JP4569080B2 - Nasal composition - Google Patents

Description

【００５２】
［結果］表１より、ジェランガムを配合することにより、薬物の鼻粘膜への付着性が高まった。
【００５３】
また、実施例１〜８で調製した各点鼻剤の噴霧性は何れも良好であった。
【００５４】
【発明の効果】
本発明により、抗ヒスタミン薬であるマレイン酸クロルフェニラミンと血管収縮薬を配合した場合には、マレイン酸クロルフェニラミンを選択的に徐放化し、その効果を持続させ、噴霧性良好な点鼻剤を提供することが可能となった。
【００５５】
【図面の簡単な説明】
【図１】 実施例１及び比較対照例１におけるマレイン酸クロルフェニラミンの放出性を示すグラフである。
【図２】 実施例１及び比較対照例１における塩酸テトラヒドロゾリンの放出性を示すグラフである。
【図３】 実施例３及び比較対照例２におけるマレイン酸クロルフェニラミンの放出性を示すグラフである。
【図４】 実施例７及び比較対照例２におけるマレイン酸クロルフェニラミンの放出性を示すグラフである。
【図５】 実施例３及び比較対照例２における塩酸テトラヒドロゾリンの放出性を示すグラフである。
【図６】 実施例７及び比較対照例２における塩酸テトラヒドロゾリンの放出性を示すグラフである。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a nasal composition containing chlorpheniramine maleate, an antihistamine, and more specifically, cyclodextrin is incorporated to selectively control the release of chlorpheniramine maleate in the nasal cavity. It is related with the long-lasting nasal composition.
[0002]
[Prior art]
Conventional nasal drops are generally prepared by preparing a water-soluble drug in the form of a solution and spraying it into the nasal cavity using a nebulizer. For this reason, water-soluble drugs have the advantage that they act directly on the surface layer of the nasal mucosa and the onset of medicinal effects is fast, but on the other hand, there is a disadvantage that the drug is absorbed quickly and the effects are not sustained.
[0003]
By the way, in recent years, the number of people using nasal drops is increasing due to an increase in hay fever, etc., but conventional nasal drops do not maintain their efficacy and require re-administration in a short time. In view of the fact that it is difficult to use, it has been desired to develop a nasal preparation with a sustained effect.
[0004]
On the other hand, some nasal drops that control drug release and maintain their efficacy have been reported. For example, there is disclosed a preparation in which the release of an active ingredient in the nasal mucosa is controlled by using an O / W type to achieve sustained drug efficacy (see Patent Document 1).
[0005]
However, this manufacturing method is complicated, which immediately bounces in the form of an increase in manufacturing cost, and is not yet suitable for practical use.
[0006]
[Patent Document 1]
Japanese Patent Laid-Open No. 7-258069
[Problems to be solved by the invention]
As inferred from the mechanism of action of nasal allergy symptoms, it seems that one of the points for the long-acting nasal drops is to retain the drug on the surface of the nasal mucosa and make it difficult to be absorbed by the nasal mucosa.
[0008]
However, nasal drops, which are a clear one-liquid phase, release the water-soluble drug as an active ingredient very rapidly, and the molecular weight of the topical drug is relatively small, so that it is quickly absorbed from the nasal mucosa. Therefore, it is easy to obtain immediate effect, but it can be said that it is originally unsuitable for retaining the drug in the surface layer of the nasal mucosa to achieve long-lasting effect.
[0009]
In short, water-soluble polymers such as hydroxypropylcellulose and carmellose sodium can be added to increase adhesion to the nasal mucosa, but the viscosity of the nasal fluid also increases, leading to poor sprayability. There is a problem of doing. Further, in this method, since all the active ingredients are uniformly sustained, the immediate effect is reduced, and the merit of nasal drops is reduced. In particular, since vasoconstrictors play an important role in improving nasal congestion, nasal drops that selectively enhance the action of antihistamines are desirable.
[0010]
Therefore, the present invention has a favorable spray property, does not affect the release of other active ingredients such as vasoconstrictors, and selectively and slowly releases chlorpheniramine maleate, an antihistamine. It is an object of the present invention to provide a nasal drop that maintains its effect.
[0011]
[Means for Solving the Problems]
As a result of intensive studies to solve such problems, the present inventors have formulated cyclodextrin with a nasal preparation containing chlorpheniramine maleate, which is an antihistamine, and a vasoconstrictor (tetrahydrozoline, naphazoline). It was found that only the release of chlorpheniramine maleate was delayed, and the release of vasoconstrictors was not affected.
