Method for making biologically active glass

Ε.Ι. RU PONT RE NEMOURS AND COMPANY “Process for the manufacture of biologically active glass

BACKGROUND TO THIS INVENTION

The present invention relates to biologically active glass precursors in the form of a. stable aqueous solution, spheroidal glass particles, precursor-coated substrates, glass-coated substrates, and methods for preparing_Jk> X the precursor solution, the coated support and the glass particles.

As pointed out by Hench. In an untitled review article entitled Biomaterials in Science¹¹. 208,820 a. 831 (1980), about 2 to 3 million artificial limbs or prostheses are implanted annually in individuals in the United States. These devices, manufactured from one. wide variety of materials are useful, for example, in the eyes, ear, and nervous system; in the heart, arms, bladder, and blood vessels; and to restore and replace bones, ligaments and teeth. In these uses, they combat both the degenerative effects of aging and the damage resulting from accidents.

Hall presented a summary of the situation of biomaterials and their associated problems in, J, Biomed ... Ma.ter, Res, Symn.osium. No. 2 (Part 1), pages 1 to 4 (19⁷!). The article highlights the importance of the interface between an implant and the patient's body tissue.

The U.S. Patent. N2 4 171 544 describes ·

<img file="PT79421B_D0001.tif" />

see numerous biologically active glass compositions.

U.S. Patent 1Q2 4,103,002 discloses a method for coating a ceramic surface. of alumina with biologically active glass. This patent states that alumina ceramic surfaces are biologically inactive and that bone tissue should not adhere to or grow on them.

U.S. Patent No. 4,159,358 describes a method for attaching a biologically active glass to a metal surface. When discussing the use of biologically active glasses as biomaterials, this patent establishes that it is impossible to build orthopedic devices with them. ✓

or teeth strong enough.

SUMMARY OF THE INVENTION

The present invention relates to an acidic aqueous solution of a biologically active glass precursor composition. The acidic aqueous solution of the present invention includes a combination of all precursors necessary to obtain a finished product when precursor mixing is dried and calcined. This invention is not limited to any particular precursors for any biologically specific glass. active. Conversely, any combination of precursors can be used because &lt;

should form a biologically active glass coating on the carrier particles.

The term biologically active glass means that the

X »X glass can form in vivo bonds with bones, muscles and other body tissues. For the sake of brevity, the term glass z

and used herein to refer to biologically active glass. The term aqueous solution means an aqueous acidic solution, suspension or dispersion of glass precursors.

ZW Z zv,

The present invention also relates to carrier particle compositions coated with the glass precursors and z

carrier particles coated with glass formed by calcination of the glass precursors. The invention also relates to biologically active glass spheroidal particles obtained by spray drying the glass precursors and calcining the spray dried particles. Also included within the scope of the present invention are methods for preparing the glass precursor solution compositions, for coating the carrier particles, for drying and calcining the precursor-coated sumps to form the coated / fused glass carrier particles and to spray-dry the solution with the glass precursor composition. The spheroid particles are characterized by their generally spherical geometry and relatively smooth surfaces. The glass particles of the present invention can be readily distinguished by microscopic observation from the essentially non-spherical rough-edged glass particles of the prior art.

DETAILS OF THIS INVENTION

Biologically Active Glass z

The following patents describe a number of biologically active glasses which may be prepared by the process of the present invention: U.S. Patent No. 4,159,358, U.S. Patent No. 4,103,002, and U.S. Patent No. 4,159,002. No. 4,171,544. In general, the present invention encompasses any glass the components of which may be prepared in a stable aqueous solution. By stable is meant that there is no substantial amount of precipitation within one hour.

The following is a typical range of compositions for a sub-class of glasses under consideration, which according to the convention used in glass chemistry is given in terms of oxides and fluoride:

Weight percentage

Component

<td>Si0₉</td><td></td><td> 40</td><td>The</td><td> 62</td>

<td>At₂0</td><td></td><td> 10</td><td>The</td><td> 32</td>

<td>Dog</td><td></td><td> 10</td><td>The</td><td> 32</td>

<td>CaP₂</td><td></td><td> 0</td><td>The</td><td> 18</td>

<td>^Β2θ5</td><td></td><td> 0,</td><td>1 to</td><td>í 12</td>

<td>^B2°3</td><td></td><td> 0</td><td>ci</td><td> 20</td>

<td></td><td></td><td>X</td><td></td><td></td>

<td>in hear the sum of Ifer</td><td>, 0 and</td><td colspan="2">of CaO and at least about</td><td>in</td>

<td>percent by weight.</td><td>From</td><td>indicated components, 0 CaB_? no</td><td>to</td><td>Q Sl</td>

Mobile in water. Accordingly, an aqueous solution of the glass precursors comprises. Cal · ^ as a component should be treated in such a way that CaF₂ stay on hold. One method of treatment includes the addition of a fluoride ion solution (via UaF or ra₄r) to a vigorously stirring Ca2 solution. Preferred glasses of this type contain about 0.5 to 6 weight percent of

1^>2θ5 * Another subclass of glass considered includes those containing boron. A typical boron containing glass comprises: 10 B by weight SiO 2, 5 wt% B 2 O,^{and go} P^eso P90%, 24.5% by weight CaO and 24.5% by weight Na 2 O.

