Saquinavir mesylate

Saquinavir is a potent inhibitor HIV protease with Ki value of 0.12 and < 0.1 nM for HIV-1 and HIV-2 protease[1].
HIV protease is essential for release of mature viral and viral replication which is a retroviral aspartyl protease[2]. HIV protease cleaves the synthesized polypeptide at the appropriate places which creates the mature protein components of HIV viral. HIV-1 protease is an attractive target of AIDS.
Saquinavir is a transition-state inhibitor which binds to the active site of HIV protease, preventing cleavage of viral polyproteins [1]. Saquinavir inhibited the cleavage of p55 (the HIV-1 gag polyprotein) to p24 which is the viral structural protein in chronically infected CEM cells [2]. The bioavailability of 20 mg/kg saquinavir increased 325-fold in mice when co-administered ritonavir at the dose of 50 mg/kg. Ritonavir prevents saquinavir from metabolizing to an inactive form by CYP3A.
Saquinavir also inhibited the level of endogenous Aβ40 from primary cultured human cortical neurons. Saquinavir significantly reduced the production of the TCA-soluble extracellular fraction at 50 or 100 μM. Saquinavir reduced Aβ production in human neurons reaching 90% at 50 μM. Saquinavir showed as high as 60, 30, 32, and 48% inhibition of BACE1 activity at 300 μM as compared to control [3].
References:
1.Roberts NA, Martin JA, Kinchington D, Broadhurst AV, Craig JC, Duncan IB, Galpin SA, Handa BK, Kay J, Krohn A et al: Rational design of peptide-based HIV proteinase inhibitors. Science 1990, 248(4953):358-361.
2.Davies DR: The structure and function of the aspartic proteinases. Annu Rev Biophys Biophys Chem 1990, 19:189-215.
3.Lan X, Kiyota T, Hanamsagar R, Huang Y, Andrews S, Peng H, Zheng JC, Swindells S, Carlson GA, Ikezu T: The effect of HIV protease inhibitors on amyloid-beta peptide degradation and synthesis in human cells and Alzheimer's disease animal model. J Neuroimmune Pharmacol 2012, 7(2):412-423.

Intranasal in situ gel loaded with saquinavir mesylate nanosized microemulsion: preparation, characterization, and in vivo evaluation.[Pubmed:25178831]

Int J Pharm. 2014 Nov 20;475(1-2):191-7.

Saquinavir mesylate (SM) is a protease inhibitor with activity against human immunodeficiency virus type 1 (HIV-1) and is available in tablet form, which has three major problems. First, the drug undergoes extensive first pass metabolism. Second, the drug has a poor aqueous solubility. And third, it has low GIT permeability and absorption. These constrains lead to decrease oral bioavailability (4% only) and administration of large doses which increase the incidence of occurrence of the side effects. The aim of this research was to utilize nanotechnology to formulate (SM) into a nasal in situ nanosized microemulsion gel (NEG) to provide a solution for the previously mentioned problems. The solubility of (SM) in various oils, surfactants, and cosurfactants was estimated. Pseudo-ternary phase diagrams were developed and various nanosized microemulsion (NE) were prepared, and subjected to characterization, stability study, and droplet size measurements. Gellan gum was used as an in situ gelling agent. The gel strength, critical ionic concentration, gelation characteristics, in vitro release, and ex vivo nasal permeation were determined. The pharmacokinetic study was carried out in rabbits. Stable NEs were successfully developed with a droplet size range of 25-61 nm. A NEG composed of 17.5% Labrafac PG, 33% Labrasol, and 11% Transcutol HP successfully provided the maximum in vitro and ex vivo permeation, and enhanced the bioavailability in the rabbits by 12-fold when compared with the marketed tablets. It can be concluded that the nasal NEG is a promising novel formula for (SM) that has higher nasal tissue permeability and enhanced systemic bioavailability.

Nanoemulsion-based intranasal drug delivery system of saquinavir mesylate for brain targeting.[Pubmed:24128122]

Drug Deliv. 2014 Mar;21(2):148-54.

