MACROLIDE PARTICULATES, METHODS FOR PREPARATION, AND MEDICAL DEVICES ASSOCIATED THEREWITH

• US 20160374998A1
• Filed: 09/12/2016
• Published: 12/29/2016
• Est. Priority Date: 05/16/2013
• Status: Active Grant

• Current Assignee: Surmodics Incorporated
• Original Assignee: Surmodics Incorporated
• Inventors: Slager, Joram
• Granted Patent: US 9,949,957 B2
• Time in Patent Office: Days
• 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 method for producing macrolide particulates, 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 polyoxyethylene sorbitan n-acyl esters, poly(ethyleneimines), and alkylated quaternary ammonium salts, where mixing comprises agitating the mixture to cause the formation of macrolide particulates.

2. The method of claim 1 where the first composition comprises ethanol.

3. The method of claim 1 where the first composition comprises the macrolide therapeutic agent at a concentration in the range of 10 mg/mL to about 100 mg/mL.

4. The method of claim 1 where the second composition is added to the first composition at a ratio of at least 10:

1 (vol;

vol), respectively.

5. The method of claim 1 where in the step of forming a 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.

6. The method of claim 1 wherein in the step of forming, the mixture is vortexed.

7. The method of claim 1 wherein the macrolide therapeutic agent is rapamycin.

8. The method of claim 1 wherein the second composition is an aqueous composition.

9. The method of claim 1 wherein the first composition further comprises an alkyl-substituted chromanol.

10. The method of claim 9 wherein the alkyl-substituted chromanol is present in the first composition in an amount in the range of 0.01 mg/mL to 10 mg/mL.

11. The method of claim 9 wherein the alkyl-substituted chromanol is a compound of Formula I:

12. The method of claim 11 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.

13. The method of claim 1 wherein the macrolide is rapamycin.

14. The method of claim 1, which provides a set of macrolide particulates having a mean diameter in the range of 0.1 μ

m to 10 μ

m.

15. The method of claim 1 wherein the method produces macrolide particulates comprising macrolide therapeutic agent in an amount of 95% or greater, 97.5% or greater, or 99% or greater, of the weight of the particulate.

16. The method of claim 1, which provides a set of macrolide particulates wherein the majority of macrolide particulates have a spherical or substantially spherical shape.

17. Macrolide particulates formed according to the process of claim 1.