Support

Materials considered to be used as carriers for glass include high melting mineral oxides, ceramic products, and the like. Indeed, any material may be used so long as it does not adversely react with the glass, the glass precursors or the body parts with which such material will come into contact. It should be understood, of course, that said material should be relatively resistant and stable at the high temperatures used to calcine the glass.

Supporting materials considered include alumina, silica, carbon, silica-aluminines, titania, clays, calcium silicate, feldspar, zinc oxide and the like, including any metal the body accepts. Preferred supports are alumina, silica, titania, and mixtures and compositions thereof. The size and concentration of the carrier media will vary depending on the particular device to be manufactured, the intended use, and the

Composição / Ζ Z intended composition for the particles. The particle size consideration is up to about 1 mm or more in diameter.

A sodium-silica containing composition such as HagOCSiOp ^ or NagSiO ^ or (MaOj ^ SiCCH ^ 4) may be used as a precursor for SiOp and other precursors for SiO 2 include seismic acid and colloidal SiO 2. CaO include the calcium salt of an alkanoic acid at 0 to C 2, preferably calcium formate, Ca (O 2 CH) p, and, if HUO 4 is used to control the pH, also Ca 2 NO.

The Precursors for ο Ρ_?O ^ and Ea ?O are sodium phosphates, Na ^ PO ^, Ka HP HPO ^, 1aHPO ^, NapH ^P_?O ^, and sodium phosphites

-6PF,¹-.'!

Na ^ PO ^, NagHPO ^ and NaH ^ PO ^. Preferred is sodium phosphate, Na 2 P0 4 .12Hp O. The other precursors for ο include E4 PO4 and the ammonium salts equivalent to the sodium salts mentioned above. Precursors for o include sodium borates, which also promote IfepO. Preferred is Na 2 B 4 O 4.

z

The precursors of Ea_?O include the sodium salts mentioned above, zzz as well as the sodium salt of an alkanoic acid at 0 ° C to C 2, preferably sodium formate, and, if HNO 4 is used for contro. ~ -2 pH, also Na2 O4. R introducing ions such as SO ^ and +3

Moreover, they would immediately precipitate with the other ions present should be avoided. Other ions that favor biological growth may also be introduced into the solution. These ions include Mg; see Jaffe Metabolic Degenerative and Inflammatory Diseases of Caps and Joints, ”lea and Peniger, Phila.

(1972) page 124 et seq. If ο 1-2.0 is intended to be a component of glass, it may be included in the precursor solution such as KHCO ,,, EMb or KOC (O) R.

Aqueous solutions of the compositions of the present invention typically have a pH typically below about 5 ° C. Preferred acids for pH control are those which decompose completely upon heating and leave no carbonaceous residues that would require prolonged burning. Such absence of deposits is a general requirement for acids whose salts or themselves are used in free form. A sufficient amount of acid is added to the solution to reach the desired pH. Acids meeting the requirements of relatively high volatility and clean zzzz decomposition include nitric acid and alkanoic acids a. C4, comprising any acid whose calcium and sodium salts are used in the preparation of. solution or dispersion. Since these salts are preferably formates, the most convenient acid is formic acid. For formic and nitric acids, in most cases, it is about 3.8 and about 3.3 to 3.8. For acetic acid, propionic acid and butyric acids, pE should in most cases be about 4.6 and preferably about 4.1 to 4.6. The optimum pH for any particular glass precursor composition can be readily determined by simple experimentation.

In the present coating operation, the support particles to be coated are intimately mixed with a freshly prepared solution of glass precursors, with stirring and preferably with. a slight crunch. In the laboratory, mixing, stirring and grinding are carried out properly with a pestle and mortar. The wet solid product may then be air dried to remove all or part of the water; the techniques rw. Spray drying are preferred. 0 solid product

It is dried and then heated to a temperature sufficiently high to remove any remaining water, volatize and / or decompose any formic acid residue and convert coating medium to the desired glass. This is equal to about 600 ° C to 155 ° C, although ph should be, preferably the temperature components and usually slightly lower temperatures can sometimes be used effectively.

