Stability of apomorphine in solutions containing ascorbic acid and bisulfite and effects of antioxidants on apomorphine-induced cage climbing and hypothermia in mice

Wilcox, Richard E.; Humphrey, David W.; Riffee, William H.; Smith, Robert V.

doi:10.1002/jps.2600690830

Cited by 24 publications

(4 citation statements)

References 25 publications

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“…Thus, we propose that the yellowish or brownish compound formation in 50 μg/mL apomorphine HCl in 0.1% AA solution or 0.1% AA plus 0.1% EDTA solution may be attributed to either the degradant(s) of AA 16 , 17 or a product of reactions between AA and apomorphine HCl. It could also be the phenanthrene degradation product of apomorphine reported by Udvardy et al 1 As expected, the rate of degradation of apomorphine HCl (in all antioxidant solutions) increased with temperature, as shown by Wilcox et al 9 previously. Notably, apomorphine HCl 50 μg/mL in 0.1% SMB solutions was stable for less than 5 hours at all experimental temperatures.…”

Section: Discussionsupporting

confidence: 70%

“…Compound 1 (m/z 264) matched the description by Abarca et al 10 and this indicated that Compound 1 was very likely to be oxoapomorphine. An earlier study by Wilcox et al 9 showed that the degradation of apomorphine HCl could be delayed by increasing the concentration of either AA or SMB in the solution. Nevertheless, Wilcox et al 9 concluded that neither AA nor SMB could significantly delay the degradation for more than 1–3 days when the solutions were stored at room temperature.…”

Section: Discussionmentioning

confidence: 99%

“…An earlier study by Wilcox et al 9 showed that the degradation of apomorphine HCl could be delayed by increasing the concentration of either AA or SMB in the solution. Nevertheless, Wilcox et al 9 concluded that neither AA nor SMB could significantly delay the degradation for more than 1–3 days when the solutions were stored at room temperature. This means that concentration increments of antioxidant for a single agent antioxidant in solution could not significantly stabilize apomorphine HCl in solution.…”

Section: Discussionmentioning

confidence: 99%

“…Although the mechanism of autoxidation has been studied extensively in recent years, there are only a few studies that have investigated formulation factors aimed to improve the stability of apomorphine in aqueous solution. 7 – 9 For example, Wilcox et al 9 identified that the addition of ascorbic acid or sodium metabisulfite (SMB) to apomorphine solution, at room temperature, could only significantly delay oxidation of apomorphine in solution for less than 1–3 days. The author also established that a higher concentration of antioxidant and lower storage temperature could also significantly reduce the rate of oxidation of apomorphine.…”

Section: Introductionmentioning

confidence: 99%

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Stability of apomorphine in solutions containing selected antioxidant agents

Ang¹,

Boddy²,

Liu³

et al. 2016

DDDT

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Apomorphine in solution undergoes rapid autoxidation, producing greenish colored solutions, making it difficult to formulate as a stable pharmaceutical solution. To identify the optimum antioxidant agent/combination for apomorphine solution, a high performance liquid chromatography assay was used to study the stability of 50 μg/mL apomorphine HCI in 0.1% L-ascorbic acid (AA), 0.1% sodium metabisulfite (SMB), 0.1% EDTA, and in selected combinations at 25°C, 32°C, and 37°C over a period of 14 days. The stability of apomorphine HCl (10 mg/mL) in 0.1% AA solution and in 0.1% EDTA solution at 25°C and 37°C was also evaluated. Apomorphine HCI solution (50 μg/mL) in 0.1% AA plus 0.1% SMB solution retained 99.7% (at 25°C) and 95.9% (at 37°C) of the initial concentration, as 0.1% AA plus SMB solution minimized the reactive oxygen content in solution which, in turn, reduced the oxidation rate of apomorphine HCl, and there was no green coloration perceptible. Conversely, apomorphine HCl solution (50 μg/mL) in 0.1% SMB solution was unstable as only 0.53% (at 25°C) and 0.06% (at 37°C) of the initial concentration was retained after 14 days. All 10 mg/mL apomorphine HCl samples were stable in both studies. The initial concentration of apomorphine HCl solution markedly affected its rate of oxidation and discoloration. The addition of 0.1% AA to a current formulation of apomorphine HCl injection (Apomine®), which contains SMB as an antioxidant, was recommended as providing the most stable solution.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Stability of apomorphine in solutions containing selected antioxidant agents

Ang¹,

Boddy²,

Liu³

et al. 2016

DDDT

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Apomorphine inhibits the growth-stimulating effect of retinal pigment epithelium on scleral cellsin vitro

Seko

Tanaka

Tokoro

1997

Cell Biochem. Funct.

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Visual deprivation of the chicken eye causes axial elongation with high myopia. The cartilaginous layer of the myopic sclera shows an increase of mitotic activity. Previous studies reported that the in vivo administration of apomorphine, a dopamine nonselective agonist, effectively prevents visual-deprivation myopia. Because the retinal pigment epithelium (RPE) regulates growth of the sclera as we and others have shown previously, it is speculated that the RPE cells may play an important role in this preventive effect of apomorphine. In this study, to clarify the mechanism by which the administration of apomorphine inhibits the proliferation of scleral chondrocytes in vivo, we have investigated the effect of apomorphine on the proliferation of scleral chondrocytes with or without co-cultured RPE cells in vitro. We previously demonstrated that cell proliferation of scleral chondrocytes remarkably increases with co-cultured RPE cells. In this study, we found that apomorphine at concentrations of higher than 2 x 10(-5) M dramatically reduced the growth-stimulatory effect of RPE cells on the scleral chondrocytes, whereas the inhibitory effect of apomorphine on the proliferation of scleral chondrocytes without RPE cells was very little. Our results strongly suggest that apomorphine may reduce the production and/or release of some humoral factors from RPE cells, which stimulate the growth of scleral cells. There is also a possibility that apomorphine reduces the reactivity of scleral cells to the humoral factors released from RPE cells.

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Effect of edetate disodium on goldfish membrane

Cascella

Kindelspire

1980

Journal of Pharmaceutical Sciences

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Stability of apomorphine in solutions containing ascorbic acid and bisulfite and effects of antioxidants on apomorphine-induced cage climbing and hypothermia in mice

Cited by 24 publications

References 25 publications

Stability of apomorphine in solutions containing selected antioxidant agents

Stability of apomorphine in solutions containing selected antioxidant agents

Apomorphine inhibits the growth-stimulating effect of retinal pigment epithelium on scleral cellsin vitro

Effect of edetate disodium on goldfish membrane

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