Influence of long-term stability conditions on microbicidal nucleoside prodrug (WHI-07)-loaded gel-microemulsion

D’Cruz, Osmond J.; Uckun, Fatih M.

doi:10.1208/pt070373

Cited by 5 publications

(4 citation statements)

References 29 publications

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“…Microemulsions can deliver larger amounts of topically applied WHI-07 and VDDTC into the vaginal mucosa than traditional vehicles because of their capacity for enhanced solubilization and greater bioavailability (Tenjarla, 1999). The microemulsion-based system composed (w/w) of Phospholipon 90G (5.1%) and Captex 300 (10.8%) as the oil phase with Cremophor EL (7.6%) as surfactant, propylene glycol (4.2%) and polyethylene glycol 200 (4.2%) as cosurfactants, and water (66.1%) as a carrier and a preservative (0.2% sodium benzoate) (D'Cruz and Uckun, 2006). Polymer suspensions of SeaSpen PF (0.9%) and Viscarin GP-209 (0.9%) carrageenans were selected as additives to the microemulsion to obtain a gel with desirable viscosity containing WHI-07 and VDDTC with thickening capability and compatibility with vaginal mucosa.…”

Section: Gel-microemulsion Formulation Of Whi-07 Plus Vddtcmentioning

confidence: 99%

Preclinical Evaluation of a Dual-Acting Microbicidal Prodrug WHI-07 in Combination with Vanadocene Dithiocarbamate in the Female Reproductive Tract of Rabbit, Pig, and Cat

D’Cruz

Uckun

2007

Toxicol Pathol

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The mucosal safety of the combination antiretroviral spermicide,WHI-07 [5-bromo-6-methoxy-5,6-dihydro-3 -azidothymidine-5 -( pbromophenyl)-methoxy alaninyl phosphate] and vanadocene dithiocarbamate (VDDTC), was evaluated in 3 different animal models. Twenty-seven NZW rabbits in four subgroups were exposed intravaginally to a gel-microemulsion (GM) with and without three dose levels of WHI-07 plus VD-DTC (0.5 + 0.06%, 1.0 + 0.12% and 2.0 + 0.25%) or 4% nonoxynol-9 (N-9; Conceptrol R ) for 14 consecutive days. Ten nonestrus gilts (Duroc) in three subgroups received either a single or daily intravaginal application of GM with and without 2.0% WHI-07 plus 0.25% VDDTC or 2.0% benzalkonium chloride (BZK)-containing gel for 6 and 4 consecutive days, respectively. Five cats received a single intravaginal application of GM incorporating 2.0% WHI-07 plus 0.25% VDDTC. Genital tract histopathology was performed in the pig and rabbit at the end of dosing period but after 18 weeks post-dosing in the cat. Porcine cervicovaginal lavage (CVL) fluid was obtained for up to 72 hours after a single exposure and changes in the levels of inflammatory cytokines (IL-1β, IL-8, IFN-γ , and TNF-α) were quantitated by a multiplexed chemiluminescence-based immunoassay. Rabbit vaginal tissues were evaluated for localized cellular inflammation and in situ apoptosis by immunohistochemical staining for CD45, nuclear factor (NF)-κB, and terminal deoxynucleotidyl transferase-mediated FITC-deoxyuridine triphosphate nick-end labeling (TUNEL) using confocal laser scanning microscopy (CLSM), respectively. Vanadium content in selected organs and body fluids from rabbits and pigs was determined by atomic absorption spectroscopy. When compared with 4% N-9 (total irritation score 13-14 out of a possible 16), none of the rabbits given WHI-07 plus VDDTC intravaginally, developed histological alterations such as epithelial erosion, edema, leukocyte influx or vascular congestion characteristic of inflammation (total irritation score 4-6). CD45 and NF-κB immunoreactivity was limited to cells within the vascular lumen of both control and WHI-07 plus VDDTC-treated vaginal tissues. TUNEL assay revealed lack of increased apoptotic cells in vaginal mucosa exposed to increasing concentrations of WHI-07 plus VDDTC. Basal levels of proinflammatory cytokines (IL-1β, IL-8, IFN-γ and TNF-α) in porcine CVL were unaffected by intravaginal exposure to WHI-07 plus VDDTC when compared with BZK used as a positive control. Endpoint histology of the reproductive tract from cats and pigs after a single or repeated intravaginal exposure to WHI-07 plus VDDTC, respectively, revealed lack of irritation/inflammation in the epithelium, subepithelium/lamina propria, vessels/perivascular tissues, and underlying/surrounding muscles. Vanadium was not preferentially incorporated into rabbit or porcine tissues and body fluids at levels above 1 µg/g. Based on comparative histologic data and surrogate markers for inflammation, repeated intravaginal administration of WHI-07 plus VDDTC v...

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Section: Gel-microemulsion Formulation Of Whi-07 Plus Vddtcmentioning

confidence: 99%

Preclinical Evaluation of a Dual-Acting Microbicidal Prodrug WHI-07 in Combination with Vanadocene Dithiocarbamate in the Female Reproductive Tract of Rabbit, Pig, and Cat