A convenient method for preparing the coating solution to minimize the possibility of precipitation is to prepare two solutions, the first containing xz calcium formate and sodium formate, if any, and the second containing silicon.

ZX. Z sodium cate and any sodium phosphate and / or sodium borate to be used. Formic acid is then dissolved in either solution and the two solutions are rapidly mixed with good stirring. The amount of formic acid to use can be readily determined by simple experimentation with parts

-8 aliquots of the two solutions. p ™ wffl) n

The relative amount of each inorganic precursor dissolved in the coating medium should be equivalent to the relative amount of the corresponding inorganic component required to form the desired glass. Usually, the concentration of precursors should be about 100 g to 200 g per liter of

The # ** Z solution. At lower concentrations, unnecessarily high amounts of water should be evaporated during the heating phase; at higher concentrations there is a greater tendency for precipitate formation. The carrier particles to be contacted with said precursors should vary in size and concentration according to the desired weight and / or volume ratio of the coated glass carrier product.

Multiple coating / drying / sintering phases may also be used.

The biologically active glasses which are produced by the precursor solution process of. The present invention are well accepted as components of biomedical products including devices, prostheses, replacement parts and implants in the body.

The utility of the supported biologically active glasses of the present invention is at least as wide as that of the unsupported biologically active glasses. In addition, supported glasses have strength / softness / stiffness and density advantages with a

ZA, &lt;

homogeneous composition of characteristics, which was not possible before.

The coated supports may be sintered and / or fused onto any compatible substrate to form large or small devices of virtually any geometry. The coated supports may also be molded or cast to form.

XZ biomedical devices consisting solely of the support and glass described herein, in a uniform, homogeneous matrix compatible with the body. |

The requirements that meet the biomedical materials made with the glass with support from. (1) their properties are similar to those of the body part which they replace or are incorporated into; (2) are accepted by the living host without adverse reactions such as inflammation or toxicity; (3) form in vivo bonds with host tissues; and (4) its implantation causes no more than the formation of a capsule.¹It is relatively thin at interfacing with the body part of the host.

EXAMPLE 1

Two solutions are prepared as follows: Solution I contained 56.9 g of calcium formate, 6.1 g of sodium formate and sufficient water to make 50 ml of solution; the pH of the solution was. equal to 6.6. Solution II contained 32.0 g of Na2 PO4, 12HgO,

158.5 g of (SiO?) 4 in 37.1% aqueous solution and sufficient water to make up to 5θθ ml of solution; The pK of the solution was 10.9.

To 37.5 ml of solution I was added 5.3 ml of formic acid and the resulting solution was rapidly added with good stirring to 37.5 ml of solution II. The combined solution was slowly added to 155 g of alumina in a mortar while stirring with the pestle. Alumina was obtained by calcination of Alp0 · 3H &lt;0.0 (Alcoa 030BP). Stirring was continued until the mixture was uniform. The product was calcined at 1200 ° C in a muffle overnight. 0 The solid product has undergone a new surface treatment by the method described in this paragraph.

-ιο-

<img file="PT79421B_D0002.tif" />

ί ο to obtain an alumina. coated with biologically active glass with a surface area of ​​35.6 m / g. 0 product contained

48.1% AI, corresponding to an overall glass / aluminum composition of about 9/91 ·

EXAMPLE 2

Alumina was coated with biologically active glass by a method essentially identical to that of Example 1, but with the following modifications: The calcined alumina was Alcoa C333B Al2 O3 .314.0; The amounts were 60 g of alumina, 180 ml of solution I, 180 ml of solution II and 25.2 ml of formic acid; After mixing with the liquid, the treated alumina was air dried overnight and then calcined at 1200 ° C for one hour.

The loose aggregates were broken up in a mixing vessel to obtain a vi'2 / dro coated particle alumina with a surface area of ​​7.4 m / g. A sample was separated z

sequentially representative through increasingly tight mesh screens, the following particle size distribution being obtained: 2% on the 80 mesh screen; 13% passing 80 and retaining 200; 45% passing through 200 and retained in 325; 35% passing 325.

EXAMPLE 3

No precipitates were formed. aqueous solution of a biologically active glass with a. following composition: 40% SiO₂, 5% B₂O₃, 6% P₂0₅, 24.5% CaO and 24.5% Na₂0.

The two precursor solutions contained the following reagents:

Solution I

2.4 g NaOpCH 56.9 g Ca (0₉CIi)₉Final volume: 600 ml (water).

