Intranasal co-delivery of berberine and evodiamine by self-assembled thermosensitive in-situ hydrogels for improving depressive disorder.

The orally administrated antidepressants not only caused side effects such as dizziness, diarrhea, and drug resistance, but also worked slowly. Therefore, new antidepressants and preparations derived from natural medicines play an important role in the study of antidepressant drugs. It was reported that the two components of Zuojin pill, berberine (BBR) and evodiamine (EVO), were used in combination to improve depressive disorder. In our study, a self-assembled thermosensitive in-situ hydrogel was prepared to achieve sustained co-delivery of BBR and EVO. The preparation process of hydrogel consists of two steps, namely, the inclusion of the drugs and thermosensitive self-assembly of the hydrogel. In vitro experimental results indicated that the prepared hydrogel showed a good thermosensitive property under physiological temperature. The hydrogel had a slow and controlled release behavior for BBR and EVO, according with first-order equation. In vivo experimental results indicated that compared to intragastric administration of drug solution, the intranasal administration of hydrogel increased bioavailability of BBR and EVO, approximately 135 and 112 folds, respectively. The hydrogel at a low dose significantly reversed behavioral despair of the mice, improved depressive symptom of rats, and treated depressive disorder by regulating the abnormal levels of monoamine neurotransmitters (including 5-hydroxytryptamine, noradrenalin and dopamine) metabolism and related metabolic pathways such as purine, citrate cycle, scorbate and aldarate, butanoate, vitamin B6, and pyrimidine metabolism. Therefore, as a drug co-delivery system, the intranasally administrated hydrogels with a good release and high bioavailability provides a non-invasive therapeutic strategy for the clinical treatment of depression, which attains antidepressant effects by regulation of the monoamine neurotransmitters metabolism and related metabolic pathways.