Styrene-isoprene-styrene (SIS) copolymer and tackifier resins can be utilized to prepare hot-melt pressure sensitive adhesives (HMPSAs) for the transdermal delivery of high lipophilic drugs. To meet the requirement of transdermal delivery of Chinese medicine (containing different ingredients including lipophilic, amphiphilic and hydrophilic drugs), amphiphilic HMPSAs were developed by melt-blending HMPSAs, poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) (RLPO) and polyethylene glycol 2000 (PEG2000). Their morphological structures and miscibility were characterized with phase microscopy and differential scanning calorimetry. Their 180° peel strength and holding power were measured for their adhesive performances. In vitro drug release experiments were carried out using a modified Franz type horizontal diffusion cells, in which three ingredients of gardenia fruit (oleanic acid, luteolin and geniposide) were chosen as representatives of lipophilic, amphiphilic and hydrophilic drugs. It was found that amphiphilic phase structures were developed with the addition of RLPO and PEG2000. As the SIS/RLPO ratio was 1:1∼1:2, the HMPSAs had miscible and amphiphilic phase structures. Drug release results showed that hydrophilic drugs could be released due to the existence of RLPO and PEG2000. Its release rate was rapidly enhanced with the increment of RLPO and PEG2000. Meanwhile, the release behavior of lipophilic and amphiphilic drugs and adhesive performance of HMPSAs were preserved in the experiment range. It was proposed that the addition of RLPO and PEG2000 did not destroy phase structures of SIS and tackifier, which insured appropriate adhesive performance and the amphiphilic polymer skeleton of SIS/RLPO/PEG2000 as release channels of various drugs.