<img file="PT79421B_D0003.tif" />

Solution II

140.7 g of a solution a. 37.1% of Va₉0 38 SiO4

13.6 g of IRa ^ B ^ Oy.lOHpO

32.1 g of Na₅POWDER₄.12H₂O

Final volume: 600 ml (water).

The mixture of solutions I and

II was as follows:

Formic acid (0.5 ml) and 5 ml of water were then added, 5 ml of I was added rapidly and with a clear solution which did not gel solution II; the agitation. Get 3 days at room temperature.

The alumina in ro was coated as follows: first calcined at 400 ° C Alcoa C-331 Α1₉0 ~ .3Π₉0 (gibsite) with a size distribution equal to

<td> 94</td><td>The</td><td> 99</td><td colspan="2">% smaller</td><td>hear</td><td> 30</td><td>micra,</td>

<td> 85</td><td>The</td><td> 93</td><td> %</td><td>smaller</td><td>what</td><td> 20</td><td>micra,</td>

<td> 56</td><td>The</td><td> 67</td><td> %</td><td>smaller</td><td>what</td><td> 10</td><td>micra and</td>

<td> 20</td><td>The</td><td> 40</td><td> %</td><td>smaller</td><td>hear</td><td colspan="2">5 microns.</td>

The alumina. (100 g) was then ground. with a biologically active glass solution consisting of 25 ml of Solution I,

XX ml ml of formic acid and 25 ml of Solution II. The wet solid product was air dried and then calcined on a platinum plate at temperaturaΟΌΟθΟ for 30 minutes to give 102 g of a freely moving solid product. This well (75 g) was

<img file="PT79421B_D0004.tif" />

Treated again using formic and 15 ri of Solution (80 g). This powder, in water, ml of Soluce ο I, 1.8 ml of acid z &lt;

> II. The final product was a white powder raises the pH to about 10.

EXAMPLE 4

Two solutions are prepared as follows:

(i) 237.6 g of calcium formate, 114.4 g of sodium formate and sufficient distilled water to give 4 liters of solution.

(II) 158.4 g of Na2 SO4 OH0 O, 1448.8 g of Na₂O.33.38 SiO₂

37 Λ / a 37,1%, and enough water to make 4 liters of solution.

To 720 ml of Solution I containing 160 ml of formic acid, 720 ml of Solution II was added in a mixing beaker with vigorous stirring. This final solution was spray dried to a fine white powder.

The knot contained water and shapes that were eliminated as follows: In a three-liter 1-neck flask of capable city with a stirrer, a thermocouple with a slow nitrogen purge, 25 g of the flask was poured. well, with heating and stirring. The particles vigorously released gases at 350-400Â ° C. More powder was added using the hot powder as a diluent. As drying continued, dust was added more rapidly. The final product (214 g s. from 409.6 g of spray dried powder) was heated to ^P00 ° C in a muffle and then reduced to dust. After heating to 920 ° C, the dark gray product consisted of a brittle porous glass foam with a composition corresponding to 53.0% SiO.₂12.8% CaO, 23.0% NaO and 6.3% ^or be that of U.S. Patent NF:

171 544.

-13'

ΈΡΙΟ-ΈΡΙΟ 5

<img file="PT79421B_D0005.tif" />

This Example was performed from one. analogous to that of Example 4.

Solution I

2.4 g of sodium format,

56.9 g of calcium formate, enough water to make 600 ml.

Solution II

140.7 g of Na₂O.33.38 SiO? to 37.1% in. Water,

13.6 g IfegB2 O4 .1OH4 O,

32.1 g of Na₅TO₄.12H₂O, enough water to make 600 ml.

To prepare the solution for spray drying, 720 ml of Solution I and 100.8 ml of formic acid were left in a mixing beaker, whereupon 720 ml of Solution II was added with vigorous stirring. The solution was then spray dried, heated and stirred as described in Example 4. After raising the heating temperature to 105 ° C, the resulting product was a white, friable soluble, easily crushable in a mortar to give a white powder. Based on the quantities of substances used, this product had the following weight composition: IfegO, 23.7 CaO, 24.8%; P₂0_[- 6.0%; SiO₂40.5%; and B₂O₅, 5,0 %.

EXAMPLE 6

Coated with Al glass₂Calcined 0 · 3H · 0 (Alcoa C30BE).

rw Ζ

The particle size distribution was as follows:

<img file="PT79421B_D0006.tif" />

85% passing through a ΓΓ2 525 sieve, ie less than 45 yum and 97 to 99% passing through a 200 sieve, ie less than 75yum.

