Pharmaceutical compositions with enhanced stability

Abstract

The present invention provides for a stabilized biodegradable polymeric composition useful as a controlled release delivery system for peptide agents. The compositions of the present invention comprise a) a beneficial salt of a peptide agent formed with a strong acid that minimizes or prevents the interaction / reaction between the peptide agent and the polymer in an organic solution; b) a biodegradable polymer; c) a pharmaceutically acceptable organic solvent; and d) optionally one or more excipients. The present invention also relates to a method of manufacturing and a method of use thereof.

Description

BACKGROUND OF THE INVENTION [0001] In recent years, a large number and variety of peptide agents such as peptides, oligopeptides, polypeptides, and proteins have been discovered and have received much attention as drug candidates. However, many peptide agents are not stable as they are easily hydrolyzed or degraded in vivo by enzymes resulting in a very short circulation half-life. Therefore, most of peptide medicines have been administered by injection, typically multiple times per day. [0002] Injection administration, however, is painful, very costly, and inconvenient. Often, the patient compliance is very challenging. For many peptide agents, particularly hormones, it requires the drug to be delivered continuously at a controlled rate over a long period of time, and thus a controlled release delivery system is desirable. Such systems may be provided by incorporating the peptide agents in biodegradable and biocompatible polymer matrices. In one approach the polymer is dissolved in...

AI Technical Summary

Benefits of technology

The present invention provides a stable injectable biodegradable polymeric composition for forming a controlled release delivery system for peptide agents. The composition is pre-filled in a single syringe in a ready-to-use configuration, and contains a beneficial salt of a peptide agent formed with a strong acid. The use of a strong acid helps to minimize interactions between the peptide agent and the polymer, resulting in enhanced stability of the composition. The composition is biodegradable, safe, and can provide therapeutic amounts of peptide agents over a desired period of time. The peptide agent can have an N-terminus that is not a primary amine, and can be modified with hydrophilic and lipophilic moieties. The strong acid can be any acid with a pKa in water less than 3, such as hydrochloric acid, hydrobromic acid, sulfuric acid, and the like. The biodegradable polymer can be any biocompatible and pharmaceutically acceptable polymer, such as polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyurethanes, polyesteramides, polyorthoesters, polycarbonates, polyacetals, polyketals, polycarbonates, polyphosphaz, and the like.

Problems solved by technology

However, many peptide agents are not stable as they are easily hydrolyzed or degraded in vivo by enzymes resulting in a very short circulation half-life.

Injection administration, however, is painful, very costly, and inconvenient.

Often, the patient compliance is very challenging.

Although these products appear to be effective, but they have drawbacks and limitations, such as the large volume of suspending fluids for microparticles or surgical insertion of solid implants.

These products are not very patient friendly.

In addition, the manufacturing processes for producing sterile and reproducible products are complicated, resulting in high cost of manufacturing.

Notwithstanding some success, those methods have not been entirely satisfactory for a large number of peptide agents that may be effectively delivered by such an approach.

Since the controlled release delivery system is commonly fabricated through a step that involves dissolving / dispersing peptide agent into biodegradable polymer solution in an organic solvent, the stabilization of all the components in the composition at this step represents a very significant formulation challenge.

However, because of the viscous nature of the polymer formulations, it is often difficult to mix the contents in two separated syringes by end users.

The uniformity of the formulations prepared by the end-user may vary significantly where contamination may also occur and the quality of the treatment can be compromised significantly.

In addition, this approach will not prevent the interaction between the peptide agent and polymer during mixing and administration.

This modification of the peptide may lead to a significant loss of activity or change of immunogenicity.

This fast degradation of the peptide and polymer will alter the release profile of the peptide and result in a compromised treatment outcome.

Therefore, precise control for the preparation process and time is critical and this significantly increases the difficulty for end-user.

Furthermore, the in vivo formation of the implant from the injectable polymeric composition is not instantaneous.

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