Modified biodegradable and medical polymer devices and a method for preparing the same

Abstract

A medical polymer device comprising a biodegradable polymer is provided, wherein the biodegradable polymer has a crystallinity of about 10% to about 80%, and preferably from about 20% to about 60%, wherein the medical polymer device comprises a small molecule organic compound which diffuses into the biodegradable polymer, the small molecule organic compound has a molecular weight of from about 100 to about 1000 Daltons, preferably from about 150 to about 500 Daltons, and more preferably from about 150 to about 250 Daltons, and the small molecule organic compound is non-evaporating or low-evaporating. The present invention also provides a method for preparing a medical polymer device according to the present invention as well as a method for modifying a medical polymer device made from a biodegradable polymer.

Claims

1. A method for preparing a medical polymer device, the method comprising: soaking a pre-formed medical polymer device made from a biodegradable polymer having a crystallinity of 10% to 80% in a small molecule organic compound that is a C.sub.1-C.sub.8 alkyl salicylate or a solution of the small molecule organic compound and one or more optional additional substances to diffuse the small molecule organic compound into the biodegradable polymer at a concentration of 0.1% to 20% by weight of the medical polymer device.

2. The method of claim 1, wherein the soaking is carried out at a temperature above the melting point of the small molecule organic compound and below the boiling point temperature of the small molecule organic compound.

3. The method of claim 1, wherein the method further comprises removing the external small molecule organic compound from the medical polymer device after soaking.

4. The method of claim 1, wherein the small molecule organic compound is in liquid form and is non-evaporating or low-evaporating.

5. The method of claim 1, wherein the small molecule organic compound has a molecular weight of 100 to 1000 Daltons.

6. The method of claim 1, wherein the small molecule organic compound has a molecular weight of 150 to 250 Daltons.

7. The method of claim 1, wherein the biodegradable polymer is selected from the group consisting of polylactic acid, polyglycolic acid, polycaprolactone, polyanhydrides, poly(β-hydroxybutyrate), polydioxanone, poly(DTH iminocarbonate), polypropylene fumarate, copolymers thereof, and mixtures thereof.

8. The method of claim 1, wherein the biodegradable polymer is poly (L-lactide), polyglycolide, or a copolymer thereof.

9. The method of claim 1, wherein the medical polymer device comprises a further polymer in addition to the biodegradable polymer, the further polymer selected from the group consisting of polycaprolactone, polyesteramides, polylactic acid and its copolymers, polyglycolic acid, poly-3-hydroxybutyrate, poly-3-hydroxyvalerate, poly-3-hydroxybutyrate-co-4-hydroybutyrate, poly-3-hydroxybutyrate-co-3-hydroxyvalerate copolymers, poly-3-hydroxybutyrate-co-3-hydroxyhexanoate, poly-3-hydroxybutyrate-co-3-hydroxyoctanoate, poly-3-hydroxybutyrate-co-3-hydroxydecanoate, poly-3-hydroxybutyrate-co-3-hydroxyoctadecanoate, succinate-based aliphatic polymers, and a combination thereof.

10. The method of claim 1, wherein the medical polymer device having the small molecule organic compound diffused therein comprise amorphous regions of the biodegradable polymer that have a higher concentration of the small molecule organic compound than crystalline regions of the biodegradable polymer.

11. The method of claim 1, wherein the small molecule organic compound is selected from the group consisting of octyl salicylate, n-butyl salicylate, iso-butyl salicylate, ethyl salicylate, methyl salicylate, and a combination thereof.

12. The method of claim 1, wherein the small molecular organic compound is n-butyl salicylate.

13. The method of claim 1, wherein the small molecule organic compound is one or a mixture of two or more compounds selected from the group consisting of octyl salicylate, n-butyl salicylate, iso-butyl salicylate, ethyl salicylate, and methyl salicylate.

14. The method of claim 1, wherein the small molecule organic compound has a vapor pressure of no more than 2000 Pa at 25° C.

15. The method of claim 1, wherein the one or more additional substances are present and comprise one or more therapeutic agents.

16. The method of claim 15, wherein the therapeutic agent is selected from the group consisting of antibiotics, anti-inflammatory agents, antitumor agents, antifungal agents, pain medications, antihistamines, anti-infective agents, wound healing agents, anti-proliferative agents, and mixtures thereof.

17. The method of claim 1, further comprising coating the surface of the medical polymer device with a composition comprising a therapeutic agent.

18. The method of claim 1, wherein the method further comprises removing the external small molecule organic compound from an exterior of the medical polymer device after the soaking.

19. The method of claim 1, wherein the medical polymer device is a surgical suture, a biodegradable bone screw, a bone plate, a tissue engineering scaffold, or a cardiovascular stent.

20. A method for modifying a medical polymer device which is made from a biodegradable polymer having a crystallinity of 10% to 80%, wherein the method comprises: soaking the medical polymer device in a small molecule organic compound that is a C.sub.1-C.sub.8 alkyl salicylate or a solution of the small molecule organic compound and one or more optional additional substances to diffuse the small molecule organic compound into the biodegradable polymer at a concentration of 0.1% to 20% by weight of the medical polymer device.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) A full and enabling disclosure of the present invention is set forth more particularly in the remainder of the specification, including reference to the accompanying figures, in which

(2) FIG. 1 illustrates the kinetic curve of the controlled infusion of the small molecule organic compound into a polymer device;

(3) FIG. 2 illustrates an HPLC chromatogram of methanol extract obtained from a methyl salicylate infused stent;

(4) FIG. 3 illustrates an HPLC chromatogram of methanol extract obtained from an ethyl salicylate infused stent;

(5) FIG. 4 illustrates an HPLC chromatogram of methanol extract obtained from a n-butyl salicylate infused stent; and

(6) FIG. 5 illustrates an HPLC chromatogram of methanol extract obtained from an iso-butyl salicylate infused stent.

