JPH10139666A - Liquid agent and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a liquid agent for suppressing lowering of content of fumaric acid ketotifen or coloring of liquid agent over a long period. SOLUTION: This liquid agent is composed of ketotifen or its fumaric acid salt, a nitrogen-containing water-soluble polymer and at least one kind of stabilizer selected from a sulfite, a hydrogensulfite and a chelating agent. The nitrogen-containing water-soluble polymer may be polyvinylpyrrolidone. The content of the nitrogen-containing water-soluble polymer is 0.1-30(W/V)% based on total amount of the liquid agent. The stabilizer may be at least one kind of compound selected from an alkali metal sulfite, an alkali metal hydrogensulfite, edetic acid or its salt and citric acid or its salt and the content of the stabilizer may be about 0.001-1.0(W/V)% based on total amount of the liquid agent. The ratio of the stabilizer is 0.1-10 pts.wt. to 100 pts.wt. nitrogen- containing water-soluble polymer.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a ketotifen or a fumarate-containing solution thereof and a method for producing the same.

[0002]

2. Description of the Related Art Ketotifen or its fumarate salt (hereinafter, ketotifen fumarate may be simply referred to as ketotifen fumarate) has an antiallergic action and an antihistamine action, and is used for nasal drops, eye drops, topical drugs and the like. Has been recognized as effective. However, in the liquid preparation containing ketotifen fumarate, the preparation is easily colored and the amount of the active ingredient is reduced with the passage of time.

[0003] With respect to an ophthalmic solution containing ketotifen fumarate,
JP-A-62-277323 proposes to improve stability over time by blending a polyhydric alcohol such as glycerin, polyethylene glycol or D-mannitol as an isotonic agent instead of an inorganic salt. Kaihei 7-32
No. 4034 proposes improving stability over time by blending boric acid, a chelating agent (sodium edetate, sodium citrate) and an amino acid. Further, JP-A-8-20538 discloses that
By using a water-soluble organic acid (C _1-5 aliphatic carboxylic acid, C _1-5 hydroxycarboxylic acid, C _1-10 polycarboxylic acid, C _1-5 aminocarboxylic acid) and / or a salt thereof in combination It has been proposed to improve the stability over time. In addition, antiallergic eye drops containing ketotifen fumarate usually contain benzalkonium chloride, glycerin and the like.

[0004] In addition, WO 91/02528 is intended to improve the stability over time of an external preparation containing ketotifen fumarate by adding bisulfite, sulfite, pyrosulfite and dibutylhydroxytoluene as additives. Has been proposed.

[0005] However, these documents do not consider the stability of a liquid preparation (decrease in the content of ketotifen fumarate or coloring of a drug solution) due to the addition of a nitrogen-containing water-soluble polymer.

Further, as a remedy for allergic rhinitis containing ketotifen fumarate, nasal drops containing polyvinylpyrrolidone, sodium pyrosulfite and ascorbic acid are known. However, this rhinitis treatment agent,
When stored in an open system, the stability of ketotifen fumarate is impaired, and the effective amount of ketotifen fumarate decreases significantly with time and becomes markedly colored. For example, after opening the bottle container containing the therapeutic agent for rhinitis, attaching a rhinitis spray and changing over time for 2 weeks and 4 weeks at 60 ° C., the content of ketotifen fumarate is 90% and 76%, respectively.
%. Also, the drug solution is colored yellow. Therefore, there is a need for the development of a liquid preparation containing ketotifen fumarate which is stable over time.

[0007]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a liquid preparation capable of suppressing a decrease in content and coloring of ketotifen or its fumarate over a long period of time, and a method for producing the same. Another object of the present invention is to
An object of the present invention is to provide a liquid preparation which has an excellent feeling in use and is useful as nasal drops and the like, and a method for producing the same.