[0012]
Furthermore, by adding a cation-responsive polymer, adhesion retention to the nasal mucosa was improved, but it was confirmed that the viscosity of the nasal fluid was hardly affected and the sprayability was not impaired.
[0013]
One of the embodiments of the present invention completed based on such findings is a nasal composition comprising chlorpheniramine maleate and cyclodextrin for activating the action of chlorpheniramine maleate. It is a thing.
[0014]
Another aspect of the present invention is a nasal composition comprising chlorpheniramine maleate, a vasoconstrictor, and a cyclodextrin for effecting the action of chlorpheniramine maleate. .
[0015]
Another aspect of the present invention is the above-mentioned nasal drop composition characterized in that a cation-responsive polymer is further blended to enhance adhesion retention in the nasal cavity.
[0016]
Another aspect of the present invention is the nasal drop composition wherein the amount of cyclodextrin is 0.4 mol or more per 1 mol of chlorpheniramine maleate.
[0017]
Another aspect of the present invention is the nasal composition described above, wherein the cyclodextrin is α-type cyclodextrin or β-type cyclodextrin.
[0018]
Another aspect of the present invention is the nasal drop composition wherein the vasoconstrictor is tetrahydrozoline or naphazoline.
[0019]
Another embodiment of the present invention is the nasal composition, wherein the cation-responsive polymer is at least one of gellan gum, pectin, and sodium alginate.
[0020]
Another aspect of the present invention is the nasal composition, wherein the cation-responsive polymer is 0.01 to 2.0% by mass of the total nasal composition.
[0021]
Examples of the “action” of “chlorpheniramine maleate” in the present invention include suppression of nasal itching, sneezing, nasal secretion, etc. by binding to histamine receptor and antagonizing histamine. The effect of is activated.
[0022]
As for the compounding quantity of chlorpheniramine maleate, 0.04-0.5 mass% is preferable with respect to the whole nasal drop composition.
[0023]
The “cyclodextrin” used in the present invention is a crown-shaped compound in which D-glucopyranose units are cyclically bonded with α-1,4-glucoside bonds, and is obtained by allowing amylase taken from Bacillus to act on starch. . The number of glucose units is known to be 6, 7 and 8, and is called α-type, β-type and γ-type cyclodextrin. The inclusion compound is formed by incorporating various cations and organic compounds into the ring. The cyclodextrin may be used alone or in combination of two or more. Cyclodextrin may be a derivative. Α-type cyclodextrin or β-type cyclodextrin is preferable in terms of long-acting antihistamines.
[0024]
The compounding amount of cyclodextrin is 0.4 mol or more with respect to 1 mol of chlorpheniramine maleate, and is preferably 0.8 to 1.5 mol in terms of long-acting chlorpheniramine maleate. 0.0 to 1.2 mol is more preferable.
[0025]
The “vasoconstrictor” used in the present invention is a drug that causes vasoconstriction, and examples thereof include epinephrine, ephedrine, naphazoline, tetrahydrozoline, phenylephrine, and methylephedrine, and these include salts. In the present invention, a tetrahydrozoline salt or a naphazoline salt is preferable. Examples of the salt include hydrochloride and nitrate.
[0026]
Examples of the “action” of a vasoconstrictor include elimination of congestion and improvement of nasal congestion by constricting blood vessels and reducing blood flow. In the present invention, the action of cyclodextrin is not affected. .
[0027]
The blending amount of the vasoconstrictor is preferably 0.01 to 0.1% by mass with respect to the entire nasal drop composition.
[0028]
The “cation-responsive polymer” used in the present invention is a polymer that gels in response to cations in the nasal mucosa or nasal mucosa, and examples thereof include gellan gum, pectin, and sodium alginate. Is gellan gum.
The compounding amount of the “cation-responsive polymer” is 0.01 to 2.0% by mass with respect to the whole nasal composition, and the adhesion retention property to the nasal mucosa and the sprayability of the nasal solution are determined. From the point of balance, 0.1 to 0.5 mass% is preferable.
[0029]
In the present invention, “long-acting” refers to adjusting the delay of the onset of the drug effect, or gradually controlling the drug release so that the pharmacological action is maintained to some extent. Synonymous with "sustained release" and "sustained".
[0030]
DETAILED DESCRIPTION OF THE INVENTION
The nasal composition of the present invention can be prepared by dissolving chlorpheniramine maleate, cyclodextrin, other vasoconstrictor, and cation-responsive polymer in purified water. And it can provide as a nasal drop by filling this into the spray device for nasal drops.
[0031]
In that case, an anti-inflammatory agent, a local anesthetic, a bactericide, 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.
[0032]
【Example】
Below, an Example and a test example are given and this invention is demonstrated further in detail.
