Pasireotide Pre-formulation Sustained Release
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Solution Overview
Problem
Current peptide delivery systems face challenges such as poor bioavailability due to rapid degradation in biological fluids, limited permeability across membranes, and undesirable 'burst' release profiles, which lead to discomfort, irritation, and the need for frequent administration, especially for peptides like pasireotide that require stable plasma concentrations.
Innovation Solution
A pre-formulation comprising diacyl glycerol, phosphatidyl choline, a biocompatible organic mono-alcoholic solvent, a polar solvent, and pasireotide, formulated in a low viscosity phase that forms a non-lamellar liquid crystalline structure upon contact with aqueous fluids, allowing for controlled and sustained release with minimal initial burst and reduced irritation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional peptide delivery systems are used, then peptides can be administered, but rapid degradation in biological fluids causes poor bioavailability and requires frequent administration
Solution Approach 1:
The peptide is pre-loaded into a delivery vehicle (liposome, micelle, or polymeric nanoparticle) before administration. This preliminary encapsulation protects the peptide from degradation in biological fluids, allowing it to maintain stability and bioavailability throughout the desired release period, thereby reducing administration frequency
Solution Approach 2:
The formulation utilizes phase transition of the delivery vehicle materials (e.g., lipid phase transitions in liposomes or polymer crystallization transitions) to control peptide release kinetics. This enables sustained release over extended periods while protecting the peptide from premature degradation, improving both bioavailability and duration of action
2Reliability
If high concentration of peptide is administered to maintain therapeutic levels, then therapeutic effect is improved, but undesirable or dangerous effects occur above upper concentration levels
Solution Approach 1:
The delivery system provides periodic or pulsatile release of the peptide at controlled concentrations that remain within the therapeutic window. By releasing the peptide in controlled amounts over time rather than as a single high concentration dose, the system maintains therapeutic efficacy while avoiding toxic side effects
Solution Approach 2:
The formulation changes the concentration parameter of peptide delivery by using a reservoir system that maintains steady-state concentrations within the functional window. The controlled release mechanism adjusts the effective concentration over time, preventing both sub-therapeutic and toxic levels, thereby improving reliability while minimizing harmful effects
3Duration of action of moving object
If polymeric dosing systems are used for controlled release, then sustained delivery is achieved, but a sizable needle (20-gauge or wider) is required for administration
Solution Approach 1:
The delivery vehicle utilizes porous or semi-permeable membranes (e.g., lipid bilayers in liposomes or porous polymeric matrices) that allow controlled diffusion of the peptide. This porous structure enables sustained release through diffusion gradients while maintaining a compact, injectable formulation that can be administered through smaller gauge needles
Solution Approach 2:
The formulation changes the physical state and size parameters of the delivery system by using nano-sized particles or vesicles instead of large polymeric implants. These nanoscale dimensions allow administration through small gauge needles while maintaining sustained release capabilities through controlled diffusion and degradation mechanisms
4Reliability
If frequent administration is required to maintain therapeutic levels, then therapeutic effect is maintained, but patient convenience decreases and compliance worsens
Solution Approach 1:
The peptide is pre-loaded into a long-acting delivery vehicle that provides sustained release over weeks or months. This preliminary preparation eliminates the need for frequent patient administrations, significantly improving convenience and compliance while maintaining reliable therapeutic effects through controlled release
Solution Approach 2:
The delivery system provides self-regulated, sustained release of the peptide over an extended period without requiring repeated patient intervention. The formulation automatically maintains therapeutic levels through its built-in release mechanism, improving both reliability of therapeutic effect and ease of operation for the patient
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The formulation enables a stable, prolonged release of pasireotide with a flat plasma concentration profile, reducing discomfort and irritation, and allowing for self-administration through a narrow needle, while maintaining therapeutic levels for extended periods with improved manufacturing ease and storage stability.
Implementation Method 1
which undergo phase transition upon exposure to aqueous fluids, such as body fluids, thereby forming a controlled release composition
Implementation Method 2
forms a non-lamellar liquid crystalline structure upon contact with aqueous fluids
Implementation Method 3
high-loading pre-formulations of amphiphilic components and at least one peptide active agent comprising pasireotide
Data Source
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AI summary
The present invention relates to compositions forming a low viscosity mixture of: a) 20-50 wt.% of at least one diacyl glycerol; b) 20-54 wt.% of at least one phosphatidyl choline (PC); c) 5-15wt.% of at least one biocompatible, organic mono-alcoholic solvent; d) 1 to 20 wt.% polar solvent e) 5 to 150 mg/ml of at least one peptide somatostatin receptor agonist comprising pasireotide; f) optionally at least one antioxidant; wherein the ratio of components a:b is in the range 40:60 to 54:46; wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with excess aqueous fluid. The invention further relates to methods of treatment comprising administration of such compositions, and to pre-filled administration devices and kits containing the formulations.