United States Patent - prsmip.com · U.S. Patent Jan. 25,2005 Sheet 8 0f 24 US 6,846,493 B2 Figure 7: Average Agglomerate Size in the Ca-P colloid as a function of colloid aging period,

(12) United States Patent Pugh et al.

US006846493B2

(10) Patent N0.: (45) Date of Patent:

US 6,846,493 B2 Jan. 25, 2005

(54)

(75)

(73)

(*)

(21) (22) (65)

(63)

(60)

(51) (52)

(58)

(56)

FR

SYNTHETIC BIOMATERIAL COMPOUND OF CALCIUM PHOSPHATE PHASES PARTICULARLY ADAPTED FOR SUPPORTING BONE CELL ACTIVITY

Inventors: Sydney M. Pugh, Glennburnie (CA); Timothy J. N. Smith, Kingston (CA); Michael Sayer, Kingston (CA); Sarah Dorthea Langsta?', Kingston (CA)

Assignee: Millenium Biologix Inc., Kingston (CA)

Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 439 days.

Appl. No.: 10/142,151

Filed: May 10, 2002

Prior Publication Data

US 2003/0003160 A1 Jan. 2, 2003

Related US. Application Data

Continuation-in-part of application No. 09/971,148, ?led on Oct. 4, 2001, now Pat. No. 6,585,992, which is a division of application No. 09/044,749, ?led on Mar. 19, 1998, now Pat. No. 6,323,146, which is a continuation-in-part of application No. 09/029,872, ?led as application No. PCT/CA96/00585 on Aug. 30, 1996, which is a continuation-in-part of appli cation No. 08/576,238, ?led on Dec. 21, 1995, now aban doned Provisional application No. 60/003,157, ?led on Sep. 1, 1995.

Int. Cl.7 .............................................. .. A61L 27/00

US. Cl. ......................... .. 424/423; 501/1; 501/123;

106/35; 623/2361; 623/2656; 423/306; 423/307; 423/308; 423/311; 423/312; 423/314;

423/315; 423/316 Field of Search ............................ .. 424/423; 501/1,

501/123; 106/35; 623/2361, 26.56; 423/306, 307, 308, 311, 312, 314, 315, 316

References Cited

U.S. PATENT DOCUMENTS

3/1985 8/1989 10/1989 1/1991 1/1991 2/1991 4/1991 7/1991 8/1993

4,503,157 4,861,733 4,871,578 4,983,182 4,988,362 4,990,163 5,011,495 5,034,352 5,232,878 5,728,395 3/1998 6,090,732 7/2000

FOREIGN PATENT DOCUMENTS

2664501

Hatahira White Adam et al. Kijima et al. Toriyama et al. Ducheyne et al. Hollinger Vit et al. Kasuga et al. Ohtsuka et al. Ito et al.

1/1992

GB 2 316 940 A 3/1998 JP 8-165216 6/1996 W0 WO 91/17965 11/1991 W0 WO 94/26882 11/1994 W0 WO 95/32008 11/1995 W0 WO 97/09286 3/1997 W0 WO 98/08773 3/1998

OTHER PUBLICATIONS

ShimiZu et al., “The effect of substrate composition and condition on resorption by isolated osteoclasts”, Bone and Mineral, 6, pp. 261—275 (1989). Jones et al., “The resorption of biological and non—biologi cal substrates by cultured avian and mammalian osteo clasts,” Anat. Embryol, 170:247—256 (1984). Kerby et al., “Derivation of Osteoclasts from Hematopoietic Colony—Forming Cells in Culture,” Journal of Bone and Mineral Research, vol. 7, No. 3, pp. 353—362 (1992). Amano et al., “An Assay System Utilizing DevitaliZed Bone For Assessment of Differentiation of Osteoclast Progeni tors,” Journal of Bone and Mineral Research, vol. 7, No. 3, pp. 321—328 (1992). Chambers et al., “Failure of Cells of the Mononuclear Phagocyte Series to Resorb Bone,” Calcif. Tissue Intl., 36:556—558 (1984). Chambers et al., “Resorption of Bone by Isolated Rabbit Osteoclasts,” J. Cell Sci., 66, pp. 383—399 (1984). Boyde et al., “Resorption of Dentine by Isolated Osteoclasts in vitro,” British Dental Journal, 156, pp. 216—220 (1984). Boyer et al., “Synthesis of phosphate—silicate apatites at atmospheric pressure,” Solid State Ionics, 95, pp. 121—129, 1997.

