ANTIBIOTIC POLYMETHYLMETHACRYLATE BONE CEMENT

• US 20190314546A1
• Filed: 06/05/2019
• Published: 10/17/2019
• Est. Priority Date: 12/22/2015
• Status: Abandoned Application

• Current Assignee: Heraeus Medical GmbH (Heraeus Holding GMBH)
• Original Assignee: Heraeus Medical GmbH (Heraeus Holding GMBH)
• Inventors: VOGT, SEBASTIAN, KLIMAS, SUSANN
• Application Number:
  US16/432,333
• Publication Number:
  US 20190314546A1
• Time in Patent Office: Days
• CPC Class Codes: A61L 2300/406 Antibiotics
• CPC Class Codes: A61L 24/001 Use of materials characterised by their function or physical properties
• CPC Class Codes: A61L 24/0015 Medicaments; Biocides
• CPC Class Codes: A61L 24/06 obtained by reactions only involving carbon-to-carbon unsaturated bonds A61L24/043, A61L24/046 take precedence
• CPC Class Codes: A61L 2430/02 for reconstruction of bones; weight-bearing implants
• CPC Class Codes: A61L 27/16 obtained by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C08L 33/12 Homopolymers or copolymers of methyl methacrylate

Abstract

An antibiotic polymethylmethacrylate bone cement that is composed of methylmethacrylate, at least one polymethylmethacrylate or a polymethylmethacrylate-copolymer, at least one polymerisation initiator, such as in radical initiator, at least one polymerisation accelerator, and at least one radiopaquer, whereby the components are present in a powdered component and a liquid monomer component or in two components that are pasty at room temperature. The polymethylmethacrylate bone cement comprises the cyclical lipopeptide, daptomycin, a pharmacologically tolerable salt of daptomycin, a solvate and/or a hydrate containing daptomycin and at least one calcium salt, which preferably comprises at least two different release profiles. The bone cement is useful in one-stage or two-stage septic revision surgery.

Claims

1. A method of conducting a one-stage or two-stage septic revision surgery, said method comprising anchoring a revision articular endoprosthesis in an area within the human body with an antibiotic bone cement, wherein the antibiotic bone cement is prepared by polymerizing an antibiotic polymerizable bone cement comprising:

(i) at least one monomer for radical polymerisation;

(a2) at least one organic polymer comprising at least one polymethylmethacrylate and/or one polymethylmethacrylate-copolymer, and

(iii) at least one polymerisation initiator;

(iv) at least one radiopaquer;

wherein

the antibiotic polymerizable bone cement comprises,

(v) as component 1, daptomycin, a pharmacologically tolerable salt of daptomycin, a polymorphous form of daptomycin, a solvate and/or a hydrate containing daptomycin; and

(vi) at least one calcium salt.

2. Method according to claim 1, wherein the polymerizable bone cement comprises, as

(vi) a combination comprising:

a) as component 2, a water-soluble calcium salt possessing a solubility in water at room temperature of more than or equal to 5 g/l; and

b) as component 3, a poorly water-soluble calcium salt possessing a solubility in water at room temperature of less than 5 g/l; and

, optionally,

c) at least one of components 1, 2 and/or 3 has a mean particle size of 1 to 250 μ

m.

3. Method according to claim 1, which comprises two components A and B, whereby

(i) component A is present as a paste and comprises

(a1) at least one monomer for radical polymerisation;

(a2) at least one organic polymer comprising at least one polymethylmethacrylate and/or one polymethylmethacrylate-copolymer; and

(a3) at least one polymerisation initiator; and

component B is present as a paste and comprises

(b1) at least one monomer for radical polymerisation;

(b2) at least one organic polymer comprising at least one polymethylmethacrylate and/or one polymethylmethacrylate-copolymer; and

(b3) at least one polymerisation accelerator;

or

(ii)component A is present as a powder and comprises

(a1) at least one powdered polymer comprising at least one polymethylmethacrylate and/or a powdered mixture comprising polymethylmethacrylate-co-polymers;