D’Cruz

Uckun

2007

Toxicol Pathol

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“…WHI-07 was solubilized in a lipophilic sub-micron (30-80 nm) particle size microemulsion using selected pharmaceutical excipients identified through systemic mapping of ternary phase diagrams and drug solubilization studies (D'Cruz and Uckun, 2001a). The microemulsion-based system was composed (w/w) of Phospholipon 90G (5.1%) and Captex 300 (10.8%) as the oil phase with Cremophor EL (7.6%) as surfactant, propylene glycol (4.2%) and polyethylene glycol 200 (4.2%) as cosurfactants, and water (66.1%) as a carrier and a preservative (0.2% sodium benzoate) (D'Cruz and Uckun, 2006). Polymer suspensions of SeaSpen PF (0.9%) and Viscarin GP-209 (0.9%) carrageenans were selected as additives to the microemulsion to obtain a gel with desirable viscosity containing 2.0% WHI-07 with thickening capability and compatibility with vaginal mucosa (D'Cruz and Uckun, 2001a).…”

Section: Gel-microemulsion Formulation Of Whi-07mentioning

confidence: 99%

“…The highest concentration of WHI-07 chosen for the porcine mucosal irritation study was based on the lack of local, systemic and reproductive toxicity observed in two 13-week subchronic studies in CD1 and B6C3F1 mice (D'Cruz et al, 2000;Uckun, 2001b, 2001c), a 14-day developmental toxicity study in NZW rabbits , and a 2-year carcinogenicity study in B6C3F1 mice . A 6month stability of 2% WHI-07-loaded gel-microemulsion revealed that the prodrug was stable in microemulsionbased formulation (D'Cruz and Uckun 2006).…”

Section: Gel-microemulsion Formulation Of Whi-07mentioning

confidence: 99%

Evaluation of local tolerance of the antiretroviral spermicide (WHI‐07)‐loaded gel‐microemulsion in the porcine female reproductive tract

D’Cruz¹,

Uckun²

2007

J of Applied Toxicology

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The local tolerance of the antiretroviral spermicide, WHI-07 (5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-bromophenyl)-methoxyalaninyl phosphate)-loaded gel-microemulsion was evaluated in a physiologically relevant and sensitive porcine model. Gilts (Duroc) in nonestrus stages of the reproductive cycle received either a single or a daily intravaginal application of 2.0% WHI-07 via a gel-microemulsion for 6 days. Cervicovaginal lavage (CVL) fluid was obtained for up to 72 h after a single exposure and the cellular profile and levels of inflammatory cytokines (IL-1beta, IL-8, IFN-gamma and TNF-alpha) were quantitated by flow cytometry and chemiluminescence-based multiplex immunoassay, respectively. The reproductive tract (vagina, cervix, uteri and Fallopian tubes) harvested on day 7 was scored histologically for evidence of mucosal irritation using a new scoring criterion for ten histological endpoints that reflect pathological changes in the epithelial/ subepithelial and vascular/perivascular compartments. When compared with irritant reactions caused by the detergent-type spermicide, benzalkonium chloride (BZK), the scatter profile of CVL immune cells and basal levels of proinflammatory cytokines (IL-1beta, IL-8, IFN-gamma and TNF-alpha) in CVL fluid were unaffected by intravaginal exposure to 2% WHI-07. Unlike BZK, endpoint histology of the proximal and distal regions of the reproductive tract from gilts treated with 2.0% WHI-07 via gel-microemulsion for 6 days did not result in mucosal irritation or alteration in the epithelium, subepithelium/lamina propria, vessels/perivascular tissues and underlying/surrounding muscles. Based on surrogate markers for inflammation, leukocyte profile and histologic data for local tolerance, repeated intravaginal administration of WHI-07 via gel-microemulsion as a prophylactic contraceptive is unlikely to cause vaginal irritation.

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“…Microemulsions have emerged as novel vehicles for drug delivery for its advantage of spontaneous formation, ease of manufacturing and scale-up, thermodynamic stability, improved drug solubility of hydrophobic drugs and bioavailability [4] . D'Cruz developed gel microemulsions GM 4 and GM 144 as vaginal spermicides and intravaginal drug delivery vehicles to prevent the HIV and other sexually transmitted diseases [5,6]. Here we prepared microemulsion to load Nifeviroc in order to improve the water solubility and studied the stability of the Nifeviroc-MEs of different load capacity (0.1%, 0.2%, 0.3%) in order to set base for the use of microbicides.…”

Section: Introductionmentioning

confidence: 99%

The Stability Study of Nifeviroc-Loaded Microemulsions

Zhou¹,

Tian

Xia³

et al. 2012

AMR

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The objective is to study the stability of Nifeviroc-loaded microemulsions (Nifeviroc-MEs). The dilution stability of Nifeviroc-MEs with different loading capacity ( 0.1%, 0.2%, 0.3%) was tested by change of mean size, pH and appearance. The centrifugal stability was evaluated by comparing the mean size of Nifeviroc-MEs and dilutions before and after high-speed centrifugation for 30, 60, 120 min at 10000 rpm. The storage stability was evaluated by the change of appearance, the mean size, PDI and the retention rate of Nifeviroc in the ME. The pH, appearance, size analysis and retention rate results showed the Nifeviroc-MEs had good dilution, centrifugal stability and good storage stability without light.

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Influence of long-term stability conditions on microbicidal nucleoside prodrug (WHI-07)-loaded gel-microemulsion

Cited by 5 publications

References 29 publications

Preclinical Evaluation of a Dual-Acting Microbicidal Prodrug WHI-07 in Combination with Vanadocene Dithiocarbamate in the Female Reproductive Tract of Rabbit, Pig, and Cat

Preclinical Evaluation of a Dual-Acting Microbicidal Prodrug WHI-07 in Combination with Vanadocene Dithiocarbamate in the Female Reproductive Tract of Rabbit, Pig, and Cat

Evaluation of local tolerance of the antiretroviral spermicide (WHI‐07)‐loaded gel‐microemulsion in the porcine female reproductive tract

The Stability Study of Nifeviroc-Loaded Microemulsions

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