A 90-day tenofovir reservoir intravaginal ring for mucosal HIV prophylaxis (2012)

Johnson TJ, Clark MR, Albright TH, Nebeker JS, Tuitupou AL, Clark JT, Fabian J, McCabe RT, Chandra N, Doncel GF, Friend DR, Kiser PF. Antimicrobial agents and chemotherapy. 56(12):6272-83.

A novel, reservoir-type intravaginal ring (IVR) was designed for controlled, sustained drug release. Thermoplastic polyurethane (TPU) tubing was filled with a paste containing tenofovir (TFV) and evaluated for safety and pharmacokinetics. In vivo sheep studies successfully demonstrated that the IVR provided elevated TFV vaginal concentrations for 90 days compared to the 1% TFV gel control. No negative toxicological findings were found, although slight to moderate increases in inflammatory infiltrates in the vaginal epithelia were observed for some animals.

A hot-melt extruded intravaginal ring for the sustained delivery of the antiretroviral microbicide UC781 (2012)

Clark MR, Johnson TJ, McCabe RT, Clark JT, Tuitupou A, Elgendy H, Friend DR, Kiser PF. Journal of pharmaceutical sciences. 101(2):576-87.

A thermoplastic polyurethane (TPU) intravaginal ring (IVR) was prepared for the sustained delivery of UC781. A matrix rod of UC781 and TPU were hot-melt extruded and subsequently demonstrated load-dependent, diffusion-limited kinetics. In vitro data showed good cell viability, tissue integrity, and barrier function of EpiVaginal tissue. Controlled drug release kinetics from the IVR were achieved both in vivo and in vitro.

A phase 1 randomized placebo-controlled safety and pharmacokinetic trial of a tenofovir disoproxil fumarate vaginal ring (2016)

Keller MJ, Mesquita PM, Marzinke MA, Teller R, Espinoza L, Atrio JM, Lo Y, Frank B, Srinivasan S, Fredricks DN, Rabe L, Anderson PL, Hendrix CW, Kiser PF, Herold BC. AIDS. 13;30(5):743-51.

A Tenofovir disoproxil fumarate (TDF)-eluting intravaginal ring was developed from thermoplastic polyurethane (TPU) and assessed for safety and pharmacokinetics in a human clinical trial. Drug concentration in cervicovaginal fluid was evaluated over a 14-day span. The results indicated that these antiviral-loaded TPU rings were safe, efficacious in continual drug delivery, and showed significant promise for HIV prevention.

An Intravaginal Ring for the Simultaneous Delivery of an HIV-1 Maturation Inhibitor and Reverse-Transcriptase Inhibitor for Prophylaxis of HIV Transmission (2015)

Ugaonkar SR, Clark JT, English LB, Johnson TJ, Buckheit KW, Bahde RJ, Appella DH, Buckheit RW Jr, Kiser PF. J Pharm Sci. 104(10):3426-39.

Hydrophobic thermoplastic polyurethane (TPU) intravaginal rings (IVRs) were investigated to deliver an antiretroviral in combination with an HIV reverse transcriptase inhibitor. The drug-loaded matrix IVRs showed no drug degradation when subjected to accelerated stability conditions. Toxicological evaluations of the IVRs indicated no evidence of formulation toxicity and in vitro assays demonstrated efficacious drug release.

Antiretroviral eluting intravaginal rings to prevent the sexual transmission of HIV (2012)

Johnson T.J. The University of Utah, Department of Bioengineering.

Several matrix and reservoir-type polyurethane intravaginal rings (IVRs) were developed for the delivery of antiretrovirals. A multi-segmented IVR design was found to be effective in delivering dapivirine and tenofivir (TFV) in vitro at acceptable concentrations. A reservoir-type IVR was found to have zero-order release of TFV in vitro for 90 days. Toxicological evaluations to determine safety, efficacy, and biocompatibility gave positive results.

Controlling the hydration rate of a hydrophilic matrix in the core of an intravaginal ring determines antiretroviral release (2016)

Teller RS, Malaspina DC, Rastogi R, Clark JT, Szleifer I, Kiser PF. Journal of controlled release: official journal of the Controlled Release Society. 224:176-183.

A Tecoflex™ thermoplastic polyurethane (TPU) intravaginal ring (IVR) was designed to expand the class of drugs that can be administered vaginally, as often this route of administration is limited to drugs with low molecular weights. A matrix-style IVR was loaded with drug pellets inside its hollow core and investigated for controlled drug release. Controlled release rates of multiple antiretrovirals were successfully achieved by altering the orifice design, drug loading, and mass of pellets loaded in the devices.

