METHODS: A prospective observational study was conducted from March to April 2022 in neonatal wards at a state hospital in Malaysia. The PHEs of interest were aspartame, benzalkonium chloride, benzyl alcohol, benzoic acid or benzoates, ethanol, parabens, polysorbate 80, propylene glycol, saccharin sodium, sorbitol and sulfites. Product information leaflets (PILs) and summaries of product characteristics (SPCs) were referred to obtain information on active pharmaceutical ingredient, strength, trade name as well as type and amount of the excipients.
RESULTS: A total of 108 neonates were recruited and 97.2% of them were exposed to at least one PHE. Parabens (47.2%) and sulfites (27.5%) were the two most commonly administered PHEs. Benzyl alcohol is contraindicated in neonates but was administered to 8% of neonates in this study. The median daily dose of ethanol (24.11 mg/kg/day, IQR 19.73, 28.49) exceeded the acceptable daily intake (ADI) by four times. However, the dose was not available for all PHEs as this information is not always available in the PIL or SPC. Administration of cardiovascular drugs was associated with a higher risk of exposure to any PHE (OR 6.38, CI 2.75, 14.79, p-value < 0.001).
CONCLUSION: The exposure of PHE among neonates in this study is high with certain PHEs exceeding the ADI. It highlights the need for certain strategies to be implemented to reduce such exposure in neonates.
METHOD: The effects of organic modifiers in mobile phase, protein precipitation agent to plasma sample ratio, and light on montelukast stability in unprocessed and processed human plasma, were evaluated. Validation was conducted in accordance with European Medicines Agency Guideline on bioanalytical method validation.
RESULTS: No interference peak was observed when acetonitrile was used as an organic modifier. Acetonitrile to plasma ratio of 4:1 produced clean plasma sample. Approximately 3 % of cis isomer was detected in unprocessed plasma samples while 21 % of cis isomer was detected in processed plasma samples after exposing to fluorescent light for 24h. The standard calibration curve was linear over 3.00-1200.00 ng/mL. All method validation parameters were within the acceptance criteria.
CONCLUSION: The validated method was successfully applied to a bioequivalence study of two montelukast formulations involving 24 healthy Malaysian volunteers. The light stability of a light sensitive drug in unprocessed and processed human plasma samples should be studied prior to pharmacokinetic/bioequivalence studies. Measures could then be taken to protect the analyte in human plasma from light degradation.
SIGNIFICANCE: The significance of this research was to successfully incorporate slightly water soluble and potent anticancer drug (cisplatin) into cubosomes, which provide slow and sustained release of drug for longer period of time.
METHODS: The delivery system was developed through top-down approach by melting GMO and poloxamer 407 (P407) at 70 °C and then drop-wise addition of warm deionized water (70 °C) containing cisplatin. The formulation then exposed to probe sonicator for about 2 min. A randomized regular two level full factorial design with help of Design Expert was used for optimization of blank cubosomal formulations. Cisplatin loaded cubosomes were then subjected to physico-chemical characterization.
RESULTS: The characterization of the formulation revealed that it had a sufficient surface charge of -9.56 ± 1.33 mV, 168.25 ± 5.73 nm particle size, and 60.64 ± 0.11% encapsulation efficiency. The in vitro release of cisplatin from the cubosomes at pH 7.4 was observed to be sustained, with 94.5% of the drug being released in 30 h. In contrast, 99% of cisplatin was released from the drug solution in just 1.5 h. In vitro cytotoxicity assay was conducted on the human lung carcinoma NCI-H226 cell line, the cytotoxicity of cisplatin-loaded cubosomes was relative to that of pure cisplatin solution, while blank (without cisplatin) cubosomes were nontoxic.
CONCLUSIONS: The obtained results demonstrated the successful development of cubosomes for sustained delivery of cisplatin.