Macromolecules formulation stability

Poor Formulation Stability for Macromolecules existing aerosol systems are not designed to protect the formulations of delicate macromolecules. 

Many drugs are administered as parenterals for speed of action because the patient is unable to take oral medication or because the drug is a macromolecule such as a protein that is unable to be orally absorbed intact due to stability and permeability issues. The U.S. Pharmacopoeia defines parenteral articles as preparations intended for injection through the skin or other external boundary tissue, rather than through the alimentary canal. They include intravenous, intramuscular, or subcutaneous injections. Intravenous injections are classified as small volume (<100 mL per container) or large volume (>100 mL per container) injections. The majority of parenteral dosage forms are supplied as ready-to-use solutions or reconstituted into solutions prior to administration. Suspension formulations may also be used,101 although their use is more limited to a subcutaneous (i.e., Novolin Penfill NOVO Nordisk) or intramuscular (i.e., Sandostatin LAR Depot Novartis) injection. Intravenous use of disperse systems is possible but limited (i.e., Doxil Injection Ortho Biotec). 

Polymer brushes were found to minimize adsorption of proteins by the soft or steric repulsion of the flexible yet immobihzed macromolecules [179], although a generally valid explanation of the protein resistant properties of some hydrophihc brushes is not available. A similar explanation can be formulated for the improvement of the colloidal stability of particle suspensions, when polymer brush-type layers are bound to small particles. This and other intriguing features of polymer brushes prompted a remarkable experimental and theoretical research activity in order to understand and exploit the unique properties of polymer brushes. 

The impact of formulation on protein absorption and disposition is also an important factor in the development and use of biologic molecules. Stability of the protein drug in subcutaneous or muscle tissues and absorption rates directly influence the overall response. Various physical and chemical approaches are used to stabilize proteins and other macromolecules as a part of optimizing dosage formulations. 

Specific formulation strategies need to be employed for macromolecule compounds. An excellent review of protein stability in aqueous solutions has been published by Chi et al. (92). In addition to solution stability of proteins and peptides, aerosolization may result in significant surface interfacial destabilization of these compounds if no additional stabilization excipients are added. This is due to the fact that protein molecules are also surface active and adsorb at interfaces. The surface tension forces at interfaces perturb protein structure and often result in aggregation (92). Surfactants inhibit interface-induced aggregation by limiting the extent of protein adsorption (92). 

Abstract The major enzymatic barrier to the absorption of macromolecules, particularly therapeutic peptides, is the pancreatic enzymes the peptidases, nucleases, lipases and esterases that are secreted in considerable quantities into the intestinal lumen and rapidly hydrolyse macromolecules and lipids. In the case of the peptidases, they work in a co-ordinated fashion, whereby the action of the pancreatic enzymes is augmented by those in the brush borders of the intestinal cells. The sloughing-off of mucosal cells into the lumen also furnishes a mixture of enzymes that are a threat to macromolecules. As the specificity and activity of the enzymes are not always predictable, during pharmaceutical development it is important to test the stability of therapeutic macromolecules, and novel macromolecular-containing or lipid-containing formulations, in the presence of mixtures of pancreatic enzymes and bile salts, or in animal intestinal washouts or ideally, aspirates of human intestinal contents. 

Strategies for In Vitro Testing of the Stability of Therapeutic Macromolecules and Macromolecular Formulations... 

Therefore, another possibility in animal studies is to wash out the upper jejunum with a small volume of bicarbonate buffer, and use this fluid as a medium to determine the stability of a test macromolecule or formulation. A similar approach can be used to study enzyme activities in the colon in animals. It should be noted that the preparations should not be centrifuged, but used in their entirety as enzymes can bind to particulate matter or are on the surfaces of bacteria in the case of colon contents (Woodley 1991). Fluid thus obtained from the upper intestine should contain all the pancreatic enzymes, bile salts and sloughed-off cells, but again getting the concentrations right is not obvious. 

Advantage can be taken of this enhanced stability of blends of low molecular polymers by chai n-extending or cross-linking the macromolecules in such mixtures after they have been formed or applied to a substrate. This procedure is the basis of many formulations in the coatings industry. 

Broad Influence on Stability. In general, when electrical surface charge is an important determinant of stability, it is easier to formulate a very stable OAV emulsion than a W/O emulsion because the electric double-layer thickness is much greater in water than in oil. (This condition is sometimes incorrectly stated in terms of greater charge being present on droplets in an OAV emulsion). This is not to say that W/O emulsions cannot be stabilized, however. Many reasonably stable oil-field W/O emulsions are stabilized by another mechanism the protective action of viscoelastic, possibly rigid, films formed on the droplets by macromolecules or solid particles. 

ICH guidelines ° describe and discuss stability issues and testing requirement for NCEs and macromolecules. These guidelines provide manufacturers and CSOs with acceptance specifications for accelerated and long-term stability studies. In addition to the drug substance and drug product, stability assessment is frequently conducted on raw materials, key intermediates, formulation excipients, and packaging materials. 

The advent of biotechnology, bioengineering and pharmaceutical delivery systems has increased the requirements for solubility and stability of macromolecules under a variety of versatile and unique conditions and subsequently the use of non-aqueous solvents. Specihc applications include a) isolation, purification, precipitation and crystallization of biopharmaceuticals, b) processing methods such as spray drying and microencapsulation, and c) formulation of proteins for delivery systems requiring high concentrations and prolonged stability, such as implants and depots. 

Among them, the use in the separation and purification of biochemically important macromolecules in molecular sieves (known as Sephadex ) [145], applications in the medical field (e.g., heparin analogs) [143], and due to its moisturizing properties and proven high stability, also in cosmetic formulations and for texture improvement in food applications [141, 142]. 

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