A novel molecular delivery system is proposed featuring complexation of organic molecules with Hyaluronic Acid.
Enhanced delivery could add significant value to many pharmaceutical products.
The concept offers the following advantages:
§ Hyaluronic acid molecular complexes are effectively created using different mechano-chemical methods (e.g., extrusion and other) instead of covalent chemical modification.
§ Rapid regulatory approval is expected per 505(b)(2) type submission based on the known API, because the components of the hyaluronic acid complexes are bound non-covalently.
§ Hyaluronic acid is natural, non-toxic, non-allergic and benign.
§ Expedited drug delivery may be achieved due in part to the hyaluronic acid receptors (CD44 and RHAMM) expression in specific organs and tissues, and over-expression in cancer cells.
§ Without structural limitations for the organic molecule, the concept of using hyaluronic acid for delivery may be extended to novel classes of organic molecules, such as peptides and proteins.
Preliminary Results (2012-2017): proof-of-concept was pursued using twelve molecular complexes of hyaluronic acid and anti-cancer drugs, which were created using mechanical extrusion methods.
Hyaluronic acid complexes exhibited improved solubility and efficacy in two different in-vitro assays. Three hyaluronic acid complexes containing the anti-cancer drugs Raloxifene, Letrozole and Irinotecan were pursued for further development.
Physical-chemical methods confirmed quantitative recovery of the drug component from the complexes. After oral dosage, hyaluronic acid - Raloxifene complexes gave four times higher drug concentrations in plasma (Cmax,) compared to neat Raloxifene at the same Tmax. Similarly, hyaluronic acid - Letrozole gave three times higher drug concentrations in plasma.
Toxicological study following oral administration in rats showed all three hyaluronic acid - drug complexes to exhibit extremely low toxicity, without adverse side effects after Maximum Feasible Dose. Notably, Maximum Tolerated Dose was not reached.
Hyaluronic acid - drug complex efficacy was compared to neat drug in mice bearing specific human cancer xenograft and untreated animals. After 20 oral administrations over 4 weeks, tumor growth was significantly lower in groups receiving Hyaluronic acid - Raloxifene and Hyaluronic acid - Letrozole complexes compared to control groups.
Publication: Kirill I. Shingel, Mikhail Selyanin, Mario C. Filion, Felix Polyak, “Solid dispersions of drugs in hyaluronan matrix: The role of the biopolymer in modulating drug activity in vivo.” Journal Of Drug Delivery Science and Technology, 2017, 39, pp.140 – 146.
Patent applications:
· COMPLEXES COMPRISING A CARBOHYDRATE POLYMER AND AN ACTIVE INGREDIENT AND PROCESSES FOR THEIR PREPARATION
U.S. Provisional Patent application No. 63/060.360
· BIOAVAILABILITY AND SOLUBILITY TECHNOLOGY WITH TARGETED DELIVERY OF ORGANIC MOLECULES
U.S. Patent Application N°62/947,919
Present state:
§ Hyaluronic acid - drug complex synthesis is effective by mechanical methods
§ Quantitative recovery of drugs from hyaluronic acid - drug complex
§ Hyaluronic acid - drug complexes improved physical-chemical properties (e.g., solubility)
§ Hyaluronic acid - drug complexes improved pharmacokinetic properties (e.g., bioavailability, oral delivery)
§ Hyaluronic acid - drug complexes have extremely low toxicity after oral delivery
§ Hyaluronic acid - drug complexes exhibited better efficacy in human cancer xenograft model
Future prospective and milestones:
§ Preparation of hyaluronic acid - drug complexes using alternative physical method to improve patent potential and achieve more significant results
§ Preparation of hyaluronic acid - drug complexes with high commercial value: e.g., peptides
§ Explore potential to use hyaluronic acid - drug complexes for oral delivery instead of injection for other drug classes
§ Perform preclinical studies on select hyaluronic acid - drug complexes for IND submission.