Ruys, “Silicone—Doped Hydroxyapatite”, J. Aust. Ceram. Soc. 29(1/2), p. 71—80, 1993. Layrolle et al, “Sol—Gel Synthesis of Zinc Containing Cal cium Phosphate Biomaterials”, Phosphorus Research Bull. vol. 6, pp. 63—66, 1996. Bigi et al, “Isomorphous Substitutions In B—Tricalcium Phosphate: The Different Effects of Zinc and Strontium”, Jour. Inorg. Biochem., vol. 66, pp. 259—265, 1997.

Primary Examiner—Jean C. WitZ (74) Attorney, Agent, or Firm—Sim & McBurney; Lola A. BartosZewicZ

(57) ABSTRACT

The present invention is directed to a synthetic biomaterial compound based on stabilized calcium phosphates and more particularly to the molecular, structural and physical char acteriZation of this compound. The compound comprises calcium, oxygen and phosphorous, wherein at least one of the elements is substituted with an element having an ionic radius of approximately 0.1 to 1.1 The knowledge of the speci?c molecular and chemical properties of the compound allows for the development of several uses of the compound in various bone-related clinical conditions.

11 Claims, 24 Drawing Sheets

U.S. Patent Jan. 25,2005 Sheet 1 0f 24 US 6,846,493 B2

Figure l: X-Ray Diffraction Spectrum (6-29) of powder prepared from the Ca-P colloid with no introduced additives and sintered at 1000°C. Overlay ofJCPDS File #9432 (HA).

100

mi

80 -

70 -

50...

40

Intensity (CPS) 30-1

20'

10 I p , I , ‘

o I] vI I I l l l I ' I

15 2O 25 3O 35 4O 45 50

29 for Cu radiation (degrees)


Figure 2: Glancing Angle X-Ray Diffraction Spectra of a thin ?lm of the Ca-P colloid sintered on quartz at I000°C. (a) Overlay of JCPDS#9-348 (a-TCP). (b) Overlay of JCPDS#9-432 (HA).

6o _ (a)

50

40—

30 Intensity (CPS) 20

10-4

Q


70

60 -

50..

(b)

Intensity (CPS) 30 —l l | : :3

. ig

20 - " l 1

1 i 10-4

O

.1! ‘I

. I ' X I

l l] ‘ I . I I, MM. 20 3O 40 5O



Figure 3: Glancing Angle X-Ray Diffraction Spectra illustrating the effect of sintering temperature on thin ?lm phase composition.

1000°C .13‘

E .3 3. i’ 900°C

aoo'c

l I I l I I I I

10 15 2O 25 30 35 40 45 5O 55



Figure 4: Glancing Angle X-Ray Di?'raction Spectra illustrating the effect of sintering time on thin ?lm phase composition.

5 min

6‘ B1

9 0Q g E .2 20 min E §

60 min

I l I l l I h

10 15 2O 25 3O 35 4O 45


U S. Patent Jan. 25,2005 Sheet 5 0f 24 US 6,846,493 B2

M'iph i lustra? the ccieria?c surfa mun ca‘ a thin ?lm at the Ba-P r can quart at 'IUHG‘R


FIG. 5(a). Brass-m3 TEN! aims C?-P 51in ‘51m in": quartz.

Film sinlramd at MEWS.

FIG. Bib ). Erma-seam TEM Bf the W ?im an quail".