[0008]

Means for Solving the Problems The present inventors have conducted intensive studies to achieve the above object, and as a result, have found that ketotifen or its fumarate salt contains a nitrogen-containing water-soluble polymer, an alkali metal sulfite, an alkali metal bisulfite and It has been found that when a stabilizer selected from chelating agents is used, ketotifen or its fumarate salt is excellent in stability over time and can be used without coloration, and the present invention has been completed. That is, the liquid preparation of the present invention is composed of ketotifen or its fumarate, a nitrogen-containing water-soluble polymer, and at least one stabilizer selected from alkali metal sulfites, alkali metal bisulfites and chelating agents. .
In this liquid preparation, the content of the nitrogen-containing water-soluble polymer may be about 0.1 to 30 (W / V)% of the whole components of the liquid preparation. The stabilizer can be at least composed of at least one of an alkali metal sulfite, an alkali metal bisulfite, edetic acid or a salt thereof, and citric acid or a salt thereof.
It may be about 001 to 1.0 (W / V)%. Further, the ratio of the stabilizer is as follows.
The ratio of the stabilizer to the weight part may be 0.1 to 10 parts by weight.

Further, the present invention relates to a ketotifen or a fumarate thereof, a nitrogen-containing water-soluble polymer, and at least one selected from an alkali metal sulfite, an alkali metal bisulfite, edetic acid or a salt thereof, and citric acid or a salt thereof. And a method for producing a liquid preparation by mixing the same.

[0010]

DETAILED DESCRIPTION OF THE INVENTION The liquid preparation of the present invention comprises ketotifen or a fumarate thereof, a nitrogen-containing water-soluble polymer, and a stabilizer selected from alkali metal sulfites, alkali metal sulfites and chelating agents. It is configured.
Hereinafter, these components will be described.

[Ketotifen or its fumarate] In the present invention, ketotifen or its fumarate is used as an active ingredient. The active ingredient may be used as free ketotifen, but is usually used as ketotifen fumarate. The amount of ketotifen or its fumarate used is, for example, 0.001 to 10 depending on the type of liquid such as nasal drops, eye drops, syrups and aerosols.
(W / V)%, preferably 0.005 to 5 (W / V)
%, More preferably about 0.01 to 1 (W / V)%, and usually about 0.01 to 0.5 (W / V)%.

[Nitrogen-containing water-soluble polymer] The type of the nitrogen-containing water-soluble polymer is not particularly limited as long as it is a water-soluble polymer containing nitrogen. For example, polyvinylpyrrolidone, animal mucilage [chondroitin sulfate or a salt thereof (sodium Salt), hyaluronic acid or a salt thereof (such as a sodium salt)], and the like. These components can function as a thickener and can be used alone or in combination of two or more.

[0013] These nitrogen-containing water-soluble polymers can be selected according to the type of liquid agent and the like. For example, when used for nasal drops or sprays, polyvinylpyrrolidone, which has good sprayability and can produce fine spray particles, is preferred.
Nitrogen-containing water-soluble polymers (especially polyvinylpyrrolidone)
When used as a viscosity modifier (thickening agent) for nasal drops, it improves the adsorptivity to the nasal mucosa, is easily removed from the nasal mucosa, can retain water for a long time, and forms a protective film. Can protect the nasal mucosa from dust and bacteria from the outside world. Therefore, when a nitrogen-containing water-soluble polymer (particularly, polyvinylpyrrolidone) is used in a liquid preparation (such as a nasal drop or a spray) that requires the formation of fine particles by spraying, the usability can be improved.

The weight-average molecular weight of the nitrogen-containing water-soluble polymer is, for example, from 0.5 × 10 ⁴ to depending on the desired viscosity increase.
100 × 10 ⁴ , preferably 1 × 10 ⁴ to 50 × 10
⁴ , in particular, about 1 × 10 ⁴ to 10 × 10 ⁴ , and usually about 2 × 10 ^{4 to} 5 × 10 ⁴ .

The amount of the nitrogen-containing water-soluble polymer used can be appropriately selected according to the purpose of the liquid preparation. In particular, the amount of the nitrogen-containing water-soluble polymer used in the case of nasal drops has a spray property,
It can be appropriately selected within a range that balances the adsorptivity and removal properties with the nasal mucosa, has water retention, and can exert the protective properties on the nasal mucosa. The amount of the nitrogen-containing water-soluble polymer to be used is, for example, 0.1 to 30 (W / V)%, preferably 0.5 to 15 (W / V)%, and more preferably 1 to 30 (W / V)% based on the whole liquid.
-10 (W / V)%, particularly 1-5 (W / V)
V)%.