Two solutions were prepared as follows: Solution

ZZ

I contained 56.9 g of calcium formate, 6.1 g of sodium formate, and sufficient water to make 500 ml of solution; Its pH was 6.6. Solution II contained. 32.0 g of Na2 PO4 .HP4 O, 158.5 g of Na2 O. (SiOr,) ^₇θ as 37.1% aqueous solution and sufficient water to make 500 ml of solution; Its pH was 10.9.

50 ml from. Solution I 7 ml of formic acid were added and the resulting solution was added rapidly with good stirring to 50 ml of Solution II. The combined solution was slowly added to 200 g of alumina in a mortar while

Z * Λ * Z stirring the mixture with a pestle The stirring was continued until mixing was uniform. The product was calcined at 1200 ° C in one. muffle at night. The solid product was subjected to a new surface treatment by the method described in this article to obtain alumina. coated, glass.

EXAMPLE 7

Spray dried biologically active glass shovel was produced as follows: Solution I - 68.3 g

Z zz calcium - 7.2 g of sodium formate - enough water to make 600 ml of solution. Solution II - 190.2 g of Na_?37.1% O, 3.38 g Si0₂ - 38.5 g of Na2 SO4 .12H₉0 and enough water to make 600 ml of solution. Additional solutions were prepared until 4 liters each were available.

To 720 ml of Solution 1 and 100 ml of formic acid

<img file="PT79421B_D0007.tif" />

720 ml of Solution II were stirred in a mixing beaker with vigorous stirring. This final solution was then spray dried.

A round-necked three-necked balloon was fitted with a paddle stirrer and Np inlet tube and filled with a Meeker nozzle. About 25 g of spray dried powder was placed in the nitrogen purge flask, the stirrer was turned on and

the burner ignited. The powder pooled as it began to distill liquids from the flask. As the heating continued, the particles began to move freely and at 580 ° C they lost gases violently, releasing a flammable gas, probably CO and Hp. Further spray dried product was added at such a rate that no agglomeration occurred. 520 g of spray dried product were added over 55 minutes. 0 Stirred solid product was heated to 50 ° C and cooled. The experiment took 45 minutes and provided 210 g of a loose brown powder. When heated to 50Â ° C in air, the product turned into a crispy white cake that was easily ground with a pestle in a leek to provide a bread.

EXAMPLE 8

This Example represents a single solution method for preparing biologically active glass and / or glass coated carrier particles. 1.6 g Na NaPO ^ .12HpO was dissolved in 15 ml of water. To this solution was added 7.9 g of a 57.1% aqueous solution of NapO.5.38 SiO2. Water was added to a volume of 25 ml and 5 ml of formic acid was added to give a clear solution. Then, with vigorous stirring, 2.8 g of

Ca (OpCH) p θ 0.5 g NaOpCH formed gel over 1 hour.

The resulting clear solution does not dry and calcined.

· Precursor daria, a biologically active glass of the following composition:

<img file="PT79421B_D0008.tif" />

SiO₂ - 45 /

At_?0 -24,5 %

CaO - 24.5%

PpO4 - 6%.

The precursor solution may be spray dried and subsequently calcined to form biologically active glass spheroidal particles. Alternatively, carrier particles

XX Λ alumina, silica, carbon, silica-alumina minerals, titania, clay, silica. Calcium, feldspar and zinc oxide, either individually or in any combination, may be added to the solution with good stirring. Subsequent drying will produce glass precursor-coated carrier particles that can be dry-cast and calcined to form biomedical devices. In another alternative, the carrier particles coated with glass precursors may be treated with one. adherent material including one or more individual biologically active glass components and the consolidated mass may be molded and calcined.

EXAMPLE 9

This Example generally illustrates how certain additives may be incorporated into a biologically active glass precursor solution. For example, Sr, Ba, Li, Al, Pe and / or Ti may be incorporated into an already prepared aqueous solution of nitric acid and precursors. Alternatively, the glass precursors and additive precursors may be formulated in one step in a modified solution of biologically active glass precursors. Additive components must be present in the acid solution.

<img file="PT79421B_D0009.tif" />

nitrate in the form of their nitrates, for example as Sr (NO ^) ^, Ba (NO ^)₂, LiNO4, AlkO4, Pe (NO4) ^ or as TiO titanyl Precautions should be taken not to mix formic acid / formates with nitric acid / nitrates due to the potential danger of deletion.

EOTT10 10

1/2 inch (1.27 cm) Cylindrical Reeds | 1/2 inch (1.27 cm) high of β-alumina were washed, dried and treated with the combined aqueous solution of Example 1, air dried and calcined at 1200 ° C. The coating, drying and calcination processes were repeated and the surfaces were observed under a scanning electron microscope. The thin holes and

X cracks in the original alumina had been filled. The surface was smooth and without cracks.