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Pharmaceutical Research Jan 2022To understand the anomalous behavior of Saquinavir Mesylate (SQVM) in sodium decyl sulfate (SDS) medium during a dissolution test through a crystallographic analysis of...
PURPOSE
To understand the anomalous behavior of Saquinavir Mesylate (SQVM) in sodium decyl sulfate (SDS) medium during a dissolution test through a crystallographic analysis of the crystal obtained. As a result, it will be possible to elucidate its crystal structure and carry out a complete solid-state characterization of the API.
METHODS
The solid form obtained was characterized by a structural analysis through X-ray single crystal and powder diffraction. The crystallographic structures of the new salt and the SQVM were compared. In addition, a complete solid-state characterization of SQVM raw material was carried out by techniques such as diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), Raman spectroscopy, scanning electron microscopy and a dissolution method.
RESULTS
A new salt consisting of SQVM and SDS was crystallized and its crystal structure was elucidated and reported herein for the first time. The anionic part of SDS interacts with the cationic segment of SQVM to obtain a new salt designated as SQV-DS, which precipitates. The main difference between the two structures occurs in the c-axis expansion, which increases from 15.966 (5) to 21.1924 (14), respectively.
CONCLUSIONS
Some of the strategies to enhance the dissolution rate of poorly aqueous soluble APIs include the use of surfactants such as SDS in the dissolution medium, as well as in the formulated products. However, there have been constant reports of a dissolution rate slowdown by some surfactants. The interaction mechanisms between the APIs and the dissolution medium containing surfactants need to be carefully investigated in current pharmaceutical formulations. Graphical Abstract.
Topics: Calorimetry, Differential Scanning; Pharmaceutical Preparations; Saquinavir; Sodium; Solubility; Spectroscopy, Fourier Transform Infrared; Sulfates; X-Ray Diffraction
PubMed: 35064418
DOI: 10.1007/s11095-022-03167-4 -
Biomolecules Jul 2022Saquinavir was the first protease inhibitor developed for HIV therapy, and it changed the standard of treatment for this disease to a combination of drugs that... (Review)
Review
Saquinavir was the first protease inhibitor developed for HIV therapy, and it changed the standard of treatment for this disease to a combination of drugs that ultimately led to increased survival of this otherwise deadly condition. Inhibiting the HIV protease impedes the virus from maturing and replicating. With this in mind, since the start of the COVID-19 outbreak, the research for already approved drugs (mainly antivirals) to repurpose for treatment of this disease has increased. Among the drugs tested, saquinavir showed promise in silico and in vitro in the inhibition of the SARS-CoV-2 main protease (3CLpro). Another field for saquinavir repurposing has been in anticancer treatment, in which it has shown effects in vitro and in vivo in several types of cancer, from Kaposi carcinoma to neuroblastoma, demonstrating cytotoxicity, apoptosis, inhibition of cell invasion, and improvement of radiosensibility of cancer cells. Despite the lack of follow-up in clinical trials for cancer use, there has been a renewed interest in this drug recently due to COVID-19, which shows similar pharmacological pathways and has developed superior in silico models that can be translated to oncologic research. This could help further testing and future approval of saquinavir repurposing for cancer treatment.
Topics: HIV Infections; HIV Protease Inhibitors; Humans; Neoplasms; SARS-CoV-2; Saquinavir; COVID-19 Drug Treatment
PubMed: 35883499
DOI: 10.3390/biom12070944 -
The Journal of the Association of... 1996
Review
Topics: Adolescent; Aged; Child; Drug Monitoring; Female; HIV Infections; HIV Protease Inhibitors; Humans; Nursing Assessment; Patient Education as Topic; Pregnancy; Saquinavir
PubMed: 8875367
DOI: 10.1016/S1055-3290(96)80059-8 -
European Journal of Drug Metabolism and... Feb 2017Although lipid-based drug delivery systems have gained much importance in recent years due to their ability to improve the solubility and bioavailability of poorly...
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.
