Abstract
Deformable nanovesicles have been extensively investigated due to their excellent ability to penetrate biological barriers. However, suffering from serious physical and chemical instabilities, the wide use of deformable nanovesicles in medical applications is still limited. Moreover, far less work has been done to pursue the lyophilization of deformable nanovesicles. Here, we aimed to obtain stable deformable nanovesicles via freeze-drying technology and to uncover the underlying protection mechanisms. Firstly, the density of nanovesicles before freeze-drying, the effect of different kinds of cryoprotectants, and the types of different reconstituted solvents after lyophilization were investigated in detail to obtain stable deformable nanovesicles based on insulin-phospholipid complex (IPC-DNVs). To further investigate the underlying protection mechanisms, we performed a variety of analyses. We found that deformable nanovesicles at a low density containing 8% lactose and trehalose in a ratio of 1:4 (8%-L-T) have a spherical shape, smooth surface morphology in the lyophilized state, a whorl-like structure, high entrapment efficiency, and deformability after reconstitution. Importantly, the integrity of IPC, as well as the secondary structure of insulin, were well protected. Accelerated stability studies demonstrated that 8%-L-T remained highly stable during storage for 6 months at 25 °C. Based on in vivo results, lyophilized IPC-DNVs retained their bioactivity and had good efficacy. Given the convenience of preparation and long term stability, the use of combined cryoprotectants in a proper ratio to protect stable nanovesicles indicates strong potential for industrial production.
Highlights
Since the discovery by Bangham in 1965, liposomal delivery technologies have been extensively investigated for delivering a wide variety of medicinal agents
The results indicated that insulin alone that is stable when entrapped in the complex which would be stable for buccal administration (The detail of this experiment can be found in Supplementary Materials)
We successfully fabricated stable lyophilized deformable nanovesicles based on an insulinphospholipid complex (IPC-DNVs) for buccal administration by combining lactose and trehalose
Summary
Since the discovery by Bangham in 1965, liposomal delivery technologies have been extensively investigated for delivering a wide variety of medicinal agents. Among these technologies, novel lipid vesicles known as deformable or elastic (flexible) vesicles, are attractive due to great ability to penetrate the stratum corneum (SC) barrier and deliver loaded drugs into the epidermis and dermis layers, and even attain systemic circulation [1,2]. After long-term storage, the risks are high that deformable nanovesicles suffer from leakage of the encapsulated drug and particle size alters due to the instability of the lipid bilayers [14,15]. The preparation of stable deformable nanovesicles is necessary to translate them into marketable products
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