(a2) at least one powdered radiopaquer; and

(a3) at least one polymerisation initiator; and

component B is present as a liquid or paste and comprises

(b1) at least one monomer for radical polymerisation;

(b2) optionally, at least one organic polymer comprising at least one polymethylmethacrylate and/or one polymethylmethacrylate-copolymer; and

(b3) at least one polymerisation accelerator; and

whereby at least component A comprises, as

(a4), at least one of components 1, 2, and 3 selected from component 1 daptomycin, a pharmacologically tolerable salt of daptomycin, a solvate and/or a hydrate containing daptomycin, component 2 a water-soluble calcium salt possessing a solubility in water at room temperature of more than or equal to 5 g/l and component 3 a poorly water-soluble calcium salt possessing a solubility in water at room temperature of less than 5 g/l, and/or

whereby component B is present as a paste and comprises, as

(b4), at least one of components 1, 2, and 3 selected from component 1 daptomycin, a pharmacologically tolerable salt of daptomycin, a polymorphous form of daptomycin, a solvate and/or a hydrate containing daptomycin, component 2 a water-soluble calcium salt possessing a solubility in water at room temperature of more than or equal to 5 g/l, and component 3 a poorly water-soluble calcium salt possessing a solubility in water at room temperature of less than 5 g/l.

4. Method according to claim 1, wherein

(v) component 1 daptomycin, a pharmacologically tolerable salt of daptomycin, a polymorphous form of daptomycin, a solvate and/or a hydrate containing daptomycin, and (vi) a) component 2 the water-soluble calcium salt possessing a solubility in water at room temperature of more than or equal to 5 g/l, and b) component 3 the poorly water-soluble calcium salt possessing a solubility in water at room temperature of less than 5 g/l, each independently is present in the form of particles of components 1, 2 or 3 or each independently is a particulate formulation containing, each independently, at least one of components 1, 2 and/or 3, and at least one pharmacological excipient and, optionally, each independently comprise a mean particle size of 1 to 250 μ

m.

5. Method according to claim 1, wherein at least component A comprises, as

(a4), at least one of components 1, 2, and 3, which each independently are present in the form of particles of components 1, 2 or 3 or each independently, as a particulate formulation, containing, each independently, at least one of components 1, 2 and/or 3 and, optionally, each independently comprise a mean particle size of 1 to 250 μ

m,

whereby component B is present as a paste and comprises, as (b4) at least one of components 1, 2, and 3, which each independently are present in the form of particles of components 1, 2 or 3 or each independently, as a particulate formulation, containing, each independently, at least one of components 1, 2 and/or 3 and, optionally, each independently comprise a mean particle size of 1 to 250 μ

m.

6. Method according to claim 1, wherein

a) the polymerizable bone cement is present, as (a4) and/or (b4), as particles of a combination at least of components 1 and 2 or, each independently, as a particulate formulation containing at least a combination of components 1 and 2 and at least one pharmacological excipient;

or

b) the polymerizable bone cement is present, as (a4) and/or (b4), as particles of a combination of components 1, 2, and 3 or, each independently, as a particulate formulation containing the combination of components 1, 2, and 3 and at least one pharmacological excipient.

7. Method according to claim 2, wherein

a) component 2, the water-soluble calcium salt possessing a solubility in water at room temperature of more than or equal to 5 g/l, comprises calcium gluconate, calcium glucuronate, calcium lactate, calcium acetate and/or calcium sorbate or a mixture containing at least two of said calcium salts.

8. Method according to claim 2, wherein

b) component 3 the poorly water-soluble calcium salt possessing a solubility in water at room temperature of less than 5 g/l, comprises calciumsulfate-dihydrate, calciumsulfat-hemihydrate, alpha-tricalciumphosphate and/or beta-tricalciumphosphate.

