Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Patent
1995-08-11
1997-09-02
Kishore, Gollamudi S.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
264 41, 264 43, A61K 9127
Patent
active
056629311
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP94/00075 filed on Jan. 20, 1994.
FIELD OF THE INVENTION
This invention relates to a process for preparing a drug-containing liposome composition comprising a drug and a lipid.
BACKGROUND OF THE INVENTION
Liposomes composed of a phospholipid have been developed as a drug carrier with high biocompatibility. Intravenous administration of a drug-liposome combination has been studied for the purposes of improving retention of a drug having a short half life in blood or of suppressing deactivation of a drug in a living body. However, liposomes are easily caught by reticuloendothelial cells as well as other colloidal particles and therefore fail to achieve the above purposes.
The rate of drug inclusion into liposomes that has been achieved to date by conventional techniques of liposome preparation is in most cases 50% or lower and this low rate of inclusion has lessened the industrial utility of a drug-liposome composition. To overcome this problem, remote loading techniques and the like have been developed, but those techniques are applicable only to those drugs having a low molecular weight and are charged.
There is a report on experimentation which demonstrates the effect of liposomes in sustaining release of a drug from a drug-liposome composition administered intramuscularly or subcutaneously. Usefulness of liposomes as a carrier in sustained release preparations is known in the art.
JP-A-4-234820 discloses a peptide-liposome composition capable of slowly releasing a peptide having a molecular weight of 500 to 10000 for a long time (at least 14 days). It is assumed that the peptide disclosed has high stability to heat and is stable under the disclosed condition for liposome preparation (the liposome is prepared at the phase transition temperature of the phospholipid used, i.e., 30.degree. C. at the lowest). However, most of physiologically active peptides are labile against heat, and preparation under a low temperature condition is desirable. Additionally, as shown in the Examples to follow, the highest rate of drug inclusion reached by the disclosed technique is no more than 30% in the case of a highly water-soluble drug.
In light of these circumstances, the present inventors conducted extensive study and found, as a result, that (1) a specific process for preparing a liposome composition inhibits decomposition of a drug to be included into liposomes, particularly a physiologically active protein having a molecular weight of 500 to 100,000 (the process per se inhibits the decomposition), (2) that process achieves a high rate of inclusion, (3) the liposome composition prepared by the process can be subcutaneously or intramuscularly administered and (4) the liposome composition makes a contribution to sustained release of the drug. The present invention has been completed based on these findings.
DISCLOSURE OF THE INVENTION
The present invention relates to a process for preparing a drug-containing liposome composition comprising (1) dissolving a lipid in a first organic solvent, (2) adding a drug-containing aqueous solution to the lipid solution, followed by emulsifying to obtain an emulsion, (3) mixing the emulsion at a low temperature with a second organic solvent in which the lipid is sparingly soluble, (4) collecting the precipitated fraction, and (5) suspending the precipitated fraction in an aqueous solvent.
(i) Drug
Drugs which can be used in the present invention particularly include physiologically active proteins having a molecular weight of 500 to 100,000. Examples of such drugs include cytokines, such as interferon (IFN), e.g. IFN-.alpha., IFN-.beta. and IFN-.gamma., colony-stimulating factors (CSF), e.g., G-CSF, M-CSF, GM-CSF and CSF-HU, calcitonin, and interleukin. Additionally included are plasminogen activators, e.g., urokinase (UK), urokinase precursor, and tissue plasminogen activator (TPA), blood clotting factors FVIII, FIX and FXIII, plasminogen, antithrombin III, .alpha..sub.1 -antiplasmin, angiotensin, kinin, androsterone, kallikrein, renin,
REFERENCES:
patent: 5141674 (1992-08-01), Leigh
Kishi Norihide
Matsuda Hiroshi
Munechika Koji
Seki Tomoyo
Ueda Yasuo
Kishore Gollamudi S.
The Green Cross Corporation
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