MXPA99009771A

MXPA99009771A - Eyedrops

Info

Publication number: MXPA99009771A
Application number: MXPA/A/1999/009771A
Authority: MX
Inventors: Fujimoto Takashi
Original assignee: Scheringplough Kabushiki Kaisha
Filing date: 1999-10-25
Publication date: 2000-07-01

Abstract

Eyedrops containing compounds represented by general formula (I) wherein H represents halogeno or hydrogen.

Description

SPECIFICATION OPHTHALMIC SOLUTION TECHNICAL FIELD The present invention relates to ophthalmic solutions containing Loratadine metabolite or a derivative thereof as an active ingredient. BACKGROUND OF THE INVENTION Loratadine, ethyl 4- (8-chloro-5,6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b] pyridine-11-ylidene) -l piperidinecarboxylate is known to be effective. , is useful as a non-anesthetic antihistamine and acts as an anti-allergen in the treatment of climatic or chronic allergic rhinitis, chronic urticaria, and the like, as described in JP 63-55513 B / 1988. We discovered that Loratadine or one of its derivatives can be used as an active ingredient of an ophthalmic solution and we made the Japanese and PCT applications of the invention, applications Nos. JP 7-280759 / 1995 and PCT / JP / 03139, respectively . DESCRIPTION OF THE INVENTION An objective of the present invention is to provide an ophthalmic solution containing Loratadine metabolite or a derivative thereof as an active ingredient.

For the first time, the present invention provides an ophthalmic solution containing the compound of formula I: H wherein X represents a halogen atom or a hydrogen atom. The halogen atoms represented by the X include Cl, Br, F and I. Of the compounds represented by the formula I, those preferred for use in the ophthalmic solution are those in which X is Cl, more preferably Loratadine metabolite which is the compound in which X is 8-C1, ie: 8-chloro-6,11-dihydro-11 (4-piperidylidene) -5H-benzo [5,6] cyclohepta [1,2-b] pyridine. The Loratadine metabolite is a known compound. The compound represented by the formula I can be easily prepared by heating the Loratadine or derivatives thereof in water under acidic or basic conditions. Loratadine and its derivatives, as raw material of the compound represented by formula I can also be prepared according to, for example, the method described in JP-63-55513 B / 1988. The ophthalmic solution according to the present invention contains an effective antihistaminic amount of the compound represented by the formula I. Usually, the effective amount of antihistaminic has a concentration of compound in the ophthalmic solution which is in the range from 0.01 to 100. mg / ml. The ophthalmic solution of the present invention may contain a stabilizer, preservative, an isotonic agent and an agent for pH adjustment. Examples of the stabilizer sodium hydrogensulfite, glycerol, sodium edetate, sodium citrate and butylated hydroxyanisole. Among these, sodium edetate is preferred because it has an excellent inhibitory action in the placement and can maintain an indicated pH of the solution and activity of the active compound. As the concentration of benzalkonium chloride increases, the pH of the ophthalmic solution and the activity of the active ingredient are stabilized. Therefore, it is preferred to incorporate benzalkonium chloride in the ophthalmic solution as a condom at a maximum concentration described in the positive list of additives for medications (0.127%). Examples of the isotonic agent include sodium chloride, D-mannitol, glucose and glycerol. Among these, mannitol is preferred since it has an excellent color inhibiting action and can maintain the indicated pH of the solution as well as the activity of the active compound. These actions do not depend on the concentration of D-mannitol, therefore the ophthalmic solution preferably contains D-mannitol in a concentration such that the osmotic pressure of the ophthalmic solution is equal to the physiological saline solution, i.e. 1.53%. Examples of the agent for pH adjustment include phosphate compounds such as sodium dihydrogenphosphate and disodium hydrogen phosphate, sodium hydroxide, and hydrochloric acid. With the aim of relieving irritation in the application of the solution, preferably the phosphate concentration is not higher than 0.01M, and it is preferred for its use as pH adjusting agents unlike other phosphate compounds. While the ophthalmic solution may have a pH of about 4 to 8, it is preferred that the pH be between 4 and 5 in order to keep the active compound stable. The ophthalmic solution of the present invention may contain solubilizers such as for example Polysorbate 80, propylene glycol, polyvinyl pyrrolidone K30 and Polozamer 188. Among these, Polysorbate 80 is preferred since it can maintain the ophthalmic solution at an appropriate osmotic pressure. The ophthalmic solution according to the present invention has excellent anti-allergenic activity and effective for conjunctivitis, pollinosis, vernal conjunctivitis and the like. In particular, it was found that the ophthalmic solution containing Loratadine metabolite which is described in the present invention has an antiallergic activity greater than the content of Loratadine itself as an active ingredient. In addition, the ophthalmic solution of the present invention has greater safety since it does not disturb the cornea, the conjunctiva iris when applied to the eye. Preferably, the ophthalmic solution of the present invention is placed and stored in a polypropylene container. The container made of polypropylene can keep the ophthalmic solution more stable and is more advantageous than those made of any other material. The dose of the ophthalmic solution according to the present invention depends on the condition to be treated. However, it is typically administered, but not limited to 1 to 4 times a day in an amount of 1 up to several drops at a time. Next, the present invention will be described in more detail with reference to the Examples. EXAMPLE 1 In approximately 300 ml of distilled water, 0.5 g of Loratadine metabolite, 1.0 ml of 10% benzalkonium chloride, 1.27 g of sodium edetate and 15.3 g of D-mannitol are dissolved. After adding 600 ml of distilled water to the solution, add 15.6 g of sodium dihydrogenphosphate and then adjust the pH of the solution to 5.0 using 0.1 M disodium hydrogen phosphate. Then, distilled water is added thereto, so that the total volume of the solution is 1000 ml to prepare the ophthalmic solution A. EXAMPLE 2 Ophthalmic solution B was prepared in the same way as in EXAMPLE 1 except that used 1.0 g of Loratadine. The results of the evaluation of ophthalmic solutions A and B as an ophthalmic preparation are shown in Table 1 below. TABLE 1 Solution A Solution B Transparent transparent appearance No. APHA 30 31 EXAMPLE TEST 1 The Loratadine metabolite was evaluated for its antihistaminic activity as compared to Loratadine, as follows: Rats peritoneal mast cells immunized with an IgE antibody were incubated rat anti-DNP, with the test compound for 15 minutes, at a temperature of 37 ° C and then stimulated with an DNP-Ascaris antigen for 10 minutes after 5 minutes after the addition of 10 μg / ml phosphatidylchloride. The amounts of released or intracellular histamine were measured by means of an autoanalyzer and then the% inhibition of histamine released and 50% concentration of inhibition were determined.

