I-novion’s proprietary PTSgel and PTSsol pentablock copolymer drug delivery technology platform creates sustained release formulations of proteins, peptides, antibodies, vaccines, siRNA and other biologic agents, as well as small molecules. PTSgels and PTSsols are synthesized through the sequential coupling of five biocompatible/biodegradable polymer blocks selected from among polyglycolide (PGA), polylactide (PLA), polycaprolactone (PCL) and polyethylene glycol (PEG). These building blocks may be coupled in a variety of sequences to address requirements defined by, e.g., molecular weight, length, backbone structure, side chains and crystallinity.

Compositions may include thermosensitive gels (PTSgel) or drug-loaded microparticles. For the time being, i-novion’s focus are PTSgels, which are liquid at ambient temperatures and progressively transform into a gel as the temperature increases to 37⁰ C, making it suitable for subcutaneous, intramuscular or intra-articular injection via a ≥27-gauge needle.

To illustrate the physicochemical behavior, a PTSgel solution kept at room temperature has been injected intracamerally via a 31-gauge hypodermic needle into the eye of a New Zealand White rabbit (please click on the video below). For topical application of ophthalmic medications to the eye in the form of eye drops, or dermal sprays, compositions can be made to prepare clear, stable drug solutions that remain liquid at body temperature and still extend the residence time of the active ingredient (PTSsols).


Figure 1: PTSgels can be pushed easily through a narrow gauge needle (such as 31g in the video above), and, at body temperature, rapidly forms a gel.

 

PTSgel compositions can be designed to produce a wide range of delivery rates. Their sustained delivery properties have been demonstrated both in vitro and in vivo, the latter with a model IgG labelled for near-infrared detection through the skin of laboratory animals (Schaefer, et al 2016).  For IgG,  a good correlation between in vitro and in vivo release rates has been demonstrated, allowing for initial screening to be conducted using cost-effective in vitro testing. I-novion has a mini-library of PTSgels for use in initial screening. Suitable leads can then be further tailored to the respective active ingredient.


Figure 2: in vivo release of model antibody (NIR-labelled IgG) after S.C. injection in mice. Intensity blue = high, green = medium, red = low, (Schaefer, et al 2016). The antibody in saline has completely cleared from the subcutaneous depot after one day, while the antibody in PTSgel remains in the subcutaneous depot through day 40. These in vivo results correlate well with the in vitro data.

 

Figure 3: in vivo release of model antibody (NIR-labelled IgG) after intercameral injection in mice. Intensity blue = high, green = medium, red = low, (Schaefer, et al 2016). The antibody in saline has completely cleared from the subcutaneous depot after one day, while the antibody in PTSgel remains in the intracameral depot through day 28. These in vivo results correlate well with the in vitro data.

 

Figure 4: Structural integrity of the antibody is maintained through the end of the release period (Day 28) as demonstrated by non-reducing (left panel) and reducing (right panel) gel electrophoresis (SDS-PAGE) and size-exclusion high performance liquid chromatography (SE-HPLC). Independently, we have demonstrated that the biological activity of the antibody is fully maintained through the end of release (data not shown).

 

Figure 5: Injection of PTSgel into the anterior chamber of the rabbit eye (50 μL of 20% 10GH PTSgel, 31G syringe). The gel and its rate of breakdown can be observed visually. At Day 28, little remaining gel can be seen, indicating absorption roughly in parallel to drug release.

 

Figure 6: Topical PTSsol formulations can provide extended topical drug delivery to the eye, as shown below. These in vivo spectroscopic images of near infrared-labeled IgG (NIR-IgG) compositions show drug present on the ocular surface as long as 21 hours following application to the mouse eye.

 

References
Schaefer E, Abbaraju S, Walsh M, Newman D, Salmon J, Amin R, Weiss S, Grau U, Velagaleti P, Gilger B. Sustained Release of Protein Therapeutics from Subcutaneous Thermosensitive Biocompatible and Biodegradable Pentablock Copolymers (PTSgels). J Drug Deliv. 2016;2016:2407459. Epub 2016 Oct 5.

Schaefer E, Smith SM, Salmon J, Abbaraju S, Amin R, Weiss S, Grau U, Velagaleti P, Gilger B. Evaluation of Intracameral Pentablock Copolymer Thermosensitive Gel for Sustained Drug Delivery to the Anterior Chamber of the Eye. J Ocul Pharmacol Ther. 2017 Jun;33(5):353-360
 
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