JP4543274B2 - Nasal composition - Google Patents

Description

  The present invention relates to a nasal drop composition containing ketotifen fumarate, and more particularly, a nasal drop composition containing ketotifen fumarate as an active ingredient, and mitigating irritation caused by ketotifen fumarate. Related to things.

  The site of administration of the nasal drops is the nasal mucosa, and improvement of the irritating feeling during nasal drop is one of the important themes for developing nasal drops.

  As a method for improving the feeling of irritation, means such as adjusting the osmotic pressure of the preparation is used. However, when the drug itself has irritation, its effect is not yet sufficient.

  And it is known that ketotifen fumarate, which is known as an antiallergic agent, also has a feeling of irritation (see Patent Document 1), and when it is added to a nasal drop, improvement of the irritation is still a problem.

JP 2001-187728 A

  An object of the present invention is to provide a ketotifen fumarate-containing nasal drop that lessens the irritating feeling of ketotifen fumarate blended in a nasal drop and has a less irritating feeling during nasal drop.

  As a result of intensive studies to solve the above problems, the inventors reduced the irritation peculiar to ketotifen fumarate by adding a certain water-soluble polymer to the nasal fluid containing ketotifen fumarate. The knowledge that it was possible was obtained.

  One of the aspects of the present invention that can be conceived based on such findings is a nasal composition containing ketotifen fumarate and polyethylene glycol.

  Another aspect of the present invention is a nasal composition containing ketotifen fumarate and hydroxypropylcellulose.

  Another aspect of the present invention is the nasal drop composition containing 1 part by mass or more of polyethylene glycol with respect to 1 part by mass of ketotifen fumarate.

  Another embodiment of the present invention is the nasal drop composition containing 0.5 parts by mass or more of hydroxypropyl cellulose with respect to 1 part by mass of ketotifen fumarate.

  The present invention has made it possible to provide a hypoallergenic nasal preparation containing ketotifen fumarate.

  The term “ketotifen fumarate” used in the present invention means binding to a histamine receptor and antagonizing histamine, or stabilizing mast cells to suppress the release of chemical mediators, thereby preventing nasal itching, sneezing and nasal discharge. It is a drug that suppresses secretion.

“Polyethylene glycol” (hereinafter abbreviated as “PEG” where appropriate) used in the present invention is an addition polymer of ethylene oxide and water, and is represented by HOCH ₂ (CH ₂ OCH ₂ ) _n CH ₂ OH. The Various types of liquids to solids exist depending on the degree of polymerization and are widely used as bases for pharmaceuticals and the like. The blending amount of PEG is 1 part by mass or more with respect to 1 part by mass of ketotifen fumarate, and is defined as follows by dividing the molecular weight of polyethylene glycol.

  In the case of a low molecular weight PEG having a molecular weight of less than 400, it is necessary to add 1 part by mass or more, preferably 10 parts by mass or more, per 1 part by mass of ketotifen fumarate. Even if 100 parts by mass or more is blended, there is no difference in the effect in terms of alleviating the irritation of ketotifen fumarate. Moreover, when 15 mass% or more is mix | blended in a formulation, since the viscosity of a nasal solution will rise and the sprayability of a nasal drop will deteriorate, it is unpreferable.

  In the case of a PEG having a medium molecular weight of 400 to 4000, it is necessary to add 1 part by mass or more, preferably 5 parts by mass or more with respect to 1 part by mass of ketotifen fumarate. . Even if 100 parts by mass or more is blended, there is no difference in the effect in terms of alleviating the irritation of ketotifen fumarate. Moreover, when 15 mass% or more is mix | blended in a formulation, since the viscosity of a nasal solution will rise and the sprayability of a nasal drop will deteriorate, it is unpreferable.

  In the case of a high molecular weight PEG having a molecular weight of more than 4000, it is necessary to blend 1 part by mass or more, preferably 5 parts by mass or more with respect to 1 part by mass of ketotifen fumarate. Even if 100 parts by mass or more is blended, there is no difference in the effect in terms of alleviating the irritation of ketotifen fumarate. Moreover, when 10 mass% or more is mix | blended in a formulation, since the viscosity of a nasal solution will rise and the sprayability of a nasal drop will deteriorate, it is unpreferable.

  Note that PEG may be used in combination of several types having different molecular weights as well as one type.

  “Hydroxypropyl cellulose” (hereinafter abbreviated as “HPC” where appropriate) used in the present invention is a water-soluble polymer that is widely used as a base for pharmaceuticals and the like. The compounding amount of HPC is 0.5 parts by mass or more with respect to 1 part by mass of ketotifen fumarate, preferably 1 part by mass or more in terms of alleviating irritating ketotifen fumarate, and 5 parts by mass or more. Has no effect. When 5 mass% or more is blended in the preparation, the viscosity of the nasal solution is increased, and the sprayability of the nasal drop is deteriorated, which is not preferable.

  The PEG and HPC can be used in combination.

  The dosage of “ketotifen fumarate” in the present invention is 0.55 mg / day (0.4 mg / day as ketotifen).

  The nasal composition of the present invention can be prepared by dissolving ketotifen fumarate, PEG or HPC in purified water. And it can provide as a nasal drop by filling this into the spray device for nasal drops.

  In that case, a vasoconstrictor, an anti-inflammatory agent, a local anesthetic, a bactericidal agent, an astringent, etc. can be mix | blended as another active ingredient in the range which does not impair the effect of this invention. Moreover, you may mix | blend well-known additives, such as a pH adjuster, a refreshing agent, a thickener, a stabilizer, antiseptic | preservative, an isotonic agent, a solubilizing agent.

  Below, an Example and a test example are given and this invention is demonstrated further in detail.

