Drug – bio-affecting and body treating compositions – Extract – body fluid – or cellular material of undetermined... – Derived from musculoskeletal system – other than cardiac muscle
Reexamination Certificate
2002-06-24
2003-11-25
Witz, Jean C. (Department: 1651)
Drug, bio-affecting and body treating compositions
Extract, body fluid, or cellular material of undetermined...
Derived from musculoskeletal system, other than cardiac muscle
C424S682000, C424S696000
Reexamination Certificate
active
06652887
ABSTRACT:
TECHNICAL FIELD
The invention relates to bone graft substitute compositions.
BACKGROUND
Compositions containing calcium sulfate can be used as filler for voids and/or defects defined by bone. In some embodiments, the compositions can promote bone growth.
SUMMARY
The invention relates to bone graft substitute compositions.
In one aspect, the invention features a composition including calcium sulfate hemihydrate, a first material that accelerates the calcium sulfate hemihydrate to calcium sulfate dihydrate, a plasticizing material, and demineralized bone matrix having a moisture content of between about 10 and about 30 weight percent.
Embodiments may include one or more of the following features. The calcium sulfate dihydrate is stabilized with sucrose. The plasticizing material includes hydroxypropylmethylcellulose. The plasticizing material includes a material selected from a group consisting of sodium carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxyethylcellulose or cellulose acetate butyrate, glycerol, vinyl alcohols, stearic acid, and hyaluronic acid. The first material includes calcium sulfate dihydrate. The composition further includes a mixing solution, such as water. The mixing solution includes a material selected from a group consisting of sodium chloride, phosphate buffered saline, potassium chloride, sodium sulfate, potassium sulfate, EDTA, ammonium sulfate, ammonium acetate, and sodium acetate. The demineralized bone matrix has a moisture content of between about 10 and about 20 weight percent, e.g., between about 10 and about 15 weight percent.
In certain embodiments, the composition includes 100 parts of calcium sulfate hemihydrate, about 0.5 to about 5 parts of the calcium sulfate dihydrate, about 0.5 to about 5 parts of the plasticizing material, about 40 to about 60 parts of the mixing solution, and about 10 to about 30 parts of the demineralized bone matrix. The composition may include 100 parts of calcium sulfate hemihydrate, about 1 to about 5, e.g., about 4.8, parts of the calcium sulfate dihydrate, about 1 to about 3 parts of the plasticizing material, about 45 to about 55 parts of the mixing solution, and about 15 to about 25 parts of the demineralized bone matrix.
In another aspect, the invention features a method of making a bone graft substitute composition. The method includes providing a mixture having calcium sulfate hemihydrate, calcium sulfate dihydrate, a plasticizing material, and demineralized bone matrix having a moisture content between about 10 and about 30 weight percent; and contacting a mixing solution with the mixture. In some embodiments, the plasticizing material includes hydroxypropylmethylcellulose, the demineralized bone matrix has a moisture content between about 10 and about 20 weight percent, and/or the mixing solution includes water.
In another aspect, the invention features a kit including a mixture having calcium sulfate hemihydrate, calcium sulfate dihydrate, a plasticizing material, and demineralized bone matrix having a moisture content between about 10 and about 30 weight percent; and a mixing solution unblended with the mixture. In some embodiments, the plasticizing material includes hydroxypropylmethylcellulose, the demineralized bone matrix has a moisture content between about 10 and about 20 weight percent, and/or the mixing solution includes water.
Embodiments may have one or more of the following advantages. The composition is capable of setting or hardening in a relatively short time. In embodiments, the composition can harden in about 5-10 minutes. The composition is capable of setting or hardening in vivo or ex vivo. The composition can promote bone growth.
Other aspects, features, and advantages of the invention will be apparent from the description of the preferred embodiments thereof and from the claims.
DETAILED DESCRIPTION
A bone graft substitute composition includes calcium sulfate hemihydrate (CaSO
4
.½
2
O); demineralized bone matrix; a material that accelerates hardening of the composition (“an accelerant”); a plasticizing material; and a mixing solution. In some embodiments, the calcium sulfate, the demineralized bone matrix, the plasticizing material, and the accelerant are provided as a mixture of powders to which the mixing solution is added to form the composition. The composition can be delivered to a target site (e.g., a void or a defect) by injecting the composition through a syringe, and/or by forming a paste or a putty of the composition and applying the composition by hand (e.g., using fingers). The composition can harden ex vivo or in vivo, e.g., to a hardness sufficient to support orthopedic hardware.
Without wishing to be bound by theory, it is believed that during use, e.g., after mixing the mixture of powders with the mixing solution, the calcium sulfate hemihydrate is converted, e.g., changes crystalline form, into calcium sulfate dihydrate (CaSO
4
. 2H
2
O), which hardens the composition. Calcium sulfate dihydrate is capable of being sorbed by the body. For purposes of describing the concentrations of materials in the bone graft substitute composition, the composition includes 100 parts of calcium sulfate, e.g., calcium sulfate hemihydrate. Methods of making a calcium sulfate hemihydrate are described in U.S. Pat. Nos. 5,614,206, 5,807,567, and 6,030,636, each of which is hereby incorporated by reference in its entirety.
The demineralized bone matrix is believed to enhance bone growth. The demineralized bone matrix, e.g., freeze-dried or air-dried, preferably includes between about 10 and about 30 weight percent (e.g., between about 10-20 weight percent, between about 10-15 weight percent, or between about 10-12 weight percent) of moisture, e.g., water. In some embodiments, the demineralized bone matrix includes greater than or equal to about 10, 12, 14, 16, 18, 20, 22, 24, 26, or 28 weight percent of moisture; and/or less than or equal to about 30, 28, 26, 24, 22, 20, 18, 16, 14, or 12 weight percent of moisture.
In certain embodiments, the demineralized bone matrix, along with other materials in the substitute composition, are packaged in a kit and subjected to sterilization, e.g., electron beam sterilization, prior to being used. Without wishing to be bound by theory, it is believed that if the demineralized bone matrix includes less than the disclosed amount of moisture, the sterilization process can affect (e.g., increase) the “free” protein in the bone matrix and affect (e.g., inhibit) the setting or hardening of the mixed composition. If the demineralized bone matrix includes the disclosed amount of moisture, the protein level in the bone matrix may be unaffected by the sterilization process. For example, it is believed that water can interact with electrons in an electron beam sterilization process, thereby reducing (e.g., preventing) the interaction between proteins in the bone matrix and electrons in the beam.
The moisture level of the demineralized bone matrix can be controlled in a number of ways. For example, the bone matrix can be air-dried rather than freeze dried. Air dried demineralized bone matrix can include greater than about 10 weight percent of moisture, while in certain circumstances, freeze dried demineralized bone matrix can include less than about 6 weight percent of moisture. In addition or alternatively, the demineralized bone matrix can be packaged separately from the other powdered ingredients (e.g., accelerant or plasticizing material), and a predetermined amount of water (e.g., about 10-20%) can be added to the bone matrix prior to the sterilization process. In addition or alternatively, a source of moisture, such as a water-sorbed sponge, can be packaged with the demineralized bone matrix. The moisture level of the demineralized bone matrix can also be increased by placing demineralized bone matrix in a humidity chamber. Demineralized bone matrix is available, e.g., from Allosource (Denver, Colo.) or DCI (Nashville, Tenn.).
In some embodiments, the demineralized bone matrix has a particle size of about 125-
Miller Leasa C.
Richelsoph Kelly Coupe
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