Development of Long-acting Formulation of Dolutegravir Sodium for Human Immunodeficiency Virus

Abstract

Human immunodeficiency virus (HIV) is an enveloped retrovirus that attacks the infected human host’s immune system by destroying CD4 lymphocytes, the cells responsible for providing protection against infections and disease. Since the discovery of the virus in the early 80’s, relentless efforts have been made to find an effective therapeutic regimen that will be curative. Currently, even with combined use of multiple potent drugs, HIV remains incurable, partly due to challenges in reaching and maintaining therapeutic drug concentrations in viral reservoirs in the lymph (nodes and tissues) that are unable to be cleared by the host immune system. Advancements of many effective drug substances have led to the development of highly active antiretroviral therapies (HAART) composed of single or multiple oral drug combinations. These orally given combination anti-retroviral therapeutics (cART), generally composed of two or three drug substances, are designed to maximally suppress HIV replication by targeting multiple viral replication checkpoints such as, reverse transcriptase (RT), protease, and/or integrase (often referred to as integrase strand transfer inhibitor or INSTI). With the worldwide implementation of HAART, the lifespan of a HIV+ patient has increased significantly from less than 1 year to a median of 77 years in the United States, as of 2020. However, HIV+ patients can enjoy virus free survival if these oral medications are taken chronically and daily. This requirement for taking daily pills for life and livelihood often leads to pill fatigue in people living with HIV. Treatment interruption and non-adherence to the prescribed daily dosing leads to viral rebound, drug resistance, disease progression to acquired immune deficiency syndrome (AIDS), and premature death. So, while modern one-pill-a-day dosing has been demonstrated to save lives, WHO reported that in 2021 approximately 1.5 million individuals were newly infected with HIV; and more than half-a-million (~650,000) people died from the virus. To address these issues, the development of HIV drugs with long-acting (LA) pharmacokinetic properties aimed to increase dosing intervals have gained significant interest. The typical approach involves selecting water insoluble HIV drug derivatives that exhibit longer terminal half-life in the blood to produce an injectable dosage form that will sustain drug levels for weeks-to-months. These hydrophobic LA medicines are typically manufactured with polymeric excipients to form small drug crystals that retain their native crystalline states to improve water solubility. However, by nature, nanocrystalline chemical species are in a metastable state and tend to reverse to a more stable larger structure of drug in a polymorphic crystalline form. Other technologies and methods have also been described to produce long-acting drug formulations: (1) conjugation of drug molecule to erodible bio-polymers that release the drug molecule as it detaches from the polymer over time, (2) encapsulation into polymeric particles that are biodegradable (e.g. PLGA or PLA); or hydrogel for slowly releasing encapsulates drug molecules, (3) encapsulating into lipid vesicles, silica, clay and other carriers, and (4) grinding of large drug crystals in insoluble suspension with polymeric excipients to form small, nano-crystalline drug product that slowly dissolve upon injection. These approaches, intended to produce long-acting and sustained release or controlled drug-release, require cumbersome and time-consuming chemical modification to derive preferred hydrophobic derivatives of the parent drug molecules. Furthermore, some of these encapsulation processes may require removal of unencapsulated materials, or involve mechanical milling processes which could introduce contamination, heat induced-degradation, increasing cost and production risks. To avoid and/or minimize such risks while producing a long-acting, stable, scalable, and reproducible drug product, we have developed and characterized a colloidal drug formulation, which enables the transformation of a single short-acting, orally active HIV drug, dolutegravir sodium, into long-active colloidal suspension (DTG-CS). DTG-CS particles exhibit long and extended plasma drug concentrations to overcome the requirement of daily oral dosing. This colloidal suspension is stabilized by lipid excipients to produce the DTG-CS particulate (d ~ 2 µm) product in suspension. When given subcutaneously to non-human primates (NHP), the plasma DTG concentrations and its presence over time provide sustained HIV viral suppression out to four months. Collectively, this data suggests that DTG in DTG-CS warrants consideration for preclinical and clinical development as a long-acting drug formulation for the treatment of HIV.