KR101519673B1 - Pirenoxine-containing suspension-type aqueous preparation - Google Patents

Abstract

It is an object of the present invention to inhibit the adhesion of pyrinoxine in a suspension type aqueous solution to a container. By containing at least one member selected from the group consisting of polyoxyethylene hardened castor oil and trometamol in the suspension type aqueous solution, it is possible to inhibit the adhesion of pyrinoxine to the container.

Description

PIRENOXINE-CONTAINING SUSPENSION-TYPE AQUEOUS PREPARATION [0002]

The present invention relates to a suspension type aqueous solution containing a pyrinoxine, wherein the aqueous solution contains at least one member selected from the group consisting of polyoxyethylene hardened castor oil and trometamol, The present invention relates to a method for inhibiting the adhesion of pyranthins contained in an inhibited aqueous solution and a suspension-type aqueous solution to a container.

Pyrrenoxine is used as a therapeutic drug for early senile cataracts, and in particular, a suspension-type eye drop (Patent Document 1) is widely used. Since this eyedrop is a suspension liquid, if it is stored in a stable state, the pyrinoxine dispersed in the liquid is precipitated, and the liquid agent becomes uneven. Therefore, it is necessary to disperse the pyrinoxine in the liquid agent uniformly by shaking the eyedropper before use.

Here, in such a suspension-type pyrinoxine-containing product, the pyrrenoxin in the suspension liquid agent may be fixed on the inner surface of the container due to the change of the preservation state (preservation posture, storage temperature, etc.). As an example in which pyrenxin is adhered to a container, pyrrenoxine in a suspension liquid settled by political preservation is exposed to the pores of the container by a change in the storage posture such as rolling of the container, It can be considered to be fixed. The attachment of the pyrinoxine to the container is unlikely to occur if the container is in an erected state, but it is believed that fixation of the pyrinoxine to the container may occur when the distribution process and the situation at the time of use are considered. In addition, depending on the storage state of the container, there may be a case where the adhesion of the pyrinoxine to the liquid contact portion of the container occurs as well as the gap portion of the container. When pyrinoxine is adhered to the container in this way, a long shaking is required to uniformly disperse the pyrinoxine.

Accordingly, there is a demand for a suspension-type aqueous liquid agent containing pyrinoxine in which the pirenoxine in the suspension liquid agent is hardly fixed to the container, that is, the attachment to the container is suppressed in the distribution process or the storage process.

Patent Document 1 discloses a pyrinoxine suspended-type eye drop, and as a prescription example thereof, polyoxyethylene hardened castor oil is contained as a surfactant. However, Patent Document 1 does not disclose that the pyrinoxine is fixed to the container.

Further, in Patent Document 2, it is described that the blending of the cellulose-based polymer in the suspension liquid makes it possible to easily disperse the pyrinoxine fixed to the container in the liquid. However, Patent Document 2 does not describe a suspension liquid containing polyoxyethylene hardened castor oil or trometamol, and further containing no cellulose-based polymer such as hydroxypropylmethylcellulose or methylcellulose.

Patent Document 1: Japanese Patent Publication No. 7-037386

Patent Document 2: International Publication No. 2006/030851 pamphlet

DISCLOSURE OF INVENTION

Problems to be solved by the invention

Accordingly, an object of the present invention is to provide a suspension type aqueous solution containing pyrinoxine, wherein the aqueous solution does not contain a cellulose-based polymer such as hydroxypropylmethylcellulose or methylcellulose, Aqueous solution containing a surfactant.

Means for solving the problem

Therefore, as a result of intensive studies, the present inventors have found that, among the commonly used additive for eyedrops, at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil and trometamol is contained, whereby hydroxypropylmethylcellulose, methylcellulose The present inventors have found that pyranthins can be prevented from sticking to a container without containing a cellulosic polymer such as polyvinyl alcohol.

That is, the present invention relates to a suspension-type aqueous solution containing pyrinoxine, wherein the aqueous solution contains at least one member selected from the group consisting of polyoxyethylene hydrogenated castor oil and trometamol, Hydroxypropyl methylcellulose, methylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.

