JP3470131B2 - Long-acting nasal drops - Google Patents

Description

Description: 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, and more particularly, to the release of said active ingredient into the nasal cavity. The present invention relates to a long-acting nasal drop that controls and enhances the retention of an active ingredient in the nasal cavity. 2. Description of the Related Art In recent years, with the increase in hay fever patients, the demand for nasal drops containing a vasoconstrictor and an antihistamine has been rapidly increasing. Nasal drops are water-soluble solutions that are administered intranasally using a sprayer or the like. However, in the conventional nasal drops, since the vasoconstrictor and the antihistamine incorporated in the nasal drops are water-soluble drugs, they are quickly absorbed from the nasal mucosa and the effect is not sustained. An object of the present invention is to improve the retention of the active ingredient in the nasal cavity in such a situation,
An object of the present invention is to provide a nasal drop having a long-lasting effect. [0003] Considering the mechanism of nasal allergy, it is important to keep the drug on the surface of the nasal mucosa. Since the topical drug has a relatively small molecular weight, it is absorbed immediately after intranasal administration. Therefore, the present inventors have found that the release of a drug can be controlled in the nasal cavity by increasing the pH of the preparation and making the preparation an O / W emulsion, and completed the present invention. That is, the present invention has a pH of 6.5 to 6.5 containing a vasoconstrictor and an antihistamine as active ingredients.
8.5 O / W emulsion nasal drop. In the present invention, as a vasoconstrictor, tetrahydrozoline hydrochloride,
Nafazoline hydrochloride, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, oxymetazoline hydrochloride, etc., as antihistamines chlorpheniramine maleate,
Examples thereof include diphenhydramine hydrochloride, isotipendyl hydrochloride, and sodium cromoglycate. 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 (glycyrrhizic acid, etc.), etc. It is. [0005] The nasal drop of the present invention is an O / W emulsion, and in order to obtain 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. Any oil, liquid, solid, or semi-solid oil may be used as long as it is insoluble in water, such as jojoba oil, sasanqua oil, avocado oil, soybean oil, olive oil, safflower oil, evening primrose oil, and corn oil. And higher polyhydric alcohols (eg, triglycerin), fatty acids, medium-chain fatty acid triglycerides, fatty acid esters, and squalene. Of these, oil components (such as soybean oil and medium-chain triglycerides) that can be dispersed in a surfactant and lecithin and can distribute a drug to an oil phase in a pH range of 6.5 to 8.5 are preferable. [0006] The surfactant may be any of a nonionic surfactant, a cationic surfactant, an anionic surfactant, an amphoteric surfactant and an amphiphilic substance. Therefore, nonionic surfactants or amphiphilic substances 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
-Acylmethyltaurine salt, imidazolium betaine,
Phospholipids (natural phospholipids, synthetic phospholipids, phospholipids obtained by hydrogenating natural phospholipids, such as lecithin), and one of these alone or a mixture of two or more thereof can be used. No problem. To adjust the pH of the preparation to 6.5 to 8.5, a pH adjuster is used. Examples of the pH adjuster include sodium hydroxide, potassium hydroxide, phosphate buffer, arginine and the like. it can. The pH of the preparation was 6.5.
If the ratio is lower than the above, the effect of the present invention (long-lasting effect) cannot be obtained, and if it exceeds 8.5, the stability of the active ingredient is deteriorated. Therefore, in the present invention, the pH is more preferably set to 7.0 to 8.0. [0008] In addition to the active ingredient, oil component, surfactant and pH adjuster, the nasal drops of the present invention include substances usually used for nasal drops, such as fungicides (hibitene, benzalkonium chloride,
Benzethonium chloride, decalinium chloride, etc.), corticosteroids (hydrocortisone acetate, etc.), thickeners (polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, etc.), tonicity agents (glycerin, etc.),
Stabilizers, cooling agents (such as l-menthol) and the like can be added in 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 to which an active ingredient is added 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.
H is adjusted to 6.5 to 8.5 using a pH adjuster. In this case, a stable milky white O / W type emulsion can be obtained by preparing with a strong shearing force such as a homomixer, manton goulin or an ultrasonic emulsifier. Industrial Applicability According to the present invention, it has become possible to provide a nasal drop which has a high effect on nasal diseases such as hay fever and rhinitis and has good persistence. 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,
