Drug eluting polymer composed of biodegradable polymers applied to surface of medical device

Patent metadata

Field	Value
Publication number	US-12115289-B2
Application number	US-201716074256-A
Country	US
Kind code	B2
Filing date	Feb 3, 2017
Priority date	Feb 5, 2016
Publication date	Oct 15, 2024
Grant date	Oct 15, 2024

Abstract

This present invention relates to drug eluting polymers, including novel biodegradable drug eluting polymers, which are added to the surface of a medical device to treat device associated complications and to deliver drug locally around the device. Methods of making polymers, for example, drug-eluting polymers, polymer compositions, and materials used therewith also are provided. The drug eluting polymers are obtained from the polymerization of macromonomers made of a connecting moiety, a biodegradable moiety and a cross-linkable moiety that are liquids at a temperature of 10° C. to 40° C.

First claim

What is claimed is:

1. A method of making a medical device comprising a drug-eluting biodegradable polymer, wherein the method comprises the steps of:
providing a liquid polymerizable mixture comprising at least a macromer that is a liquid at a temperature between about 10° C. and about 40° ° C. without addition of a solvent, wherein the macromer comprises a first and a second cross-linkable moieties, a first and a second biodegradable moieties, and polyethylene glycol (PEG) 200 as a central moiety, wherein the macromer is comprised of one selected from the group consisting of the covalent bonding of:
(A) the first cross-linkable moiety, the first biodegradable moiety, PEG 200 as a connecting moiety, the second biodegradable moiety, and the second cross-linkable moiety,
(B) the first cross-linkable moiety, the first biodegradable moiety, PEG 200 as a connecting moiety, the second cross-linkable moiety, and the second biodegradable moiety,
(C) the first biodegradable moiety, the first cross-linkable moiety, PEG 200 as a connecting moiety, the second cross-linkable moiety, and the second biodegradable moiety, and
(D) the first biodegradable moiety, the second cross-linkable moiety, PEG 200 as a connecting moiety, the second biodegradable moiety, and the second cross-linkable moiety;
wherein the first and the second cross-linkable moieties are the same or different;
wherein the first and the second biodegradable moieties are the same or different;
mixing with at least one bioactive agent without addition of a solvent, thereby forming a liquid, bioactive agent-containing polymerizable mixture;
applying the liquid polymerizable mixture without addition of a solvent onto at least one surface of an implant;
initiating polymerization by an external stimulus without addition of a solvent;
polymerizing for a period of time; thereby forming the medical device comprising the biodegradable drug-eluting polymer.

2. A method of making a medical device comprising a drug-eluting polymer, wherein the method comprises the steps of:
providing a liquid polymerizable mixture comprising at least a macromer that is a liquid at a temperature between about 10° C. and about 40° ° C. without addition of a solvent, wherein the macromer comprises a first and a second cross-linkable moieties, a first and a second biodegradable moieties, polyethylene glycol (PEG) 200 as a central moiety, wherein the macromer is comprised of one selected from the group consisting of the covalent bonding of:
(A) the first cross-linkable moiety, the first biodegradable moiety, PEG 200 as a connecting moiety, the second biodegradable moiety, and the second cross-linkable moiety,
(B) the first cross-linkable moiety, the first biodegradable moiety, PEG 200 as a connecting moiety, the second cross-linkable moiety, and the second biodegradable moiety,
(C) the first biodegradable moiety, the first cross-linkable moiety, PEG 200 as a connecting moiety, the second cross-linkable moiety, and the second biodegradable moiety, and
(D) the first biodegradable moiety, the first cross-linkable moiety, PEG 200 as a connecting moiety, the second biodegradable moiety, and the second cross-linkable moiety;
wherein the first and the second cross-linkable moieties are the same or different;
wherein the first and the second biodegradable moieties are the same or different;
mixing with an anesthetic agent without addition of a solvent, thereby forming a liquid, bioactive agent-containing polymerizable mixture;
applying the liquid polymerizable mixture onto at least one surface of an implant;
initiating polymerization by an external stimulus without addition of a solvent;
polymerizing for a period of time; thereby forming the medical device comprising the drug-eluting biodegradable polymer for drug elution.

