Re: Surmodics presentations at ARVO 2007
There are 5, some look very interesting... notice the emphasis of subretinal technology:
1) Hydrophobic Biodegradable Polysaccharide Devices for Controlled Drug Delivery
Looks like SRDX is tring to develop a biodegradable implant for TA (or other hydrophobic small molecule drug), possibly for subretinal use but perhaps also this could be fabricated into an I-Vation like screw that does not need to be removed (this would be a nice feature if it is mechanically feasible). Based on the composition, this sounds like a hybrid of Eureka and PEG (The polymer Novocell licenses from SRDX is made from PEG). This one may last up to a year.
Purpose: Evaluate a hydrophobic biodegradable polysaccharide device capable of delivering pharmaceutical agents in a controlled manner in an in vitro model.
Methods: Biodegradable devices comprised of a hydrophobically modified polysaccharide (h-PS), 40-50% w/w; polyethylene glycol (PEG), 20 kD average molecular weight, 0-10%; and triamcinolone acetonide (TA), 50% w/w; were fabricated by a solventless extrusion process. Materials were fed in dry powder or pellet form to an extruder which uniformly mixed the components at a temperature sufficient to melt the polymeric materials but not the TA. The resulting mixture was forced through a heated die and elongated into a 500 micrometer diameter cylindrical shape. The cooled extrudate was cut to 5 millimeter lengths to form devices with a total mass of 1 mg.
Elution of the TA was determined by repeated exchanges of 4 ml phosphate buffered saline, pH 7.4, agitated and maintained at 37oC, at appropriate time intervals. Concentration of TA at each time point was quantified by UV-vis spectroscopy. Content and purity of TA in devices was determined by extracting TA with tetrahydrofuran and assaying via HPLC. Solid form of TA was confirmed by X-ray powder diffraction.
Results: Tunability of TA elution rate from 0.1 to 5.0 μg/day was demonstrated by varying device formulation. See Figure 1. 95-105% of the TA was recovered from assayed devices and the impurities profile was unchanged. Crystalline polymorphic form of the TA was not altered. Devices were implanted into cadaveric porcine eyes via a minimally invasive technique, and were found to have appropriate mechanical integrity.
Conclusions: A device has been developed that provides controlled release of TA. Extrapolation of elution data predicts release will last longer than 1 year in some cases. The device may be fabricated into a shape and size suitable for minimally invasive implantation
2)Safety and Pharmacokinetics of a Sustained Release Triamcinolone Implant in the Subretinal Space of the Rabbit Eye
This work is based on subretinal rods composed of the durable Bravo polymer (PEVA/PBMA), which makes it less interesting IMHO. However, extrapolation of the data suggests elution of TA for up to 5 years, which is a very long time indeed!
Purpose: To evaluate the safety and pharmacokinetics of a subretinal triamcinolone drug delivery implant in rabbit eyes.
Methods: Subretinal implants 3.5 mm in length and 350 μm in diameter were developed using a fine 100 μm diameter wire scaffold coated with a non-biodegradable poly(n-butyl methacrylate) and polyethylene vinyl acetate polymer matrix containing triamcinolone acetonide (TA). Two formulations were developed, Dose 1 (100 μg TA) and Dose 2 (175 μg TA). Dose 1, Dose 2, and Control (no drug) test articles were implanted into the subretinal space of Dutch Belted rabbits. The implants were introduced transvitreally through a 20 gauge sclerotomy. A partial vitrectomy was performed adjacent to the implant site. A small volume of BSS was injected beneath the retina through a 39 gauge flexible cannula, creating a limited dome-shaped retinal detachment. Using micro-forceps, the implant was deployed into this fluid space and released. At sacrifice intervals of 1 week, 1 month, and 3 months, 8 test articles each of Dose 1 and Dose 2 were explanted, examined by SEM, and assayed for remaining drug content by HPLC. At 1 month, 4 eyes for each treatment group were additionally prepared for histological evaluation. In parallel, in vitro drug elution was monitored in PBS buffer at 37°C.
