Stabilization of Pharmaceuticals to Oxidative Degradation

Waterman, Kenneth C.; Adami, Roger C.; Alsante, Karen M.; Hong, Jinyang; Landis, Margaret S.; Lombardo, Franco; Roberts, Christopher J.

doi:10.1081/pdt-120002237

Cited by 196 publications

(115 citation statements)

References 74 publications

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“…MYR was seen to be fairly labile when introduced to an oxidizing agent. From the chemical structure, it is evident that MYR contains several hydroxyl groups which can be susceptible to a number of oxidation reactions, when exposed to a peroxide, including nucleophilic addition reactions (20). Degradation as a result of oxidation can often be stabilized by the addition of antioxidants (21).…”

Section: Discussionmentioning

confidence: 99%

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Solid-State and Solution Characterization of Myricetin

Franklin

Myrdal

2015

AAPS PharmSciTech

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Abstract. Myricetin (MYR) is a natural compound that has been investigated as a chemopreventative agent. MYR has been shown to suppresses ultraviolet B (UVB)-induced cyclooxygenase-2 (COX-2) protein expression and reduce the incidence of UVB-induced skin tumors in mice. Despite MYR's promise as a therapeutic agent, minimal information is available to guide the progression of formulations designed for future drug development. Here, data is presented describing the solid-state and solution characterization of MYR. Investigation into the solid-state properties of MYR identified four different crystal forms, two hydrates (MYR I and MYR II) and two metastable forms (MYR IA and MYR IIA). From solubility studies, it was evident that all forms are very insoluble (<5 μg/ml) in pure water. MYR I was found to be the most stable form at 23, 35, and 56°C. Stability determination indicated that MYR undergoes rapid apparent first-order degradation under basic pH conditions, and that degradation was influenced by buffer species. Apparent first-order degradation was also seen when MYR was introduced to an oxidizing solution. Improved stability was achieved after introducing 0.1% antioxidants to the solution. MYR was found to have good stability following exposure to ultraviolet radiation (UVR), which is a consideration for topical applications. Finally, a partitioning study indicated that MYR possess a log P of 2.94 which, along with its solid-state properties, contributes to its poor aqueous solubility. Both the solid-state properties and solution stability of MYR are important to consider when developing future formulations.

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Section: Discussionmentioning

confidence: 99%

“…In this study, improved stability was achieved with addition of ascorbic acid and sodium metabisulfite, with greater stability seen in the latter. Both antioxidants can be classified as sacrificial reductants, which effectively scavenge oxygen while being consumed themselves (20).…”

Section: Discussionmentioning

confidence: 99%

Solid-State and Solution Characterization of Myricetin

Franklin

Myrdal

2015

AAPS PharmSciTech

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“…Several antioxidants are currently used in pharmaceutical products, including chelating agents, reducing agents, oxygen scavengers, and chain terminators. 59 The most common antioxidants are the sacrificial reductants, or compounds that oxidize more readily than the protein, thereby reducing the concentration of oxidants in the protein solutions and protecting the protein from the oxidative degradation. Met is a sulfur-containing amino acid and a sacrificial antioxidant.…”

Section: Discussionmentioning

confidence: 99%

Development of a stable low-dose aglycosylated antibody formulation to minimize protein loss during intravenous administration

Morar-Mitrica

Puri

Sassi

et al. 2015

mAbs

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The physical and chemical integrity of a biopharmaceutical must be maintained not only during long-term storage but also during administration. Specifically for the intravenous (i.v.) delivery of a protein drug, loss of stability can occur when the protein formulation is compounded with i.v. bag diluents, thus modifying the original composition of the drug product. Here we present the challenges associated with the delivery of a low-dose, highly potent monoclonal antibody (mAb) via the i.v. route. Through parallel in-use stability studies and conventional formulation development, a drug product was developed in which adsorptive losses and critical oxidative degradation pathways were effectively controlled. This development approach enabled the i.v. administration of clinical doses in the range of 0.1 to 0.5 mg total protein, while ensuring liquid drug product storage stability under refrigerated conditions.

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“…Sucrose and cellulose did not significantly affect the protease activity (no significant differences were found after applying the t-test at the 95 % confidence level for comparison with standard pancreatin). This effect is likely due to the chiral centers of enzymes (14). The presence of mannitol, magnesium stearate and talc further decreased protease activities.…”

Section: Stability Of Proteasementioning

confidence: 99%

Evaluation of pancreatin stability through enzyme activity determination

et al. 2016

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Evaluation of pancreatin stability through enzyme activity determinationPancreatin is a biotechnological product containing an enzyme complex, obtained from porcine pancreas, that is employed in treating pancreatic diseases. Experiments regarding the stability of the pharmaceutical formulation containing pancreatin were performed using standard binary mixtures with 6 excipients in a 1:1 ratio (m/m) and a commercial formulation. To accomplish these goals, samples were stored for 1, 3 and 6 months at 40 ± 1 °C and 75 ± 5 % relative humidity (RH) and 40 ± 1 °C and 0 % RH. Stress testing was also performed. All samples were analyzed to evaluate the α-amylase, lipase and protease activities through UV/Vis spectrophotometry. The results revealed that the excipient proprieties and the storage conditions affected enzyme stability. Humidity was a strong influencing factor in the reduction of α-amylase and protease activities. Stress testing indicated that pH 9.0 and UV light did not induce substantial alterations in enzyme activity.Keywords: α-amylase, lipase, protease, stress testing, pancreatin stability, biopharmaceutical, UV/VIS spectrophotometry Stability of pharmaceutical products depends on various factors, including environmental factors (e.g., temperature, humidity and light) and other factors related to the product itself, such as the physicochemical properties of active substances and pharmaceutical excipients, the shape and composition of the pharmaceutical, the fabrication process, and the type and properties of packaging materials (1).For pharmaceutical products, the stability of biopharmaceuticals could require special attention because of their inherent physicochemical complexity. In this sense, stability tests are performed to determine the expiration date, the utilization period and the storage conditions. During the various fabrication stages of these biopharmaceuticals, aggregates and degradation products might form and compromise the stability, quality and security of the formulations (2).Pancreatin is a biopharmaceutical obtained from swine pancreas, and according to the United State Pharmacopoeia, it is defined as a substance that contains enzymes, mainly

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Stabilization of Pharmaceuticals to Oxidative Degradation

Cited by 196 publications

References 74 publications

Solid-State and Solution Characterization of Myricetin

Solid-State and Solution Characterization of Myricetin

Development of a stable low-dose aglycosylated antibody formulation to minimize protein loss during intravenous administration

Evaluation of pancreatin stability through enzyme activity determination

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