Nitrogen-containing water-soluble polymers include other water-soluble polymers such as cellulose derivatives (methylcellulose, ethylcellulose, hydroxyethylcellulose,
Hydroxypropylcellulose, hydroxypropylmethylcellulose, carmellose sodium, etc.), carboxyvinyl polymer, polyvinyl alcohol, polyoxyalkylene glycol (polyethylene glycol,
It may be used in combination with an ethylene oxide-propylene oxide block copolymer), a plant mucilage (such as sodium alginate), and the like.

[Stabilizer] The stabilizer used in the liquid preparation of the present invention contains at least one of a sulfite, a bisulfite and a chelating agent. When such a stabilizer is combined with a nitrogen-containing water-soluble polymer (particularly, polyvinylpyrrolidone), it is possible to prevent a decrease in the content of ketotifen or fumarate and a coloring while maintaining good usability by the nitrogen-containing water-soluble polymer. it can. Sulfites and bisulfites are known to have a reducing action. The type of the sulfite or bisulfite is not particularly limited, and examples thereof include a sulfite [ammonium sulfite, an alkali metal sulfite (K, Na, Li salt)] and a bisulfite [ammonium hydrogen sulfite, an alkali metal bisulfite. Salt (K, N
a, Li salt)].

The pyrosulfite or ascorbic acid or a salt thereof described in the above-mentioned literature also has a reducing action, similarly to the sulfite and the bisulfite. However, the function of sulfites and bisulfites is different from the combination of pyrosulfite and ascorbic acid or a salt thereof when combined with a nitrogen-containing water-soluble polymer. For example, in a state where it can come into contact with air,
When stored at 60 ° C. for 4 weeks, when a sulfite or a bisulfite is used, the ketotifen fumarate in the solution is 95%.
Residue by weight or more and hardly colored. On the other hand, when pyrosulfite and ascorbic acid or a salt thereof and a nitrogen-containing water-soluble polymer are combined, stability is unexpectedly remarkably reduced, and the effective amount of ketotifen fumarate is reduced to about 75% by weight under the above storage conditions. Decreases and coloring is remarkable.

The type of the chelating agent is not particularly limited, and examples thereof include polyaminocarboxylic acids (eg, ethylenediaminetetraacetic acid or a salt thereof (eg, sodium edetate)) and oxycarboxylic acids (eg, citric acid, tartaric acid, malic acid, etc.). C _2-6 oxycarboxylic acid) or a salt thereof (an alkali metal salt of C _2-6 oxycarboxylic acid such as an ammonium salt, a sodium salt, and a potassium salt).

These stabilizers can be used alone or in combination of two or more. Preferred compounds include sulfites (eg, sodium sulfite), bisulfites (eg, sodium bisulfite), and preferred chelating agents are ethylenediaminetetraacetates (particularly, alkali metal edetates such as sodium edetate). , Citric acid or a salt thereof (such as sodium citrate).

The stabilizer is appropriately selected in consideration of the content of ketotifen or fumarate and the type and amount of the nitrogen-containing water-soluble polymer, as long as the content of ketotifen or fumarate can be prevented from being reduced or colored. it can. The amount of the stabilizer used is, for example, 0.001 to 1.0 of the entire solution.
(W / V)%, preferably 0.002 to 0.5 (W / V)
V)%, more preferably 0.005 to 0.3 (W /
V)%. The amount of the stabilizer used is, for example, based on 100 parts by weight of the nitrogen-containing water-soluble polymer.
0.1 to 10 parts by weight (for example, 0.2 to 8 parts by weight), preferably about 0.2 to 5 parts by weight.

[Additives] The liquid preparation of the present invention may further comprise, as an isotonic agent, polyhydric alcohols (such as glycerin, propylene glycol, sorbitol, mannitol, and xylitol), boric acid or a salt thereof, sodium chloride, and phosphate. May be included. The amount of the tonicity agent can be appropriately selected according to the type of the liquid agent. For example, when used for nasal drops, the osmotic pressure ratio of the liquid preparation (the ratio of the osmotic pressure of the sample to the osmotic pressure of a 0.9 (W / V)% sodium chloride solution) is 0.1.
It can be selected in the range of about 5 to 2. The addition amount of the tonicity agent is usually 0.1 to 10 (W / V)%, preferably 0.5 to 7 (W / V)%, more preferably 0.5 to 5 (W / V)% of the whole liquid preparation. (W / V)%. In addition, the liquid preparation of the present invention further includes, as preservatives, paraoxybenzoic acid esters, chlorobutanol, phenethyl alcohol, sorbic acid and salts thereof, and cationic preservatives (quaternary ammonium salts such as benzalkonium chloride). May be used. The preservative can be appropriately selected according to the type of the liquid preparation.