Results: In vitro steady state elution rates of triamcinolone were approximately 0.03 μg/day and 0.50 μg/day for Dose 1 and Dose 2, respectively. Of the 30 implanted animals, all remained in good general health throughout the study. Follow-up clinical examinations reflected good biocompatibility. Based upon drug content of the explanted test articles, dose separation was preserved in vivo. The average elution rate in vivo between 1 and 3 months was calculated to be 0.04 μg/day for Dose 1 and 0.5 μg/day for Dose 2. At 3 months, 88% and 39% of the drug payload still remained on the Dose 1 and Dose 2 implants, respectively. Extrapolation of these elution rates to longer timepoints suggests an achievable release duration of approximately 5 years with the 0.04 μg/day device.. Examination by SEM revealed the explanted coatings for Dose 1 had a slight bumpy surface texture with occasional holes in the coating that ranged in size from 20 μm to 50 μm. For, Dose 2 the overall appearance of the explanted coatings was relatively smooth with a slightly bumpy surface texture.
Conclusions: An implantable system has been developed which provides local therapeutic delivery to the subretinal space. This system appears well tolerated in the rabbit eye and is capable of long-term sustained delivery.
3) Biodegradable Polysaccharide Devices for the Controlled Delivery of Bioactive Agents
Sounds like a Eureka-type polymer is being groomed for theraputic proteins such as Lucentis
Purpose: Evaluate feasibility of an enzymatically-controlled degradable polysaccharide matrix system for sustained, controlled release of bioactive proteins in the vitreous.
Methods: Rod-shaped devices 5 mm in length and 0.5 mm in diameter were formed using modified, low molecular weight polysaccharides (PS) and incorporating known amounts of a 49 kD rabbit-anti-goat antibody fragment [f(ab)] as a model protein. Devices containing f(ab) [PS Formulation 1, with 53 ug of f(ab); PS Formulation 2 with 73 ug f(ab)] were implanted in the vitreous of Dutch-belted rabbit eyes. At 7, 28, and 56 days, the devices were explanted and assayed for remaining active and total f(ab) using ELISA. Vitreous samples at these timepoints were similarly assayed via ELISA for active f(ab).
Results: Of the 29 implanted animals, all remained in good general health throughout the study. Follow-up clinical examinations reflected good biocompatibility tolerance. Following enucleation, the devices were removed from the eyes either fully intact, or in smaller, multiple pieces. Explantated Formulation 1 devices showed an average f(ab) activity (active f(ab)/total f(ab)) of 76, 71, and 86% at day 7, 28, and 56 timepoints, respectively, while Formulation 2 devices showed f(ab) activity of 76% at days 7 and 28. No f(ab) was detected in the explanted devices at day 56 for Formulation 2. Mass-loss calculations on day 56 explants showed Formulation 1 lost approximately 63% of the device mass, while Formulation 2 lost approximately 80% of the device mass. Average active f(ab) detected in the vitreous for the Formulation 1 group was 1.6, 1.3 and 0.1 ug/g, and 2.2, 0.95, and 0.2 ug/g for the Formulation 2 group at days 7, 28, and 56 respectively.
Conclusions: It is possible to form devices from modified, low molecular weight polysaccharides that have sufficient density to inhibit the diffusion of entrained proteins through the matrix and exclude digesting enzymes from penetrating the matrix. The polysaccharide devices were demonstrated to be safe and well tolerated in this study. The implanted devices showed sustained delivery of substantial active f(ab) molecule into the vitreous at each timepoint, while the remaining f(ab) in the explanted devices remained stable at each timepoint, as demonstrated by the high % retained activity.
4) Sustained Delivery of Bioactive Protein With the I-Vation Intravitreal Implant
This if one of the durable/biodegradable hybrid polymers that SRDX has been talking about -- a very nice idea IMHO. Such a device might deliver Lucentis from an I-Vation type coil.
Purpose: Demonstrate feasibility of a novel durable matrix system for sustained delivery of a bioactive protein in the rabbit eye
Methods: A model protein, Rabbit anti Goat F(ab) fragment, was used to study the activity and controlled delivery of the protein from a novel durable matrix. An ultrasonic spray method was used to mix hydrophobic polymers with the F(ab) fragment to deposit 300 ug F(ab) onto a coating on the helical I-vationTM intravitreal implant. The polymer coating used in the study consisted of a blend of durable polymers and degradable (poly)ethylene glycol (PEG)-containing polymers. All polymers used have extensive biocompatibility records. Two ultrasonic deposition techniques were utilized (Method 1 and Method 2). Once coated, the implants were implanted into the vitreous of rabbit eyes through a 25 gauge needlestick and removed at 1 and 4 weeks. Using an ELISA method, the concentration of protein and the protein activity were measured in the explanted test articles, choroid, retina, and vitreous. A parallel in vitro study was conducted in which coated coils eluted in buffer (PBS + 0.2% BSA) at 37 0C. The amount of total and active protein eluting was assayed by ELISA at regular time intervals.