[0033]
Example 1
Tetrahydrozoline hydrochloride 0.1g
Chlorpheniramine maleate 0.5g
Benzethonium chloride 0.02g
α-cyclodextrin 1.25 g
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 to prepare a total amount of nasal solution of 100 mL. This was filled into a nasal spray device to obtain a nasal spray.
[0034]
(Example 2)
Naphazoline hydrochloride 0.05g
Chlorpheniramine maleate 0.5g
Benzethonium chloride 0.02g
α-cyclodextrin 1.25 g
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 to prepare a total amount of nasal solution of 100 mL. This was filled into a nasal spray device to obtain a nasal spray.
[0035]
(Example 3)
Tetrahydrozoline hydrochloride 0.1g
Chlorpheniramine maleate 0.5g
α-cyclodextrin 1.25 g
Gellan gum 0.2g
Citric acid Appropriate amount Sodium citrate Appropriate amount Glycerin Appropriate amount Disperse gellan gum in purified water and dissolve it. To a total amount of 100 mL of nasal solution.
This was filled into a nasal spray device to obtain a nasal spray.
[0036]
Example 4
Tetrahydrozoline hydrochloride 0.1g
Chlorpheniramine maleate 0.5g
Benzethonium chloride 0.02g
α-cyclodextrin 1.25 g
L-Menthol 0.01g
Polysorbate 80 0.02g
Ethanol 0.1mL
Citric acid Appropriate amount Sodium citrate Appropriate amount Glycerin Appropriate amount Tetrahydrozoline hydrochloride, chlorpheniramine maleate and benzethonium chloride were dissolved in purified water, and then an ethanol mixed aqueous solution of polysorbate 80 in which L-menthol was dissolved was added to pH 4.0, total amount 100 mL of nasal solution was prepared. This was filled into a nasal spray device to obtain a nasal spray.
[0037]
(Example 5)
Tetrahydrozoline hydrochloride 0.1g
Chlorpheniramine maleate 0.5g
Benzethonium chloride 0.02g
β-cyclodextrin 1.25 g
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 to prepare a total amount of nasal solution of 100 mL. This was filled into a nasal spray device to obtain a nasal spray.
[0038]
(Example 6)
Naphazoline hydrochloride 0.05g
Chlorpheniramine maleate 0.5g
Benzethonium chloride 0.02g
β-cyclodextrin 1.25 g
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 to prepare a total amount of nasal solution of 100 mL. This was filled into a nasal spray device to obtain a nasal spray.
[0039]
(Example 7)
Tetrahydrozoline hydrochloride 0.1g
Chlorpheniramine maleate 0.5g
β-cyclodextrin 1.25 g
Gellan gum 0.2g
Citric acid Appropriate amount Sodium citrate Appropriate amount Glycerin Appropriate amount Disperse gellan gum in purified water and dissolve it, then mix aqueous solution in which tetrahydrozoline hydrochloride, chlorpheniramine maleate and β-cyclodextrin are dissolved in advance, and adjust the pH to 5.0 To a total amount of 100 mL of nasal solution.
This was filled into a nasal spray device to obtain a nasal spray.
[0040]
(Example 8)
Tetrahydrozoline hydrochloride 0.1g
Chlorpheniramine maleate 0.5g
Benzethonium chloride 0.02g
β-cyclodextrin 1.25 g
L-Menthol 0.01g
Polysorbate 80 0.02g
Ethanol 0.1mL
Citric acid Appropriate amount Sodium citrate Appropriate amount Glycerin Appropriate amount Tetrahydrozoline hydrochloride, chlorpheniramine maleate and benzethonium chloride were dissolved in purified water, and then an ethanol mixed aqueous solution of polysorbate 80 in which L-menthol was dissolved was added to pH 4.0, total amount 100 mL of nasal solution was prepared. This was filled into a nasal spray device to obtain a nasal spray.
[0041]
(Test Example 1) In vitro drug release test (FIGS. 1 and 2)
[Specimen] The nasal solution prepared in Example 1 was used as a specimen. As a comparative sample, a nasal solution prepared by removing α-cyclodextrin from the formulation of Example 1 (Comparative Control Example 1 in FIGS. 1 and 2) was used.
[0042]
[Test method] In order to evaluate the drug release from nasal drops in an in vitro system, a release test was conducted by applying the paddle method described in the Japanese Pharmacopoeia using a dissolution tester. That is, the specimen was sealed in a cellulose membrane (dialysis membrane, size 36: manufactured by Wako Pure Chemical Industries, Ltd.) sufficiently hydrated with purified water in advance, and immersed in a pseudo-nasal fluid at 37 ° C. (composition is shown below). Then, the amount of the drug that permeated the cellulose membrane was measured over time. The results are shown in FIGS.
