Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Phosphorus or phosphorus compound
Reexamination Certificate
2001-01-05
2003-05-06
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Phosphorus or phosphorus compound
C106S690000, C106S691000, C423S299000, C423S304000, C423S305000, C423S306000, C424S490000, C424S493000, C424S494000, C424S495000, C424S601000, C424S606000, C514S769000, C514S772000, C514S781000, C514S951000, C514S952000
Reexamination Certificate
active
06558709
ABSTRACT:
BACKGROUND OF THE INVENTION
The field of this invention is in the preparation of calcium phosphate minerals for bone cement or bone filler applications. More specifically, this invention relates to a calcium phosphate bone cement which consists of a mixture of tetra-calcium phosphate and di-calcium phosphate in an aqueous mixture, which mixture then sets to form a bone cement with a substantial portion of the cement being hydroxyapatite.
Hydroxyapatite is the major natural building block of bone and teeth. It has been found useful in fixing fractures and bone defects to use bone cements which are formed by combining calcium and phosphate precursors in an aqueous solution which initially forms a paste but then hardens into a hydroxyapatite bone cement. Hydroxyapatite has a calcium to phosphorous ratio of approximately 1.67 which is generally the same as the calcium phosphate ratio in natural bone structures. The paste may be placed in situ prior to setting in situations where bone has been broken, destroyed, degraded, become too brittle or has been the subject of other deteriorating effects. Numerous calcium phosphate bone cements have been proposed such as those taught by Brown and Chow in U.S. Pat. Nos. Reissue 33,161 and 33,221 and by Constantz in U.S. Pat. Nos. 4,880,610 and 5,047,031, the teachings of these patents are incorporated herein by reference.
It has been well known since the initial use of calcium phosphate cements that the addition of sodium phosphate solutions, potassium phosphate solutions or sodium carbonate solutions to the aqueous setting solution of the calcium phosphate precursors can speed setting times. This is documented in the Chow et al. April, 1991 IADR Abstract No.: 2410 and AADR, 1992 Abstract No.: 666 and was well known to those skilled in the art prior to these publications. In addition, such is discussed in Constantz et al. U.S. Pat. Nos. 5,336,264, 5,820,632 and 6,002,605.
Controlling bone cement or filler setting time is important because it is necessary for the material to be initially flowable and then moldable but it also must be able to set in place even though quantities of blood may be present. This blood creates problems in providing too much fluid so that the mineral salts are either washed away or dissolved prior to setting up. Obviously, if the material sets up too quickly, the surgeon has difficulty in mixing the calcium phosphate mineral cement and then placing it at the necessary bone site.
It has been found that the addition of sodium phosphate to the aqueous solutions mixed with the dry calcium phosphate precursors speeds the setting of calcium phosphate bone cement, such as those disclosed by Brown and Chow. However, the sodium phosphate may cause the setting to occur more quickly than desired. Thus, a method for better controlling the setting time of such cements has been found desirable.
SUMMARY OF THE INVENTION
It is an object of the invention to provide a method for better controlling the setting times of calcium phosphate cements.
It is an additional object of the invention to provide a method for coating dry highly water soluble sodium phosphate particles with a water soluble material, the thickness of which can be varied to control the time in which the sodium phosphate particle solubilize in the aqueous setting solution. The dry coated sodium phosphate particles are pre-mixed with the dry powdered calcium phosphate precursors to thereby better control setting times.
These objects are achieved by a method for forming a calcium phosphate bone treatment material comprising mixing at least one dry calcium phosphate mineral power in an aqueous solution causing a reaction which forms a settable material. The rate of reaction is controlled by mixing, as a dry ingredient, a water soluble alkaline/acidic material, such as Na
2
HPO
4
or a water soluble NaH
2
PO
4
which materials have a water soluble coating, with the dry calcium phosphate mineral precursors prior to or simultaneously with the addition of the aqueous solution. The rate of reaction may be controlled by varying the thickness of the water soluble coating surrounding the water soluble alkaline/acidic material and may be controlled to a lesser degree by the concentration of the sodium phosphate in the mixture. The water soluble coating may be cellulose, such as cellulose acetate, cellulose acetate butyrate, hydroxypropyl cellulose, hydroxymethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, sodium ethyl cellulose sulfate, sodium carboxymethyl cellulose and combinations thereof. The alkaline/acidic material may be any material which is water soluble and forms a solution containing the phosphate ion.
