Macrolide particulates, methods for preparation, and medical devices associated therewith

• US 10,449,180 B2
• Filed: 04/23/2018
• Issued: 10/22/2019
• Est. Priority Date: 05/16/2013
• Status: Active Grant

• Current Assignee: Surmodics Incorporated
• Original Assignee: Surmodics Incorporated
• Inventors: Slager, Joram
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): Mercier, Melissa S
• Application Number:
  US15/959,589
• Publication Number:
  US 20180303803A1
• Time in Patent Office: 547 Days
• Field of Search: None
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/1688 resulting in pure drug agglomerate optionally containing up to 5% of excipient
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61K 9/5123 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61K 9/5138 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5146 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
• CPC Class Codes: A61L 29/085 Macromolecular materials
• CPC Class Codes: A61L 29/16 Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
• CPC Class Codes: Y10T 428/2982 Particulate matter [e.g., sphere, flake, etc.]

Abstract

The disclosure provides macrolide particulates including a macrolide therapeutic agent such as rapamycin at high concentration in the particulate. In one method the particulates are made by adding a composition containing an polyoxyethylene sorbitan n-acyl ester, poly(ethyleneimine), or alkylated quaternary ammonium salt to a composition including macrolide dissolved in an alcohol such as ethanol. In another method the particulates are made by adding a non-solvent composition to a composition including macrolide and an alkyl-substituted chromanol dissolved in an alcohol such as ethanol. The formed macrolide particulates have one or more desirable properties including sizes in the range of 0.1 μm to 10 μm, spherical or near spherical shapes, low polydispersity, and/or stability. The macrolide particulates can be used for therapeutic compositions, or in association with an implantable or insertable medical device, such as associated with a polymeric coating on a device.

Claims

1. An implantable or insertable medical device comprising a macrolide particulate, the macrolide particulate comprising macrolide therapeutic agent in an amount of 95% or greater of the weight of the particulate, a component selected from the group consisting of poly(alkyleneimines), alkylated quaternary ammonium salts, and alkyl-substituted chromanols, and having a spherical or substantially spherical shape and a diameter in the range 0.1 μ

m to 10 μ

m.

2. The implantable or insertable medical device of claim 1 which is a balloon catheter.

3. The implantable or insertable medical device of claim 2 wherein the balloon catheter comprises a polymeric coating and the macrolide particulates are associated with the coating.

4. The implantable or insertable medical device of claim 1, wherein the macrolide particulates are produced by a method comprising steps of

providing a first composition comprising a macrolide therapeutic agent dissolved in a liquid selected from the group consisting of C1-C4 alcohols,

forming a mixture by adding to the first composition a second composition that is a non-solvent for the macrolide therapeutic and comprises a component selected from the group consisting of poly(ethyleneimines), and alkylated quaternary ammonium salts, where mixing comprises agitating the mixture to cause the formation of macrolide particulates.

5. The implantable or insertable medical device of claim 1, wherein the macrolide particulates are produced by a method comprising steps of

providing a first composition comprising a macrolide therapeutic agent and an alkyl-substituted chromanol dissolved in a liquid selected from the group consisting of C1-C4 alcohols,

forming a mixture by adding to the first composition a second composition that is aqueous, where mixing comprises agitating the mixture to cause the formation of macrolide particulates.

6. The implantable or insertable medical device of claim 1, wherein the macrolide therapeutic agent is rapamycin.

7. The implantable or insertable medical device of claim 1, wherein the alkyl-substituted chromanol is a compound of Formula I:

8. The implantable or insertable medical device of claim 7, wherein the alkyl-substituted chromanol is selected from the group consisting of alpha (α

) tocopherol, beta (β

) tocopherol, gamma (γ

) tocopherol, and delta (δ

) tocopherol.

9. The implantable or insertable medical device of claim 7, wherein the macrolide therapeutic agent is present in an amount of 99% or greater, of the weight of the particulate.

10. A balloon catheter comprising a drug delivery coating composition comprising

macrolide particulates comprising macrolide therapeutic agent in an amount of 95% or greater of the weight of the particulate and having a size of less than 1 um,

wherein the macrolide particulates have a thin coating, a shell, or are encapsulated to promote release of macrolide from the coating composition, the thin coating, shell, or encapsulating material having a thickness that is less than the diameter of the macrolide particulates,

wherein the coating composition comprises lipid.

11. The balloon catheter of claim 10 wherein the macrolide therapeutic agent is present in an amount of 99% or greater, of the weight of the particulate.

12. The balloon catheter of claim 10 wherein the macrolide particulates have a size in the range of 10 nm to 500 nm.

13. The balloon catheter of claim 10 wherein the balloon catheter comprises a polymeric coating and the macrolide particulates are associated with the coating.

14. The balloon catheter of claim 13 wherein the polymeric coating is in the form of a flexible hydrogel matrix.

15. The balloon catheter of claim 10 wherein the majority of macrolide particulates have a spherical or substantially spherical shape.

16. The balloon catheter of claim 10 wherein the lipid is a fatty acid.

17. The balloon catheter of claim 10 further comprising, a component selected from the group consisting of polyoxyethylene sorbitan n-acyl esters, poly(alkyleneimines), alkylated quaternary ammonium salts, and alkyl-substituted chromanols, in minor or trace amounts in the particulates.