?nsintemd ?lm, (mam i?'?él'?rl?g pm?cia size of ?-i?nm).


Figure 7: Average Agglomerate Size in the Ca-P colloid as a function of colloid aging period, as determined nsin g light scattering particle analysis.

-5 m

A .b l

A N 1

A Q l

00 I

O) I Mean Agglomerate Diameter (microns)

N is | |

0 | l l T F l

O 5 1O 15 20 25 30

Aging Time (hours)

U.S. Patent

Intensity (CPS)

10D

75

Sheet 10 0f 24 US 6,846,493 B2 Jan. 25, 2005

Figure 9: X-Ray Diffraction Spectrum (9-29) of powder prepared from the Ca-P colloid with silicon as the introduced additive. Approximate phase ratio: 33 d: 5% HA and 67 d: 5% Si-TCP.

15 20 I F l I T

25 30 35 40



Figure 10: The Effect of Silicon Content on Phase Composition of Si-mHA powders, as determined by x-ray diffraction (8-29).

100

+ %HA —I—— % Si-TCP

B0 _ + % B-TCP

8 P2 ‘'21 E 60 -1 O u 0

5 O.

in 40 - ‘6 0

2 =2

20 -

i o I I I I Y I

0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75

M01 Fraction Si/HA


miwm I

U.S. Patent Jan. 25,2005 Sheet 13 of 24 US 6,846,493 B2

Figure 12: X-Ray Diffraction Spectra (6-29) of powder prepared from the Ca-P colloid with titanium as the introduced additive.

(a) Overlay of JCPDS File #9-432 (HA). (b) Overlay of JCPDS File #9469 (B-TCP).

(a)

6? D

E’, 2*

5 J 1 l . L I: '1; (b) .3 E 82

' f

. I I. I l .‘ l l r I millet.

v20 30 4O 5O

29 for Cr radiation (degrees)


' G, '1 Ma}. GEM Mimagraplw me mlcmstmclura uf Sim petlats fmmetl imm me [Ia-F m?uid

versus materiais prepared mam mmmamial mamas. SbmHApmparaci- u?ng TFDE as the immmd addiiiva.

SEN! Misrcrgraphs‘ wmparlng the micmsh‘ucmre 0f EI-mI-M pellets fanned fmm the Ca~P nulluéd

‘Hers-‘us mter-iais prepare? fmm mmmemia‘i sources. cl-EA as a physiuai mixtm'e with TFD&

U.S. Patent

Intensity

Intensity

Jan. 25, 2005 Sheet 16 0f 24 US 6,846,493 B2

Figure 15: X-Ray Diffraction Spectra for the physical mixture of 25% (IaSiOJ and 75% B-TCP (sintcred at 1250°C for 8 hours). (a) Overlay of JCPDS File #9-348 (Cl-TC?) (b) Overlay of JCPDS File #9469 (B-TCP).

(a)

(b)

Jill - . " I. ]_

20 30

L I

40 I 5G



Figure 16: High Resolution X-Ray Diffraction Spectrum of Si-mHA powder. Overlay of JCPDS File #9-348 (a-TCP) assuming a Gaussian peak shape with a peak width of 0.225".

200 -— XlDSpectra

...... -. —- JCPDS?'9-348 summation I)

I... ‘I 150 _ . '

Qn : ‘

B 5- 100 - \

Z5’ .

50 q ” ‘»

O I u - . . , _ _ - . . _ ‘I I

30.0 30.5 31.0



Figure 18: IR Spectra for powders sintered at 1000°C: (a) am, (b) mHA and (c) Si-mHA.

(c) M 2 if 8 i (b) .2 :a a2

(a)

I I I

1500 1250 1000 750 500

Wavenumber (cm")

Documents

United States Patent - prsmip.com · U.S. Patent Jan. 25,2005 Sheet 8 0f 24 US 6,846,493 B2 Figure 7: Average Agglomerate Size in the Ca-P colloid as a function of colloid aging period,