Liposomal drug delivery system for bone cements

Patent metadata

Field	Value
Publication number	US-9895466-B2
Application number	US-201414903803-A
Country	US
Kind code	B2
Filing date	Jul 9, 2014
Priority date	Jul 10, 2013
Publication date	Feb 20, 2018
Grant date	Feb 20, 2018

Abstract

The invention relates to a novel antibiotic delivery vehicle for impregnating bone cement wherein said vehicle is an antibiotic encapsulated liposome having a block co-polymer on its surface; a method for the manufacture of a bone cement impregnated with antibiotic or a mixture of antibiotics using said vehicle; and also a novel bone cement made therewith and/or thereby.

First claim

The invention claimed is:

1. A bone cement having dispersed therein a vehicle for delivering and dispersing at least one antibiotic in said bone cement, wherein said vehicle comprises a liposome containing said at least one antibiotic, further wherein said liposome also comprises a block co-polymer adsorbed or absorbed onto the liposome, the block co-polymer having an average molecular weight less than 2000 and a higher proportion of polypropylene oxide to polyethylene oxide.

2. The bone cement according to claim 1 wherein said liposome is selected from the group comprising: a liposome less than 600 nm in diameter when measured using laser diffraction; a liposome less than 150 nm in diameter when measured using Transmission Electron Microscopy (TEM); and a liposome about 100 nm in diameter using TEM.

3. The bone cement according to claim 1 wherein said liposome is made from a phospholipid selected from the group consisting of: cationic phospholipids, neutral phospholipids, anionic phospholipids and one or more combinations thereof.

4. The bone cement according to claim 1 wherein said liposome is made from at least one phospholipid selected from the following groups: phospatidylcholine, phosphatidylethanolamine, sphingomyelin, phosphatidic acid, phospatidylglycerol, phospatidylserine and phospatidylinositol.

5. The bone cement according to claim 1 wherein said liposome is made from at least one cationic lipid selected from the following groups: 1,2 dioleoyl-3-trimethylammonium-propane (DOTAP), dioctadecyldimethylammonium chloride (DODAc), 1,2-dimyristoyloxypropyl-3-dimethyl-hydroxyethyl ammonium (DMRIE), 2,3-dioleoyloxy-N-(2(sperminecarboxamide)ethyl)-N,N-dimethyl-1 propananninium (DOSPA), 1,2-dimethyl-dioctadecylammoniumbromide (DDAB), 2-dioleyl-3-N,N,N-trimethylaminopropanechloride (DOTMA), 1,2-dimyristoyl-3-trimethylammoniumpropane DMTAP, 1,2-distearoyl-3-trimethylammoniumpropane (DSTAP), 1,2-Dioleoyl-3-dimethylammonium-propane (DODAP), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propan-1-aminium (DOBAQ) and dioctadecylamidoglycylspermine (DOGS).

6. The bone cement according to claim 1 wherein said liposome is selected from the group consisting of: dimyristoyl-phosphatidylcholine (DMPC), dimyristoylphosphatidylglycerol (DMPG), hydrogenated soy phosphatidylcholine (HSPC), distearoylphosphatidylglycerol-cholesterol (DSPG), cholesteryl sulfate, 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC), 1.2-dipalmitoyl-sn-3-glycero-[phosphorrac-(1-glycerol)] (DPPG), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), egg yolk phosphatidylcoline (EPC), Dioleoylphosphatidylethanolamine, egg phosphatidylglycerol (ePG), Polyethylene glycol (PEG)-dendron phospholipids, Dipalmitoylphosphatidylcholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (PEG200 DSPE), monostearoylphosphatidylcholine (MSPC), 1-stearoyl-L-α-phosphatidyl (SHPC), Soybean phospholipids (SPC), egg sphingomyelin, stearylamine (SA), and 1,2-dimyristyloxypropyl-3-dimethyl-hydroxyl ethyl ammonium bromide (DMRIE).

7. The bone cement according to claim 1 wherein said block co-polymer is selected from the group consisting of: Pluronic L31, Pluronic L43 and Pluronic L61.

8. The bone cement according to claim 1 wherein said antibiotic is selected from the list consisting of: gentamicin, vancomycin, tobramycin, ampicillin, benzylpenicillin, erythromycin, kanamycin, methicillin, neomycin, streptomycin, tetracycline, co-trimoxazole, cloxacillin, chloramphenicol, cephaloridine, cephazolin, oxacillin, ciprofloxacin, aztreonam and imipenem.

9. The bone cement according to claim 1 wherein said antibiotic comprises two or more antibiotics.

10. The bone cement according to claim 1 wherein said cement is selected from the group consisting of: poly(methyl methacrylate) (PMMA), methacrylate-cements and acrylic resins.

11. The bone cement according to claim 1 wherein said cement comprises a plurality of said liposomes.

12. The bone cement according to claim 11 wherein said plurality of liposomes is selected from one or more of the groups consisting of: liposomes made from the same lipid; liposomes made from the same two or more different lipids; different liposomes made from a different lipid; different liposomes made from two or more different lipids; liposomes made from the same one or more lipid(s) but containing different antibiotics; and liposomes made from different one or more lipids but containing different antibiotics.

13. The bone cement according to claim 1 wherein said vehicle or said cement also comprises an agent selected from the group consisting of: other antimicrobial agents, drugs to stimulate bone formation, therapeutic agents, strontium, bisphosphonates and bone morphogenetic proteins.

14. A method for the manufacture of bone cement comprising mixing together a polymer suitable for making bone cement, or a precursor thereof, with a vehicle for delivering and dispersing at least one antibiotic within said bone cement; wherein said vehicle comprises a liposome containing said antibiotic; and further wherein said liposome comprises a block co-polymer adsorbed or absorbed onto the liposome, the block co-polymer having an average molecular weight less than 2000 and a higher proportion of polypropylene oxide to polyethylene oxide.

15. The method according to claim 14 wherein said precursor is a monomer.

16. The method according to claim 14 wherein a suspension of said vehicle is mixed into a liquid component of the bone cement prior to mixing this liquid component with the polymer or precursor thereof.

Assignees

• Univ College Cardiff Consultants Ltd

Inventors

• Denyer Stephen
• Evans Samuel
• Ayre Wayne
• Birchall James

Classifications

• A61K9/1271

  Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911}) · CPC title

• A61L24/046

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds (A61L24/043 takes precedence) · CPC title

• A61L2300/406

  Antibiotics · CPC title

• A61L24/0015 Primary

  Medicaments; Biocides · CPC title

• A61L27/54

  Biologically active materials, e.g. therapeutic substances {(A61L27/227 takes precedence)} · CPC title