Soluble Hydrophobic Core Carrier Compositions for Delivery of Therapeutic Agents, Methods of Making and Using the Same

Abstract

The present invention relates to a soluble hydrophobic-core carrier composition comprising (i) a linear polymeric backbone; (ii) a plurality of hydrophilic polymeric protective chains covalently linked and pendant to the polymeric backbone and (iii) at least one hydrophobic moiety covalently linked and pendant to the polymeric backbone. In certain embodiments, the weight ratio of hydrophilic protective chains to hydrophobic moieties in the carrier is at least 15:1. In other embodiments, at least 90% of the residues of the polymeric backbone are coupled to a hydrophilic polymeric protective chain or a hydrophobic moiety. In other embodiments, the composition further comprises (iv) a hydrophobic load molecule dissociably linked to the hydrophobic moiety of the carrier.

Description

GOVERNMENTAL LICENSE RIGHTS [0001]Work described herein was made in part with government support under 5 R43 DK069727 awarded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The U.S. Government may have certain rights in subject matter provided herein.BACKGROUND OF THE INVENTION [0002]The development of new drugs, formulations and other systems for administration of physiologically active peptides and proteins, and other hydrophobic drugs or therapeutics is driven by the need to achieve the desirable physiological effects. Peptides and proteins have been observed to be unstable in blood and the gastro-intestinal tract and therefore may need to be stabilized or protected prior to delivery and remain protected once in either the gastrointestinal tract or the circulation. Once the active pharmaceutical gets into the systemic circulation, those that have low molecular masses tend to have short biological half-lives due to their efficient removal from sys...

AI Technical Summary

Benefits of technology

[0010]The present invention is directed towards novel drug delivery systems and methods of making and using the same. It is an object of the present invention to provide a delivery system for a therapeutic agent that has a sustained release capability, is safe, biocompatible, readily prepared from known chemistries and compounds, whose release rate can be readily adjusted by simple mechanisms, and is amenable to a wide variety of therapeutic agents such as peptides, proteins and other hydrophobic drugs. The invention provides a novel protected graft co-polymeric carrier with a linear polymeric backbone made up of repeating units (called residues), preferably between 30 to 500 residues, with modifiable functional groups (such as amino, carboxyl, hydroxyl, sulfur, and phosphate), modified in such a way to contain at least one hydrophobic moiety and a plurality of hydrophilic protective groups pendant to the polymeric backbone in a weight ratio that renders the composition soluble in water and size that allows for subcutaneous delivery. The large number of protective groups acts as a shield to protect load molecules from being exposed to the surface of the carrier prior to release by dissociation.

[0011]The invention provides means to deliver hydrophobic peptides, hydrophobic proteins and hydrophobic drugs in patients in a controlled manner without the use of vesicles. Controlled manner means that the level of the active therapeutic molecules in the circulation will neither exceed a toxic level nor drop below the therapeutically effective level for the desired period of time (see FIG. 7). The ability of the carrier of the present invention to release free and active therapeutic agent, or in a broader sense, a “load molecule”, when the level of free load molecule in the circulation goes below the therapeutically effective level may be readily adjusted. The carriers of the present invention may be prepared to have both high loading capacity and adjustable release rates by controlling the length, number and density of hydrophobic moieties in which alkyl chains are more commonly used. Release rate can also be controlled by the size of the carrier. The carriers of the present invention are safe and non-immunogenic due to the presence of multiple non-immunogenic protective chains that shield the more immunogenic core of the carrier.

[0015]In some embodiments the carrier may optionally include a second protective chains covalently linked to the hydrophobic moiety for enhancing solubility or maintaining the hydrophilic protective chains to hydrophobic moieties weight ratio above 15:1, thus preventing vesicle formation and precipitation.

Problems solved by technology

Once the active pharmaceutical gets into the systemic circulation, those that have low molecular masses tend to have short biological half-lives due to their efficient removal from systemic circulation via kidneys.

This strategy is proven efficient in clinical practice but may be impractical for outpatients requiring high levels of mobility, associated disadvantages of quality of life and potential intravenous (I.V.) line infections.

Due to limited volume of these capsules, peptides and proteins are often used in a concentrated formulation which leads to a loss of solubility due to aggregation and potential loss of specific activity.

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