Development and Pharmacokinetics of a 90-Day Intravaginal Ring for the Sustained Co-Delivery of the Microbicide Tenofovir and Contraceptive Levonorgestrel (2013)

Clark M.R, Clark J.T, Shelke N.B, Doncel G.F. Annual Meeting of the American Association of Pharmaceutical Sciences.

Segmented polyurethane intravaginal rings (IVRs) were formulated via hot melt extrusion and investigated for the simultaneous release of Tenofovir (TFV) and Levonorgestrel (LNG). A relatively hydrophobic polyurethane was used to form the segment containing LNG and a hydrophilic polyurethane was used to form the segment containing TFV. In vitro release testing was conducted along with in vivo pharmacokinetic studies, both of which yielded positive results.

Development of polyether urethane intravaginal rings for the sustained delivery of hydroxychloroquine (2014)

Chen Y, Traore YL, Li A, Fowke KR, Ho EA. Drug design, development and therapy. 8:1801-15.

Tecophilic thermoplastic polyurethane (TPU) intravaginal rings (IVRs) were investigated for delivery of hydroxychloroquine (HCQ). Matrix and reservoir-type IVRs were fabricated via hot melt injection molding and evaluated for drug release kinetics, stability, and biocompatibility with positive results.

Engineering a segmented dual-reservoir polyurethane intravaginal ring for simultaneous prevention of HIV transmission and unwanted pregnancy (2014)

Clark JT, Clark MR, Shelke NB, Johnson TJ, Smith EM, Andreasen AK, Nebeker JS, Fabian J, Friend DR, Kiser PF. PloS one. 9(3):e88509.

Dual-reservoir intravaginal rings were designed to deliver tenofovir and levonorgestrel. Some sections of the ring were manufactured with thermoplastic polyurethane via coaxial extrusion. Sustained, dose dependent drug release from the ring was achieved in vitro and in vivo for up to 90 days.

Impact of Hydroxychloroquine-Loaded Polyurethane Intravaginal Rings on Lactobacilli (2015)

Traore YL, Chen Y, Bernier AM, Ho EA. Antimicrobial agents and chemotherapy. 59(12):7680-6.

Hydrophilic thermoplastic polyurethane (TPU) intravaginal rings were fabricated using hot-melt injection molding and loaded with hydroxychloroquine (HCQ). The effect on vaginal epithelial cells and microflora was evaluated. The rings successfully released HCQ continuously for a 24-day span and were found to have no adverse effects on vaginal health or lactobacilli when compared to control.

Segmented polyurethane intravaginal rings for the sustained combined delivery of antiretroviral agents dapivirine and tenofovir (2010)

Johnson TJ, Gupta KM, Fabian J, Albright TH, Kiser PF. European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences. 39(4):203-12.

Dual segment polyurethane intravaginal rings (IVRs) were fabricated via hot melt extrusion and solvent casting for the sustained release of antiretroviral agents. This was achieved in vitro for the release of tenofovir over a 30-day period, while dapivirine exhibited linear release over the time period. Accelerated stability studies yielded positive results.

Tenofovir disoproxil fumarate intravaginal ring protects high-dose depot medroxyprogesterone acetate-treated macaques from multiple SHIV exposures (2015)

Smith JM, Srinivasan P, Teller RS, Lo Y, Dinh CT, Kiser PF, Herold BC. Journal of acquired immune deficiency syndromes. 68(1):1-5.

Hydrophilic thermoplastic polyurethane (TPU) intravaginal rings were loaded with tenofovir disoproxil fumarate (TDF) and clinically tested in monkeys in combination with a medroxyprogesterone acetate depot. The monkeys were virally challenged weekly for twelve weeks and the TPU intravaginal rings were found to provide significantly improved protection when compared to placebo.

Thermoplastic polyurethane-based intravaginal rings for prophylaxis and treatment of (recurrent) bacterial vaginosis (2017)

Verstraete G, Vandenbussche L, Kasmi S, Nuhn L, Brouckaert D, Van Renterghem J, Grymonpré W, Vanhoorne V, Coenye T, De Geest BG, De Beer T, Remon JP, Vervaet C. International journal of pharmaceutics. 529(1-2):218-226.

Thermoplastic polyurethane (TPU) intravaginal rings were processed via hot melt extrusion/injection molding in combination with lactic acid or metronidazole. These rings were evaluated for sustained drug release, homogeneous drug distribution within the polymer matrix, irritation potential, biofilm formation, and mechanical properties. Positive results were achieved in many cases, with hydrophobic TPUs found to be suitable for continual release of lactic acid and hydrophilic TPU rings determined to be well suited for metronidazole elution.

Thermoplastic Polyurethanes (TPU) in Drug Delivery Applications