In another aspect of the present invention, there is provided a method for producing a water-in-oil type aqueous solution, which comprises blending at least one member selected from the group consisting of polyoxyethylene hardened castor oil and trometamol in a suspension type aqueous solution containing pyrinoxine, It is a method to inhibit the fixation of the ginseng to the container.

Examples of the polyoxyethylene hydrogenated castor oil used in the present invention include polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60. The concentration of the polyoxyethylene hydrogenated castor oil is not particularly limited as long as it is a concentration at which the effect of inhibiting the fixation of pyrrenoxine in the aqueous solution to the container can be confirmed, but is preferably 0.0005 to 0.5% (W / V) (W / V), more preferably 0.005 to 0.05% (W / V), and most preferably 0.01 to 0.03% (W / V).

The concentration of trometamol used in the present invention is not particularly limited as long as it is a concentration at which the effect of inhibiting the fixation of pyrrenoxine in the aqueous solution to the container can be confirmed, but is preferably 0.1 to 3.0% (W / V) More preferably, it is 0.5 to 2.0% (W / V).

The content of pyrrenoxine used in the present invention is not particularly limited as long as it is a concentration capable of exerting a therapeutic effect, but is preferably 0.001 to 0.01% (W / V), more preferably 0.005% (W / V) to be. Currently, the concentration used for treatment is 0.005 g in 100 ml.

The pyrenoxin source powder used in the present invention is preferably sterilized by a commonly used method such as dry heat sterilization, gamma sterilization, electron beam sterilization or ethylene oxide gas sterilization, and sterilized by gamma radiation. The gamma-ray sterilization treatment is not particularly limited as long as it is a commonly used method of sterilization treatment using a gamma ray. For example, the sterilization treatment is carried out by irradiating pyrethrosine raw material with an irradiation dose of 25 kGy or more.

The material of the container for preserving the aqueous liquid preparation of the present invention may be any material that is generally used as a container for eyedrops, and examples thereof include polypropylene, propylene-ethylene copolymer, polyethylene, polyethylene terephthalate, polyvinyl chloride, acrylic resin, polystyrene And the like.

The aqueous liquid agent according to the present invention can inhibit the adhesion of pyrinoxine to the container, even if it does not contain a cellulose-based polymer. Here, the "cellulose-based polymer" refers to a cellulose-based polymer described in WO2006 / 030851, and specifically refers to hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, or hydroxypropylcellulose.

The eyedrops of the present invention can be prepared by the method according to Patent Document 1. If necessary, an isotonic agent, a preservative, a pH adjusting agent, a surfactant and the like can be added. As a representative example of the preparation method of the present invention, the following methods can be mentioned. First, isotonic agents, preservatives, pH adjusters, surfactants, stabilizers, etc., which are excipients commonly used as eye drops, are added to sterilized purified water as needed and dissolved. After adding pyrinoxine to this solution, it is suspended using various homogenizer, mixer, mill or ultrasonic waves. If necessary, adjust the pH by adding a pH adjuster. The pH of the eye drop of the present invention is preferably in the range of 3 to 5.5, more preferably in the range of 3 to 4.5.

Examples of isotonic agents include glycerin, propylene glycol, polyethylene glycol, trihalose, sucrose, sorbitol, mannitol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like.

Examples of the preservative include benzalkonium chloride, methylparaben, ethylparaben, propylparaben, butylparaben, and chlorobutanol.

Examples of the pH adjusting agent include hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like.

Examples of the surfactant include polysorbate 80, polyoxyl 35 castor oil, sucrose fatty acid ester, and stearic acid polyoxyl 40.

Examples of the stabilizer include edetic acid and sodium edetate.

