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

• US 9,439,892 B2
• Filed: 05/16/2014
• Issued: 09/13/2016
• 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:
  US14/280,054
• Publication Number:
  US 20140343491A1
• Time in Patent Office: 851 Days
• Field of Search: None
• US Class Current: 1/1
• 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. A 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 macrolide particulate of claim 1 further comprising a plurality of macrolide particulates comprising a particulate set.

3. An implantable or insertable medical device comprising a macrolide particulate according to claim 1.

4. The implantable or insertable medical device of claim 3 which is a balloon catheter.

5. The implantable or insertable medical device of claim 4 wherein the balloon catheter comprises a polymeric coating and the macrolide particulates are associated with the coating.

6. An injectable therapeutic composition comprising a macrolide particulate according to claim 1.

7. The macrolide particulate of claim 1, wherein the macrolide is rapamycin.

8. The macrolide particulate of claim 1, wherein the component is a poly(alkyleneimine).

9. The macrolide particulate of claim 1, wherein the component is an alkyl-substituted chromanol of Formula I:

10. The macrolide particulate of claim 9 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.

11. The macrolide particulate of claim 1 wherein the poly(alkyleneimine), alkylated quaternary ammonium salt, or alkyl-substituted chromanol, is present in an amount in the range of 0.01% to 5% of the weight of the particulate.

12. The macrolide particulate of claim 1 which is prepared by a method comprising steps of:

providing a first composition comprising the macrolide therapeutic agent and the 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.

13. The macrolide particulate of claim 1 which is prepared by a method comprising steps of

providing a first composition comprising a macrolide therapeutic agent dissolved in ethanol at a concentration in the range of 10 mg/mL to 100 mg/mL,

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, where the second composition is added to the first composition at a ratio of at least 10:

1 (vol;

vol), respectively.

14. The macrolide particulate of claim 13 where in the step of forming the mixture the second composition is added to the first composition at a first rate until precipitation of the macrolide therapeutic agent, and then the second composition is added to the first composition at a second rate, with the second rate being greater than the first rate.