Topics: Administration, Intravenous; Administration, Oral; Animals; Biological Availability; Dogs; Drug Delivery Systems; Emulsions; Lipids; Male; Models, Biological; Saquinavir
PubMed: 26846485
DOI: 10.1007/s13318-016-0321-x -
Diabetes Care Dec 2013
Topics: Adult; Blood Glucose; Diabetes Mellitus; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Hypoglycemic Agents; Insulin; Male; Saquinavir
PubMed: 24265371
DOI: 10.2337/dc13-1645 -
Clinical Pharmacokinetics Mar 1998Saquinavir is an HIV protease inhibitor with no, or limited, effect on the activity of other structurally related human aspartic proteinases. As with other HIV protease... (Review)
Review
Saquinavir is an HIV protease inhibitor with no, or limited, effect on the activity of other structurally related human aspartic proteinases. As with other HIV protease inhibitors, saquinavir inhibits the cleavage of the gag-pol protein substrate leading to the release of structurally defective and functionally inactive viral particles. It is active on both HIV-1 and HIV-2, and also has activity on chronically infected cells and HIV strains resistant to reverse transcriptase inhibitors. Synergy of action has been observed with other antiretroviral drugs. Saquinavir is characterised by a low bioavailability which is further reduced in the fasting state. Metabolism is mainly hepatic through cytochrome P450 (CYP) 3A4, but intestinal metabolism through the same system has also been reported. To achieve higher drug plasma concentrations and increase the antiviral effect, a new formulation of saquinavir with a higher bioavailability has recently been introduced. Higher plasma drug concentrations may also be obtained by combining the drug with CYP blockers, such as ritonavir or ketoconazole. Because of its metabolic interference with the CYP system, saquinavir cannot be coadministered with astemizole, terfenadine or cisapride. Rifampicin (rifampin) is also contraindicated because coadministration can lead to decreases in saquinavir concentrations. Interactions have also been reported with other drugs metabolised through the same system, including non-nucleoside reverse transcriptase inhibitors and HIV protease inhibitors. Resistance has been observed after both in vitro and in vivo drug exposure, with a relatively specific mutation profile compared with other protease inhibitors. Saquinavir is generally well tolerated, with mild gastrointestinal symptoms representing the most commonly observed adverse effects. Although characterized by low bioavailability, in phase III trials saquinavir has been shown to have clinical efficacy in terms of survival and progression rate. As with the other protease inhibitors, saquinavir should be used in combination with other antiretroviral drugs. Current therapeutic guidelines, however, recommend the selection of an initial treatment regimen with other protease inhibitors with higher in vivo activity in terms of RNA and CD4 response. The results of ongoing studies will clarify to what extent a new saquinavir formulation, recently introduced, is superior to the previous one in terms of antiviral activity and to provide comparisons with other protease inhibitors. Further studies are also needed to define the best place of saquinavir within treatment strategies based on protease inhibitors, particularly in respect to the optimal sequence for its use with other protease inhibitors, and the dynamics of cross-resistance and its role within regimens based on the combination of protease inhibitors.
Topics: Anti-HIV Agents; HIV Infections; HIV Protease Inhibitors; Humans; Saquinavir; Virus Replication
PubMed: 9533981
DOI: 10.2165/00003088-199834030-00002 -
International Journal of Nanomedicine 2019Saquinavir mesylate (SQR) tablets are widely used against human immunodeficiency virus. SQR has bioavailability issues owing to its poor aqueous solubility, extensive...
Development Of Saquinavir Mesylate Nanoemulsion-Loaded Transdermal Films: Two-Step Optimization Of Permeation Parameters, Characterization, And Ex Vivo And In Vivo Evaluation.
BACKGROUND
Saquinavir mesylate (SQR) tablets are widely used against human immunodeficiency virus. SQR has bioavailability issues owing to its poor aqueous solubility, extensive first-pass metabolism, and even low gastrointestinal tract permeability and absorption.
OBJECTIVE
An in-depth optimization process was carried out using factorial design to improve the permeation parameters and thereby the bioavailability of SQR by formulating self-nanoemulsifying drug delivery system (SNEDDS)-loaded polymeric transdermal films.
METHODS
The solubility of SQR in different nanoemulsion components was examined. Various combinations of selected components were prepared in an extreme vertices mixture design to identify the useful nanoemulsion zone and to develop SNEDDS with minimum globule size. The optimized SQR-SNEDDS was loaded in polyvinyl alcohol (PVA)-based transdermal films. The Box-Behnken design was used to optimize and evaluate SQR permeability. The prepared films were characterized for thickness, tensile strength, elongation, folding endurance, and accelerated stability studies. The optimized film was examined for ex vivo skin permeation and in vivo pharmacokinetic parameters.
RESULTS
The optimized SQR-SNEDDS was prepared in proportions of 0.1, 0.55, and 0.35 of clove oil, labrasol, and Transcutol, respectively. The implemented Box-Behnken design indicated the optimized film consisted of 1.0% PVA, 0.25% propylene glycol, and clove oil as the oil phase. The tensile strength, thickness, percent elongation, and folding endurance of the optimized SQR-SNEDDS film were 0.93 ± 0.013 kg/cm, 0.22 ± 0.006 mm, 43.1 ± 0.022%, and >200 times, respectively. A higher Cmax and double the AUC were observed for SQR-SNEDDS-loaded film in comparison to pure SQR-loaded films.
CONCLUSION
Implementation of a two-step design to optimize and control experimental factors in the preparation of SQR-SNEDDS and its loading onto PVA-based transdermal films was achieved. The films indicated improved ex vivo skin permeation, enhanced bioavailability, and overcame the limitations of the oral dosage form.
Topics: Administration, Cutaneous; Administration, Oral; Animals; Drug Delivery Systems; Emulsions; Humans; Male; Nanoparticles; Permeability; Phase Transition; Rats, Wistar; Saquinavir; Skin; Solubility; Surface-Active Agents; Tablets
PubMed: 31802871
DOI: 10.2147/IJN.S230747 -
International Journal of Nanomedicine 2020Low bioavailability and poor permeability of the blood-brain barrier are problematic when delivering therapeutic agents and particularly anti-human immunodeficiency...
