Preparation of bone cement compositions

• US 9,180,137 B2
• Filed: 02/08/2011
• Issued: 11/10/2015
• Est. Priority Date: 02/09/2010
• Status: Active Grant

• Current Assignee: Bone Support AB (BONESUPPORT HOLDING AB)
• Original Assignee: Bone Support AB (BONESUPPORT HOLDING AB)
• Inventors: Sandell, Veronica, Nilsson, Malin, Liden, Eva, Karr, Jeffrey C.
• Primary Examiner(s): LOVE, TREVOR M
• Application Number:
  US13/022,771
• Publication Number:
  US 20120129761A1
• Time in Patent Office: 1,736 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/545 Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula: , e.g. cephalosporins, cefaclor, or cephalexine
• CPC Class Codes: A61K 31/546 containing further heterocyclic rings, e.g. cephalothin
• CPC Class Codes: A61K 31/702 Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
• CPC Class Codes: A61K 31/7036 having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
• CPC Class Codes: A61K 31/7052 having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
• CPC Class Codes: A61L 2300/406 Antibiotics
• CPC Class Codes: A61L 24/0015 Medicaments; Biocides
• CPC Class Codes: A61L 24/02 containing inorganic materials
• CPC Class Codes: A61L 2400/06 Flowable or injectable implant compositions
• CPC Class Codes: A61L 2430/02 for reconstruction of bones; weight-bearing implants
• CPC Class Codes: A61L 27/025 Other specific inorganic materials not covered by A61L27/04 - A61L27/12
• CPC Class Codes: A61L 27/12 Phosphorus-containing materials, e.g. apatite
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Abstract

A method for the preparation of injectable ready-to-use paste bone cement compositions by mixing a dry inorganic bone cement powder comprising a particulate calcium sulfate hemihydrate capable of hardening in vivo by hydration of the calcium sulfate hemihydrate forming calcium sulfate dihydrate, an aqueous liquid and an additive that normally retards the setting process, said method comprising

• a) providing a bone cement powder comprising calcium sulfate hemihydrate, an accelerator for the hardening of the calcium sulfate hemihydrate by hydration, said accelerator being selected from the group consisting of saline and calcium sulfate dihydrate, and a powdered calcium phosphate component
• b) mixing the bone cement powder with the aqueous liquid for a period of time
• c) leaving the mixture for the time needed for allowing the hydration reaction of the calcium sulfate hemihydrate to proceed and allowing calcium sulfate dihydrate crystals to form and grow, and
• d) admixing the additive by means of a short-duration mixing using a minimum of energy
  surprisingly shortens the setting times for the cement comprising the additive that retard the setting process to the level observed in the absence of the additive and enables a complete hydration of calcium sulfate hemihydrate to calcium sulfate dihydrate, even when using additives else preventing the hardening.

Claims

1. A method for the preparation of an injectable ready-to-use bone cement paste composition comprising

a) preparing a mixture consisting of calcium sulfate hemihydrate, a powdered calcium phosphate component, and calcium sulfate dihydrate to form a bone cement powder,

b) mixing the bone cement powder from step a) with water, saline, or an iohexol solution for a period of time,

c) allowing the mixture from step b) to sit for a period of time and

d) admixing a bioactive agent to the mixture from step c) by means of a short-duration mixing using a minimum of energy, wherein the bioactive agent has a retarding effect on the hardening of the bone cement paste, and

wherein the injectable ready-to-use bone cement paste composition from step d) has an initial setting time of not less than 5 minutes, and

wherein the calcium phosphate component is hydroxyl apatite in an amount ranging from 30 to 50 wt % of the dry powder.

2. The method of claim 1, wherein the calcium phosphate component is hydroxyl apatite or tricalcium phosphate.

3. The method of claim 1, wherein the mixture is left for at least 2 minutes in step c).

4. The method according to claim 1, wherein the bioactive agent is an antibiotic agent.

8. The method of claim 1, wherein the mixing occurs for a period of time ranging from 10 seconds to 5 minutes.

9. The method of claim 1, wherein the mixing occurs for a period of time ranging from 20 seconds to 2 minutes.

10. The method of claim 1, wherein the mixing occurs for a period of about 30 seconds.

11. The method of claim 1, wherein the time in step c) is at least 15 seconds.

12. The method of claim 1, wherein the time in step c) is at least 1 minute.

13. The method of claim 1, wherein the initial setting time ranges from 5 minutes to 20 minutes.

16. The method of claim 1, wherein the bioactive agent is selected from an antioxidant, a vitamin, a hormone, an antibiotic, a cytostatic, a bisphosphonate, a growth factor, a bone marrow aspirate, or demineralised bone.

5. An injectable paste composition comprising a particulate calcium sulfate hemihydrate, an aqueous liquid, and a bioactive agent, said agent having a retarding effect on the hardening of the inorganic bone mineral substitute composition when admixed together with an aqueous liquid, prepared by

a) preparing a mixture consisting of calcium sulfate hemihydrate, a powdered calcium phosphate component, and calcium sulfate dihydrate, wherein the calcium phosphate component is hydroxyl apatite in an amount ranging from 30 to 50 wt % of the dry powder to form a bone cement powder,

b) mixing the bone cement powder from step a) with water, saline, or an iohexol solution for a period of time,

c) allowing the mixture from step b) to sit for a period of time, and

d) admixing the bioactive agent with the mixture from step c) by means of a short-duration mixing using a minimum of energy,

wherein the injectable ready-to-use bone cement paste is capable of being used as a medicament for prophylactic or therapeutic treatment of a disorder related to supportive tissues in a human or non-human animal subject, which method comprises local administration to said subject of said composition comprising a prophylactic or therapeutic amount of said at least one bioactive agent, which is released from said composition, optionally while systemically and/or concomitantly administrating a pro-phylactic or therapeutic amount of at least one bioactive agent, wherein the composition from step d) has an initial setting time of not less than 5 minutes.

6. The paste according to claim 5, wherein the bioactive agent is an antibiotic agent.

7. The paste according to claim 5, wherein said paste is capable of being used as antibiotic beads for treatment of osteomyelitis.

14. A method for the preparation of injectable ready-to-use bone cement paste compositions comprising

a) preparing a mixture consisting of 59.6 wt % calcium sulfate hemihydrate, 0.4 wt % calcium sulfate dihydrate, and 40 wt % hydroxylapatite to form a bone cement powder,

b) mixing the bone cement powder from step a) with water, saline, or an iohexol solution for a period of time,

c) allowing the mixture from step b) to sit for a period of time, and

d) admixing a bioactive agent to the mixture from step c) by means of a short-duration mixing using a minimum of energy, wherein the bioactive agent has a retarding effect on the hardening of the bone cement paste, and

wherein the injectable ready-to-use bone cement paste composition from step d) has an initial setting time of not less than 5 minutes.

15. The method of claim 14, wherein the bone cement powder of step a) is mixed with an iohexol solution.