9. Method according to claim 1, which contains at least one second antibiotic selected from the group of the aminoglycoside antibiotics and/or the lincosamide antibiotics and/or the ansamycin antibiotics and/or the fluoroquinolone antibiotics and/or the β

-lactam antibiotics.

10. The method according to claim 1, wherein the area within the human body has been subjected to radical debridement after explantation of an infected articular endoprosthesis.

11. The method according to claim 10, wherein the infected articular endoprosthesis is infected with gram-positive bacteria.

12. The method according to claim 11, wherein the gram-positive bacteria is selected from the group consisting of methicillin-resistant staphylococci and vancomycin-resistant staphylococci.

13. The method according to claim 12, wherein the gram-positive bacteria is selected from the group consisting of vancomycin-resistant staphylococci.

14. The method according to claim 1, wherein the antibiotic bone cement is adapted to provide synchronous release of daptomycin and calcium ions over a period of several days.

15. The method according to claim 1, wherein the antibiotic bone cement is in the form of a revision implant, screw, nail, or surgical plate used to mechanically fix the revision articular endoprosthesis in place.

16. A method of conducting a one-stage or two-stage septic revision surgery, said method comprising removing an infected articular endoprosthesis from an area within the human body and temporarily introducing a spacer into that area, wherein the spacer is composed of an antibiotic bone cement prepared by polymerizing an antibiotic polymerizable bone cement comprising:

(i) at least one monomer for radical polymerisation;

(a2) at least one organic polymer comprising at least one polymethylmethacrylate and/or one polymethylmethacrylate-copolymer; and

(iii) at least one polymerisation initiator;

(iv) at least one radiopaquer;

wherein

the antibiotic polymerizable bone cement comprises,

(v) as component 1, daptomycin, a pharmacologically tolerable salt of daptomycin, a polymorphous form of daptomycin, a solvate and/or a hydrate containing daptomycin; and

(vi) at least one calcium salt.

17. Method according to claim 16, wherein the polymerizable bone cement comprises, as

(vi) a combination comprising:

a) as component 2, a water-soluble calcium salt possessing a solubility in water at room temperature of more than or equal to 5 g/l; and

b) as component 3, a poorly water-soluble calcium salt possessing a solubility in water at room temperature of less than 5 g/l; and

, optionally,

c) at least one of components 1, 2 and/or 3 has a mean particle size of 1 to 250 μ

m.

18. Method according to claim 16, which comprises two components A and B, whereby

(i) component A is present as a paste and comprises

(a1) at least one monomer for radical polymerisation;

(a2) at least one organic polymer comprising at least one polymethylmethacrylate and/or one polymethylmethacrylate-copolymer; and

(a3) at least one polymerisation initiator; and

component B is present as a paste and comprises

(b1) at least one monomer for radical polymerisation;

(b2) at least one organic polymer comprising at least one polymethylmethacrylate and/or one polymethylmethacrylate-copolymer; and

(b3) at least one polymerisation accelerator;

or

(ii)component A is present as a powder and comprises

(a1) at least one powdered polymer comprising at least one polymethylmethacrylate and/or a powdered mixture comprising polymethylmethacrylate-co-polymers;

(a2) at least one powdered radiopaquer; and

(a3) at least one polymerisation initiator; and

component B is present as a liquid or paste and comprises

(b1) at least one monomer for radical polymerisation;

(b2) optionally, at least one organic polymer comprising at least one polymethylmethacrylate and/or one polymethylmethacrylate-copolymer; and

(b3) at least one polymerisation accelerator; and

whereby at least component A comprises, as

(a4), at least one of components 1, 2, and 3 selected from component 1 daptomycin, a pharmacologically tolerable salt of daptomycin, a solvate and/or a hydrate containing daptomycin, component 2 a water-soluble calcium salt possessing a solubility in water at room temperature of more than or equal to 5 g/l and component 3 a poorly water-soluble calcium salt possessing a solubility in water at room temperature of less than 5 g/l, and/or whereby component B is present as a paste and comprises, as

(b4), at least one of components 1, 2, and 3 selected from component 1 daptomycin, a pharmacologically tolerable salt of daptomycin, a polymorphous form of daptomycin, a solvate and/or a hydrate containing daptomycin, component 2 a water-soluble calcium salt possessing a solubility in water at room temperature of more than or equal to 5 g/l, and component 3 a poorly water-soluble calcium salt possessing a solubility in water at room temperature of less than 5 g/l.