3. The method according to claim 1 , wherein the medical device is selected from the group consisting of a fracture plate, an internal fixation (fracture) plate, an acetabular shell, an acetabular cup or femoral stem of a total hip replacement implant, a femoral or tibial component or patellar component of a total knee replacement implant, any component of a total hip replacement, any component of a hip resurfacing implant, femoral heads, modular or nonmodular femoral necks, tibial inserts, tibial baseplates, fixation pins, rods, screws, and shoulder implants.

4. The method according to claim 1 , wherein the first cross-linkable moiety and the second cross-linkable moiety are selected from the group consisting of acrylates, methacrylates, thiols, carboxyls, hydroxyls, amino groups, isocyanates, azides, isothiocyanates, epoxides, and a combination thereof.

5. The method according to claim 1 , wherein the first biodegradable moiety and the second biodegradable moiety are selected from the group consisting of poly(lactide) (PLA), poly(glycolide) (PGA), poly(epsilon-caprolactone) (PCA), poly(dioxane) (PDA), poly(trimethylene carbonate) (PTMC), and any combination thereof.

6. The method according to claim 1 , wherein the first connecting moiety and the second connecting moiety are selected from the group consisting of polyethylene glycol, polypropylene glycol, 1,6-hexanediol, 2,2,6,6-Tetrakis(hydroxymethyl)cyclohexanol, ethylene glycol, and cyanuric acid.

7. The method according to claim 1 , wherein the external stimulus to initiate polymerization of the liquid polymerizable mixture is carried out by
at least one selected from the group consisting of:
(i) heating with a power of 700 mW/cm2 to 1400 mW/cm2, and
(ii) changing pH.

8. The method according to claim 1 , wherein the polymerization is carried out for 15 to 30 seconds.

9. The method according to claim 1 , wherein the liquid polymerizable mixture comprises an initiator selected from the group consisting of camphorquinone, ethyl 4-(dimethylamino) benzoate (EDMAB), 2,4,6-trimethylbenzoyldiphenylphosphine oxide, 1-Phenyl-1,2 propanedione, N,N-dimethyl-p-toluidine, benzoyl peroxide, and any combination thereof.

10. The method according to claim 1 , wherein the liquid polymerizable mixture comprises an inhibitor selected from the group consisting of hydroquinone, mono methyl ether hydroquinone, 4-methoxyphenol, 4-tert-butylcatechol, and any combination thereof.

11. The method according to claim 1 , wherein there are pre-formed reservoirs on the surface(s) of the medical device.

12. The method according to claim 11 , wherein the reservoirs are formed on the surface(s) of the medical device before the liquid polymerizable mixture is applied.

13. The method according to claim 1 , wherein the macromer comprises a block co-polymer composed of covalently bonded (polylactic acid)2-PEG 200-(polylactic acid)2 and end-capped with at least one of acrylate and methacrylate groups at both ends.

14. The method according to claim 1 , wherein the macromer comprises a covalently bonded (polylactic acid)4-PEG 200-(polylactic acid)4 and end-capped with at least one of acrylate and methacrylate groups at both ends.

15. The method according to claim 2 , wherein the anesthetic agent is selected from the group consisting of bupivacaine, lidocaine, and ropivacaine.

16. The method according to claim 1 , wherein one bioactive agent is an antimicrobial agent selected from the group consisting of penicillin, imipenem, cefotaxime, ceftaroline, kanamycin, gentamycin, tobramycin, carbapenems, teicoplanin, dalbavancin, vancomycin, cefazolin, oritavancin, daptomycin, dalfopristin, amphomycin, colistins, ramoplanin, azithromycin, cethromycin, erythromycin, rifamycin, rifapentin, rifaximin, minocycline, tigecicline, linezolid, clinda

Assignees

• Massachusetts Gen Hospital

Inventors

• Oral Ebru
• Suhardi Jeremy V
• Muratoglu Orhun K
• Malchau Henrik
• Rubash Harry E
• Freiberg Andrew A

Classifications

• C08L71/02

  Polyalkylene oxides · CPC title

• C08F2/44

  Polymerisation in the presence of compounding ingredients, e.g. plasticisers, dyestuffs, fillers · CPC title

• A61L2400/04

  Materials for stopping bleeding · CPC title

• A61L2300/418

  Agents promoting blood coagulation, blood-clotting agents, embolising agents · CPC title

• A61L31/148

  Materials at least partially resorbable by the body · CPC title