
`mgjkg mgfkg
`
`37.6
`mgfkg mgfkg mgfkg
`
`12.1
`
`1.0
`
`55.3
`
`0.9
`
`1883
`
`424000 252000
`
`mgfkg mgfkg mgfkg mgfkg mgfkg
`
`B
`A
`
`Carbonate
`
`sr
`
`Ba
`
`Cu
`
`Fe
`
`Al
`
`Na
`
`Mg
`
`Si
`
`p
`
`Ca
`
`Sample
`
`TABLE 3
`
`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 15
`
`

`

`W098/08773
`
`PCT/GB97/02325
`
`- 14 -
`
`EXAMPLE 4
`
`44.46g of calcium hydroxide was dissolved in
`600ml of double distilled water. 0.564g of silicon
`acetate 4-hydrate was dissolved in the calcium
`hydroxide solution. The solution was named as
`Solution A.
`38.02g of orthophosphoric acid was dissolved in
`360ml of double distilled water. The solution was
`named as Solution B.
`Solution B was added dropwise to Solution A over
`a period of about 2 hours at a temperature of about
`3°C. The precipitate so formed, designated
`precipitate A, was stirred for 1 hour and left
`overnight. Precipitate A was filtered using a Buchner
`funnel and washed several times using double distilled
`water. The filtered cake was dried for about 20 hours
`in a drier at about 85°C in filtered air. The dried
`material was powdered using a pestle and mortar.
`This procedure was repeated, using amounts of
`2.82, 5.64 and 8.46g of silicon acetate 4-hydrate.
`The precipitations were again carried out at about
`3°C. to give precipitates B, C and D, respectively.
`The precipitates A, B, c and D were subjected to
`ICPS analysis and the results are given in Table 4
`below:
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 16
`
`

`

`()I
`N
`~
`...... a;
`= \0
`"CC n g
`
`! ......
`~
`
`tj
`
`Ul
`......
`
`---
`
`110500
`
`60000
`
`45000
`
`50000
`
`mgfkg
`
`2.0
`
`4.5
`
`2.1
`
`2.9
`
`<0.1
`
`<0.5
`
`31.6
`
`10.8
`
`27.1
`
`23.7
`
`5634
`
`390000 271000
`
`<0.1
`
`0.8
`
`28.4
`
`22.3
`
`54.7
`
`27.5
`
`5337
`
`395000 250000
`
`<0.1
`
`<0.5
`
`27.1
`
`18.8
`
`115.3
`
`31.4
`
`2957
`
`433000 240000
`
`2.6
`
`0.5
`
`24.6
`
`mgfkg
`
`mgfkg mgfkg mgfkg
`
`424000
`17.5
`mg/kg mg/kg mg/kg mgfkg mg/kg mgfkg
`
`48.4
`
`41.0
`
`814
`
`244000
`
`D
`
`c
`B
`
`A
`
`Carbonate
`
`sr
`
`Ba
`
`cu
`
`Fe
`
`Al
`
`Na
`
`Mg
`
`Si
`
`p
`
`Ca
`
`Sample
`
`TABLE 4
`
`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 17
`
`

`

`W098/08773
`
`PCT/GB97/02325
`
`- 16 -
`
`ElQ\MPLE S
`
`The silicon-substituted apatite material of
`Example 2A was pressed and sintered at about 1200°C at
`a heating rate of about 2.5°Cfminute and a dwell time
`of about 4 hours at the final temperature. The
`sintered sample was polished with diamond paper and a
`mirror-like surface was obtained. Hydroxyapatite was
`also pressed and sintered under the same conditions.
`The samples were soaked in a simulated body
`fluid. After 1 day, thin film X-ray diffraction
`spectra indicated that the sintered silicon
`substituted apatite material of Example 2A had formed
`a bone-like apatite layer, whereas the sintered
`hydroxyapatite formed a similar layer only after
`immersion in the fluid for 14 days.
`
`5
`
`10
`
`15
`
`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 18
`
`