19. Method according to claim 16, wherein

(v) component 1 daptomycin, a pharmacologically tolerable salt of daptomycin, a polymorphous form of daptomycin, a solvate and/or a hydrate containing daptomycin, and (vi) a) component 2 the water-soluble calcium salt possessing a solubility in water at room temperature of more than or equal to 5 g/l, and b) component 3 the poorly water-soluble calcium salt possessing a solubility in water at room temperature of less than 5 g/l, each independently is present in the form of particles of components 1, 2 or 3 or each independently is a particulate formulation containing, each independently, at least one of components 1, 2 and/or 3, and at least one pharmacological excipient and, optionally, each independently comprise a mean particle size of 1 to 250 μ

m.

20. Method according to claim 16, wherein at least component A comprises, as

(a4), at least one of components 1, 2, and 3, which each independently are present in the form of particles of components 1, 2 or 3 or each independently, as a particulate formulation, containing, each independently, at least one of components 1, 2 and/or 3 and, optionally, each independently comprise a mean particle size of 1 to 250 μ

m,

whereby component B is present as a paste and comprises, as (b4) at least one of components 1, 2, and 3, which each independently are present in the form of particles of components 1, 2 or 3 or each independently, as a particulate formulation, containing, each independently, at least one of components 1, 2 and/or 3 and, optionally, each independently comprise a mean particle size of 1 to 250 μ

m.

21. Method according to claim 16, wherein

a) the polymerizable bone cement is present, as (a4) and/or (b4), as particles of a combination at least of components 1 and 2 or, each independently, as a particulate formulation containing at least a combination of components 1 and 2 and at least one pharmacological excipient;

or

b) the polymerizable bone cement is present, as (a4) and/or (b4), as particles of a combination of components 1, 2, and 3 or, each independently, as a particulate formulation containing the combination of components 1, 2, and 3 and at least one pharmacological excipient.

22. Method according to claim 17, wherein

a) component 2, the water-soluble calcium salt possessing a solubility in water at room temperature of more than or equal to 5 g/l, comprises calcium gluconate, calcium glucuronate, calcium lactate, calcium acetate and/or calcium sorbate or a mixture containing at least two of said calcium salts.

23. Method according to claim 17, wherein

b) component 3 the poorly water-soluble calcium salt possessing a solubility in water at room temperature of less than 5 g/l, comprises calciumsulfate-dihydrate, calciumsulfat-hemihydrate, alpha-tricalciumphosphate and/or beta-tricalciumphosphate.

24. Method according to claim 16, which contains at least one second antibiotic selected from the group of the aminoglycoside antibiotics and/or the lincosamide antibiotics and/or the ansamycin antibiotics and/or the fluoroquinolone antibiotics and/or the β

-lactam antibiotics.

25. The method according to claim 16, wherein the area within the human body has been subjected to radical debridement after explantation of an infected articular endoprosthesis.

26. The method according to claim 25, wherein the infected articular endoprosthesis is infected with gram-positive bacteria.

27. The method according to claim 26, wherein the gram-positive bacteria is selected from the group consisting of methicillin-resistant staphylococci and vancomycin-resistant staphylococci.

28. The method according to claim 27, wherein the gram-positive bacteria is selected from the group consisting of vancomycin-resistant staphylococci .

29. The method according to claim 16, wherein the antibiotic bone cement is adapted to provide synchronous release of daptomycin and calcium ions over a period of several days.