Pantoprazole, esomeprazole continuous infusion, 지속 점적 주사, 안정성

판토라인 주, 넥시움 주, 지속점적주사 시 고려사항(안정성, stability)

 

pantoprazole, esomeprazole와 같은 주사제 PPI는 소화성 궤양으로 인한 위장관 출혈 중 활동성 출혈 또는 재출혈 고위험군인 경우 지속점적 투여할 수 있다.

24시간 희석된 상태로 상온(room temperature)에 방치되기 때문에 해당 약제들의 안정성(stability)이 중요한 요인이 된다. 간단한 예로 약물의 희석 후 안정성에 따라서 24시간 동안 투여되는 약제를 한꺼번에 희석하여 투여할 것인지 안정성 시간을 고려하여 분할하여 투여할 것인지를 결정할 수 있다. 

 

허가사항

성분명	허가사항(FDA)
Pantoprazole (revised: 2020.11.)	The reconstituted solution may be stored for up to 6 hours at room temperature prior to further dilution. The admixed solution may be stored at room temperature and must be used within 24 hours from the time of initial reconstitution. Both the reconstituted solution and the admixed solution do not need to be protected from light.  😀 희석 후 실온에서 24시간 안정성(재구성 시간으로부터), 재구성과 희석 후 차광은 필요하지 않음 Pantoprazole sodium is freely soluble in water, very slightly soluble in phosphate buffer at pH 7.4, and practically insoluble in n-hexane. The stability of the compound in aqueous solution is pH dependent. The rate of degradation increases with decreasing pH. The reconstituted solution of PROTONIX I.V. for injection is in the pH range 9.0 to 10.5. PROTONIX I.V. is supplied for intravenous administration as a sterile, freeze-dried powder in a single-dose clear glass vial fitted with a rubber stopper and crimp seal. Each vial contains 40 mg pantoprazole (equivalent to 45.1 mg of pantoprazole sodium), edetate disodium (1 mg), and sodium hydroxide to adjust pH. 😀 pH와 안정성 반비례(pH 낮아질수록[산성] 분해 속도 증가)/재구성 용매 부피에 따라 pH에 영향을 받으므로 권장되는 부피로 재구성
Esomeprazole (revised: 2020.11.)	😀 NS 희석 후 실온에서 12시간 안정성/5DW 희석 후 실온에서 6시간 안정성 NEXIUM I.V. is supplied as a sterile, lyophilized, white to off-white, porous cake or powder in a 5 mL single-dose vial, intended for intravenous administration after reconstitution with 0.9% Sodium Chloride Injection, USP; Lactated Ringer’s Injection, USP or 5% Dextrose Injection, USP. NEXIUM I.V. contains 40 mg esomeprazole (equivalent to 42.5 mg esomeprazole sodium), edetate disodium 1.5 mg and sodium hydroxide q.s. for pH adjustment. The pH of reconstituted solution of NEXIUM I.V. depends on the reconstitution volume and is in the pH range of 9 to 11. The stability of esomeprazole sodium in aqueous solution is strongly pH dependent. The rate of degradation increases with decreasing pH 😀 pH와 안정성 반비례(pH 낮아질수록[산성] 분해 속도 증가)/재구성 용매 부피에 따라 pH에 영향을 받으므로 권장되는 부피로 재구성

Esomeprazole (revised: 2020.11.)

