Sustained release formulations using non-aqueous membrane emulsification

Patent metadata

Field	Value
Publication number	US-12239687-B2
Application number	US-202117535267-A
Country	US
Kind code	B2
Filing date	Nov 24, 2021
Priority date	Nov 25, 2020
Publication date	Mar 4, 2025
Grant date	Mar 4, 2025

Abstract

Non-aqueous membrane emulsion methods for producing polymeric and polymer-coated microparticles are provided. Some embodiments provide methods for producing a sustained release or controlled release microparticle by combining micronized protein powder and a polymer into a hydrocarbon solvent to form a non-aqueous first solution, agitating the first non-aqueous solution to form a suspension, feeding the suspension into a dispersion pump, wherein the suspension is infused through a porous membrane into a continuous phase comprising a fluorocarbon liquid and a fluorosurfactant to form a hydrocarbon-in-fluorocarbon emulsion. The hydrocarbon solvent, the fluorocarbon liquid, and the fluorosurfactant are removed, and the microparticles are collected.

First claim

We claim:

1. A method of producing encapsulation efficient polymer-coated microparticles, wherein the method comprises:
combining micronized protein powder and a polymer into a hydrocarbon solvent to form a non-aqueous first solution, wherein the micronized protein powder comprises at least one selected from the group consisting of an antibody and an Fc-fusion protein;
agitating the first non-aqueous solution to form a suspension;
feeding the suspension to a dispersion cell, wherein the suspension is infused through a porous membrane into a continuous phase comprising a fluorocarbon liquid and a fluorosurfactant under a tangent flow of the continuous phase to form a hydrocarbon-in-fluorocarbon emulsion;
adding a hydrofluoroether to the hydrocarbon-in-fluorocarbon emulsion;
removing the hydrocarbon solvent to provide hardened microparticles; and
removing the fluorocarbon liquid to isolate the microparticles, wherein the microparticles comprise protein encapsulated within a matrix of polymer, wherein the protein is encapsulated at an efficiency of about 80% measured by protein loading in the polymer-coated microparticles or the theoretical protein loading from the first non-aqueous solution.

2. The method of claim 1 , further comprising the steps of removing residual fluorosurfactant from the microparticles by washing the microparticles in the fluorocarbon liquid and removing the fluorocarbon by vacuum and collecting the microparticles using a polyethersulfone membrane filter.

3. The method of claim 1 wherein the fluorocarbon liquid comprises a perfluoro C 5 -C 18 compound.

4. The method of claim 1 , wherein the hydrocarbon solvent is selected from the group consisting of dichloromethane, chloroform, toluene, ethyl acetate, tetrahydrofuran, or a combination thereof.

5. The method of claim 1 , wherein the fluorocarbon solution comprises 1,1,2,2,3,3,4,4,4-nonafluoro-N,N-bis (1,1,2,2,3,3,4,4,4-nonafluorobutyl) butan-1-amine.

6. The method of claim 1 , wherein the fluorosurfactant comprises Perfluoropolyether-b-Polyethylene glycol-b-Perfluoropolyether.

7. The method of claim 1 , wherein the polymer comprises polyorthoester (POE).

8. The method of claim 1 , wherein the polymer is selected from the group consisting of polylactic acid and poly (lactic-co-glycolic acid).

9. The method of claim 1 , wherein the hydrofluoroether is 2-(trifluoromethyl)-3-ethoxydodecafluorohexane.

10. The method of claim 1 , wherein the porous membrane is a fluorophilic-coated stainless steel membrane.

11. The method of claim 10 , wherein the pores of the porous membrane are 3 to 300 μm in diameter.

12. The method of claim 1 , wherein the fluorosurfactant is present in fluorocarbon liquid at about 0.1 to 5% w/v.

13. The method of claim 1 , wherein the protein powder to polymer ratio is 0.1%-30%.

14. The method of claim 1 , wherein the Fc-fusion protein is a vascular endothelial growth factor (VEGF) Trap fusion protein.

15. The method of claim 14 , wherein the VEGF-trap fusion protein is aflibercept.

16. A method of producing encapsulation efficient polymer-coated microparticles, wherein the method comprises:
combining a polymer and 1 to 30% w/w of total solid spray dried-protein suspended in a hydrocarbon solution to form a non-aqueous first solution, wherein the protein is selected from the group consisting of an antibody and an Fc-fusion protein;
agitating the first non-aqueous solution to form a suspension;
feeding the suspension to a dispersion pump, wherein the suspension is infused through a porous membrane into a continuous phase comprising a fluorocarbon liquid and 0.1 to 5.0% w/v fluorosurfactant under a tangent flow of the continuous phase to form a hydrocarbon-in-fluorocarbon emulsion;
removing the hydrocarbon solvent to provide hardened polymer-coated microparticles;
and removing the fluorocarbon liquid to isolate the microparticles, wherein the polymer-coated microparticles comprise protein encapsulated within a matrix of polymer, wherein the protein is encapsulated at an efficiency of about 80% measured by protein loading in the polymer-coated microparticles or the theoretical protein loading from the first non-aqueous solution.

17. The method of claim 16 , further comprising the step of adding a hydrofluoroether into the fluorocarbon liquid of the hydrocarbon-in-fluorocarbon emulsion prior to removing the hydrocarbon solvent.

18. The method of claim 16 , wherein the protein is aflibercept.

19. The method of claim 1 , where the protein is encapsulated at an efficiency of 80.7% measured by protein loading in the polymer-coated microparticles or the theoretical protein loading from the first non-aqueous solution.

20. The method of claim 16 , where the protein is encapsulated at an efficiency of 80.7% measured by protein loading in the polymer-coated microparticles or the theoretical protein loading from the first non-aqueous solution.

Assignees

• Regeneron Pharma

Inventors

• Chen Hunter
• Zhao Yiming

Classifications

• A61K9/1694

  resulting in granules or microspheres of the matrix type containing more than 5% of excipient · CPC title

• A61K9/1658

  Proteins, e.g. albumin, gelatin · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61K9/0019 Primary

  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 title

• A61K38/179 Primary

  for growth factors; for growth regulators · CPC title