BACKGROUND
Low bioavailability and poor permeability of the blood-brain barrier are problematic when delivering therapeutic agents and particularly anti-human immunodeficiency virus therapy to the central nervous system. The intranasal route offers an alternative for central nervous system delivery. Cubosomes have been reported as helpful vehicles for intranasal delivery of therapeutics to enable brain targeting.
OBJECTIVE
In this study, we aimed to develop the intranasal cubosomal thermogelling dispersion of saquinavir mesylate for central nervous system delivery.
METHODS
The Box-Behnken design was applied to study the effect of monoolein, Poloxamer 407, and polyvinyl alcohol as independent factors and the particle size, entrapment efficiency, gelation temperature, and stability index as responses. The optimized cubosomes were evaluated using transmission electron microscopy, ex vivo permeation, and in vivo pharmacokinetics.
RESULTS
The optimized formula consisting of monoolein (8.96%), Poloxamer 407 (17.45%), and polyvinyl alcohol (7.5%) was prepared and evaluated. Higher values for the steady-state flux, permeability coefficient, and enhancement factor were observed for the cubosomal thermogelling dispersion of saquinavir during ex vivo permeation in comparison with an aqueous suspension of saquinavir. From the pharmacokinetic profile, the relative bioavailability for the intranasal optimized formula was approximately 12-fold higher when compared with oral aqueous suspension and 2.5-fold greater when compared to the intranasal aqueous suspension of saquinavir.
CONCLUSION
Overall, the saquinavir-loaded cubosomal thermogelling formulation is promising for central nervous system delivery by intranasal administration.
Topics: Administration, Intranasal; Animals; Biological Availability; Blood-Brain Barrier; Drug Carriers; Gels; Glycerides; Liquid Crystals; Male; Nanostructures; Particle Size; Permeability; Poloxamer; Polyvinyl Alcohol; Saquinavir; Temperature
PubMed: 32764940
DOI: 10.2147/IJN.S261855 -
European Journal of Pharmaceutical... Dec 2023Saquinavir mesylate (SQV) is a protease inhibitor commonly employed for the treatment of human immunodeficiency virus-1 infection. It is generally administered orally as...
Saquinavir mesylate (SQV) is a protease inhibitor commonly employed for the treatment of human immunodeficiency virus-1 infection. It is generally administered orally as tablets in combination with other antiviral drugs. Another promising route of administration can be represented by the vaginal one through topically applied formulations. This delivery can reduce the first-pass effect in the case of systemic drug adsorption or prevent HIV infection. We propose the formulation of a Carbopol® 974 (C974) hydrogel containing biodegradable mPEG-PL(L)GA nanoparticles (NPs) for the vaginal delivery of SQV, intended both as a prevention and a therapeutic strategy. mPEG-PL(L)GA NPs were incorporated into the C974 polymeric matrix, leading to a reduction of the hydrogel consistency dependent on NPs and C974 concentrations. Despite the moderate drug loading into NPs, the presence of the NPs had an impact on the in vitro release of the drug from the hydrogel at pH 5.5 using immersion cells. A higher amount of the drug was released, probably due to the effect of NPs in promoting the incorporation of the drug into the hydrogel at a high SQV dose. These findings can be useful for the development of topically applied hydrogels for SQV delivery, possibly having improved in vivo therapeutic outcomes.
Topics: Female; Humans; Pregnancy; Saquinavir; Hydrogels; HIV Infections; Nanoparticles; Delivery, Obstetric
PubMed: 37774955
DOI: 10.1016/j.ejps.2023.106599 -
Expert Opinion on Drug Metabolism &... Oct 2009The treatment of HIV infection underwent a major change in 1995 when saquinavir was the first protease inhibitor introduced into the market. This drug made the use of... (Comparative Study)
Comparative Study Review
BACKGROUND
The treatment of HIV infection underwent a major change in 1995 when saquinavir was the first protease inhibitor introduced into the market. This drug made the use of combination therapy in the treatment of HIV possible and increased the success rate of treatment.
OBJECTIVE
This article will review recent literature on saquinavir to define its current role in HIV treatment, among the newer antiretroviral drugs.
METHODS
Scientific literature and conference presentations were evaluated for relevant information pertaining to saquinavir.
RESULTS/CONCLUSIONS
Although underused, saquinavir has good efficacy and tolerability when compared to other protease inhibitors. The film-coated tablet formulation improved pill burden. Saquinavir still has potential in the treatment of adults, children and pregnant women.
Topics: Adult; Antiretroviral Therapy, Highly Active; Child; Clinical Trials as Topic; Female; HIV Infections; HIV Protease Inhibitors; Humans; Pregnancy; Saquinavir
PubMed: 19737048
DOI: 10.1517/17425250903273160