Lexicomp

성분명	Lexicomp
Pantoprazole	Prior to reconstitution, store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Do not freeze. Protect from light prior to reconstitution; upon reconstitution, protection from light is not required. Do not freeze reconstituted solution. Per manufacturer's labeling, reconstituted solution is stable at room temperature for up to 6 hours; further diluted (admixed) solution in D5W, LR, or NS should be stored at room temperature and used within 24 hours from the time of initial reconstitution. However, studies have shown that reconstituted solution (4 mg/mL) in polypropylene syringes is stable up to 96 hours at room temperature (Johnson 2005). Upon further dilution, the admixed solution should be used within 96 hours from the time of initial reconstitution. The preparation should be stored at 3°C to 5°C (37°F to 41°F) if it is stored beyond 48 hours to minimize discoloration.
Esomeprazole	Powder for injection: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light. Per the manufacturer, following reconstitution, solution for injection prepared in NS, and solution for infusion prepared in NS or LR should be used within 12 hours; solution for infusion prepared in D5W should be used within 6 hours. Refrigeration is not required following reconstitution. Additional stability data: Following reconstitution, solutions for infusion prepared in D5W, NS, or LR in PVC bags are chemically and physically stable for 48 hours at room temperature (25°C) and for at least 120 hours under refrigeration (4°C) (Kupiec 2008).

⇒ 허가사항의 내용보다 추가적인 데이터로 안정성이 더 확보된 것을 확인할 수 있다. 하지만 해당 내용은 허가사항에는 반영되지 않음을 명시해야 한다.

 

 

관련 문헌 1

2006년에 나온 문헌의 내용을 살펴보자

Stability of omeprazole sodium and pantoprazole sodium diluted for intravenous infusion

2006년 당시 제약사 자료에 의하면 NS 희석 후 안정성은 각각 esomeprazole이 12시간, pantoprazole이 3시간이었다. 
Currently, the manufacturers of omeprazole and pantoprazole injections recommend that infusions prepared by dilution in NaCl 0.9% should be used within 12 or 3 hours, respectively.

Methods:
Intravenous 500 mL bags of NaCl 0.9% or dextrose 5% containing 200 mg of either omeprazole or pantoprazole were prepared.(농도 0.4 mg/mL) While stored at 22 °C, samples were withdrawn at intervals up to 10 days, and pH and drug content were measured. ANOVA was used to compare drug concentrations at preparation with those after storage.

Results:
The pH of the infusions did not alter by more than 0.2 units over 48 hours, but decreased subsequently. The measured concentrations of both omeprazole and pantoprazole decreased during storage. The decrease in concentration was greater in dextrose 5% than in NaCl 0.9% and was related to storage time. However, for both drugs, the mean decrease did not exceed 6% over the first 48 hours.

😀 PPI 분해에 중요한 요소인 pH의 변화는 48시간동안 0.2 unit을 초과하지 않음
😀 5DW 희석과 NS 희석을 비교하였을 때, 5DW 희석한 약의 분해 정도가 더 컸지만 두 희석 용액의 약의 분해는 48시간 동안 6%를 초과하지 않음

 

 

관련 문헌 2

2008년에 나온 문헌의 내용을 살펴보자

Objective:
To evaluate the stability of esomeprazole sodium in 5% dextrose, 0,9% sodium chloride, and lactated Ringer's injection, at 2 concentrations, at room temperature and when refrigerated.

Methods:
Triplicate samples of esomeprazole 0.4 and 0.8 mg/mL as the sodium salt were prepared in the solutions required. Stability evaluations were performed initially, over 2 days stored at 23 °C, and over 5 days stored at 4 °C. Physical stability was assessed using turbidimetric and particulate measurement, as well as visual observation. Chemical stability was evaluated by stability-indicating high-performance liquid chromatography.(HPLC로 화학적 안정성 평가)

Results:
The samples in all 3 infusion solutions were physically stable throughout the study. None of the samples had evidence of visible haze or particulates. Most samples developed a slight yellow discoloration within 24 hours, but this discoloration was not accompanied by an excessive loss of drug content. The esomeprazole sodium samples in all 3 infusion solutions exhibited less than 7% loss over 2 days at 23 °C and over 5 days at 4 °C.


reference:
1) Carpenter, Jane F., et al. "Stability of omeprazole sodium and pantoprazole sodium diluted for intravenous infusion." Journal of Pharmacy Technology 22.2 (2006): 95-98.
2) Kupiec, Thomas C., et al. "Physical and chemical stability of esomeprazole sodium solutions." Annals of Pharmacotherapy 42.9 (2008): 1247-1251.
3) FDA 허가사항
4) lexicomp
5) KIMS