Method of amphiphatic drug loading in liposomes by ammonium ion gradient

• US 5,316,771 A
• Filed: 12/18/1992
• Issued: 05/31/1994
• Est. Priority Date: 09/28/1988
• Status: Expired due to Term

• Current Assignee: Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. (Hebrew University of Jerusalem)
• Original Assignee: Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. (Hebrew University of Jerusalem)
• Inventors: Haran, Gilad, Barenholz, Yechezkel
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): HARRISON, ROBERT H
• Application Number:
  US07/992,997
• Time in Patent Office: 529 Days
• Field of Search: 424/450, 424/710, 264/4.1, 264/4.3, 264/4.6, 428/402.2, 436/829
• US Class Current: 424/450
• CPC Class Codes: A61K 49/227 Liposomes, lipoprotein vesicles, e.g. LDL or HDL lipoproteins, micelles, e.g. phospholipidic or polymeric
• CPC Class Codes: A61K 9/1278 Post-loading, e.g. by ion or pH gradient
• CPC Class Codes: Y10S 436/829 Liposomes, e.g. encapsulation
• CPC Class Codes: Y10T 428/2984 Microcapsule with fluid core [includes liposome]

Abstract

An improved simple, efficient, safe, economical, and fast transmembrane ling procedure for efficient active loading of weak amphiphatic drugs into liposomes using the transmembrane gradient. The resulting liposomes loaded with the amphiphatic drug are stable and safe. A storagable form of loadable liposomes has extended period of stability. The reversed procedure is applicable for sustained release of liposome encapsulated drugs from ammonium liposomes.

Claims

1. A method for loading into liposomes, an amphiphatic compound having a protonatable amine group, said method comprising:

(a) preparing a suspension of liposomes having a greater concentration of ammonium ions inside the liposomes than outside the liposomes, where said preparing includes treating the liposomes to reduce their sizes,

(b) adding said compound to the liposome suspension, and

(c) by said adding, achieving uptake of the compound into the liposomes, to a final concentration of compound within the liposomes which is greater than that outside the liposomes.

2. The method of claim 1, wherein said preparing includes preparing the liposomes in the presence of an ammonium salt, and replacing ammonium ions outside the liposomes with a non-ammonium salt.