BIODEGRADABLE POLYMERS

• US 20100256746A1
• Filed: 03/23/2010
• Published: 10/07/2010
• Est. Priority Date: 03/23/2009
• Status: Abandoned Application

• Current Assignee: Micell Technologies Inc.
• Original Assignee: Micell Technologies Inc.
• Inventors: Schmitt, Edward E., McClain, James B., Taylor, Douglas
• Application Number:
  US12/729,603
• Publication Number:
  US 20100256746A1
• Time in Patent Office: Days
• US Class Current: 623/1.420
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61L 2300/416 Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2420/02 Methods for coating medical devices
• CPC Class Codes: A61L 2420/06 Coatings containing a mixture of two or more compounds
• CPC Class Codes: A61L 2420/08 Coatings comprising two or more layers
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/148 Materials at least partially resorbable by the body
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: B05D 2254/06 Applying the material on the interior and exterior of the tube
• CPC Class Codes: B05D 3/12 by mechanical means
• CPC Class Codes: C08G 2150/20 Compositions for powder coatings
• CPC Class Codes: C08G 2230/00 Compositions for preparing biodegradable polymers
• CPC Class Codes: C08G 63/06 derived from hydroxycarboxylic acids
• CPC Class Codes: C08G 63/08 Lactones or lactides
• CPC Class Codes: C08G 63/90 Purification; Drying
• CPC Class Codes: C08J 7/0427 with only one layer of a composition containing a polymer binder with more layers C08J7/042
• CPC Class Codes: C08J 7/043 Improving the adhesiveness of the coatings per se, e.g. forming primers adhesives in the form of films or foils characterised by the primer layers between the polymer carriers and the adhesives C09J7/50
• CPC Class Codes: C08J 7/044 Forming conductive coatings; Forming coatings having anti-static properties
• CPC Class Codes: C08L 67/04 Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence
• CPC Class Codes: C09D 167/04 Polyesters derived from hydroxycarboxylic acids, e.g. lactones C09D167/06 takes precedence
• CPC Class Codes: C09D 5/033 : characterised by the additives

Abstract

Provided herein is a composition comprising a poly(alpha-hydroxycarboxylic acid) substantially free of acidic impurities wherein the poly(alpha-hydroxycarboxylic acid) is selected from poly(D,L-lactic-co-glycolic acid), poly(L-lactic acid), poly(D-lactic acid) and poly(D,L-lactic acid). Also provided is a device comprising: a substrate, and a coating wherein the coating comprises poly(D,L-lactic-co-glycolic acid) substantially free of acidic impurities.

Claims

1. A composition comprising a poly(alpha-hydroxycarboxylic acid) substantially free of acidic impurities wherein the poly(alpha-hydroxycarboxylic acid) is selected from poly(D,L-lactic-co-glycolic acid), poly(L-lactic acid), poly(D-lactic acid), poly(D,L-lactic acid) and mixtures thereof.

2. The composition of claim 1, wherein the poly(alpha-hydroxycarboxylic acid) contains less than 0.5% (wt/wt), less than 1.0% (wt/wt), or less than 1.5% (wt/wt) of acidic impurity.

3. The composition of claim 1, wherein the poly(D,L-lactic-co-glycolic acid) has a ratio of lactic acid monomer to glycolic acid monomer ranging from 82:

18 to 88;

12, from 72;

28 to 78;

22, from 62;

38 to 68;

32, or from 47;

53 to 53;

47.

4. The composition of claim 1, wherein the poly(D,L-lactic-co-glycolic acid) has a weight average molecular weight of about 4,000 to about 8,000, about 8,000 to about 12,000, about 12,000 to about 16,000, or up to about 90,000 Dalton.

10. A device comprising:

a substrate, and

a coating wherein the coating comprises the composition comprising poly(D,L-lactic-co-glycolic acid) substantially free of acidic impurities of claim 1.

20. The method of claims 16, where the at least one polymer comprising poly(D,L-lactic-co-glycolic acid) substantially free of acidic impurities is the composition of claim 1.

5. A method for the preparation of a composition comprising poly(D,L-lactic-co-glycolic acid) substantially free of acidic impurities, said method comprising:

contacting poly(D,L-lactic-co-glycolic acid) containing acidic impurities with a solid base;

forming a salt of the acidic impurity; and

separating the poly(D,L-lactic-co-glycolic acid) from the salt of the acidic impurity.