`

`W098/08773
`
`PCT/GB9710232S
`
`- 17 -
`
`EXAMPLE 6
`
`36.671g of calcium hydroxide was dissolved in
`1000ml of double distilled water. 1.917g of silicon
`acetate 4-hydrate was dissolved in the calcium
`hydroxide solution. The solution was named as
`Solution A.
`33.331g of orthophosphoric acid (GPR 85% assay)
`was dissolved in 1000ml of double distilled water.
`The solution was named as Solution B.
`Solution B was added dropwise to Solution A over
`a period of about 2 hours at a temperature of
`approximately 20°C. The pH of the mixture was
`adjusted to approximately 10.5 using a concentrated
`ammonia solution. The precipitate so formed,
`designated precipitate A, was stirred for 1 hour and
`left overnight. Precipitate A was filtered using a
`Buchner funnel and washed several times using double
`distilled water. The filtered cake was dried at about
`85°C in filtered air. The dried material was powdered
`using a pestle and mortar.
`The powder was then subjected to chemical
`analysis and the results are given in Table 5 below.
`Next, the powder was heated at approximately
`1200°C for about 2 hours and the phases present were
`determined using x-ray diffraction. With reference to
`Figure 1, the heated powder contained only one phase
`which matched the standard diffraction pattern for
`pure hydroxyapatite (Joint Committee for Powder
`Diffraction Standards, JCPDS card no. 9-432).
`The lattice parameters of the heated silicon(cid:173)
`substituted hydroxyapatite were calculated from the
`diffraction data using a least squares refinement
`method. The values are listed in Table 6, along with
`the values for pure hydroxyapatite prepared by the
`above method, with 0.5 moles of Ca(OH) 2 and 0.3 moles
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 19
`
`

`

`W098/08773
`
`- 18 -
`
`PCT/GB97/0232S
`
`of H3P04 , which does not contain any silicon. The
`increase in the lattice parameters is evidence of the
`substitution of silicon in the hydroxyapatite lattice.
`
`Tabla s
`
`Sample
`
`p
`ca
`Mg
`Si
`Al
`Na
`mgjkg mgjkg mg/kg mgjkg mgjkg mgjkg
`
`A
`
`381600 171900
`
`3410
`
`15
`
`65
`
`21
`
`Sample
`
`A
`
`Fe
`mg/kg
`
`32
`
`cu
`mgjkg
`
`Ba
`mgjkg
`
`Sr
`mgfkg
`
`Carbonate
`mgjkg
`
`2
`
`0.2
`
`62
`
`5000
`
`Tabla 6
`
`Pure hydroxyapatite
`
`0.94159(1)
`
`0.68798(1)
`
`a-axis (nm)
`
`c-axis (nm)
`
`Single phase silicon-
`substituted
`hydroxyapatite prepared
`in accordance with the
`invention
`
`0.94208(2)
`
`0.68889(2)
`
`SUBSTITUTE SHEET (RULE 26)
`
`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 20
`
`

`

`W098/08773
`
`PCT/GB97/02325
`
`- 19 -
`
`CLAIMS:
`
`A synthetic silicon-substituted apatite or
`1.
`hydroxyapatite which comprises from 0.1% to 5% by
`weight of silicon.
`
`A synthetic silicon-substituted apatite or
`2.
`hydroxyapatite as claimed in claim 1 which comprises
`from 0.1% to 1.6% by weight of silicon.
`
`A synthetic silicon-substituted apatite or
`3.
`hydroxyapatite as claimed in claim 1 or claim 2 which
`comprises from 0.5% to 1.0% by weight of silicon.
`
`A synthetic bone material which comprises a
`4.
`synthetic silicon-substituted apatite or
`hydroxyapatite as claimed in any one of the preceding
`claims.
`
`A synthetic bone material as claimed in
`5.
`claim 4 which comprises silicon-substituted
`hydroxyapatite and calcium oxide or tricalcium
`phosphate.
`
`An essentially phase pure synthetic bone
`6.
`material of synthetic silicon-substituted
`hydroxyapatite as claimed in any one of claims 1 to 3
`having substantially no impurity phases of calcium
`oxide and/or tricalcium phosphate.
`
`A composition which comprises a synthetic
`7.
`bone material as claimed in any one of claims 4 to 6
`together with a pharmaceutically acceptable diluent or
`carrier.
`
`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 21
`
`

