AIDS treatment breakthroughs! Drug delivery was extended to one year, is expected to achieve a single dose, valid for one year!

HIV is a human immunodeficiency virus (HIV), about 38 million people infected worldwide. Anti-retroviral drugs (ARV) therapy can effectively prevent people living with HIV die, but once the withdrawal, the latent virus in the human body will breed a new population actively replicating virus in the blood, therefore, the need for lifelong infection medication. The long-term drug injection will bring a series of related side effects, therefore, the development of long-acting drugs is of great significance. 2019, the world\’s first long-term AIDS drugs CABOTEGRAVIR market, long-term \”cabotegravir + rilpivirine\” nanoparticles Duplex direction FDA to submit a listing application, by intramuscular injection of the drug, once a month, can significantly improve long-term patient medication compliance, and help the long-term benefit AIDS patients. recent US Nebraska Medical Center Howard S. Fox , Benson J . Edagwa and Howard E. Gendelman re break, the long-term resistance to extension year , after one year of administration, the effective concentration of the drug in blood is still higher than the 90% inhibitory concentration regulator protein (PA-IC90), maintaining antiviral properties . relevant papers to \”A year-long extended release nanoformulated cabotegravir prodrug\” in the title, published in Nature Materials on. 艾滋病治疗新突破!药物缓释延长至一年,有望实现一次给药,一年有效!

Preparation of long-acting nanocrystals

of the first containing the different carbon chain lengths to cabotegravir (CAB a long-acting inhibitor of HIV,) before the fatty acid esters prepared drug , the number of carbon atoms in the aliphatic chain 14,18,22, respectively, were obtained referred to as CAB prodrug MCAB, M2CAB and M3CAB. These prodrugs have not active, is activated only after enzyme or hydrolysis under physiological conditions to produce antiviral activity.

1 CAB FIG prodrug synthesis

Then, the author poloxamer 407 (P407) as stabilizer, by a high-pressure homogenization these three prodrugs crystal nanorods prepared (NMCAB, NM2CAB and NM3CAB) . Such negatively charged nanocrystals only excellent stability, and compared to the corresponding prodrug, since the drug prior to hydrolysis should undergo a process of dissolution of nanocrystals half maximum effective concentration (the EC50 of) improved significantly, further improving long-term nature. Since the NM3CAB long carbon chain, prodrugs into CAB reduced speed, but decreased the EC50 of, and therefore not tested on animals.

Synthesis of FIG. 2 and CAB CAB prodrugs nanocrystals and Characterization

up to a year long-acting

To assess the pharmacokinetic dynamics nanocrystals vivo distribution and female mice were intramuscularly NSG NCAB, NMCAB and NM2CAB nanocrystals, holding CAB dosage of 45 mg / kg. 126 days later, mice NCAB CAB blood concentration fell below the detection limit, while groups of mice CAB NMCAB blood concentration decay slowed significantly, still higher than PA-IC90 168 days, 364 days, however, only the concentration of 8.5 ng CAB / mL. NM2CAB concentration in mice blood CAB slowest decay , 231 days, the concentration is higher than 4 × PA-IC90 (inhibitory concentration protein modulator 100%), 364 days, still higher than PA-IC90, anti comprising viral activity. Long-term nature was as long as a year. In rhesus monkey animal model of long-term NM2CAB nanocrystals remain up to a year, further demonstrated its superiority. compared with the long-term CAB, NM2CAB prepared author has the following advantages:

(1) Preparation of NM2CAB concentration of up to 400 mg / mL, twice the long-term CAB, but also conducive to large-scale production ; (2) NM2CAB each only injection of <1 mL,注射频率为一年一次, and long-term monthly injections required CAB 2 mL, NM2CAB can effectively prevent adverse injection site reactions.

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