Majalah Ilmu Kefarmasian Majalah Ilmu Kefarmasian
Volume 9 Number 1 Article 6
4-30-2012
Archaeosomes and Tetraether Lipid Liposome Archaeosomes and Tetraether Lipid Liposome
Hans-Joachim Freisleben
University of Indonesia, Faculty Medicine, [email protected]
Follow this and additional works at: https://scholarhub.ui.ac.id/mik
Part of the Natural Products Chemistry and Pharmacognosy Commons, Other Pharmacy and Pharmaceutical Sciences Commons, and the Pharmaceutics and Drug Design Commons
Recommended Citation Recommended Citation
Freisleben, Hans-Joachim (2012) "Archaeosomes and Tetraether Lipid Liposome," Majalah Ilmu Kefarmasian: Vol. 9 : No. 1 , Article 6.
DOI: 10.7454/psr.v9i1.3358
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