Results: Upon explantation all polymer coatings maintained mechanical integrity. No damage, cracking or delamination of the coating was observed at either time point. Of the 16 implanted animals, all remained in good health throughout the study. A significant difference in the elution profile was observed between the two formulations. In vitro elution results of Method 2 exhibited a 72% protein burst over 3 days followed by a slower sustained release. The tissue concentrations of active protein with this formulation were 9581 ng/g vitreous, 2.97 ng/mg choroid and 6.4 ng/mg retina at week 1 and 5914 ng/g vitreous, 19.04 ng/mg choroid and 8.9 ng/mg retina at week 4. In vitro results of Method 1 exhibited a zero order release profile with 90% protein activity for more than 70 days. The tissue concentrations of active protein detected with this formulation were 52.7 ng/g vitreous, 0.23 ng/mg choroid and 0.041 ng/mg retina at week 1 and 91.1 ng/g vitreous, 5.2 ng/mg choroid and 0.11 ng/mg retina at week 4.
Conclusions: The coating techniques utilized with the I-vation™ implant exhibit excellent in vivo mechanical properties. Implants coated with Method 1 demonstrated controlled release of active F(ab) for more than 28 days studied in vivo and more than 70 days studied in vitro. The processing technique used in Method 1 results in sustained release maintaining a high % protein activity.
5) Clinical Safety and Preliminary Efficacy of an Intravitreal Triamcinolone Implant (I-vationTM TA) in DME]
More color on the I-Vation clinical trial.
Purpose: A prospective, randomized, double-masked, multi-center study is being conducted to evaluate 30 patients with Diabetic Macular Edema following implantation of I-vation TA.
Methods: The I-vation Sustained Release Drug Delivery System was designed to provide controlled delivery of therapeutics to the back of the eye in a platform that balances minimally invasive implantation, duration, and retrievability. Its unique coiled geometry allows for implantation through a 25 gauge transscleral needlestick, while maximizing the surface area available for drug delivery. The platform is comprised of a metallic backbone and is coated with a polymer/drug matrix. I-vation TA is capable of delivering triamcinolone acetonide into the vitreous for up to 2 years. Patients were randomized to either a slow-release or fast-release formulation, each containing 925 μg triamcinolone. Patients were stratified by baseline visual acuity and presence or absence of prior laser treatment. The implant was anchored against the eye wall without sutures.
Results: At 6 months, mean IOP increased in the study eye from 13.9 mmHg at screening to 16.1 mmHg in the slow group, and from 14.3 mmHg at screening to 16.4 mmHg in the fast group. In the fellow eye, mean IOP remained unchanged. BCVA improved over the course of the study to the time of the interim analysis. From screening to 6 months, the proportion of subjects with BCVA of at least 70 ETDRS letters with the study eye increased from 14% to 46% in the slow group and from 18% to 41% in the fast group. A gain of more than 15 letters in the study eye by 6 months was reported for 8% of subjects in the slow group and 18% in the fast group. Improvement of any degree at 6 months was reported for 85% and 76% of subjects in the slow group and fast group, respectively. Mean macular thickness in the study eye, as measured as the center foveal minimum by OCT, decreased in the slow group from 529 μm at screening to 364 μm at 6 months, and in the fast group from 376 μm at screening to 230 μm at 6 months. A decrease of at least 50 um at 6 months was reported for 62% of subjects in the slow group and 65% of subjects in the fast group.
Conclusions: Results of the 6-month interim analysis suggest that both the slow-release and the fast-release formulations of I-vation TA are well tolerated as evaluated by the occurrence of adverse events and IOP. Both formulations also appear to be associated with improvements in BCVA and macular thickness.
AI
