JPH07258069A - Sustained release nasal drop - Google Patents

Abstract

PURPOSE:To obtain a sustained release nasal drop controlling release of an active ingredient in a nasal cavity, having raised retention in a nasal cavity of the active ingredient, comprising a vasoconstrictor and an antihistamine agent as active ingredients. CONSTITUTION:This sustained release nasal drop contains a vasoconstrictor (e.g. tetrahydrozoline hydrochloride) and an antihistamine agent (e.g. chlorpheniramine maleate) as active ingredients. The sustained release nasal drop is further mixed with 1-50-wt.% of an oil component, 0.05-5wt.% of a surfactant, water, a pH adjustor and components useful for an ordinary nasal drop and pharmaceutically manufactured into an O/W emulsion having pH 6.5-8.5. The sustained release nasal drop has high effect on nasal diseases such as pollinosis or rhinitis and has sustained release.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a nasal drop containing a vasoconstrictor and an antihistamine as active ingredients. More specifically, the release of the active ingredient into the nasal cavity is controlled to retain the active ingredient in the nasal cavity. Relates to a long-acting nasal drop.

[0002]

2. Description of the Related Art With the increase in the number of patients with hay fever in recent years, the demand for nasal drops having a long-lasting effect containing a vasoconstrictor and an antihistamine has rapidly increased. Nasal drops are water-soluble liquids that are administered into the nasal cavity using a sprayer or the like. However, in the conventional nasal drops, since the vasoconstrictor and the antihistamine that are mixed in the nasal drops are water-soluble drugs, they are quickly absorbed from the nasal mucosa, and the effect was not sustained. The object of the present invention is to improve the retention of the active ingredient in the nasal cavity in such a situation,
It is to provide a nasal drop with a long-lasting effect.

[0003]

[Means for Solving the Problems] Considering the mechanism of nasal allergy, it is important to maintain the drug on the surface of the nasal mucosa. Topical drugs have a relatively low molecular weight and are rapidly absorbed after intranasal administration. Therefore, the present inventors have found that the drug release can be controlled in the nasal cavity by increasing the pH of the preparation and making the preparation an O / W type emulsion, and completed the present invention.

That is, the present invention contains a vasoconstrictor and an antihistamine as active ingredients and has a pH of 6.5 to 5.
It is an O / W emulsion nasal drop of 8.5. In the present invention, as a vasoconstrictor, tetrahydrozoline hydrochloride,
Naphazoline hydrochloride, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, oxymetazoline hydrochloride, etc., as antihistamines, chlorpheniramine maleate,
Diphenhydramine hydrochloride, isothipendyl hydrochloride, sodium cromoglycate and the like can be mentioned. Also,
In the present invention, other active ingredients can be blended,
Examples include local anesthetics (dibucaine hydrochloride, lidocaine, lidocaine hydrochloride, procaine hydrochloride, etc.), secretion inhibitors (belladonna total alkaloids, etc.), enzyme anti-inflammatory agents (lysozyme chloride, etc.), anti-inflammatory agents (glycyrrhizinic acid, etc.), etc. Is.

The nasal drop of the present invention is an O / W type emulsion, and in order to have such a constitution, an oil component (1 to 50, preferably 20 to 40% by weight), a surfactant ( 0.05-5.0, preferably 0.1-3.0% by weight) and water. The oil component may be liquid, solid or semi-solid as long as it is insoluble in water, for example, jojoba oil, southern oil, avocado oil, soybean oil, olive oil, safflower oil, evening primrose oil, corn oil. , Higher polyhydric alcohols (eg, triglycerin), fatty acids, medium-chain fatty acid triglycerides, fatty acid esters, squalene and the like. Among these, an oil component (soybean oil, medium-chain fatty acid triglyceride, etc.) which is dispersed by a surfactant, lecithin and the like and which can distribute the drug to the oil phase in the pH range of 6.5 to 8.5 is preferable.

The above-mentioned surfactant may be a nonionic surfactant, a cationic surfactant, an anionic surfactant, an amphoteric surfactant or an amphipathic substance, but in terms of safety. Therefore, nonionic surfactants or amphiphiles usually used for nasal drops are desirable. For example, sorbitan fatty acid ester, glycerin fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, N
-Acylmethyl taurine salt, imidazolium betaine,
Examples thereof include phospholipids (natural phospholipids, synthetic phospholipids, phospholipids obtained by hydrogenating natural phospholipids, such as lecithin). Among these, one kind may be used alone, or two or more kinds may be used in combination. I don't mind.

A pH adjusting agent is used to adjust the pH of the preparation to 6.5 to 8.5. Examples of the pH adjusting agent include sodium hydroxide, potassium hydroxide, phosphate buffer, arginine and the like. it can. The pH of the formulation is 6.5.
If it is below the range, the effect (sustained release) of the present invention cannot be obtained, and if it exceeds 8.5, the stability of the active ingredient is deteriorated. Therefore, in the present invention, it is more preferable to set the pH to 7.0 to 8.0.

In the nasal drops of the present invention, in addition to active ingredients, oil components, surfactants and pH adjusters, substances usually used in nasal drops, such as bactericides (hibiten, benzalkonium chloride,
Benzethonium chloride decalinium chloride, etc.), adrenocortical hormone (hydrocortisone acetate, etc.), thickener (polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, etc.), tonicity agent (glycerin, etc.),
Stabilizers, cooling agents (l-menthol, etc.) and the like can be added within a range that does not impair the effects of the present invention.

