Method for the antibiotic coating of bodies with interconnecting microcavities as well as coated bodies and their usage

• US 7,358,232 B2
• Filed: 06/19/2002
• Issued: 04/15/2008
• Est. Priority Date: 08/31/2001
• Status: Expired due to Fees

• Current Assignee: Heraeus Medical GmbH (Heraeus Holding GMBH)
• Original Assignee: Heraeus Kulzer GmbH (Mitsui Chemicals)
• Inventors: Kühn, Klaus-Dieter, Schnabelrauch, Matthias, Vogt, Sebastian
• Primary Examiner(s): Hartley; Michael G.
• Assistant Examiner(s): Ebrahim; Nabila G
• Application Number:
  US10/174,682
• Publication Number:
  US 20030049324A1
• Time in Patent Office: 2,127 Days
• Field of Search: 424/423
• US Class Current: 514/25
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents

Abstract

The invention relates to a method for the antibiotic coating of bodies with interconnecting microcavities as well as bodies coated this way and their usage. The invented method is characterized in that in the microcavities of non-metallic bodies an aqueous solution 1, which contains at least one easily water-soluble antibiotic component from the groups of the aminoglycoside antibiotics, the tetracycline antibiotics, the lincosamide antibiotics and the 4-quinolone antibiotics, and an aqueous solution 2, which contains at least one easily water-soluble amphiphilic component from the groups of the alkyl sulfates, alkyl sulfonates, alkylaryl sulfates, dialkylaryl sulfates, alkylaryl sulfonates, dialkylaryl sulfonates, cycloalkyl sulfates, cycloalkyl sulfonates, alkylcycloalkyl sulfates, are introduced, wherein between the introduction of solutions 1 and 2 the water is basically removed through vaporization and/or evaporation, and whereby from the components of solutions 1 and 2 in the microcavities a deposit is formed, which is sparingly soluble in water.

Claims

1. Method for the antibiotic coating of bodies with interconnecting microcavities, said method comprising the following steps:

a) introducing into the microcavities an aqueous solution 1, which comprises at least one easily water-soluble antibiotic component selected from the group consisting of the aminoglycoside antibiotics, the tetracycline antibiotics, the lincosamide antibiotics, the 4-quinolone antibiotics and the chlorhexidines, and an aqueous solution 2, which comprises at least one easily water-soluble amphiphilic component selected from the group consisting of the alkyl sulfates, alkyl sulfonates, alkylaryl sulfates, dialkylaryl sulfates, alkylaryl sulfonates, dialkylaryl sulfonates, cycloalkyl sulfates, cycloalkyl sulfonates, and alkylcycloalkyl sulfates,

b) removing water between the introduction of solutions 1 and 2, and

c) forming a coating from components of solutions 1 and 2 in the microcavities, which consists of a sparingly water-soluble deposit.

2. Method according to claim 1, wherein the aqueous solution 1 is introduced into the microcavities first and aqueous solution 2 is subsequently introduced upon removal of the water.

3. Method according to claim 1, wherein the aqueous solution 2 is introduced into the microcavities first and aqueous solution 1 is subsequently introduced upon removal of the water.

4. Method according to claim 1, wherein solution 1 comprises at least one antibiotic substance selected from the group consisting of:

allomycin, amicetin, amikacin, apramycin, bekanamycin, betamicin, butirosin, destomycin, dibekacin, dihydrostreptomycin, flambamycin, fortimcycin A, fortimycin B, framycetin, gentamicin, hikizimycin, homomycin, hybrimicin, hygromycin B, kasuhamycin, lividomycin, minosamino[m]ycin, neomycin, netimicin, paromomycin, parvulomycin, puromycin A, ribostamycin, rimocidin, ristosamine, ristomycin, sagamycin, sisomicin, sorbistin, specinomycin, streptomycin, tobramycin, tunicamycin, verdamycin, clindamycin and lincomycin, tetracyline, chlortetracycline, oxytetracycline, dimethylchlortetracycline, methacycline, doxycycline, rolitetracycline, minocycline, ciproflaxin, enfloxacin, moxifloxacin, chlorhexidine-di-hydrochloride, chlorhexidine-diacetate and chlorhexidine-di-gluconate.

5. Method according to claim 1, wherein the easily water-soluble antibiotic component is contained in the aqueous solution 1 from 0.1 to 60 percent by mass.

6. Method according to claim 1, wherein the water-soluble amphiphilic component is contained in the aqueous solution 2 from 0.1 to 60 percent by mass.

7. Method according to claim 1, wherein the ratio of the substance quantity of the easily water-soluble antibiotic component of the aqueous solution 1 to the substance quantity of the water-soluble amphiphilic component in the aqueous solution 2 is from 1:

1 to 6;

1.

8. Method according to claim 1, wherein the antibiotic component in the aqueous solution 1 is in the form of a protonized salt.

