Effect of textured eye drop bottles on the photostability of pranoprofen 0.1% ophthalmic solution.

CONTEXT: Ophthalmic solutions are usually filled in a plastic bottle due to its durability and disposability. In Japan, photostability is one of the concerns for the quality control because an eye drop bottle must be a transparent container. OBJECTIVE: The present work studied the effect of textured eye drop bottles on its light blocking to improve the photostability of ophthalmic solutions. MATERIALS AND METHODS: We investigated the photostability of Pranoprofen ophthalmic solution filled in a variety of textured eye drop bottles. Pranoprofen content was analyzed by high-performance liquid chromatography and surface structure of textured eye drop bottles was evaluated by transmittance, calculated average roughness (Ra) and haze intensity. RESULTS: We observed that eye drop bottle which had greater than Ra value of 1.0 µm and haze intensity 62% clearly showed photostability improvement. CONCLUSIONS: This report is the first one which shows that photostability of ophthalmic solution is improved by using textured eye drop bottle. Moreover, this approach is a simple and effective method to improve the photostability. This method is available for not only various ophthalmic applications but also other liquid pharmaceuticals or food products.

Replacement of the hydrophobic part of 9-cis-retinoic acid with cyclic terpenoid moiety results in RXR-selective agonistic activity.

Retinoid X receptor (RXR) agonists are interesting candidates for the treatment of metabolic syndrome. 9-Cis-retinoic acid (9cRA: 1) is a natural RXR agonist, that also works as a retinoic acid receptor (RAR) agonist. This fact prompted us to study the structure-activity relationship (SAR) of RXR agonists derived from 1. Though 3 and 4, in which the cyclohexene part of 1 is replaced with bulkier hydrophobic moieties, show RXR-selective agonistic activity, some analogs containing other ring structures show RAR agonistic activity. Thus, we were interested in establishing what kind of ring skeleton is required for RXR-selective agonistic activity. In this study, we systematically prepared 5 and 6, in which the cyclohexene ring of 1 is replaced with various cyclic terpenoid moieties, and evaluated their RXR and RAR agonistic activities. Our previously reported CsF-promoted Stille coupling reaction was employed as a key step for the comprehensive synthesis of 5 and 6. The results of transcriptional assay showed that compounds 5b-f, which possess a menthane skeleton, exhibit RXR-selective agonistic activity. These results should be helpful for the design of superior RXR-selective agonists based on the structure of 1.

Caesium fluoride-promoted Stille coupling reaction: an efficient synthesis of 9Z-retinoic acid and its analogues using a practical building block.

A highly efficient and rapid total synthesis of 9Z-retinoic acid was accomplished by caesium fluoride-promoted Stille coupling reaction; using a common building block, 9Z-retinoic acid analogues were also prepared by the same method without isomerisation of the Z-double bond.

Comparative studies of N-glycans and glycosaminoglycans present in SIRC (Statens Seruminstitut rabbit cornea) cells and corneal epithelial cells from rabbit eyes.

PURPOSE: We compared cultured Statens Seruminstitut rabbit cornea (SIRC) cells and corneal epithelial cells from rabbit eyes by analyzing their N-glycans and glycosaminoglycans (GAGs). This work is a fundamental study on the efficacy of using cultured cells instead of animals for drug development. MATERIALS AND METHODS: N-Glycans and GAGs from SIRC cell monolayers and corneal epithelial cells of rabbit eyes were analyzed by capillary electrophoresis (CE) and a combination of high-performance liquid chromatography (HPLC) and mass spectrometry. RESULTS: High mannose-type glycans and a hybrid-type glycan were the common N-glycans in SIRC cells and corneal epithelial cells of rabbit eyes. Mono-fucosylated biantennary glycans with or without one N-acetylneuraminic acid residue were observed only in SIRC cells. Hyaluronic acid was the only measurable GAG in the corneal epithelial cells of rabbit eyes. In contrast, hyaluronic acid and chondroitin sulfates were abundantly present in SIRC cells. CONCLUSIONS: Profiles of both N-glycans and GAGs were conspicuously different between SIRC cells and corneal epithelial cells of rabbit eyes. This report will be useful for the evaluation of pharmaceutical candidates when animals or cultured cells are employed in drug development studies.

Free glycans derived from glycoproteins present in human sera.

During the course of studies on the analysis of O-glycans in biological samples, we found that significant amount of free glycans are present in normal human serum samples. The most abundant free glycan was disialo-biantennary glycan typically observed in transferrin which is one of the abundant glycoproteins found in sera. Minor glycans were also considered to be mainly due to transferrin, but some glycans were derived from mucin-type O-glycans, although the amount was quite minute. However, high mannose-type glycans could not be detected at all. Although there have been many reports on the presence of intracellular "free" N-glycans (mainly derived from high mannose-type glycans) generated either from lipid-linked oligosaccharides or from misfolded glycoproteins through endoplasmic-reticulum associated protein degradation pathway, there is little information on the presence of free glycans in extracellular matrix and biological fluids such as serum. This report is the first one which demonstrates the presence of free glycans due to glycoproteins in sera.

Comparative studies of HPLC-fluorometry and LC/MS method for the determination of N-acetylneuraminic acid as a marker of deteriorated ophthalmic solutions.

Methods for determining the deterioration of ophthalmic solutions using both high-performance liquid chromatography (HPLC) with fluorescence detection and liquid chromatography coupled with selected ion monitoring mass spectrometry (LC/MS) are described. The methods are based on the determination of N-acetylneuraminic acid (NeuAc) released by the hydrolysis of foreign bodies that contaminate eye drops during use. The released NeuAc was either labeled with 1,2-diamino-4,5-methylenedioxybenzene (DMB) for fluorometric detection or detected without derivatization by mass spectrometry. The calibration curves for NeuAc showed good linearity between 1.2 ng/mL and 39 ng/mL for fluorometric HPLC and 5.0 ng/mL and 100 ng/mL for LC/MS, respectively. Detection limits for fluorometric HPLC and LC/MS were 0.20 ng/mL and 0.88 ng/mL, respectively. The NeuAc content of some model glycoproteins determined by LC/MS method were 62-78% of those determined by fluorometry. The differences are attributed to matrix effects but the LC/MS method afforded sufficiently high sensitivity that NeuAc in the foreign bodies could be determined in eight of nine test samples.