11. A device comprising:

a substrate, and

a coating wherein the coating comprises the composition comprising poly(D,L-lactic-co-glycolic acid) substantially free of acidic impurities, formed by the method of claim 5.

6. A method for the preparation of a composition comprising poly(D,L-lactic-co-glycolic acid) substantially free of acidic impurities, said method comprising:

dissolving the poly(D,L-lactic-co-glycolic acid) containing acidic impurities in an inert solvent;

contacting poly(D,L-lactic-co-glycolic acid) solution with a metal hydride;

forming a metal salt of the acidic impurity; and

separating the poly(D,L-lactic-co-glycolic acid) from the metal salt of the acidic impurity.

7. A method for the preparation of a composition comprising poly(D,L-lactic-co-glycolic acid) substantially free of acidic impurities, said method comprising:

forming the poly(D,L-lactic-co-glycolic acid) containing acidic impurities into a thin film;

contacting said poly(D,L-lactic-co-glycolic acid) thin film with a layer of solid base;

diffusing the acidic impurities from said poly(D,L-lactic-co-glycolic acid) thin film; and

separating the poly(D,L-lactic-co-glycolic acid) thin film from the layer of solid base.

8. A method for the preparation of a composition comprising poly(D,L-lactic-co-glycolic acid) substantially free of acidic impurities, said method comprising subjecting the poly(D,L-lactic-co-glycolic acid) containing acidic impurities to electrophoresis.

9. A device comprising:

a substrate, and

a coating wherein the coating comprises poly(D,L-lactic-co-glycolic acid) substantially free of acidic impurities.

12. The device of claim 9, wherein the substrate comprises a stent.

13. The device of claim 9, wherein said substrate is a biomedical implant selected from the group consisting of stents (e.g., vascular stents), electrodes, catheters, leads, implantable pacemaker, cardioverter or defibrillator housings, joints, screws, rods, ophthalmic implants, femoral pins, bone plates, grafts, anastomotic devices, perivascular wraps, sutures, staples, shunts for hydrocephalus, dialysis grafts, colostomy bag attachment devices, ear drainage tubes, leads for pace makers and implantable cardioverters and defibrillators, vertebral disks, bone pins, suture anchors, hemostatic barriers, clamps, screws, plates, clips, vascular implants, tissue adhesives and sealants, tissue scaffolds, various types of dressings (e.g., wound dressings), bone substitutes, intraluminal devices, and vascular supports.

14. The device of claim 9, wherein the coating comprises rapamycin wherein at least part of rapamycin is in crystalline form.

15. The device of claim 14, wherein said device provides an elution profile wherein about 10% to about 50% of rapamycin is eluted at week 1 after the composite is implanted in a subject under physiological conditions, about 25% to about 75% of rapamycin is eluted at week 2 and about 50% to about 100% of rapamycin is eluted at week 4.

16. A method of depositing a coating onto a substrate, said coating comprising:

at least one polymer comprising poly(D,L-lactic-co-glycolic acid) substantially free of acidic impurities; and

at least one pharmaceutical agent in a therapeutically desirable morphology and/or at least one active biological agent;

said method comprising the following steps;

discharging the at least one pharmaceutical agent and/or at least one active biological agent in dry powder form through a first orifice;

discharging the at least one polymer in dry powder form through a second orifice;

depositing the polymer and pharmaceutical agent and/or active biological agent particles onto said substrate, wherein an electrical potential is maintained between the substrate and the polymer and pharmaceutical agent and/or active biological agent particles, thereby forming said coating; and

sintering said coating under conditions that do not substantially modify the morphology of said pharmaceutical agent and/or the activity of said biological agent.

19. The method of claim 16, where the at least one polymer comprising poly(D,L-lactic-co-glycolic acid) substantially free of acidic impurities is formed by the method of claim 5.

17. A method of depositing a coating onto a substrate, said coating comprising:

at least one polymer comprising poly(D,L-lactic-co-glycolic acid) substantially free of acidic impurities; and

at least one pharmaceutical agent in a therapeutically desirable morphology and/or at least one active biological agent;

said method comprising the following steps;

discharging the at least one pharmaceutical agent and/or at least one active biological agent in dry powder form through a first orifice;

forming a supercritical or near supercritical fluid solution comprising at least one supercritical fluid solvent and at least one polymer and discharging said supercritical or near supercritical fluid solution through a second orifice under conditions sufficient to form solid particles of the polymer;

depositing the polymer and pharmaceutical agent and/or active biological agent particles onto said substrate, wherein an electrical potential is maintained between the substrate and the polymer and pharmaceutical agent and/or active biological agent particles, thereby forming said coating; and

sintering said coating under conditions that do not substantially modify the morphology of said pharmaceutical agent and/or the activity of said biological agent.

