Development and Evaluation of a Water-Free In Situ Depot Gel Formulation for Long-Acting and Stable Delivery of Peptide Drug ACTY116

In situ depot gel is a type of polymeric long-acting injectable (pLAI) drug delivery system; compared to microsphere technology, its preparation process is simpler and more conducive to industrialization. To ensure the chemical stability of peptide ACTY116, we avoided the use of harsh conditions suc...

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Bibliographic Details
Published in:Pharmaceutics 2024-05, Vol.16 (5), p.620
Main Authors: Xiong, Yingxin, Liu, Zhirui, Wang, Yuanqiang, Wang, Jiawei, Zhou, Xing, Li, Xiaohui
Format: Article
Language:English
Subjects:
Bioavailability
Body temperature
Comparative analysis
Diabetes
Drug delivery systems
Drug dosages
Drugs
Efficiency
in situ depot gel
Laboratory animals
long-acting injectable
Molecular dynamics
Octreotide acetate
Particle size
peptide
Peptides
Signal transduction
stability
Vehicles
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Summary:In situ depot gel is a type of polymeric long-acting injectable (pLAI) drug delivery system; compared to microsphere technology, its preparation process is simpler and more conducive to industrialization. To ensure the chemical stability of peptide ACTY116, we avoided the use of harsh conditions such as high temperatures, high shear mixing, or homogenization; maintaining a water-free and oxygen-free environment was also critical to prevent hydrolysis and oxidation. Molecular dynamics (MDs) simulations were employed to assess the stability mechanism between ACTY116 and the pLAI system. The initial structure of ACTY116 with an alpha helix conformation was constructed using SYBYL-X, and the copolymer PLGA was generated by AMBER 16; results showed that PLGA-based in situ depot gel improved conformational stability of ACTY116 through hydrogen bonds formed between peptide ACTY116 and the components of the pLAI formulation, while PLGA (Poly(DL-lactide-co-glycolide)) also created steric hindrance and shielding effects to prevent conformational changes. As a result, the chemical and conformational stability and in vivo long-acting characteristics of ACTY116 ensure its enhanced efficacy. In summary, we successfully achieved our objective of developing a highly stable peptide-loaded long-acting injectable (LAI) in situ depot gel formulation that is stable for at least 3 months under harsh conditions (40 °C, above body temperature), elucidating the underlying stabilisation mechanism, and the high stability of the ACTY116 pLAI formulation creates favourable conditions for its in vivo pharmacological activity lasting for weeks or even months.
ISSN:1999-4923
1999-4923
DOI:10.3390/pharmaceutics16050620