Photostability evaluation of manidipine tablets and structural determination of its photoproducts.

Manidipine (MP) is a dihydropyridine drug, which is treated for the reduction of high blood pressure. The aim of this study is to clarify the photochemical behavior of MP in the case of ultraviolet light (UV) irradiation for MP tablets (Calslot® tablets). The tablets and its altered forms (powders and suspensions) were UV-irradiated using a black light, and residual amounts of active pharmaceutical ingredients (APIs) were monitored by high-performance liquid chromatography (HPLC). Due to the photoproducts of MP were detected in HPLC chromatograms, the elucidation of their chemical structures was carried out utilizing electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). As a result, APIs in Calslot® tablets were almost completely photodegraded in the case that Calslot® tablets were suspended in an aqueous media along with the generation of some MP photoproducts. LC-ESI-MS/MS analysis clarified the chemical structures of three MP photoproducts, indicating that they were a pyridine analogue, benzophenone and a hydrolysate. Benzophenone was a main MP photoproduct. It was possible that MP might be firstly oxidized to form its pyridine analogue, followed by the oxidation of a dimethyl methylene moiety. This moiety seemed to be eliminated as a benzophenone, and the cleavage of an ester bond of the residual moiety resulted in the generation of a hydrolysate. Finally, toxicological potencies of MP and its photoproducts were predicted in silico toxicity evaluation, suggesting some of biological effects of the photoproducts might be altered compared with MP.

Evaluation of photostability of azelnidipine tablets and structure determination of its photoproducts.

Photo-exposure has a crucial effect on the natures of photosensitive pharmaceuticals in addition to their contents in medicines through the photodegradation. Generated photoproducts might be more bioactive and contribute to the expression of adverse side effects. This study aimed to clarify the photochemical behavior of medicines of azelnidipine, which is a member of dihydropyridine antihypertensive drugs, by the evaluation of its photostability and the determination of chemical structures of generated photoproducts. Calblock® tablets and its altered forms (powders and suspensions) were UV-irradiated by a black light. Residual amounts of active pharmaceutical ingredients (APIs) were monitored by high-performance liquid chromatography. The chemical structures of two photoproducts were determined by electrospray ionization tandem mass spectrometry. API of Calblock® tablets was photodegraded with the generation of several photoproducts. Its photodegradability was more significant when Calblock® tablets were crushed or suspended. Structural determination revealed that two photoproducts were benzophenone and a pyridine derivative. It was speculated that these photoproducts were generated by the elimination of diphenyl methylene radical and additional chemical reaction including oxidation and hydrolysis. Azelnidipine was photosensitive and its photodegradation in Calblock® tablets was promoted by the change of the dosage form. This difference might be derived from the light emission efficiency. This study suggests that API contents of Calblock® tablets might decrease when tablets or its altered forms are exposed to sunlight irradiation with the generation of benzophenone, which is a toxicological potent.

Structure Determination of Felodipine Photoproducts in UV-Irradiated Medicines Using ESI-LC/MS/MS.

Dihydropyridine drugs are well known as photodegradable pharmaceuticals. Herein, we evaluate the photostability of felodipine (FL) medicine (Splendil® (SPL) tablets) and its altered forms (powders and suspensions). FL is a type of dihydropyridine drug, but its photochemical behavior is unknown. FL contents after ultraviolet light (UV) irradiation for 24 h were monitored using high-performance liquid chromatography (HPLC). Values of the residual amounts of FL in UV-irradiated SPL powders and suspensions were 32.76 ± 4.88% and 0.79 ± 0.74%, respectively, with the generation of two photoproducts (FL photoproduct 1 and 2). To identify the chemical structures of these photoproducts, electrospray ionization liquid chromatography mass spectrometry (ESI-LC/MS/MS) analysis was performed. Based on their mass-to-charge ratio values and fragment patterns, it was proposed that FL photoproduct 1 was a pyridine derivative and FL photoproduct 2 was an FL dimer. Interestingly, generation rates of FL photoproduct 1 and 2 were dependent on the presence of the aqueous media. The photodimerization of FL was induced in UV-irradiated SPL suspensions. This is the first report evaluating the photostability of SPL tablets and its altered forms and estimating FL photoproducts induced by UV irradiation in the formulation of SPL.