Effects of the Invention

Although it will be described in detail in the section of Examples to be described later, in the tests of the examples, it was confirmed that by containing a polyoxyethylene hydrogenated castor oil or trometamol in a suspension type aqueous solution containing pyrinoxine, And it is possible to inhibit sticking to the container. That is, the present invention relates to a suspension-type aqueous solution containing pyrinoxine, wherein the aqueous solution contains at least one member selected from the group consisting of polyoxyethylene hydrogenated castor oil and trometamol, And to provide an aqueous liquid agent containing no cellulose-based polymer.

Example 1

To determine whether the pyrinoxine in the suspension type aqueous solution adhered to the container.

(Preparation of Test Solution)

1) Comparative formulation 1 was prepared as follows.

To the sterilized purified water (80 ml), concentrated glycerin (2.6 g), polysorbate 80 (0.005 g) and benzalkonium chloride (0.005 g) were added and dissolved and diluted hydrochloric acid and aqueous sodium hydroxide solution were added to adjust the pH to 3.5. After that, pyrrenoxine (0.005 g) was added and the whole was suspended by a homogenizer. When a change in pH was confirmed, the pH was adjusted to 3.5 by adding diluted hydrochloric acid and aqueous sodium hydroxide, and sterilized purified water And the total volume was adjusted to 100 ml. Thus, an aqueous solution of comparative formulation 1 was obtained.

2) Comparative formulation 2 was prepared as follows.

Comparative preparation 2 was prepared by carrying out the same operations as those in the preparation method of comparative formulation 1 except that 0.005 g of stearic acid polyoxyl 40 was used instead of polysorbate 80 (0.005 g).

3) Prescription 1 was prepared as follows.

Preparation 1 was prepared by carrying out the same operations as in the preparation method of Comparative Preparation 1 except that polyoxyethylene hardened castor oil 60 (0.005 g) was used instead of polysorbate 80 (0.005 g).

4) Prescription 2 was prepared as follows.

Formulation 2 was prepared by carrying out the same operations as the preparation method of Comparative Preparation 1 except that polyoxyethylene hardened castor oil 60 (0.01 g) was used instead of polysorbate 80 (0.005 g).

5) Prescription 3 was prepared as follows.

Preparation 3 was prepared by carrying out the same procedure as in the preparation method of Comparative Preparation 1 except that trometamol (1.8 g) was used instead of concentrated glycerin (2.6 g).

Table 1 shows comparative prescriptions 1 to 2 and prescriptions 1 to 3. The polyoxyethylene hardened castor oil 60 was manufactured by Nihon Surfectant Kogyo Co., and the trometamol manufactured by Wako Pure Chemical Industries, Ltd. was used.

[Table 1]

(Effect Judging Method 1-1)

The test liquids of Comparative Preparations 1 and 2 and Preparations 1 and 3 prepared above were filled into 10 ml of 5 ml dropper containers. The container was set and stored for 1 week under the condition of 25 ° C / 40% RH, then the container was slowly rolled and stored for 1 week under the same conditions. After the preservation was completed, the inhibitory effect on the fixation of pyrinoxine on the bottom of the container in each prescription was examined.

(Effect Judging Method 1-2)

The test liquids of Comparative Preparations 1 and 2 and Preparations 1 to 3 prepared above were filled into 10 ml of 5 ml dropper containers. The container was set and stored for one week under the conditions of 25 ° C / 40% RH, and then the container was slowly rolled and stored for two weeks under the same conditions. After the preservation was completed, the inhibitory effect on the fixation of pyrinoxine on the bottom of the container in each prescription was examined.

(Effect determination method 1-3)

The test liquids of Comparative Preparations 1 and 2 and 3 prepared above were filled into 10 ml of 5 ml dropper containers. The container was set and stored for 1 week under conditions of 25 ° C / 40% RH, then the container was slowly rolled and stored for 1 month under the same conditions. After the preservation was completed, the inhibitory effect on the fixation of pyrinoxine on the bottom of the container in each prescription was examined.

Table 2 shows the results according to the effectiveness judging method 1-1 (formulation; one week → transverse; one week).

Table 3 shows the results according to the effectiveness judging method 1-2 (formulation: 1 week → transverse phase; 2 weeks).