Further, in the case of a liquid preparation, a p-adjusting agent (for example, a base such as sodium hydroxide, an acid such as hydrochloric acid, etc.)
H3 to 7 may be adjusted. Further, other components, for example, alcohols and surfactants may be added according to the type of the liquid preparation.

[Production Method] The liquid preparation of the present invention is prepared by mixing the above ketotifen or fumarate, a nitrogen-containing water-soluble polymer, a stabilizer, and, if necessary, an isotonic agent and a preservative together with water. Can be prepared by dissolution.
The water is not limited to sterilized water or purified water, and may be an isotonic solution (such as a physiological saline solution or an aqueous boric acid solution) or a buffer solution. The liquid agent can be usually obtained by adjusting the pH of the mixed solution with a base such as sodium hydroxide or an acid such as hydrochloric acid, and adjusting the total amount to a predetermined amount, followed by filtration, and may be subjected to a sterilization treatment. The solution can be sterilized by filtration sterilization, pressure sterilization by a high-pressure steam method, or the like.

[Use Aspects] The liquid preparations of the present invention include various liquid preparations utilizing the activity of ketotifen or fumarate, such as mucosal preparations (such as nasal drops and eye drops), oral liquid preparations (such as syrups), It can be used for external preparations for transdermal administration (aerosols, lotions, creams, etc.). In particular, it is preferably used for nasal drops in view of the balance between sprayability, adsorbability to nasal mucosa and removability, water retention, and excellent use sensation with excellent protection against nasal mucosa. Preferred nasal drops are, as the whole liquid, 0.01 to 1 (W / V)% of ketotifen fumarate, 1 to 10 (W / V)% of polyvinylpyrrolidone, sulfite, bisulfite, edetic acid or the like. Salt, at least one stabilizing agent selected from citric acid or a salt thereof,
0.3 (W / V)%.

The nasal solution is usually stored in a sealed container. In use, it is usually used by attaching a spray to the container and spraying. The liquid preparations of the present invention (such as nasal drops) are not only sealed but also stored in a state in which they can be brought into contact with air. For a long period of time, the content of ketotifen fumarate does not decrease and the liquid preparations are colored. Absent.

[0027]

EXAMPLES The present invention will be described below in more detail with reference to Examples, but the present invention is not limited to these Examples. [Nitrogen-containing water-soluble polymer] The nitrogen-containing water-soluble polymer used was polyvinylpyrrolidone (povidone).
Povidone K-17 (weight average molecular weight about 1 × 10 ⁴ ),
Povidone K-25 (weight average molecular weight about 2.5 × 1
0 ^4), povidone K-30 (weight average molecular weight of about 4 × 1
0 ⁴ ).

Example 1 Ketotifen fumarate 75.6 mg, glycerin 280
0 mg, 2000 mg of povidone K-30, 80 mg of sodium bisulfite and 10 mg of benzalkonium chloride are dissolved in purified water, and the pH is adjusted to 4.2 with sodium hydroxide. The total amount was adjusted to 100 ml, and nasal drops were obtained after filtration.

Example 2 Ketotifen fumarate 75.6 mg, glycerin 280
0 mg, 2000 mg of povidone K-30, 10 mg of sodium bisulfite, and 10 mg of benzalkonium chloride are dissolved in purified water, and the pH is adjusted to 4.2 with sodium hydroxide. The total amount was adjusted to 100 ml, and nasal drops were obtained after filtration.

Example 3 Ketotifen fumarate 75.6 mg, glycerin 280
0 mg, 2000 mg of povidone K-30, 25 mg of sodium sulfite, and 10 mg of benzalkonium chloride are dissolved in purified water, and adjusted to pH 4.2 with hydrochloric acid. 10 total
The volume was adjusted to 0 ml, and nasal drops were obtained after filtration.

