[Changes in Test Methods for Internationalization in the Japanese Pharmacopoeia (Part 3): Establishment of a Quantitative Method for Sodium Cromoglicate and Trihexyphenidyl Hydrochloride Using HPLC Analysis].

The Japanese Pharmacopoeia (JP) is an official normative publication for establishing the authenticity and properties and maintaining the quality of pharmaceutical products in Japan. The JP is revised every five years and partially revised in order to respond to the progress of science and technology, the demand for medical care, and international harmonization. Thus, "Internationalization of the JP" is one of the most important issues to address for the revision of the JP, which is also referred to the basic principles for the preparation of the JP 19th edition. For instance, the incorporation of the test methods that have been used in other pharmacopeias, such as the European Pharmacopoeia (EP) and the United States Pharmacopeia (USP), into the JP is one of promising approaches. From this perspective, we have recently reported changes in test methods, establishment of a quantitative test method for the JP-listed clonidine hydrochloride as well as lorazepam from using a potentiometric titration method to using HPLC method. As our ongoing study to change test methods for internationalization, we selected sodium cromoglicate and trihexyphenidyl hydrochloride. Each pharmaceutical product is analyzed using a potentiometric titration method as listed in the 18th JP; however, both the EP and the USP use HPLC method for quantitative analysis of these drugs. In this study, we synthesized the related impurities of sodium cromoglicate and trihexyphenidyl hydrochloride listed in the EP and determined their purities using quantitative NMR. The separation conditions of these compounds were examined using HPLC and simultaneous analyses were performed.

Stability-indicating assay of sodium cromoglicate in ophthalmic solution using mixed-mode hydrophilic interaction chromatography.

A hydrophilic interaction chromatographic (HILIC) procedure for the quantification of Sodium Cromoglicate (SCG) in ophthalmic solution is developed. Mobile phase consists of ACN and buffer, 86:14 v/v. Atlantis HILIC-Si column, 25 cm x 4.6 mm, is used as stationary phase. Detection is carried out using a variable wavelength UV-Vis detector at 326 nm. Linearity range and percent recoveries for SCG were 50-400 mug/mL and 100.44%, respectively. The SCG HILIC-UV assay was validated according to the International Conference on Harmonization guidelines. The method separates two impurities and degradation products resulting from stress environment. Influence of organic solvent, ionic strength and mobile phase pH on the retention of SCG is studied. The paper provides optimization of polar anionic solute (SCG) on unmodified silica by HILIC. Proposed method can be used as a stability-indicating assay for SGC and can be proved to be beneficial in ESI-MS for enhanced sensitivity.

Allergen-induced increase in airway responsiveness is not inhibited by acute treatment with ketotifen or clemastine.

Allergen-induced increase in airway responsiveness to histamine or methacholine provides a useful model for investigation of prophylactic or "antiinflammatory" asthma treatments. This can be inhibited by corticosteroids or by sodium cromoglycate but not by beta agonists or by theophylline. A single-blind, crossover, random-order trial was conducted to compare ketotifen, clemastine, and placebo in six atopic subjects undergoing allergen inhalation tests. Ketotifen, 2 mg; clemastine, 1 mg; and placebo one tablet were administered twice daily for four days (eight doses) up to and including one hour before allergen inhalation. None of the three produced a significant reduction in the allergen-induced early or late asthmatic responses, or in the allergen-induced fall in methacholine PC20. There was a subtle nonsignificant suggestion of a reduction in the early portion of the early asthmatic response induced by both ketotifen and clemastine. Both ketotifen and clemastine produced a similar 8-fold inhibition of histamine skin test endpoint indicating equal systemic H1 blocking effect at the time of allergen inhalation. Sodium cromoglycate, 10 mg, single dose, by metered dose inhaler ten minutes before allergen challenge, added as an unblinded "positive control", inhibitory effects on the allergen-induced late and presumed inflammatory sequelae. It is possible that longer treatment periods (several weeks or months) might prove effective.

Double-blind comparison of levocabastine nasal spray with sodium cromoglycate nasal spray in the treatment of seasonal allergic rhinitis.

Nasal levocabastine (0.5 mg/mL) was evaluated for efficacy and tolerance against sodium cromoglycate (20 mg/mL) in a 2-week double-blind trial in 27 and 29 patients with seasonal allergic rhinitis. Globally at 2 weeks, the investigators found a 74% response rate in the levocabastine patients versus a 50% response rate in the cromoglycate patients (P less than .10). Sneezing responded better to levocabastine than to cromoglycate according to three efficacy indicators derived from patient diary ratings of symptom severity: sum of severity scores over the total treatment period as a percentage of the theoretical maximum sum of severity scores (median: 19% versus 41%, P = .01); percentage of symptom-free days (median: 46% versus 22%, P less than .07); percentage of days with moderate or severe symptoms (median: 0% versus 29%, P = .004). Further, the percentage of days with moderate or severe runny nose was lower than in cromoglycate patients (median: 0% versus 25%, P = .09). Although no significant differences were found for itchy nose, blocked nose, and ocular symptoms, severities tended to be generally less under levocabastine than under sodium cromoglycate. Adverse experiences were low level and of similar incidence in the two groups. It is concluded that in a q.i.d. schedule, levocabastine nasal spray is more efficacious than sodium cromoglycate in relieving sneezing and that it is equally well tolerated.

Cromolyn sodium in the treatment of asthma: its effectiveness and use.

Thirty-six asthmatic children received placebo and cromolyn sodium, a new drug, in a double-blind crossover study; the majority were not using corticosteroids. Significant decreases in wheezing, breathlessness at rest, and cough occurred when the active drug was compared to placebo. Marked preference for cromolyn over placebo was expressed at the end of the study. Our results agree with previous reports on the effectiveness of cromolyn sodium. We found this drug to be especially useful as an adjunct to other treatment in the control of asthmatic children.