Table 4 shows the results according to the effectiveness judgment method 1-3 (formulation; one week → transverse phase; one month).

[Table 2]

[Table 3]

[Table 4]

The numbers in Tables 2 to 4 are the number of samples in which the pyrenoxin was adhered to the bottom of the container. A sample to which pyrinoxine is fixed refers to a sample in which pyrinoxine is in a state in which it can be observed visually.

"20 revolutions" in the table indicates the number of samples in which pyrinoxine was adhered to the bottom of the container after a sample was placed in a box immediately after storage and slowly rotated the container 20 times by hand. "20 revolutions + 20 hand swings" in the table indicates the number of samples in which pyrinoxine was adhered to the bottom of the container after shaking the container 20 times by hand after rotating the container 20 times. Likewise, " 20 revolutions + 50 hand swings " in the table indicates the number of samples in which pyrenxin is adhered to the bottom of the container after shaking the container 50 times by hand after rotating the container 20 times.

As can be seen from Tables 2 to 4, in Formulations 1 to 3, the number of samples to which pyrenoxin was fixed on the bottom of the container was decreased in comparison with Comparative Formulations 1 and 2. That is, it was shown that among the commonly used additives of eyedrops, the incorporation of polyoxyethylene hydrogenated castor oil or trometamol inhibited the adhesion of pyrinoxine to the container.

As can be seen from Table 3, the number of samples in which Pyrinoxine was adhered to the bottom of the container was further reduced in Formulation 2 compared to Formulation 1. In addition, as shown in Table 4, it was not confirmed that the formulation of Pyrinoxine was adhered to the container under the harsh condition of Formulation 2, after 1 week of formulation and 1 month of transplantation. That is, the formulation 2 in which the blending amount of the polyoxyethylene hydrogenated castor oil was 0.01% (W / V) showed that the adhesion of the pyrenoxin to the container was markedly suppressed as compared with the other formulations.

Example 2

Pyrrenoxine, which had been subjected to another sterilization treatment, was used to investigate the effect on the fixation to the container.

(Preparation of Test Solution)

1) Prescription 4 was prepared as follows.

Diluted hydrochloric acid and an aqueous solution of sodium hydroxide were added to 80 ml of sterilized purified water to add the concentrated glycerin (2.6 g), polyoxyethylene hardened castor oil 60 (0.01 g) and benzalkonium chloride (0.005 g) Respectively. Thereafter, pyrrenoxine (0.005 g) previously subjected to dry heat sterilization treatment (180 DEG C, 1H) was added and the whole was suspended by a homogenizer. When variation in pH was confirmed, diluted hydrochloric acid and aqueous sodium hydroxide solution The pH was adjusted to 3.5, and sterilized purified water was added to make the total volume to 100 ml. Thus, an aqueous solution of Formulation 4 was obtained. The polyoxyethylene hydrogenated castor oil 60 was prepared from Nippon Surfectant Kogyo Co.,

2) Prescription 5 was prepared as follows.

Prescription 5 was prepared by carrying out the same procedure as in Preparation 4 of Preparation 4, except that the sterilization treatment for pyrrenoxine previously performed was sterilized by gamma irradiation (30 kGy, no temperature control) instead of dry heat sterilization.

(Effect Determination Method 2-1)

The test solution of formulations 4 and 5 prepared above was filled into a 5 ml dropper container (Prescription 4: 50, Formulation 5: 40). The container was set and stored for 1 week under the condition of 25 ° C / 40% RH, then the container was slowly inverted and stored under the same conditions for 1 day. After completion of preservation, the incidence (%) of fixation in each prescription was calculated.

(Effect judging method 2-2)

The test solutions of formulations 4 and 5 prepared above were filled into a 5 ml dropper bottle (Prescription 4: 30, Formulation 5: 20). The container was set and stored for one week under the conditions of 25 ° C / 40% RH, and then the container was slowly rolled and stored for two weeks under the same conditions. After the storage was completed, the dispersibility of the drug adhering to the bottom of the container in each prescription was examined.