Example 4 Ketotifen fumarate 75.6 mg, glycerin 280
0 mg, 2000 mg of povidone K-30, 25 mg of sodium edetate, and 10 mg of benzalkonium chloride are dissolved in purified water, and adjusted to pH 4.2 with sodium hydroxide. The total amount was adjusted to 100 ml, and nasal drops were obtained after filtration.

Example 5 Ketotifen fumarate 75.6 mg, glycerin 280
0 mg, 2000 mg of povidone K-30, 15 mg of sodium edetate, and 10 mg of benzalkonium chloride are dissolved in purified water, and adjusted to pH 4.2 with sodium hydroxide. The total amount was adjusted to 100 ml, and nasal drops were obtained after filtration.

Example 6 75.6 mg of ketotifen fumarate, glycerin 280
0 mg, 2000 mg of povidone K-30, 25 mg of sodium citrate and 10 mg of benzalkonium chloride are dissolved in purified water, and adjusted to pH 4.2 with sodium hydroxide. The total amount was adjusted to 100 ml, and nasal drops were obtained after filtration.

Example 7 Ketotifen fumarate 75.6 mg, glycerin 280
0 mg, 3000 mg of povidone K-30, 50 mg of sodium bisulfite and 10 mg of benzalkonium chloride are dissolved in purified water, and adjusted to pH 4.2 with sodium hydroxide. The total amount was adjusted to 100 ml, and nasal drops were obtained after filtration.

Example 8 Ketotifen fumarate 75.6 mg, glycerin 280
0 mg, 4000 mg of povidone K-30, 100 mg of sodium bisulfite, 10 mg of benzalkonium chloride
Is dissolved in purified water and adjusted to pH 4.2 with sodium hydroxide. The total amount was adjusted to 100 ml, and nasal drops were obtained after filtration.

Comparative Example 1 Ketotifen fumarate 75.6 mg, glycerin 280
0 mg, 3500 mg of povidone K-17 and 10 mg of benzalkonium chloride are dissolved in purified water, and adjusted to pH 4.2 with sodium hydroxide. The total amount was adjusted to 100 ml, and nasal drops were obtained after filtration.

Comparative Example 2 Ketotifen fumarate 69 mg, glycerin 2500 m
g, 2000 mg of povidone K-25 and 10 mg of benzalkonium chloride are dissolved in purified water, and adjusted to pH 5.3 with sodium hydroxide. The total amount was adjusted to 100 ml, and nasal drops were obtained after filtration.

Comparative Example 3 Ketotifen fumarate 69 mg, glycerin 2500 m
g, boric acid 320 mg, povidone K-25 2000 m
g, 10 mg of benzalkonium chloride dissolved in purified water,
Adjust to pH 5.3 with sodium hydroxide. 10 total
The volume was adjusted to 0 ml, and nasal drops were obtained after filtration.

Comparative Example 4 Ketotifen fumarate 69 mg, glycerin 2500 m
g, 150 mg of sodium chloride and 2 parts of povidone K-25.
000 mg and 10 mg of benzalkonium chloride are dissolved in purified water and adjusted to pH 5.3 with sodium hydroxide. The total amount was adjusted to 100 ml, and nasal drops were obtained after filtration.

Comparative Example 5 Ketotifen fumarate 75.6 mg, glycerin 250
0 mg, sodium chloride 500 mg, povidone K-17
Is dissolved in purified water, and the pH is adjusted to 4.2 with sodium hydroxide. 3,000 mg, 25 mg of sodium pyrosulfite, 50 mg of ascorbic acid and 10 mg of benzalkonium chloride are dissolved in purified water. The total amount was adjusted to 100 ml, and nasal drops were obtained after filtration. Table 1 shows the proportions of the examples and comparative examples.

[0041]

[Table 1] The nasal solutions obtained in Examples 1 to 8 and Comparative Examples 1 to 5 were filled into plastic nasal containers to prepare samples, which were stored at 60 ° C for 2 weeks and 4 weeks. The change with time was examined by evaluating the residual ratio and the coloring property.

[Residual rate] The residual amount of ketotifen fumarate was measured by a liquid chromatographic method for the sample after storage for a predetermined time. Table 2 shows the results.