Identification of allergens for food-dependent exercise-induced anaphylaxis to shrimp.

Shrimp is a causative food that elicits food-dependent exercise-induced anaphylaxis (FDEIA). In this study, we sought to identify IgE-binding allergens in patients with shrimp-FDEIA. Sera were obtained from eight patients with shrimp-FDEIA and two healthy control subjects. Proteins were extracted from four shrimp species by homogenization in Tris buffer. Immunoblot analysis revealed that IgE from patient sera bound strongly to a 70-kDa and a 43-kDa protein in a preparation of Tris-soluble extracts from Litopenaeus vannamei. Mass spectrometry identified the 70-kDa and 43-kDa proteins as a P75 homologue and fructose 1,6-bisphosphate aldolase (FBPA), respectively. To confirm that the putative shrimp allergens were specifically recognized by serum IgE from shrimp-FDEIA patients, the two proteins were purified by ammonium sulfate precipitation followed by reversed-phase HPLC and/or anion-exchange hydrophobic interaction chromatography and then subjected to immunoblot analysis. Purified P75 homologue and FBPA were positively bound by serum IgE from one and three, respectively, of the eight patients with shrimp-FDEIA, but not by sera from control subjects. Thus, P75 homologue and FBPA are identified as IgE-binding allergens for shrimp-FDEIA. These findings could be useful for the development of diagnostic tools and desensitization therapy for shrimp-FDEIA patients.

Photoprotective Effects of Selected Amino Acids on Naproxen Photodegradation in Aqueous Media.

It is important to develop a photostabilization strategy to ensure the quality of photosensitive compounds, including pharmaceuticals. This study focused on the protective effects of 20 amino acids on the photodegradation of naproxen (NX), a photosensitive pharmaceutical, to clarify the important nature of a good photostabilizer. Our previous report indicated the photodegradability of NX and the protective effects of some antioxidants on its photodegradation, therefore, this compound was used as a model compound. The degradation of NX in aqueous media during ultraviolet light (UV) irradiation and the protective effects of selected amino acids were monitored through high-performance liquid chromatography (HPLC), equipped with a reverse-phase column. Addition of cysteine, tryptophan, and tyrosine induced the significant suppression of NX photodegradation after UV irradiation for 3 h (residual amount of NX; 15.35%, 6.82%, and 15.64%, respectively). Evaluation of the antioxidative activity and UV absorption spectrum showed that cysteine suppressed NX degradation through its antioxidative ability, while tryptophan and tyrosine suppressed it through their UV filtering ability. Furthermore, three amino acids at higher concentrations (more than 100 µmol/L) showed more protective effects on NX photodegradation. For 10 mmol/L, residual amounts of NX with cysteine, tryptophan, and tyrosine were 58.51%, 69.34%, and 82.40%, respectively. These results showed the importance of both photoprotective potencies (antioxidative potency and UV filtering potency) and stability to UV irradiation for a good photostabilizer of photosensitive pharmaceuticals.

Protective Effect of Selected Antioxidants on Naproxen Photodegradation in Aqueous Media.

A photostabilization strategy is an important aspect of quality assurance for photosensitive compounds. This study focused on the photoprotective effects of selected antioxidants including the effect of L-ascorbic acid (AA) on naproxen (NX) photodegradation in aqueous media. NX degradation during ultraviolet light (UV) irradiation and the protective effects of selected antioxidants were monitored by high-performance liquid chromatography (HPLC). The addition of AA induced the suppression of NX photodegradation, although the protective effect disappeared after AA was degraded completely. The results of the evaluations on the photoprotective effects on NX photodegradation and antioxidative activities of AA and other antioxidants showed that the protective effects of antioxidants are dependent on reducing power and photostability under UV irradiation. In this experiment, quercetin (QU) is the most effective antioxidant on account of the residual rate of QU after UV irradiation and the antioxidative activity in the potential antioxidant (PAO) test was significantly higher compared to other antioxidants following the higher protective effect on NX photodegradation.