(Effect Determination Method 2-3)

The test solution of formulations 4 and 5 prepared above was filled into a 5 ml dropper container (Prescription 4: 50, Formulation 5: 40). The container was set and stored for 1 week under conditions of 25 ° C / 40% RH, then the container was slowly rolled and stored for 1 month under the same conditions. After the storage was completed, the dispersibility of the drug adhering to the bottom of the container in each prescription was examined.

The adhesion occurrence rate (%) referred to in the effect determination methods 2-1 to 2-3 indicates the ratio of the adhesion occurrence sample in all the samples and can be obtained by the following equation.

Sticking occurrence rate (%) = number of sticking samples / number of all samples × 100

Here, the number of samples with sticking occurred refers to the number of samples in which the sample is placed in a box, the container is slowly rotated 20 times by hand, and the container is shaken 50 times by hand and then the sample is fixed to the bottom of the container. A sample to which pyrinoxine is fixed refers to a sample in which pyrinoxine is visible to the naked eye as particles.

Table 5 shows the results of the effectiveness judging methods 2-1 to 2-3.

[Table 5]

As can be seen from Table 5, in Formulation 5, it was confirmed that the number of samples to which pyrenoxin adhered to the bottom of the container tended to decrease compared to Formulation 4. That is, it was shown that pyranthosin treated with gamma ray can inhibit sticking to the container.

Example 3

(Preparation example)

The following formulation was obtained according to the preparation method described in Example 1. In the following formulation examples, the blending amount of each component is described in an amount of 100 ml.

Formulation example  One

Ingredient content

Pyrrenoxine 0.005 g

Polyoxyethylene hardened castor oil 60 0.01 g

Concentrated glycerin 2.6 g

0.005 g of benzalkonium chloride

Sodium edetate suitable amount

Dilute hydrochloric acid qs

Sodium hydroxide qs

Sterile purified water volume

In the above-mentioned prescription, the same formulation as in Preparation Example 1 can be obtained by changing the blending amount of polyoxyethylene hardened castor oil 60 to 0.005, 0.01, 0.05 or 0.1 g.

Formulation Example 2

Ingredient content

Pyrrenoxine 0.005 g

1.8 g of trometamol

Polysorbate 80 0.005 g

0.005 g of benzalkonium chloride

Sodium edetate suitable amount

Dilute hydrochloric acid qs

Sodium hydroxide qs

Sterile purified water volume

The same formulation as in Preparation Example 2 can be obtained by changing the compounding amount of trometamol to 0.5, 1.0, 1.5, 2.0 or 3.0 g in the above-mentioned prescription.

The present invention relates to a suspension-type aqueous solution containing pyrinoxine, wherein the aqueous solution contains at least one member selected from the group consisting of polyoxyethylene hydrogenated castor oil and trometamol, and the aqueous solution contains cellulose Based polymer which does not contain a polymer.

Claims (7)

A suspension-type aqueous solution containing pyrinoxine, wherein the pyrinoxine is a pyrinoxine that has been subjected to sterilization treatment by gamma rays, and the aqueous solution contains at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil and trometamol And the aqueous liquid preparation does not contain hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. The aqueous liquid preparation according to claim 1, wherein the concentration of pyrinoxine is 0.001 to 0.01% (W / V). The aqueous liquid preparation according to claim 1, wherein the concentration of the polyoxyethylene hardened castor oil is 0.0005% to 0.5% (W / V). The aqueous liquid preparation according to claim 1, wherein the concentration of the polyoxyethylene hardened castor oil is 0.01% to 0.1% (W / V). The aqueous liquid preparation according to claim 1, wherein the concentration of trometamol is 0.1% to 3.0% (W / V). delete By mixing at least one member selected from the group consisting of polyoxyethylene hydrogenated castor oil and trometamol in a suspension type aqueous liquid containing a pyrinoxine which has been sterilized by a gamma ray, A method for inhibiting sticking to a container.