The central nervous system (CNS) is an immunological privileged sanctuary site-providing reservoir for HIV-1 virus. Current anti-HIV drugs, although effective in reducing plasma viral levels, cannot eradicate the virus completely from the body. The low permeability of anti-HIV drugs across the blood-brain barrier (BBB) leads to insufficient delivery. Therefore, developing a novel approaches enhancing the CNS delivery of anti-HIV drugs are required for the treatment of neuro-AIDS. The aim of this study was to develop intranasal nanoemulsion (NE) for enhanced bioavailability and CNS targeting of Saquinavir mesylate (SQVM). SQVM is a protease inhibitor which is a poorly soluble drug widely used as antiretroviral drug, with oral bioavailability is about 4%. The spontaneous emulsification method was used to prepare drug-loaded o/w nanoemulsion, which was characterized by droplet size, zeta potential, pH, drug content. Moreover, ex-vivo permeation studies were performed using sheep nasal mucosa. The optimized NE showed a significant increase in drug permeation rate compared to the plain drug suspension (PDS). Cilia toxicity study on sheep nasal mucosa showed no significant adverse effect of SQVM-loaded NE. Results of in vivo biodistribution studies show higher drug concentration in brain after intranasal administration of NE than intravenous delivered PDS. The higher percentage of drug targeting efficiency (% DTE) and nose-to-brain drug direct transport percentage (% DTP) for optimized NE indicated effective CNS targeting of SQVM via intranasal route. Gamma scintigraphy imaging of the rat brain conclusively demonstrated transport of drug in the CNS at larger extent after intranasal administration as NE.

Identification of degradation products of saquinavir mesylate by ultra-high-performance liquid chromatography/electrospray ionization quadrupole time-of-flight tandem mass spectrometry and its application to quality control.[Pubmed:28233930]

Rapid Commun Mass Spectrom. 2017 May 15;31(9):771-781.

RATIONALE: Saquinavir mesylate (SQM) is an antiviral drug used for the treatment of HIV infections. The identification and characterization of all degradation products are essential for achieving the quality in pharmaceutical product development and also for patient safety. METHODS: The drug was subjected to hydrolytic (HCl, NaOH and water), oxidative (H2 O2 ), photolytic (UV and fluorescence light) and thermal (dry heat) forced degradation conditions as per ICH guidelines. The best chromatographic separation of the drug and all degradation products (DPs) was achieved on a CSH-Phenyl Hexyl column (100 x 2.1 mm, 1.7 mum) with ammonium acetate (10 mM, pH 5.0) and methanol as mobile phase in gradient mode at a flow rate of 0.28 mL/min. RESULTS: Nine DPs were obtained under various forced degradation conditions. All the DPs were characterized by using ultra-high-performance liquid chromatography/electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC/ESI-QTOF MS/MS) and the degradation pathway of the drug was justified by mechanistic explanations. The main DPs were formed by amide hydrolysis, conversion into diastereomers, an N-oxide and dehydration as well as oxidation of the alcohol from the drug. The method was validated and can be used in a quality control (QC) laboratory to assure the quality of SQM in bulk and finished formulations. CONCLUSIONS: A simple UHPLC/photodiode array (PDA) method was developed and successfully transferred to UHPLC/ESI-Q-TOF MS/MS for the identification and characterization of DPs. Very interestingly, diastereomeric DPs were obtained and successfully resolved by the chromatographic method. Copyright (c) 2017 John Wiley & Sons, Ltd.

Pharmacokinetics of Saquinavir Mesylate from Oral Self-Emulsifying Lipid-Based Delivery Systems.[Pubmed:26846485]

Eur J Drug Metab Pharmacokinet. 2017 Feb;42(1):135-141.

BACKGROUND AND OBJECTIVES: Although lipid-based drug delivery systems have gained much importance in recent years due to their ability to improve the solubility and bioavailability of poorly soluble drugs, compartmental pharmacokinetic analyses have not been extensively explored. The oral pharmacokinetics of commercial liquid formulation and a developed semisolid system containing Saquinavir mesylate (SQVM) were compared in Beagle dogs. A compartmental analysis after intravenous bolus administration of this drug (1 mg/kg) was also performed. METHOD: Pharmacokinetic profiles were analyzed using both non-compartmental and compartmental approaches. Plasma concentration of the drug was determined by high-performance liquid chromatography/tandem mass spectrometry (LC/MS/MS). RESULTS: The disposition curve of SQVM given intravenously was better described by a three-compartment model. In contrast, plasma profiles obtained following the oral administration were fitted to a two-compartment model with lag time due to the fact that the distribution phase was masked by the absorption phase in these formulations. CONCLUSION: The proposed semisolid lipid system was found to be a promising formulation for commercial purposes given the similarity of SQVM absorption rate to that from the commercial liquid formulation.