0.1% by weight of tetrahydrozoline hydrochloride, lidocaine 0.1%
3% by weight and 1.5% by weight of glycerin were dissolved in purified water, and 20% by weight of Panassate 810 (trade name of medium-chain fatty acid triglyceride) was added to 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 solution in which 5% by weight was dissolved was stirred and mixed, emulsified, and adjusted to a pH of 8 using a suitable amount of sodium hydroxide to make the total amount 10%.
0 g. Sample 2: Chlorpheniramine maleate as active ingredient
5% by weight, tetrahydrozoline hydrochloride 0.1% by weight and lidocaine 0.3% by weight, using an appropriate amount of sodium hydroxide,
The pH of the preparation was adjusted to 8, and the total amount was adjusted to 100 g with purified water. [Test Method] Male Wistar rats (7
-10 weeks old, body weight 200-250 g) were used as 3 animals per group. After anesthetizing the rat, the neck was incised to expose the airway and esophagus. Insert a polyethylene tube into the airway,
After securing the airway, an equal diameter cannula was inserted from the esophagus into the posterior nasal cavity (nasal cannula). The nasal palate through the oral cavity and nasal cavity was closed with a synthetic adhesive to prevent leakage of the test solution. 25 μl of each sample was administered from one nostril, and after a certain period of time, physiological saline was injected into the nasal cavity from the posterior nasal cavity with a metering pump connected to the nasal cannula to wash the nasal cavity, and the washing solution flowing out of the nasal cavity was collected. did. Various active components in the washing solution were quantified by high performance liquid chromatography, the residual ratio was determined, and the retention of the various active components was evaluated. Table 1 shows the results. [Table 1] Example 1 Ingredients Compounding amount (% by weight) Chlorpheniramine maleate 0.5 Tetrahydrozoline hydrochloride 0.1 Lidocaine 0.3 Benzethonium chloride 0.02 Panassate 810 30 Resinol S-10 0.5 Glycerin 2 l-menthol 0.05 Sodium hydroxide Appropriate amount (preparation pH 8.5) Purified water Total 100 g Chlorpheniramine maleate, tetrahydrozoline hydrochloride, lidocaine, glycerin and benzethonium chloride are dissolved in purified water, and panassate 810 is added to resinol S
-10 0.5% and l-menthol dissolved therein were stirred and mixed, emulsified, and a suitable amount of sodium hydroxide was used to adjust the pH of the preparation to 8.5 and the total amount to 100 g to prepare a nasal drop. Example 2 Ingredients Compounding amount (% by weight) Chlorpheniramine maleate 0.3 Naphazoline hydrochloride 0.1 Lidocaine 0.1 Benzethonium chloride 0.02 Panaceate 810 10 HCO-60 0.2 Resinol S-10 3 Glycerin 1.5 1-Menthol 0.03 Hydroxymethylcellulose 0.02 Sodium hydroxide Appropriate amount (formulation pH 7.5) Purified water Total 100 g A nasal drop was prepared substantially in the same manner as in Example 1. Example 3 Ingredients Compounding amount (% by weight) Chlorpheniramine maleate 0.3 Naphazoline hydrochloride 0.1 Benzethonium chloride 0.02 Soybean oil 20 Tween 80 0.2 Resinol S-10 0.3 Glycerin 1.0 Water Sodium oxide Appropriate amount (formulation pH 8.0) Purified water Total 100 g A nasal drop was prepared substantially in the same manner as in Example 1. Example 4 Ingredients Compounding amount (% by weight) Chlorpheniramine maleate 0.5 Hydrocortisone acetate 0.1 Dipotassium glycyrrhizinate 0.5 Benzethonium chloride 0.02 Panassate 810 10 HCO-60 0.2 Resinol S- 10 0.3 Glycerin 1.5 Hydroxymethylcellulose 0.02 Sodium hydroxide Appropriate amount (preparation pH 7.5) Purified water Total 100 g A nasal drop was prepared substantially in the same manner as in Example 1. Example 5 Ingredients Compounding amount (% by weight) Chlorpheniramine maleate 0.5 Tetrahydrozoline hydrochloride 0.1 Lidocaine 0.3 Benzethonium chloride 0.02 Panassate 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 substantially in the same manner as in Example 1.

──────────────────────────────────────────────────続 き Continuation of the front page (72) Fumio Urushizaki 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (56) References JP-A-4-26617 (JP, A) JP-A-63 -101318 (JP, A) JP-A-6-40949 (JP, A) JP-A-56-49313 (JP, A) JP-A-4-69331 (JP, A) JP-A-5-58884 (JP, A) JP-A-6-100436 (JP, A) JP-A-6-172199 (JP, A) JP-A-5-500062 (JP, A) WO 94/22426 (WO, A1) (58) Fields investigated (Int.Cl. ⁷ , DB name) A61K 9/00-9/72 A61K 47/00-47/48 A61K 45/00-45/08

Claims (1)

(57) [Claim 1] A soybean oil and medium-chain triglyceride containing a vasoconstrictor and an antihistamine as active ingredients.
Oil component 1 to 50 containing at least one selected from lid
An O / W emulsion nasal drop having a pH of 6.5 to 8.5 and containing a surfactant and water in an amount of 0.05 to 5.0 % by weight.