[0043]
[Composition of simulated nasal discharge]
NaCl 6.81g
KCl 1.91g
CaCl ₂ · 2H ₂ O 0.59 g
MgCl ₂ · 6H ₂ O 0.13 g
Purified water total 1000mL
[0044]
The pseudo nasal discharge was prepared with reference to the composition of “artificial nasal discharge” described in Toshiyasu Sabe et al. “Rupture of cedar pollen by nasal discharge” (Japan Public Health Magazine Vol. 39, No. 6, P341-P346). Is.
[0045]
[Results] In the formulation of Example 1, there was no change in the release of tetrahydrozoline hydrochloride, but the release of chlorpheniramine maleate was suppressed.
[0046]
(Test Example 2) In vitro drug release test (FIGS. 3-6)
[Specimen] The nasal solution prepared in Example 3 and Example 7 was used as a specimen. As a comparative sample, a nasal solution prepared by removing α-cyclodextrin from the formulation of Example 3 (Comparative Example 2 in FIGS. 3 to 6) was used.
[0047]
[Test Method] A release test was conducted in the same manner as in Test Example 1, and the drug amount was measured. The results are shown in FIGS.
[0048]
[Results] Even when gellan gum, which is a cation-responsive polymer, was blended, the release properties of tetrahydrozoline hydrochloride were not changed in the formulations of Examples 3 and 7 in which cyclodextrin was blended. The release of pheniramine was suppressed.
[0049]
(Test Example 3) Rat Nasal Mucoadhesion Test [Sample] The nasal solution prepared in Example 3 was used as a sample. As a comparative sample, a nasal solution prepared by removing gellan gum from the formulation of Example 3 (Comparative Control Example 3 in Table 1 below) was used.
[0050]
[Test Method] For the purpose of evaluating drug retention in the nasal cavity, a nasal mucosa adhesion test was conducted using rats. Specifically, 25 μL of each specimen was dropped into each rat's nasal cavity using a micropipette, and the nasal mucosa was washed with physiological saline after a certain period of time. The washing liquid was collected, and the amount of drug contained therein (the amount of drug remaining in the nasal cavity) was measured. The results are shown in Table 1 as the ratio (mass%) of the residual drug amount to the drug amount when dropped.
[0051]
[Table 1]
Nasal mucosa adhesion test (in vivo)

[0052]
[Results] From Table 1, the adhesion of the drug to the nasal mucosa was enhanced by adding gellan gum.
[0053]
Moreover, the sprayability of each nasal drop prepared in Examples 1 to 8 was good.
[0054]
【The invention's effect】
According to the present invention, when chlorpheniramine maleate, which is an antihistamine, is combined with a vasoconstrictor, chlorpheniramine maleate is selectively and sustainedly released to maintain its effect and nasal spray with good sprayability. It became possible to provide an agent.
[0055]
[Brief description of the drawings]
FIG. 1 is a graph showing the release properties of chlorpheniramine maleate in Example 1 and Comparative Example 1.
FIG. 2 is a graph showing the release properties of tetrahydrozoline hydrochloride in Example 1 and Comparative Example 1.
FIG. 3 is a graph showing the release properties of chlorpheniramine maleate in Example 3 and Comparative Example 2.
4 is a graph showing the release properties of chlorpheniramine maleate in Example 7 and Comparative Example 2. FIG.
FIG. 5 is a graph showing the release properties of tetrahydrozoline hydrochloride in Example 3 and Comparative Example 2.
6 is a graph showing the release properties of tetrahydrozoline hydrochloride in Example 7 and Comparative Example 2. FIG.

Claims (6)

A nasal composition comprising chlorpheniramine maleate, tetrahydrozoline hydrochloride , and α-type or β-type cyclodextrin for activating the action of chlorpheniramine maleate. A nasal preparation composition comprising chlorpheniramine maleate, naphazoline hydrochloride, and α-type or β-type cyclodextrin for effecting the action of chlorpheniramine maleate. The nasal drop composition according to claim 1 or 2 , further comprising a cation-responsive polymer to enhance adhesion retention in the nasal cavity. The nasal drop composition according to claim 1 or 2 , wherein the amount of α-type or β-type cyclodextrin is 0.4 mol or more per 1 mol of chlorpheniramine maleate. The nasal drop composition according to claim 3 , wherein the cation-responsive polymer is at least one of gellan gum, pectin and sodium alginate. Nasal composition according to claim 3 cation-responsive polymer is 0.01 to 2.0% by weight of the total nasal composition.

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