The calcium phosphate mineral may be tetra-calcium phosphate, di-calcium phosphate, tri-calcium phosphate, mono-calcium phosphate and mono-calcium phosphate monohydrate, hydroxyapatite, either alone or in combinations.
DETAILED DESCRIPTION
In the preferred embodiment the calcium phosphate dry component is composed of tetra-calcium phosphate and di-calcium phosphate in a 1:1 molar ratio to which about 1% by weight of a powdered and coated sodium phosphate mineral has been added. The preferred sodium phosphate is either Na
2
HPO
4
or NaH
2
PO
4
which is coated with a cellulose coating by using the method described herein. The amount of sodium phosphate dry particles added, by weight, can be varied to vary the setting time. In the preferred embodiment, from 0.5% to 1.5% by weight of the coated sodium phosphate dry mineral powder is added to the dry calcium phosphate precursors. To ensure complete solubility of the sodium phosphate particles in the aqueous wetting solution, the initial size of the sodium phosphate powder to be coated should be less than 100 &mgr; in size with the coated particles being no more than 100 &mgr; microns in size.
The amount of coated sodium phosphate, by weight, in the powdered component must be varied depending on the liquid to powder ratio used in the bone cement. For example, if the liquid to powder ratio of aqueous solution to calcium phosphate coated sodium phosphate (by weight) is 0.25 and approximately 10 grams total of calcium phosphate/coated sodium phosphate dried powder are used (i.e. the 10 grams including 0.75% by weight coated sodium phosphate powder), then if the liquid to powder ratio is raised to 0.3 (i.e. 20% above the 0.25 ratio) then the sodium phosphate, by weight, must be increased 20% in order to maintain the same setting time (i.e. to 0.9%).
Furthermore, setting times can be varied by varying the thickness of the coating of the sodium phosphate particles. Having a somewhat thicker coating results in a somewhat longer time for the coating to dissolve thereby releasing the phosphate ions. The increase in coating thickness can be accomplished by increasing the amount of cellulose acetate butyrate in the solution or allowing the solution to sit for a longer period of time (30 to 60 minutes rather than 15 to 30 minutes) after the sodium phosphate particles are added.
REFERENCES:
patent: 4832955 (1989-05-01), Snipes et al.
patent: 4863743 (1989-09-01), Hsiao et al.
patent: 4880610 (1989-11-01), Constantz
patent: RE33161 (1990-02-01), Brown et al.
patent: RE33221 (1990-05-01), Brown et al.
patent: 4929447 (1990-05-01), Yang
patent: 4983730 (1991-01-01), Domeshek et al.
patent: 5047031 (1991-09-01), Constantz
patent: 5092888 (1992-03-01), Iwamoto et al.
patent: 5336264 (1994-08-01), Constantz et al.
patent: 5589191 (1996-12-01), Ukigaya et al.
patent: 5651984 (1997-07-01), Powell
patent: 5820632 (1998-10-01), Constantz et al.
patent: 5824339 (1998-10-01), Shimizu et al.
patent: 5976507 (1999-11-01), Wong et al.
patent: 6002065 (1999-12-01), Constantz et al.
Composite of Calcium Phosphate Cement and Protein Bioadhesive Setting Reactions, Compressive and Diametral Tensile Strength, IADR 1991, Abstract No. 2410, R. Strausburg et al, pp. 1-10.
Effects of Additives on Setting Reaction of Calcium Phosphate Cement, AADR 1992, Abstract No. 666, N Sanin et al., pp. 1-10.
Skeletal Repair by in Situ Formation of the Mineral
Choi Frank
Hartley Michael G.
Howmedica Osteonics Corp.
Lerner David Littenberg Krumholz & Mentlik LLP
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