臨時調配的clopidogrel（plavix）懸液劑的穩定性
不過我想台灣應該比較沒有這種問題，因為我們頂多就是磨粉，不可能特地幫病患調成懸液劑。
Katherine L. Skillman, Regine L. Caruthers and Cary E. Johnson
Purpose. The stability of an extemporaneously prepared clopidogrel oral suspension was studied.
Methods. Clopidogrel oral suspension (5 mg/mL) was prepared using clopidogrel bisulfate tablets, Ora-Plus, and Ora-Sweet. Six 2-oz samples were prepared; three were stored at room temperature and three under refrigeration. One milliliter was withdrawn from each sample, diluted to 10 mL with methanol, and exposed to high-frequency sound waves in a water bath to ensure complete dissolution of clopidogrel. A 300-µL sample was then withdrawn, diluted with mobile phase to an expected concentration of 15 µg/mL, and assayed in duplicate using high- performance liquid chromatography immediately after preparation and at 7, 14, 28, and 60 days. The stability of the clopidogrel suspension was determined by calculating the percentage of the initial concentration remaining on each test day. Stability was defined as retention of at least 90% of the initial concentration.
Results. At least 97% of the initial clopidogrel concentration remained throughout the 60-day study period, regardless of storage conditions. There were no detectable changes in color, odor, taste, or pH and no visible microbial growth in any sample. The preparation was palatable, with a slightly gritty consistency and a slightly bitter aftertaste; the bitterness intensified slightly between 28 and 60 days but remained fairly mild.
Conclusion. Extemporaneously compounded suspensions of clopidogrel, 5 mg/mL, in a 1:1 mixture of Ora-Plus and Ora-Sweet were stable for at least 60 days when stored in amber plastic bottles at room temperature and under refrigeration.
Methods
Sample preparation An oral suspension of clopidogrel bisulfate 5 mg/mL (a concentration that allows an adequate volume of suspension for accurate measurement and easy ingestion) was prepared by thoroughly grinding four 75-mg clopidogrel bisulfate tablets, USP,a in a glass mortar. Thirty milliliters of Ora-Plusb and 30 mL of Ora-Sweetc were added to the powder to make a final volume of 60 mL. Details of the procedure are provided in the appendix.
Six identical samples were prepared and placed in 2-oz amber plastic bottles with child-resistant caps.d Three bottles were stored at room temperature (23–25 °C) and three bottles were stored under refrigeration (2–8 °C). A 1-mL volume was withdrawn from each of the six bottles with a micropipette immediately after preparation and at 7, 14, 28, and 60 days. Samples were diluted with methanol to 10 mL and then exposed to high-frequency sound waves in a water bath for 10 minutes to ensure clopidogrel dissolution. A 300-µL sample was further diluted with mobile phase to 10 mL (expected concentration, 15 µg/mL) and assayed in duplicate by high-performance liquid chromatography (HPLC).
HPLC method A modification of the reverse-phase stability- indicating HPLC method described by Gandhimathi and Ravi7 was adapted for use. The instrumentation included a constant-flow solvent delivery systeme and a 5-µm particle column (150 mm x 3.9 mm).f A variable-volume injector,g an ultraviolet (UV) light detectorh set at 225 nm, and a recording integratori were also used. The mobile phase consisted of 0.1% triethylamine in water adjusted to pH 4j with dilute phosphoric acid and UV-grade acetonitrile (25:75, v/v) delivered at a flow rate of 1 mL/min.
The stability-indicating capability of the assay was reevaluated in the laboratory. Degradation of clopidogrel bisulfate was forced by preparing three separate samples; 1-mL volumes of 5-mg/mL suspension were mixed with three drops of 3% hydrogen peroxide, adjusted to pH 2 with 1 N hydrochloric acid or to pH 12 with 1 N sodium hydroxide, and stored at room temperature for 60 days. Samples were then heated to 90 °C for two hours. The pH was adjusted to 7, and the samples were diluted with methanol and mobile phase to an expected concentration of 15 µg/mL and assayed. Approximately 40% degradation was achieved with the hydrogen peroxide and basic solutions and 16% with the acidic solution. No interfering peaks were identified at three different wavelengths (225, 240, and 254 nm). The peak for clopidogrel appeared at 3.16 minutes, with small peaks for unknown degradation products at 1.7 and 2.9 minutes with the hydrogen peroxide at a wavelength of 225 nm.
Standard solutions and standard curve A 750-µg/mL stock solution was prepared on each day of sample analysis by crushing one 75-mg tablet, dissolving it in 100 mL of methanol, and exposing it to high-frequency sound waves in a water bath for 10 minutes to ensure full dissolution of clopidogrel (analytical-grade powder was not available). Standard samples of clopidogrel were prepared by diluting the stock solution with mobile phase to expected concentrations of 7.5, 11.25, 15, 18.75, and 22.5 µg/mL. A standard curve was produced by linear regression of the peak heights of clopidogrel against clopidogrel concentration. The standard curve was linear (r2 > 0.999) over the working range of concentrations. A 15-µg/mL concentration of clopidogrel was assayed in duplicate approximately every 10th sample as an external control. The intraday and interday coefficients of variation for the clopidogrel assay were 1% and 5.6%, respectively.
Sample analysis Each clopidogrel sample was gently shaken by hand for approximately 15 seconds immediately before assay. Ten microliters of each sample was injected into the HPLC system, and each sample was assayed in duplicate. Samples were evaluated for visual and pH changes on each day of analysis, as well as for changes in odor and taste at the beginning, middle, and end of analysis. Microbiological testing was not performed, since each commercial vehiclec contained effective preservatives.
Data analysis The stability of clopidogrel in an oral suspension at room temperature and with refrigeration was determined by calculating the percentage of the initial concentration remaining at each time interval. Stability was defined as retention of at least 90% of the initial concentration.
Results and discussion
At least 97% of the initial concentration of clopidogrel remained throughout the 60-day study period in all suspensions (Table 1). There was no detectable change in color, odor, or taste, and no visible microbial growth was observed in any sample. The preparation was a well-distributed suspension after gentle shaking. The preparation was palatable with a slightly gritty consistency and a slightly bitter aftertaste that remained for approximately 30 seconds; the bitterness intensified slightly between 28 and 60 days but remained fairly mild. No appreciable change in mean ± S.D. pH occurred in any of the samples, regardless of storage at room temperature (2.65 ± 0.09) or with refrigeration (2.65 ± 0.05).
The bioavailability of the clopidogrel formulations in the current study was not evaluated; however, the absorption and therapeutic effectiveness of a drug in a suspension compounded from crushed tablets are unlikely to differ appreciably from those of the original dosage form.
Conclusion
Extemporaneously compounded suspensions of clopidogrel 5 mg/mL in a 1:1 mixture of Ora-Plus and Ora-Sweet were stable for at least 60 days when stored in 2-oz amber plastic bottles at room temperature and under refrigeration.
上文之前提到的附錄在這邊：
Appendix. Procedure for compounding clopidogrel bisulfate suspension, 5 mg/mL
留言列表
醫藥類 (14)