(IC50) • The results obtained in this way are shown in Table 2 below. In this table, the% inhibition value was expressed in terms of the mean (n = 5) +/- standard error. TABLE 2 Inhibitory effect of histamine released by stimulation with an antigen of rat peritoneal mastocytes IgE immunized Active ingredient Conc. (ΜM)% inhibition of IC5o (μM) (95% CL *) histamine released 0.3 14.6 + / - 6.82 Loratadine 1 20.9 +/- 6.02 9.57 Metabolite 3 35.6 +/- 7.19 (3.92 - 136) 10 49.8 +/- 8.40 0.3 19.8 +/- 5.77 Loratadine 1 27.1 +/- 4.72 2.41 3 45.8 +/- 9.26 (1.14 - 6.86) 10 73.3 +/- 16.8 * CL: Reliable limit

Claims

CLAIMS 1. An ophthalmic solution containing a compound represented by formula I: wherein X represents a halogen atom or a hydrogen atom.
2. The ophthalmic solution according to claim 1, wherein X is 8-Cl.
3. The use of the compound defined in claim 1 or 2 in an ophthalmic solution.
4. The ophthalmic solution according to claim 1 or 2, wherein the ophthalmic solution further contains a stabilizer.
5. The ophthalmic solution according to claim 4, wherein the stabilizer is sodium hydrogensulfite, glycerol, sodium edetate, sodium citrate or hydroxyanisole butylate.
6. The ophthalmic solution according to claim 1 or 2, wherein the ophthalmic solution also contains a condom.
7. The ophthalmic solution according to claim 6, wherein the condom is benzalkonium chloride.
8. The ophthalmic solution according to claim 1 or 2, wherein the ophthalmic solution further contains an isotonic agent.
9. The ophthalmic solution according to claim 8, wherein the isotonic agent is sodium chloride, D-mannitol, glucose or glycerol.
10. The ophthalmic solution according to claim 1 or 2, wherein the ophthalmic solution further contains a phosphate compound in a concentration not greater than 0.01M.
11. The ophthalmic solution according to claim 1 or 2, wherein the ophthalmic solution has a pH of 4 to 5.
The ophthalmic solution according to claim 1 or 2, wherein the ophthalmic solution contains sodium hydrogensulfite. , glycerol, sodium edetate, sodium citrate hydroxyisoisole butylate as a stabilizer; Benzaconium chloride as a preservative; sodium chloride, D-mannitol, glucose or glycerol as an isotonic agent; a phosphate compound at a concentration not greater than 0.01 M; and it has a pH of 4 to 5.
13. A product of the ophthalmic solution in which the ophthalmic solution according to any one of the preceding claims 1, 2 and 4 through 12 is placed in a polypropylene container. SOLUTION OFT LMICA SUMMARY An ophthalmic solution containing a compound represented by formula I is presented: H wherein X represents a halogen atom or a hydrogen atom.