The nasal drop of the present invention can be prepared, for example, as follows. That is, an aqueous phase containing an active ingredient is added to an oil phase containing an oil component and a surfactant, and the mixture is vigorously stirred and prepared according to a usual emulsification method.
Adjust H to 6.5-8.5 with pH adjuster. At that time, a stable milky white O / W type emulsion can be obtained by preparing with a strong shearing force such as a homomixer, Mantongourin or an ultrasonic emulsifier.

[0010]

INDUSTRIAL APPLICABILITY According to the present invention, it becomes possible to provide a nasal drop which is highly effective against nasal diseases such as pollinosis and rhinitis and has good durability.

[0011]

EXAMPLES The present invention will be described in more detail with reference to the following examples and test examples.

Test Example (Test of Retention of Active Ingredient in Nasal Cavity) [Preparation of Sample] Sample 1: 0.5% by weight of chlorpheniramine maleate,
Tetrahydrozoline hydrochloride 0.1% by weight, lidocaine 0.
3% by weight and 1.5% by weight of glycerin were dissolved in purified water, and 20% by weight of Panacet 810 (trade name of medium-chain fatty acid triglyceride), HCO-60 (trade name of polyoxyethylene hydrogenated castor oil 60) 0.2 % By weight and Resinol S-10 (trade name of hydrogenated soybean lecithin).
A mixture containing 5% by weight dissolved therein is stirred and mixed, emulsified, and a suitable amount of sodium hydroxide is used to adjust the pH of the preparation to 8 and the total amount is
It was set to 0 g. Sample 2: Chlorpheniramine maleate 0.
5% by weight, tetrahydrozoline hydrochloride 0.1% by weight, lidocaine 0.3% by weight, and sodium hydroxide in appropriate amounts,
The pH of the preparation was adjusted to 8 and the total amount was adjusted to 100 g with purified water.

[Test method] Wistar male rats (7
10 to 10 weeks old, body weight 200 to 250 g) were used as 3 animals per group. After anesthetizing the rat, the neck was incised to expose the respiratory tract and esophagus. Insert a polyethylene tube into the airway,
After securing the airway, a cannula of the same diameter was inserted from the esophagus to the posterior nasal cavity (nasal cannula). The nasal palate tube through the oral cavity and nasal cavity was closed with synthetic glue to prevent leakage of test liquid. 25 μl of each sample was administered from one nostril, and after a certain time, physiological saline was injected from the posterior nasal cavity to the nasal cavity by a metering pump connected to the nasal cannula to wash the inside of the nasal cavity and collect the lavage fluid that flowed out from the nostril did. Various active ingredients in the cleaning liquid were quantified by high performance liquid chromatography, the residual ratio was determined, and the retention of various active ingredients was evaluated. The results are shown in Table 1.

[0014]

[Table 1]

Example 1 Ingredients Amount (wt%) Chlorpheniramine maleate 0.5 Tetrahydrozoline hydrochloride 0.1 Lidocaine 0.3 Benzethonium chloride 0.02 Panacet 810 30 Recinol S-10 0.5 Glycerin 2 1-menthol 0.05 Sodium hydroxide suitable amount (Formulation pH 8.5) Purified water Total 100g Chlorpheniramine maleate, tetrahydrozoline hydrochloride, lidocaine, glycerin and benzethonium chloride are dissolved in purified water, and Panacet 810 and Recinol S are added.
A nasal drop was prepared by stirring and mixing a mixture of -10 0.5% and 1-menthol, emulsifying the mixture, adjusting the pH of the preparation to 8.5 using sodium hydroxide, and adjusting the total amount to 100 g.

Example 2 Ingredients Amount (% by weight) Chlorpheniramine maleate 0.3 Naphazoline hydrochloride 0.1 Lidocaine 0.1 Benzethonium chloride 0.02 Panaceto 810 10 HCO-60 0.2 Recinol S-10 0. 3 Glycerin 1.5 1-menthol 0.03 Hydroxymethylcellulose 0.02 Sodium hydroxide Suitable amount (formulation pH 7.5) Purified water 100 g A nasal drop was prepared in substantially the same manner as in Example 1.

Example 3 Ingredients Amount (% by weight) Chlorpheniramine maleate 0.3 Naphazoline hydrochloride 0.1 Benzethonium chloride 0.02 Soybean oil 20 Tween 80 0.2 Recinol S-10 0.3 Glycerin 1.0 Water Sodium oxide: Appropriate amount (pH of formulation 8.0) Purified water: 100 g A nasal drop was prepared in substantially the same manner as in Example 1.

Example 4 Ingredients Amount (wt%) Chlorpheniramine maleate 0.5 Hydrocortisone acetate 0.1 Dipotassium glycyrrhizinate 0.5 Benzethonium chloride 0.02 Panacet 810 10 HCO-60 0.2 Recinol S- 10 0.3 Glycerin 1.5 Hydroxymethylcellulose 0.02 Sodium hydroxide Suitable amount (Formulation pH 7.5) Purified water 100 g All In the same manner as in Example 1, a nasal drop was prepared.

Example 5 Ingredients Amount (% by Weight) Chlorpheniramine Maleate 0.5 Tetrahydrozoline Hydrochloride 0.1 Lidocaine 0.3 Benzethonium Chloride 0.02 Panacetate 810 30 Presome 0.5 Glycerin 1.5 Phosphate Buffer Appropriate amount (formulation pH 8) Purified water Total 100 g A nasal drop was prepared in substantially the same manner as in Example 1.

Front Page Continuation (72) Inventor Fumio Urushizaki 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd.

Claims (1)

[Claims] 1. An O / W emulsion nasal drop having a pH of 6.5 to 8.5 and containing a vasoconstrictor and an antihistamine as active ingredients.