Controlled Drug Release from Polymeric Delivery Devices II: Differentiation Between Partition-Controlled and Matrix-Controlled Drug Release Mechanisms

Chien, Yie W.; Lambert, Howard J.

doi:10.1002/jps.2600630405

Cited by 70 publications

(12 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…At all time points, in vitro–released MIV-150 levels were >859 times the IC 50 against HIV ADA , HIV MN , and SHIV-RT (19, 23). The cumulative release profiles for all three MIV-150 IVRs in the SNaC buffer exhibited partition-controlled kinetics [typical of nonsink conditions (24)] of Q α time, where Q is the cumulative percentage of MIV-150 released. Q for the 50-mg silicone, 50-mg EVA, and 100-mg EVA IVRs was 2.8, 8.7, and 5.3%, respectively.…”

Section: Discussionmentioning

confidence: 99%

An Intravaginal Ring That Releases the NNRTI MIV-150 Reduces SHIV Transmission in Macaques

et al. 2012

View full text Add to dashboard Cite

Microbicides may prevent HIV and sexually transmitted infections (STIs) in women; however, determining the optimal means of delivery of active pharmaceutical ingredients remains a major challenge. We previously demonstrated that a vaginal gel containing the non-nucleoside reverse transcriptase inhibitor MIV-150 partially protected macaques from SHIV-RT (simian/HIV reverse transcriptase) infection, and the addition of zinc acetate rendered the gel significantly protective. We test the activity of MIV-150 without the addition of zinc acetate when delivered from either ethylene vinyl acetate (EVA) or silicone intravaginal rings (IVRs). MIV-150 was successfully delivered, because it was detected in vaginal fluids and tissues by radioimmunoassay in pharmacokinetic studies. Moreover, EVA IVRs significantly protected macaques from SHIV-RT infection. Our results demonstrate that MIV-150–containing IVRs have the potential to prevent HIV infection and highlight the possible use of IVRs for delivering drugs that block HIV and other STIs.

show abstract

Section: Discussionmentioning

confidence: 99%

An Intravaginal Ring That Releases the NNRTI MIV-150 Reduces SHIV Transmission in Macaques

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Typically, in vitro drug release testing utilizes sink conditions, wherein the API concentration in the release medium never exceeds one-third the equilibrium saturation concentration (42). Conversely, nonsink conditions exist when the concentration of API in the release medium nears its maximum solubility, resulting in attenuated drug release due to a smaller concentration gradient as well as API partitioning between the polymer and medium (6,17). Although utilization of sink conditions does in fact classify the device type-the most common being time dependent (matrix devices) or time independent (reservoir devices)-it seldom reflects in vivo pharmacokinetics.…”

Section: Discussionmentioning

confidence: 99%

“…This assumption holds true only for uncharged molecules such as the PYDs, as mucus is known to bind charged molecules and thereby hinder transport (9,10). Crystallized PYD was also observed on the surface of the 14 wt% PYD2 IVR after removal, suggesting partition-controlled drug release where dissolution into vaginal fluid is the ratelimiting step as a result of the PYDs' high polymer solubility and low aqueous solubility (6). This phenomenon may be advantageous, as the matrix IVR could provide relatively constant drug release throughout the dosage duration, as suggested with the PYD2 14wt% IVR vaginal fluid levels.…”

Section: Discussionmentioning

confidence: 99%

Safe and Sustained Vaginal Delivery of Pyrimidinedione HIV-1 Inhibitors from Polyurethane Intravaginal Rings

Johnson

Srinivasan²,

Albright

et al. 2012

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The potent antiretroviral pyrimidinediones IQP-0528 (PYD1) and IQP-0532 (PYD2) were formulated in polyurethane intravaginal rings (IVRs) as prophylactic drug delivery systems to prevent the sexual transmission of HIV-1. To aid in the selection of a pyrimidinedione candidate and the optimal loading of the drug in the IVR delivery system, four pyrimidinedione IVR formulations (PYD1 at 0.5 wt% [PYD1 0.5wt% ], PYD1 1wt% , PYD2 4wt% , and PYD2 14wt% ) were evaluated in pigtail macaques over 28 days for safety and pyrimidinedione vaginal biodistribution. Kinetic analysis of vaginal proinflammatory cytokines, native microflora, and drug levels suggested that all formulations were safe, but only the high-loaded PYD2 14wt% IVR demonstrated consistently high pyrimidinedione vaginal fluid and tissue levels over the 28-day study. This formulation delivered drug in excess of 10 g/ml to vaginal fluid and 1 g/g to vaginal tissue, a level over 1,000 times the in vitro 50% effective concentration. The in vitro release of PYD1 and PYD2 under nonsink conditions correlated well with in vivo release, both in amount and in kinetic profile, and therefore may serve as a more biologically relevant means of evaluating release in vitro than typically employed sink conditions. Lastly, the pyrimidinediones in the IVR formulation were chemically stable after 90 days of storage at elevated temperature, and the potent nanomolar-level antiviral activity of both molecules was retained after in vitro release. Altogether, these results point to the successful IVR formulation and vaginal biodistribution of the pyrimidinediones and demonstrate the usefulness of the pigtail macaque model in evaluating and screening antiretroviral IVR formulations prior to preclinical and clinical evaluation.

show abstract

“…Like mono-drug patches, it was found that Higuchi's model was the most suitable for describing the release kinetics of drugs from the composite patches examined in the present study. Higuchi's rate constants calculated are summarized in Table 2 (Chien and Lambert 1974).…”

Section: Resultsmentioning

confidence: 99%

The effects of terpenes on the permeation of lidocaine and ofloxacin from moisture-activated patches

2009

View full text Add to dashboard Cite

Controlled Drug Release from Polymeric Delivery Devices II: Differentiation Between Partition-Controlled and Matrix-Controlled Drug Release Mechanisms

Cited by 70 publications

References 12 publications

An Intravaginal Ring That Releases the NNRTI MIV-150 Reduces SHIV Transmission in Macaques

An Intravaginal Ring That Releases the NNRTI MIV-150 Reduces SHIV Transmission in Macaques

Safe and Sustained Vaginal Delivery of Pyrimidinedione HIV-1 Inhibitors from Polyurethane Intravaginal Rings

The effects of terpenes on the permeation of lidocaine and ofloxacin from moisture-activated patches

Contact Info

Product

Resources

About