Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-04-08
2000-01-18
Fay, Zohreh
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514912, A67K 3155
Patent
active
060158107
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to an aqueous ophthalmic solution containing apafant as an active ingredient and a method for attaining stabilization of apafant in the aqueous ophthalmic solution by lowering ionic strength (0.05 or below) depending on additives contained in the solution.
BACKGROUND ART
Apafant is a compound represented by a chemical name of 4-(2-chlorophenyl)-9-methyl-2-[3-(4-morpholinyl)-3-propanon-1-yl]-6H-thien o[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepine (see the following structural formula [I]) and is known to exhibit a high antagonistic activity on a triazolodiazepine platelet activating factor (hereinafter referred to as PAF) (Japanese Laid-open Patent Publication No. 176591/1986). ##STR1##
PAF is an inflammatory chemical mediator which has a very high physiological activity and is proved to participate in diseases such as inflammatory diseases (e.g. asthma, nephritis), disseminated intravascular coagulation syndrome and shock.
Various medicinal uses are already known regarding apafant, which has strong antagonism to PAF. For example, WO93/07129 discloses that apafant is useful as a therapeutic agent for osteoporosis because it has an inhibitory effect on absorption of bones. Japanese Laid-open Patent Publication No. 106826/1991 discloses that apafant is useful for cardiopathy such as heart failure because it was recognized to inhibit .beta.-adrenoreceptor-mediated contraction decrease in hearts of rats whose spinae had been broken. WO90/01927 discloses that apafant is useful for autoimmune diseases because it was recognized to increase platelets in patients with idiopathic thrombocytopenic purpura. It was also reported that apafant increased survival rates concentration-dependently against anaphylactic shock (J. Pharmacol. Exp. Ther., 260, 748-755 (1992)) and exhibited antagonism to hypotension induced by endotoxin or PAF (Eur. J. Pharmacol., 135, 117-122 (1987)). In addition, it was reported that apafant completely prevented any increase in airway resistance after PAF inhalation and inhibited development of cardiovascular and side effects induced by PAF in double-blind clinical pharmacological tests (Clin. Pharmacol. Ther., 47, 456-462 (1990)).
As ophthalmic application, WO91/18608 discloses that apafant can also be used in eyes etc. topically as an antipruritic because it inhibits an itching-inducing activity of PAF. However, it does not disclose an aqueous ophthalmic solution containing apafant as an active ingredient.
Thus, stability of apafant in an aqueous ophthalmic solution is discussed in order to develop the aqueous ophthalmic solution containing apafant, which is useful as a medicine, i.e., as an active ingredient. However, there exists the problem that a stable aqueous ophthalmic solution of apafant cannot be obtained if the formulation of apafant is attempted using conventional techniques. Accordingly, it is necessary to solve the instability problem of apafant in the aqueous ophthalmic solution in order to develop the aqueous ophthalmic solution containing apafant as the active ingredient.
SUMMARY OF THE INVENTION
The inventors studied extensively in order to provide an aqueous ophthalmic solution containing apafant as the active ingredient and being excellent in stability. As a result, the inventors found out that the aqueous ophthalmic solution which is excellent in stability can be prepared by adjusting ionic strength of the ophthalmic solution to 0.05 or below.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an aqueous ophthalmic solution containing apafant and additives wherein apafant is stabilized by lowering ionic strength to 0.05 or below and a method of stabilizing apafant. (This solution is hereinafter referred to as the present ophthalmic solution.) The additives in the present ophthalmic solution are agents which are usually used in ophthalmic preparations such as pH adjusting agents (e.g. hydrochloric acid, sodium hydroxide); isotonic agents, which have an action to adjust an osmotic pressure ratio,
REFERENCES:
Terashita et al, "Beneficial Effects of TCV-309, A Novel Potent and Selective Platelet Activating Factor Antagonist in Endotoxin and Anaphylactic Shock in Rodents", The Journal of Pharmacology and Experimental Therapeutics, vol. 260, No. 2, pp. 748-755 (1992).
Casals-Stenzel, "Protective Effect of Web 2086, A Novel Antagonist of Platelet Activating Factor, In Endotoxin Shock", European Journal of Pharmacology, vol. 135, pp. 117-122 (1987).
Kunou Noriyuki
Kuwano Mitsuaki
Miyagi Syogo
Fay Zohreh
Santen Pharmaceutical Co. Ltd.
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