Accelerated optimization of medical protein preparations using differential scanning calorimetry

The therapeutic biomolecule must remain stable in an active native form until it is administered to the patient and delivered to the site of action. The initial screening of biopharmaceuticals to help ensure that further research is focused on the formulations most likely to be used for further drug discovery. Differential Scanning Calorimetry (DSC) can be used to quickly determine the optimal solution conditions for protein formulation stability, to help determine the best candidate formulation and to speed up the development process. This application note describes the Malvern MicroCal DSC technology and its use in formulation development.

Introduction

An earlier decision in the development of biopharmaceuticals was to determine whether the biopharmaceutical would be provided in the form of a liquid or a lyophilized powder. In general, liquid formulations are less expensive to produce and easier to use, but require storage under refrigeration and are less stable. Lyophilized proteins are costly to produce and require dissolution prior to administration to a patient, but they can be stored at room temperature with high stability. Convenient end users are also factors to consider (1, 2). The preparation scientist must determine if the protein in the solution will remain stable for a sufficient period of time, or only to remain stable in lyophilized form.

The protein in the aqueous solution is in an equilibrium state between the native (folded) and denatured (unfolded) conformations. Hydrophobic interaction and hydrogen bonding are the main stabilizing forces and are the forces that must be overcome for protein unfolding and denaturation. The conformational entropy weakens the stabilizing force and thus allows the biopolymer to be unfolded (3). The protein unfolds when heated or denatured chemicals such as sodium lauryl sulfate and guanidine hydrochloride are added to the solution. Denatured proteins are easier (4-7) irreversible chemical processes such as proteolysis (8), oxidation (9) and deamidation (10), which in turn leads to inactivation. Denatured proteins are also more susceptible to polymerization, and polymerization leads to decreased stability and protein breakdown (11-14).

Proteins must be characterized prior to development of the formulation. This includes determining its molecular weight, amino acid composition, three-dimensional structure, presence or absence of disulfide bonds, glycosylation reactions, cofactor requirements, inhibitors, solubility, thermodynamic parameters, functionality, isoelectric point, hydrophobicity, and surface area. All of this information is important for designing the best formulation for the protein. By using a rational drug design approach, bioengineered proteins can also be engineered to maintain maximum stability and maximum efficacy in selected solutions.

The liquid formulation of the protein should help maintain the stability and biological activity of the biopolymer during production, packaging, storage and transportation until it is ultimately delivered to the target site in the patient. Parameters to be considered during formulation development include concentration, presence of additives (auxiliaries), pH, storage temperature, container, and exposure to light, air, and humidity.

Another factor involved in the development of the formulation is the drug delivery mechanism. For example, a biological agent delivered by intravenous injection must be dilutable, and if the protein is not readily soluble, it will precipitate in the patient's blood. In addition, if the drug is injected, the ingredients of the formulation may not cause tissue damage or pain to the patient. Another point to consider is that the surface of the container or device (syringe, pump, etc.) may absorb protein.

Protein stability is typically determined using a variety of analytical methods, including accelerated and real-time stability studies. The extent of polymerization/precipitation, oxidation, protein degradation and/or disulfide rearrangement are also typically assessed. The transport conditions are tested to ensure that the drug does not lose its biological activity when delivered.

Lip Cosmetics

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