9. Method according to claim 8, wherein chloride ions, bromide ions, hydrogen sulfate ions, sulfate ions, dihydrogen phosphate ions, hydrogen phosphate ions, phosphate ions, acetate ions, succinate ions and lactate ions are used as counter-ions.

10. Method according to claim 1, wherein the solutions 1 and/or 2 are introduced into the microcavities through dipping, spraying or dripping.

11. Method according to claim 1, wherein an introduction of an aqueous solution of gentamicin sulfate into the microcavities occurs through dipping or spraying or dripping, a subsequent drying process for removal of the water from the microcavities and a subsequent introduction of an aqueous solution of sodium dodecyl sulfate and/or an aqueous solution of sodium dodecyl sulfonate through dipping or spraying or dripping take place;

or in that an introduction of an aqueous solution of ciprofloxacin hydrochloride into the microcavities occurs through dipping or spraying or dripping, a subsequent drying process for removal of the water from the microcavities and a subsequent introduction of an aqueous solution of sodium dodecyl benzyl sulfonate through dipping or spraying or drying take place;

or in that an introduction of an aqueous solution of tetracycline hydrochloride and/or chlortetracycline hydrochloride and/or minocycline hydrochloride and/or doxycycline hydrochloride into the microcavities occurs through dipping or spraying or dripping, a subsequent drying process for removal of water from the microcavities and a subsequent introduction of an aqueous solution of sodium dodecyl sulfate and/or an aqueous solution of sodium dodecyl sulfonate taking place through dipping or spraying.

12. Method according to claim 1, wherein upon introduction of the first aqueous solution into the microcavities, the water is removed partially or completely through drying at normal pressure or in a vacuum at temperatures of −

200°

C. to 1200°

C.

13. Method according to claim 1, wherein the bodies are molded bodies, and upon formation of the slightly water-soluble deposits, the molded bodies are dried at normal pressure or in a vacuum at temperatures of −

200C to 1200C.

14. Method according to claim 1, wherein the water-soluble amphiphilic component of the aqueous solution 2 comprises at least one substance selected from the group consisting of:

sodium dodecyl sulfate, sodium dodecyl sulfonate, sodium tetradecyl sulfate, sodium tetradodecyl sulfonate, sodium hexadecyl sulfate, sodium hexadecyl sulfonate, sodium octadecyl sulfate, sodium octadecyl sulfonate and sodium dodecyl benzyl sulfonate.

15. Method according to claim 1, wherein the microcavities are pores.

16. Method according to claim 1, wherein the body with interconnecting microcavities consists of hydroxyl apatite, tricalcium phosphate, calcium carbonate, calcium sulfate, resorbable glass and resorbable glass ceramics.

17. Method according to claim 1, wherein the bodies with interconnecting microcavities consist of polymers, which are based on L-lactic acid and/or D-lactic acid and/or glycolic acid and/or 2-hydroxyethyl-oxy acetic acid.

18. Method according to claim 17, wherein the bodies with interconnecting microcavities are porous bodies, and are in the form of sponges, foam bodies, shaped masses, felt, fabrics or knits.

19. Method according to claim 1, wherein the bodies consist of titanium, titanium alloys or stainless steel.

20. Method according to claim 1, wherein the antibiotic coating does not completely fill in the volume of the interconnecting microcavities.

21. Method according to claim 1, wherein methanol, ethanol, isopropanol, N,N-dimethyl formamide and/or dimethyl sulfoxide are added as co-solvents to aqueous solution 1 and/or to aqueous solution 2.

22. Method according to claim 1, wherein the antibiotically coated bodies with interconnecting microcavities are used as implants.

23. Method according to claim 1, wherein solution 2 is introduced into the bodies with interconnecting microcavities and that upon removal of the water the bodies treated this way, comprising interconnecting micro hollow space systems, are used as implant material, and solution 1 is not introduced to the implant material until immediately before implantation.

24. A method for the antibiotic coating of bodies with interconnecting microcavities, said method comprising the following steps:

a) introducing into the microcavities an aqueous solution 1, which comprises at least one easily water-soluble antibiotic component selected from the group consisting of the aminoglycoside antibiotics, the tetracycline antibiotics, the lincosamide antibiotics, the 4-quinolone antibiotics and the chlorhexidines, and an aqueous solution 2, which comprises at least one easily water-soluble amphiphilic component selected from the group consisting of the alkyl sulfates, alkyl sulfonates, alkylaryl sulfates, dialkylaryl sulfates, alkylaryl sulfonates, dialkylaryl sulfonates, cycloalkyl sulfates, cycloalkyl sulfonates, and alkylcycloalkyl sulfates;

b) removing water between the introduction of solutions 1 and 2; and

c) forming a coating from components of solutions 1 and 2 in the microcavities, which coating comprises a sparingly water-soluble salt or complex.