Example 1
Ketotifen fumarate 0.076 g
Tetrahydrozoline hydrochloride 0.1g
Benzethonium chloride 0. 02g
Polyethylene glycol 400 0.1g
Citric acid appropriate amount Sodium citrate appropriate amount Glycerin appropriate amount The above components were dissolved in purified water, and the pH was adjusted to 4.0 and isotonic with glycerin to prepare a total amount of 100 mL of nasal solution. This was filled into a nasal spray device to obtain a nasal spray.

Example 2
Ketotifen fumarate 0.076 g
Tetrahydrozoline hydrochloride 0.1g
Benzethonium chloride 0.02g
Polyethylene glycol 400 5.0g
Citric acid appropriate amount Sodium citrate appropriate amount Glycerin appropriate amount The above components were dissolved in purified water, and the pH was adjusted to 4.0 and isotonic with glycerin to prepare a total amount of 100 mL of nasal solution. This was filled into a nasal spray device to obtain a nasal spray.

Example 3
Ketotifen fumarate 0.076 g
Tetrahydrozoline hydrochloride 0.1g
Benzethonium chloride 0.02g
Polyethylene glycol 4000 0.1g
Citric acid appropriate amount Sodium citrate appropriate amount Glycerin appropriate amount The above components were dissolved in purified water, and the pH was adjusted to 4.0 and isotonic with glycerin to prepare a total amount of 100 mL of nasal solution. This was filled into a nasal spray device to obtain a nasal spray.

Example 4
Ketotifen fumarate 0.076 g
Tetrahydrozoline hydrochloride 0.1g
Benzethonium chloride 0.02g
Polyethylene glycol 4000 5.0g
Citric acid appropriate amount Sodium citrate appropriate amount Glycerin appropriate amount The above components were dissolved in purified water, and the pH was adjusted to 4.0 and isotonic with glycerin to prepare a total amount of 100 mL of nasal solution. This was filled into a nasal spray device to obtain a nasal spray.

Example 5
Ketotifen fumarate 0.076 g
Tetrahydrozoline hydrochloride 0.1g
Benzethonium chloride 0.02g
Hydroxypropylcellulose 0.1g
Citric acid appropriate amount Sodium citrate appropriate amount Glycerin appropriate amount The above components were dissolved in purified water, and the pH was adjusted to 4.0 and isotonic with glycerin to prepare a total amount of 100 mL of nasal solution. This was filled into a nasal spray device to obtain a nasal spray.

Example 6
Ketotifen fumarate 0.076 g
Naphazoline hydrochloride 0.05g
Benzethonium chloride 0.02g
Polyethylene glycol 4000 0.1g
Citric acid appropriate amount Sodium citrate appropriate amount Glycerin appropriate amount The above components were dissolved in purified water, and the pH was adjusted to 4.0 and isotonic with glycerin to prepare a total amount of 100 mL of nasal solution. This was filled into a nasal spray device to obtain a nasal spray.

Example 7
Ketotifen fumarate 0.076 g
Naphazoline hydrochloride 0.05g
Benzethonium chloride 0.02g
Hydroxypropylcellulose 0.1g
Citric acid appropriate amount Sodium citrate appropriate amount Glycerin appropriate amount The above components were dissolved in purified water, and the pH was adjusted to 4.0 and isotonic with glycerin to prepare a total amount of 100 mL of nasal solution. This was filled into a nasal spray device to obtain a nasal spray.

Example 8
Ketotifen fumarate 0.076 g
Tetrahydrozoline hydrochloride 0.1g
Benzalkonium chloride 0. 01g
Polyethylene glycol 400 0.1g
Citric acid appropriate amount Sodium citrate appropriate amount D-sorbitol appropriate amount The above components were dissolved in purified water to make the pH 4.0 and isotonic with D-sorbitol to prepare a total amount of 100 mL of nasal solution. This was filled into a nasal spray device to obtain a nasal spray.

Example 9
Ketotifen fumarate 0.076 g
Naphazoline hydrochloride 0.05g
Benzalkonium chloride 0.01g
Polyethylene glycol 4000 0.1g
Citric acid appropriate amount Sodium citrate appropriate amount D-sorbitol appropriate amount The above components were dissolved in purified water to make the pH 4.0 and isotonic with D-sorbitol to prepare a total amount of 100 mL of nasal solution. This was filled into a nasal spray device to obtain a nasal spray.

Test example 1
Nasal solutions described in Table 1 below were prepared and filled in a nasal spray device. The nasal drops of Experimental Examples 1 to 5 and Control Examples 1 and 2 were sprayed on the nasal cavity for 5 healthy individuals, and the degree of irritation was scored and evaluated according to the following criteria. The results are shown in the lower column of the same table.

Evaluation criteria 0: Almost no irritation
1: Slightly irritating
2: There is a sense of irritation (stimulation is stronger than evaluation standard score 1)

  In the nasal drops of Experimental Examples 1 to 5 according to the present invention, scores 0.2 to 0.6 and the result that the feeling of irritation was low were shown, but in Control Examples 1 and 2, the scores 1.6 and 1. 2 showed the result that there was a feeling of irritation.

Test example 2
[Reduced glutathione (GSH) release test]
Experimental animal: JW white rabbit / male Experimental method: 250 μL of the specimen shown in Table 2 was administered to one eye of a rabbit using a micropipette, and 50 μL of tear fluid was collected using a micropipette after 2 minutes. The collected tears were immediately mixed with a pH 3.3 buffer, and GSH was quantified by HPLC (fluorescence detector). The results are shown in FIG.

It is a graph which shows the result of a GSH release property test.

Claims (2)

A nasal drop composition comprising ketotifen fumarate and polyethylene glycol. The nasal drop composition of Claim 1 which contains polyethyleneglycol 1 mass part or more with respect to 1 mass part of ketotifen fumarate.

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