BEST MODE FOR CARRYING OUT THE INVENTION

(7) The polymer device used in present invention can be immersed completely in the solvent within a container at a set temperature. A typical weight ratio increase curve is shown in FIG. 1.

(8) The weight increase ratio is calculated as:
Q=(W.sub.t−W.sub.o)/W.sub.o×100% Where Q is the weight increase ratio, W.sub.t is the weight of the device at immersion time t, and W.sub.o is the weight of the device before immersion.

(9) By controlling the immersion time, the amount of the solvent diffused into the polymer device can be controlled at a given temperature.

Example 1—the Diffusion Process for the Small Molecule Organic Compound Infusion into the Polymeric Device as a Function of Time

(10) The kinetics of the small molecule organic compound diffusing into the polymer stent was studied. Intraluminal stents, in the sizes of 6 mm in diameter and 36 mm in length, were made by braiding a single PLLA fiber with a crystallinity of 30% on a mandrel. Three stents were studied. Each stent was immersed in 10 ml liquid of ethyl salicylate for 24 hours at 55 C. At different time intervals the stents were taken out, rinsed briefly with ethanol and padded dry with drying cloth. The weight of stents was then measured by a high accuracy stent balance (METTLER XP-6). FIG. 1 shows the kinetic curve of ethyl salicylate uptake in the stent as a function of time.

Example 2—Treatment of a Surgical Poly(L-Lactide)(PLLA) Mono-Filament Suture

(11) A PLLA mono filament suture with a diameter of 150 micrometer was produced using a polymer extruder equipped with a 200 micrometer diameter nozzle. The PLLA suture has a crystallinity about 20%. The PLLA suture was completely immersed in n-butyl salicylate at 70° C. for 5 hours. The weight increase ratio of the device is 3%. A tensile test using sample length of 76 mm and pulling speed of 127 mm/min was performed on the fibers with and without the n-butyl salicylate infusion treatment. The results showed that the small molecule infusion treatment had a significant effect on the break elongation of the PLLA suture which increased from 10% to 105% due to the treatment as shown in Table 1.

(12) TABLE-US-00001 TABLE 1 Effect of Small Molecule Infusion on the Mechanical Property of PLLA Fibers Fibers Without Fibers With Tensile Parameter Treatment Treatment Young's Modulus (GPa) 10.6 5.5 Yield Strength (MPa) 250 193 Break Strength (MPa) 263 247 Break Elongation (%) 10.2 104.5

Example 3—the Presence of the Small Molecule Organic Compound Infused into a PLLA-Made Device after Immersion in the Solvent was Identified and Quantified by High Performance Liquid Chromatography (HPLC) Using the Method Described as Follows

(13) Intraluminal stents, in the sizes of 3 mm in diameter and 13-18 mm in length, were made by braiding a single PLLA fiber on a mandrel. The stents were immersed respectively in 5 ml liquids of methyl salicylate, ethyl salicylate, n-butyl salicylate and iso-butyl salicylate for 2 hours at 50° C. The stents were removed off the excessive liquids by drying cloth and further dried in vacuum at 45° C. for several hours till the weight gains became constant. The treated and dried stents were then extracted in 10 ml methanol. The aliquots of extracts were analyzed by HPLC using a solvent mixture of acetonitrile and water running at 0.8:0.2 ml/s ratio at 40° C. The HPLC chromatograms that identify the elution peaks for methyl salicylate (3.9 min), ethyl salicylate (4.4 min), n-butyl salicylate (5.8 min) and iso-butyl salicylate (5.7 min) in the extracts are shown in FIGS. 2-5.

(14) TABLE-US-00002 TABLE 2 Small Molecule Organic Compound Infusion into Stent Measured by HPLC Amount of Solvent Infused The weight The weight of the into Stent Measured by increment percent Infusion Molecules stent (μg) HPLC (μg) (%) Methyl Salicylate 2400 480 20.0% Ethyl Salicylate 2400 312 13.0% n-Butyl Salicylate 2400 346 14.4% iso-Butyl Salicylate 2400 230 9.6%

Example 4—the Presence of the Small Molecule Organic Compound Infused into a Polyglycolide-Made Device after Immersion in the Solvent was Identified and Quantified by High Performance Liquid Chromatography (HPLC) Using the Method Described as Follows

(15) Intraluminal stents, in the sizes of 3 mm in diameter and 13-18 mm in length, were made by braiding a single polyglycolide fiber on a mandrel. The weight of stents before immersion was then measured by a high accuracy stent balance (METTLER XP-6). The stents were immersed respectively in 5 ml liquids of methyl salicylate, ethyl salicylate, n-butyl salicylate and iso-butyl salicylate for 2 hours at 50° C. The stents were removed of the excessive liquids by drying cloth and further dried in vacuum at 45° C. for several hours till the weight gains became constant. The weight of stents was then measured by a high accuracy stent balance (METTLER XP-6).

(16) TABLE-US-00003 TABLE 3 Small Molecule Infusion into Stent Measured by a high accuracy stent balance The weight Weight Gain of Stent After increment percent Infusion Molecules Immersion Treatment (μg) (%) Methyl Salicylate 468 18.7% Ethyl Salicylate 337 13.5% n-Butyl Salicylate 275 11.0% iso-Butyl Salicylate 237 9.5%

(17) While the invention has been described in detail with respect to the specific embodiments thereof, it will be appreciated that those skilled in the art, upon attaining an understanding of the foregoing, may readily conceive of alterations to, variations of, and equivalents to these embodiments. Accordingly, the scope of the present invention should be assessed as that of the appended claims and any equivalents thereto.