18. A method of depositing a coating onto a substrate, said coating comprising:

at least one polymer comprising poly(D,L-lactic-co-glycolic acid) substantially free of acidic impurities; and

at least one pharmaceutical agent in a therapeutically desirable morphology in dry powder form and/or at least one active biological agent;

said method comprising the following steps;

discharging the at least one pharmaceutical agent and/or at least one active biological agent through a first orifice;

forming a first stream of a polymer solution comprising at least one solvent and at least one polymer;

forming a second stream of a supercritical or near supercritical fluid comprising at least one supercritical fluid;

contacting said first and second streams, whereby said supercritical or near supercritical fluid acts as a diluent of said solution under conditions sufficient to form particles of said polymer;

depositing the polymer and pharmaceutical agent and/or active biological agent particles onto said substrate, wherein an electrical potential is maintained between the substrate and the polymer and pharmaceutical agent and/or active biological agent particles, thereby forming said coating; and

sintering said coating under conditions that do not substantially modify the morphology of said pharmaceutical agent and/or the activity of said biological agent.

21. A method for depositing a coating comprising a polymer and pharmaceutical agent on a substrate, wherein the polymer comprises poly(D,L-lactic-co-glycolic acid) substantially free of acidic impurities and wherein the method comprises:

forming a supercritical or near critical fluid mixture that includes at least one polymer and at least one pharmaceutical agent

discharging a spray of the supercritical or near critical fluid mixture through a constriction under conditions sufficient to form particles of the pharmaceutical agent and particles of the polymer that are substantially free of supercritical fluid solvent or solvents, wherein the constriction comprises an insulator material;

providing a first electrode that is secured to the constriction and that can generate an electrical field for charging the solid pharmaceutical particles and/or the polymer particles to a first electric potential after they exit the constriction;

depositing the charged solid pharmaceutical particles and polymer particles to form a coating onto said substrate; and

sintering said coating under conditions that do not substantially modify the morphology of said solid pharmaceutical particles.

22. The method of claim 21, where the poly(D,L-lactic-co-glycolic acid) substantially free of acidic impurities is formed by the methods of claim 5.

23. The method of claim 21, where the poly(D,L-lactic-co-glycolic acid) substantially free of acidic impurities is formed by the method of claim 5.

24. A device comprising

a. a substrate;

b. a plurality of layers deposited on said stent to form said coronary stent;

wherein at least one of said layers comprises a polymer comprising poly(D,L-lactic-co-glycolic acid) substantially free of acidic impurities and at least one of said layers comprises rapamycin;

wherein at least part of rapamycin is in crystalline form and said rapamycin is provided at a reduced dose compared to a conventional drug eluting stent.

25. A device, comprising:

a stent; and

a rapamycin-polymer coating wherein at least part of rapamycin is in crystalline form and the rapamycin-polymer coating comprises one or more resorbable polymers and said rapamycin is provided at a reduced dose compared to a conventional drug eluting stent, and wherein the resorbable polymer comprises poly(D,L-lactic-co-glycolic acid) substantially free of acidic impurities.

26. A method of preparing a coated device comprising:

a. providing a substrate;

b. depositing a plurality of layers on said substrate to form said coated device;

wherein at least one of said layers comprises a drug-polymer coating wherein at least part of the drug is in crystalline form and the polymer is a bioabsorbable polymer comprising poly(D,L-lactic-co-glycolic acid) substantially free of acidic impurities.

27. The method of claim 26, wherein the substrate is a stent.

28. A coated stent, comprising:

a stent;

a first layer of bioabsorbable polymer; and

a rapamycin-polymer coating comprising rapamycin and a second bioabsorbable polymer wherein at least part of rapamycin is in crystalline form and wherein the first polymer is a slow absorbing polymer and the second polymer is a fast absorbing polymer, and wherein at least one of the first polymer and the second polymer is poly(D,L-lactic-co-glycolic acid) substantially free of acidic impurities.