Use of non-ionic cloud point modifiers to minimize nanoparticle aggregation during sterilization

• US 5,346,702 A
• Filed: 12/04/1992
• Issued: 09/13/1994
• Est. Priority Date: 12/04/1992
• Status: Expired due to Term

• Current Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Original Assignee: Sterling Winthrop, Inc. (GSK plc)
• Inventors: Rajagopalan, Natarajan, Na, George C.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Spear, James M.
• Application Number:
  US07/985,424
• Time in Patent Office: 648 Days
• Field of Search: 424/490, 424/493, 424/494, 424/497, 424/498, 424/499
• US Class Current: 424/490
• CPC Class Codes: A61K 47/6923 the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
• CPC Class Codes: A61K 47/6929 the form being a nanoparticle, e.g. an immuno-nanoparticle
• CPC Class Codes: A61K 49/049 Surface-modified nanoparticles, e.g. immune-nanoparticles
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: Y10S 977/745 having a modified surface
• CPC Class Codes: Y10S 977/773 Nanoparticle, i.e. structure having three dimensions of 100 nm or less
• CPC Class Codes: Y10S 977/847 Surface modifications, e.g. functionalization, coating
• CPC Class Codes: Y10S 977/915 Therapeutic or pharmaceutical composition

Abstract

This invention discloses a composition comprised of nanoparticles having a surface modifier adsorbed on the surface thereof and a non-ionic cloud point modifier associated therewith, which cloud point modifier is present in an amount-sufficient to increase the cloud point of the surface modifier. A preferred surface modifier is a poloxamine such as Tetronic 908, and preferred non-ionic cloud point modifiers include polyethylene glycol, propylene glycol, ethanol, hydroxypropylcyclodextrin and/or glycerol. This invention further discloses a method of making nanoparticles having a surface modifier adsorbed on the surface and a non-ionic cloud point modifier associated therewith, comprised of contacting said nanoparticles with the cloud point modifier for a time and under conditions sufficient to increase the cloud point of the surface modifier.

Claims

1. A composition comprised of nanoparticles containing a diagnostic or having a nonionic surfactant as a surface modifier adsorbed on the surface thereof and a non-ionic cloud point modifier associated therewith, which cloud point modifier is present in an amount of 0.01-50 % by weight based on the total weight of the composition and sufficient to increase the cloud point of the surface modifier wherein said nanoparticles are resistant to size growth when said composition is heat sterilized at 121°

C. for 15 minutes.

2. The composition of claim 1 wherein said nanoparticles contain a diagnostic agent.

3. The composition of claim 2 wherein said diagnostic agent is ethyl 3,5-diacetoamido-2,4,6-triiodobenzoate.

5. The composition of claim 1 wherein said nonionic surfactant is a poloxamine.

6. The composition of claim 2 wherein said surface modifier is a poloxamine, said cloud point modifier is polyethylene glycol, and said diagnostic agent is ethyl 3,5-diacetoamido-2,4,6-triiodobenzoate

7. The composition of claim 1 wherein said cloud point modifier is selected from the group consisting of polyethylene glycol, propylene glycol, ethanol, hydroxypropylcyclodextrin and glycerol.

8. The composition of claim 1 in wherein said cloud point modifier increases the cloud point of said surface modifier above the sterilization temperature of the nanoparticles.

9. A method of making the composition of claim 1 comprised of contacting said nanoparticles with said cloud point modifier for a time and under conditions sufficient to increase the cloud point of the surface modifier.

10. The method of claim 9 further comprising the step of sterilizing said nanoparticle.

11. The method of claim 10 wherein said sterilizing is by steam heat autoclaving.

12. The composition of claim 1 wherein said nanoparticles contain a therapeutic agent.

13. The composition of claim 1 wherein said nanoparticles have a mean particle size of less than 400 nm.

14. The composition of claim 1 wherein said nonionic surfactant is selected from the group consisting of polyoxyethylene alkyl ethers, polyoxyethylene stearates, tyloxapol, poloxamers and poloxamines.

4. A composition comprised of nanoparticles containing a diagnostic or therapeutic agent having a nonionic surfactant as a surface modifier adsorbed on the surface thereof and a nonionic cloud point modifier associated therewith, which cloud point modifier is selected from the group consisting of polyethylene glycol, propylene glycol, ethanol, hydroxypropylcyclodextrin, and glycerol and is present in an amount of 0.01-50% by weight based on the total weight of the composition and sufficient to increase the cloud point of the surface modifier above the sterilization temperature of the nanoparticles, wherein said nanoparticles are resistant to particle size growth when said composition is heat sterilized at 121°

C. for 15 minutes.