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

[0007] It was surprisingly discovered that injectable biodegradable polymeric compositions comprising peptide agents in the form of a salt formed with a strong acid (e.g., hydrochloric acid) exhibit much higher stability than those in the form of a salt formed with a weak acid (e.g., acetic acid) or in the form of the free base. Such beneficial salts of peptide agents may be formed through the neutralization of any basic groups of the peptide agents with a strong acid. When such beneficial salts of peptide agents formed with a strong acid were formulated into injectable biodegradable polymeric compositions, the interactions / reactions between the peptide agents and the polymer are minimized or prevented. Using such beneficial salts of peptide agents formed with a strong acid allows for the preparation of a stabilized injectable composition pre-filled in a single syringe in a ready-to-use configuration with satisfactory storage stability. The use of the salt of peptide agent formed with a strong acid of the present invention to enhance the stability of the injectable polymeric compositions is not contemplated by the prior art.

[0008] Accordingly, the present invention provides a stabilized injectable biodegradable polymeric composition for forming an economical, practical, and efficient controlled release delivery system for peptide agents. The present invention also provides a method of manufacturing and a method of use thereof. According to the present invention, the drug delivery system is produced easily and delivered conveniently to a subject such as a mammal or human. The compositions deliver therapeutic amount of peptide agents over a desired, extended period of time, preferably from several weeks to one year. The compositions are both biocompatible and biodegradable, and disappear harmlessly after delivering the dose of the peptide agents.

[0009] The compositions in accordance with 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. According to the invention, the pharmaceutical composition may optionally include excipients to achieve optimal delivery of the peptide agent. The pharmaceutical composition may be a viscous or non-viscous liquid, gel or semisolid that moves as a fluid so that it may be injected using a syringe. The pharmaceutical composition may be pre-filled into one syringe to form a product in a ready-to-use configuration.

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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