Method of fabricating an implantable medical device comprising a rapamycin derivative

Patent metadata

Field	Value
Publication number	US-9610385-B2
Application number	US-201313789473-A
Country	US
Kind code	B2
Filing date	Mar 7, 2013
Priority date	Mar 7, 2013
Publication date	Apr 4, 2017
Grant date	Apr 4, 2017

Abstract

This invention relates to an method of manufacture of an implantable medical device comprising an oxygen-sensitive rapamycin derivative that is protected by addition of an antioxidant during the manufacturing process where the amount of antioxidant added at the outset of the processing is such that when the device is fully fabricated, sterilized and packaged the amount of antioxidant has reduced to a minimal, preferably non-detect, amount.

First claim

What is claimed:

1. A method of fabricating an implantable medical device comprising a rapamycin derivative drug, the method comprising:
synthesizing a rapamycin derivative drug;
purifying the rapamycin derivative drug using a technique that results in a substantially pure rapamycin derivative drug dissolved in a solvent, wherein:
the solvent used in the purification technique is used for preparation of a coating composition comprising the rapamycin derivative drug;

determining the percent by weight of the rapamycin derivative drug in the solvent;
adjusting the amount of the solvent such that the weight percent of the rapamycin derivative drug in the solvent is that desired in the coating composition to be applied to an implantable medical device;
adding a desired weight percent, based on the weight of the rapamycin derivative drug, of an pharmaceutically acceptable antioxidant stabilizer to form the coating composition; and
disposing the coating composition on the implantable medical device to form a drug reservoir layer;
wherein the substantially pure rapamycin derivative drug is not isolated as a dry solid after the purifying step and before the disposing step.

2. The method of claim 1 , further comprising addition of a matrix polymer to the coating composition before disposing the composition on the implantable medical device.

3. The method of claim 1 , further comprising drying the drug reservoir layer.

4. The method of claim 2 , further comprising mounting the implantable medical device on a carrier vehicle.

5. The method of claim 4 , wherein the carrier vehicle is a catheter.

6. The method of claim 5 , wherein the carrier vehicle with mounted implantable device is sterilized.

7. The method of claim 6 , wherein sterilization comprises ethylene oxide sterilization, e-beam sterilization or gamma sterilization.

8. The method of claim 7 , wherein the sterilized carrier vehicle with mounted implantable device is packaged in a light-tight container under an inert atmosphere.

9. The method of claim 1 , wherein the synthesized rapamycin derivative drug is selected from the group consisting of a 40-O-substituted rapamycin, everolimus, temsirolimus, deforolimus, ridaforolimus, merilimus, biolimus, umirolimus and 16-pent-2-ynyloxy-32 (S)-dihydrorapamycin.

10. The method of claim 1 , wherein the synthesized rapamycin derivative drug is selected from the group consisting of zotarolimus, 16-pent-2-ynyloxy-32 (S)-dihydrorapamycin, novolimus, and myolimus.

11. The method of claim 1 , wherein the pharmaceutically acceptable antioxidant stabilizer is selected from the group consisting of a butylated phenol, butylated hydroxytoluene (BHT), butylated hydroxyanisole, t-butylhydroquinone, quinone, an alkyl gallate, methyl gallate, ethyl gallate, propyl gallate, octyl gallate, docecyl gallate, resveratrol, cysteine, n-acetylcysteine, bucillamine, glutathione, 7-hydroxyethylrutoside, carvedilol, vitamin C, ascorbyl palmitate, fumaric acid, a tocopherol, α-tocopherol, α-tocopherol acetate, a tocotrienol, vitamin E, lycopene, a flavonoid, a carotenoid, carotene and combinations thereof.

12. The method of claim 11 , wherein the pharmaceutically acceptable antioxidant stabilizer is BHT.

13. The method of claim 1 , wherein purifying the synthesized rapamycin derivative drug is selected from the group consisting of elution (column) chromatography, high performance liquid chromatography, high performance countercurrent chromatography, planar chromatography, supercritical fluid chromatography, liquid-liquid extraction and liquid-solid extraction.

14. The method of claim 13 , wherein the solvent used in the purification process that is also suitable as a solvent for the coating composition is selected from the group consisting of methanol, ethanol, propanol, n-propanol, isopropanol, butanol, pentane, hexane, heptane, octane, nonane, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, toluene, xylene, acetone, methyl ethyl ketone (MEK), cyclopentanone, cyclohexanone, diethyl ether, dipropyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyl formamide, dimethylacetamide, dimethyl sulfoxide and combinations thereof.

15. The method of claim 1 , wherein adjusting the amount of solvent to give the desired percent by weight of the rapamycin derivative drug in the solvent comprises removing solvent from or adding solvent to the coating composition.

16. The method of claim 2 , wherein the matrix polymer is selected from the group consisting of a polyester, poly(L-lactide), poly(D-lactide), poly(D,L-lactide), poly(meso-lactide), poly(L-lactide-co-glycolide), poly(D-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(meso-lactide-co-glycolide), poly(caprolactone), poly(L-lactide-co-caprolactone), poly(glycolide-co-caprolactone), poly(hydroxyvalerate), poly(hydroxybutyrate), poly(ethylene glycol-co-butylene terephthalate), poly(n-butyl methacrylate), a fluoropolymer, poly(vinylidene fluoride-co-hexafluoropropylene) and blends and copolymer thereof.

17. The method of claim 16 , wherein the matrix polymer is poly(vinylidene fluoride-co-hexafluoropropylene).

18. The method of claim 1 , wherein disposing the coating composition on the implantable medical device to form the drug reservoir layer comprises spray coating.

19. The method of claim 1 , wherein the implantable medical device is a stent.

20. The method of claim 2 , wherein the implantable medical device is a stent.

21. The method of claim 20 , wherein the pharmaceutically acceptable antioxidant stabilizer is BHT.

22. The method of claim 21 , wherein the rapamycin derivative drug is everolimus or novolimus.

23. The method of claim 22 , wherein when the rapamycin derivative drug is everolimus, the weight percent BHT based on the weight of everolimus present on the stent is about 0.001 to about 0.01%; and wherein when the rapamycin derivative drug is novolimus, the weight percent BHT based on the weight of novolimus present on the stent is about 0.001 to about 0.01%.

24. The method of claim 22 , wherein the amount of BHT remaining on the stent after all of the process steps are completed is non-detectable.

Assignees

• Abbott Cardiovascular Systems Inc

Inventors

• Pacetti Stephen D
• Fox Julia

Classifications

• A61L31/143

  Stabilizers · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• B65B55/12

  Sterilising contents prior to, or during, packaging · CPC title

• A61L2300/416

  Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus · CPC title

• A61K31/436

  the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin · CPC title