The liquid chromatography was carried out as follows. The sample solution accurately measures 2 ml of nasal drops,
2 ml of an internal standard solution (a solution of ethyl parahydroxybenzoate in methanol) was precisely added, and the following mobile phase was further added to adjust the volume to 20 ml. On the other hand, the standard solution was prepared in the same manner as the sample solution after weighing the ketotifen fumarate for quantification corresponding to the sample solution and adding and dissolving the mobile phase.

Mobile phase: 0.0433 (W / V)% of 1-
A mixed solution of 5 parts by volume of an aqueous solution (pH 3.3) containing octanesulfonic acid and 0.136 (W / V)% potassium dihydrogen phosphate and 2 parts by volume of acetonitrile and liquid chromatography [detection wavelength: 280 n
m, column: Inertsil ODS-2 (4.
6 mm, 150 mm in length, filled with octadecylsilylated silica gel having a particle diameter of 5 μm) and a temperature of 40 ° C.], to determine the peak area ratio of the sample solution and the standard solution to the internal standard solution, respectively, Calculated.

[0045]

[Table 2] As is clear from Table 2, the liquid preparations of Examples 1 to 8 have a high residual ratio of ketotifen fumarate of 95% or more over a long period of time as compared with the comparative examples, and can stabilize ketotifen fumarate.

[Colorability] The color of the sample before storage and after storage for a predetermined time was measured at a wavelength of 400 nm. Note that the absorbance was measured with the ultraviolet absorbance of water at a wavelength of 400 nm set to “0”. Table 3 shows the results.

[0047]

[Table 3] As is clear from Table 3, the liquid preparations of Examples 1 to 8 were almost colorless and transparent and did not cause coloring, whereas the comparative examples were colored yellow. Therefore, when the liquid preparation of the present invention is used, coloring of the liquid preparation can be effectively prevented for a long period of time.

[0048]

Since the liquid preparation of the present invention comprises ketotifen or its fumarate, a nitrogen-containing water-soluble polymer and a specific stabilizer, the content of ketotifen or its fumarate over a long period of time is reduced. And coloring of the liquid preparation can be greatly suppressed.

Further, since a nitrogen-containing water-soluble polymer is used, the feeling of use can be improved.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 47/32 A61K 47/32 J (72) Inventor Isao Hanase 148 Shimo-Iino, Toyama City, Toyama Prefecture (72) Inventor Tatsuaki Soma 426 Aiki, Uozu City, Toyama Prefecture

Claims (8)

[Claims] 1. Ketotifen or a fumarate thereof,
A liquid formulation comprising a nitrogen-containing water-soluble polymer and at least one stabilizer selected from sulfites, bisulfites and chelating agents. 2. The liquid preparation according to claim 1, wherein the nitrogen-containing water-soluble polymer is composed of polyvinylpyrrolidone. 3. The liquid preparation according to claim 1, wherein the stabilizer is at least one selected from an alkali metal sulfite, an alkali metal bisulfite, edetic acid or a salt thereof, and citric acid or a salt thereof. 4. The liquid preparation according to claim 1, wherein the content of the nitrogen-containing water-soluble polymer is 0.1 to 30 (W / V)% of the whole liquid preparation. 5. The method according to claim 1, wherein the content of the stabilizer is 0.0
The liquid preparation according to claim 1, wherein the liquid preparation is from 0.01 to 1.0 (W / V)%. 6. The liquid preparation according to claim 1, wherein the ratio of the stabilizer is 0.1 to 10 parts by weight based on 100 parts by weight of the nitrogen-containing water-soluble polymer. 7. The liquid solution as a whole, comprising 0.01 to 1 (W / V)% of cytokefen fumarate, 1 to 10 (W / V)% of polyvinylpyrrolidone, sulfite, bisulfite, edetic acid or At least one stabilizer selected from the group consisting of a salt thereof, citric acid and a salt thereof, in an amount of 0.005 to 0.3 (W /
V) Nasal drops containing%. 8. Ketotifen or a fumarate thereof,
A method for producing a liquid preparation, comprising mixing a nitrogen-containing water-soluble polymer with at least one stabilizer selected from a sulfite, a hydrogen sulfite, and a chelating agent.