`

`wo 98/08773
`
`PCT/GB97/02325
`
`- 20 -
`
`A bone implant, filler or cement which
`8.
`comprises a synthetic bone material as claimed in any
`one of claims 4 to 6 or a composition as claimed in
`claim 7.
`
`A hydroxyapatite-polymer composite material
`9.
`comprising a synthetic bone material as claimed in any
`one of claims 4 to 6 or a composition as claimed in
`claim 7.
`
`10. A process for the preparation of a silicon(cid:173)
`substituted apatite, which process comprises reacting
`a calcium salt or calcium hydroxide with
`orthophosphoric acid or a salt of orthophosphoric acid
`in the presence of a silicon-containing compound, the
`molar ratio of calcium ions to phosphorous-containing
`ions being from 1:0.5 to 1:0.7 and the molar ratio of
`calcium ions to silicon-containing ions being at least
`1:0.2, whereby a precipitate of a silicon-substituted
`apatite is formed.
`
`11. A process as claimed in claim 10, wherein
`the molar ratio of calcium ions to phosphorous(cid:173)
`containing ions is from 1:0.55 to 1:0.65.
`
`12. A process as claimed in claim 10 or claim
`11, wherein the molar ratio of calcium ions to
`silicon-containing ions is at least 1:0.16.
`
`13. A process as claimed in any one of claims 10
`to 12, wherein an aqueous solution of a calcium salt
`and a silicon compound at a pH of from 9 to 13 is
`reacted with an aqueous solution comprising a salt of
`orthophosphoric acid at a pH of from 9 to 13.
`
`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 22
`
`

`

`W098/08773
`
`PCT/GB97102325
`
`- 21 -
`
`14. A process as claimed in any one of claims 10
`to 13, wherein the calcium salt comprises calcium
`nitrate.
`
`15. A process as claimed in any one of claims 10
`to 14, wherein the salt of orthophosphoric acid
`comprises diammonium orthophosphate.
`
`16. A process as claimed in any one of claims 13
`to 15, wherein the pH of the aqueous solution of the
`calcium salt andjor the pH of the aqueous solution of
`the salt of orthophosphoric acid is adjusted using
`ammonia.
`
`17. A process as claimed in claim 16 wherein the
`pH of each solution is adjusted to approximately 11.
`
`18. A process as claimed in any one of claims 10
`to 12, wherein an aqueous solution comprising calcium
`hydroxide and a silicon-containing compound is reacted
`with an aqueous solution comprising orthophosphoric
`acid.
`
`19. A process as claimed in any one of claims 10
`to 18, wherein the silicon-containing compound
`comprises a silicon carboxylate.
`
`20. A process as claimed in claim 19, wherein
`the silicon carboxylate comprises silicon acetate.
`
`21. A process as claimed in any one of claims 10
`to 20, wherein the precipitated silicon-substituted
`apatite is separated from the solution and dried.
`
`22. A process as claimed in any one of claims 10
`
`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 23
`
`

`

`W098/08773
`
`PCT/GB97/02325
`
`- 22 -
`
`to 21, wherein the silicon-substituted apatite is
`heated and/or sintered.
`
`23. A process as claimed in claim 22, wherein
`the silicon-substituted apatite is heated andfor
`sintered at a temperature of from 500°C to 1400°C,
`whereby part or substantially all of the silicon(cid:173)
`substituted apatite transforms to silicon-substituted
`hydroxyapatite.
`
`24. A synthetic silicon-substituted apatite or
`hydroxyapatite as claimed in any one of claims 1 to 3
`or a synthetic bone material as claimed in any one of
`claims 4 to 7 for use in a method of treatment of the
`human or animal body by surgery or therapy.
`
`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 24
`
`

`

`W098/08773
`
`PCT/GB97/02325
`
`1 I 1
`
`5000
`
`E ....
`.0
`
`3000
`
`- 4000
`1;1) -.....
`~ "= -~ 2000
`-·;;; = Q) -s:::
`-
`
`1000
`
`0
`25
`
`30
`
`2 Theta
`
`35
`
`40
`
`Petitioners – Baxter Healthcare Corp., Apatech, Inc., and Apatech, Ltd.
`Exhibit 1025, p. 25
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`I
`A. CLASSIFICATION OF ~BJECT MATTER
`IPC 6 C01833 24
`A61L27 00
`
`A61L25/00
`
`lnt~
`
`.ional Application No
`PCT/GB 97/02325
`
`Accordrng to International Patent Classltication(IPC) or to both national classifrcalion and IPC
`
`B. FIELDS SEARCHED
`Minimum documentation searched (classification system followed by c1assifica11on symbols)
`IPC 6
`COlB
`
`Documentation searched other than