(W1130-07-39) A Solvent Free Thermo-Sensitive Gel Using Bioresorbable Polymers for Sustained Delivery of Biologic APIs

Purpose: Bioresorbable polymers critically contribute to the quality attributes of sustained-release injectable formulations, such as controlling release, reducing burst release, and extending stability. Polylactic-co-glycolic acid (PLGA) is a commonly used matrix for release of active pharmaceutical ingredients (API) over sustained periods and is generally well tolerated in vivo. However, many novel compounds, such as biologics, are sensitive to the solvents required in preparation methods commonly used in biodegradable sustained-release formulations, while also being poorly soluble in organic solvents. Therefore, understanding the properties of aqueous polymer solutions exhibiting thermo-responsive gelling while controlling release is crucial for the success of an aqueous based delivery system.

Methods: In this study Viatel^TM triblock copolymers (Ashland Specialty Ingredients) consisting of PLGA, and polyethylene glycol (PEG) in the sequence of PLGA-PEG-PLGA was designed for its aqueous solubility. Their thermal attributes were examined at various polymer concentration, and release of a model compound from their aqueous matrix was evaluated. Polymer solutions of 15% w/w, 20% w/w, 25% w/w, and 30% w/w were prepared using a Thinky ® AR-100 mixer (Thinky USA). Polymer solutions obtained were analyzed using Discovery Hybrid Rheometer (DHR-3) with Peltier stage for rheology data. Shaker bathes were used to evaluate in vitro dissolution at 37^oC. HPLC was used for potency and stability analyses, and Instron to evaluate the flow characteristics of the polymer solutions through syringes as well as PTFE sterilizing filters (0.2 µm).

Results: Rheometric and visual inversion data demonstrate phase transition from solution to gel as temperature approached physiological in solutions containing 15-30% w/w triblock PLGA/PEG. While transition temperatures retained in the physiological range (30-37 ^oC) for all tested samples with different polymer concentrations, the storage modulus intensity significantly increased with increasing polymer concentration. Instron mechanical analysis showed dynamic glide forced and breakaway forces ranging from 1.3-2.8 N and 1-2 N respectively as polymer concentration increased while still being able to be sterile filtered and passed through needles up to 33G for all concentrations of PLGA/ PEG triblock copolymer tested, with polymer solutions up to 25% w/w being able to pass through a 33G unblocked. Using in vitro release via shaker bath and HPLC, sustained release over the course of 11 days has been demonstrated yielding a cumulative release of 98.5% of the 20 mg insulin loaded into the biodegradable matrix while exhibiting little burst release. Lastly stability of insulin encapsulated within the PLGA/PEG matrix was observed at reduced temperatures over the course of 6 weeks as detailed by HPLC analysis of assay and impurities. Insulin contained within a 30% w/w polymer solution in PBS stored at 5 ^oC and -20 ^oC demonstrated a purity of 96.31% and 98.43% respectively after storage for 6 weeks. Insulin stored within a 30% w/w polymer solution in PBS at 25 ^oC experienced a drastic purity loss over the same period.

Conclusion: The examination of PLGA / PEG triblock copolymers as an organic-solvent free sustained drug delivery platform highlighted numerous desirable characteristics required for controlled release of sensitive or hydrophilic APIs in a bioresorbable system. Gelling strengths driven by polymer concentration can be used to guide release rates while having minimal impact on API stability when stored below ambient temperatures. These factors plus ease of sterile filtering the polymer / API solution prior to injection make this technology attractive for sustained drug delivery.


Figure 1: Rheological data of PLGA triblock polymer in PBS Showing solution to gel transitions. 30% polymer by weight (blue), 25% polymer by weight (green), 20% polymer by weight (Red), 15% polymer by weight (pink).


Figure 2: In Vitro Release of insulin from 30% w/w at 37C, no shaking. Error bars are present.


Figure 3: Insulin Purity within a 30% w/w polymer solution, as shown by HPLC over 6 weeks. 5C (Left), 25C (Middle), and -20C (Right).