JPS6391331A - Ophthalmic aqueous composition - Google Patents

Abstract

PURPOSE:To obtain an ophthalmic aqueous composition useful for dissolution for interferon, containing a quaternary ammonium salt, a paraoxybenzoic ester, boric acid and a nonionic surface active agent. CONSTITUTION:The aimed substance containing 0.001-0.003% preferably 0.002% quaternary ammonium salt, 0.02-0.05%, preferably 0.03% paraoxybenzoic ester, 0.5-2%, preferably 1-1.5 boric acid and 0.03-0.07% preferably 0.05% polysorbate and adjusted to pH of neutrality. An aqueous solution of interferon which maintains activity of interferon for a fixed period, prevents multiplication of microorganisms and does not produce changes such as occurrence of precipitate, etc., unfavorable as dye drops is prepared.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to an ophthalmic aqueous composition that can be used to dissolve interferon or has interferon dissolved therein.

(Prior art) Interferon has α type 1. There are β type, γ type, etc.
Regarding its properties, for example, it is known that the α-type and β-type are stable at pT (2), and the γ-type is unstable to acids (Merck Index 1st Theta Edition 4870), and its pharmacological effects. It is known to have antiviral and antitumor properties, and its clinical use has been attempted in various fields.However, its use in the ophthalmology field, especially as an eye drop, has not yet been attempted. This was due to the coexistence of the various formulations required for eye drops, the difficulty in producing no suspended solids or turbidity for a long period of time in an appropriate pH range, and having sufficient preservative properties. .

(Problems to be solved by the invention) The present inventors have proposed the application of interferon to the ophthalmology field,
In particular, for use as eye drops, an aqueous solution containing materials that are acceptable to be included as components of eye drops is used to maintain the activity of interferon for a certain period of time, to prevent the growth of microorganisms, and to prevent the formation of precipitates, etc. An attempt was made to prepare an aqueous solution of interferon that would not cause any undesirable changes when used as eye drops.

(Means for solving the problem) The present inventors conducted a test shown in the following reference example as a preliminary tin experiment.

Reference example 1 M! ■Folds Tests were conducted using various aqueous compositions shown in Table 1.

(Left below) Preparation of bacterial solution The bacterial strain used is Staphylococcus aureus (SLAphylor, oecus aureus).
AT CC6538, Escherichia collie (Es
cherichia c.

1i) ATCC8739, P, ssudomonas aeruginosa
) AT CC9027, the same NU was used as a fungus, Candida albicans (Candida albicans).
s) N HL 4019, Aspergillus niger (
Aspergillus n:ger) NHL50
88, the bacteria were grown on an agar medium (Soybean Nutritional Chemicals KK) at 3.
Cultured at 7°C for 24 hours, and Candida albicans was grown in G.
P (Glucose Peptone Broth
) Cultured on agar medium (Soybean Nutritional Chemicals KK) at 25°C for 48 hours, and Aspergillus niger was cultured on CP agar medium at 25°C.
After culturing for 1 hour, each was separately suspended in sterile physiological saline to obtain a bacterial suspension for inoculation.

The number of bacteria in the suspension is approximately 10" to 1G' CFU (c
olony forming unit)/m
1, and about 10' to 10'' CFU/a+1 for fungi.

(Test Method) Interferon having the following composition was dissolved aseptically in each of the various aqueous compositions 51 shown in Table 1 prepared aseptically.

α-type interferon 5X10' Summer U human serum albumin Appropriate amount Sodium chloride Trace amount Ammonium acetate Trace amount Each aqueous composition in which this interferon is dissolved is prepared as part 1.
For each type, 2t)+1 was dispensed into six sterilized test tubes with stoppers, and 0.1ml each of the above six types of bacterial suspension was inoculated therein separately. The aqueous composition after inoculation is at 30°C.
The number of surviving bacteria in the composition was measured over time by an agar plate pouring method using SCD medium for bacteria and GP medium for others. In order to prevent the preservative contained in the aqueous composition from affecting the growth of the bacteria, polysorbate 80 (Wako Pure Chemical Industries KK) 0.7
% and egg yolk lecithin (Wako Pure Chemical Industries, Ltd.) 0.1%.

Preliminary tests have confirmed that these additions can neutralize preservatives.

First, formulation No. 091 shown in Table 1 was tested, and as shown in Table 2 below, Shademonas aeruginosa grew, and the aqueous composition became cloudy after the third day.

In each table below, the bacterial names are abbreviated as follows.

Abbreviation: Staphylococcus aureus ^TCC6538S,
a.

Escherichia collie ATCC8739E, c.

S1-Tomonas aeruginosa ATCC9027P, a,
AN U P, a, N Candida albicans NHL4019
C.a.

Aspergillus niger NHL, 5088
A, n.

(Left below) Therefore, in order to enhance the efficacy of the composition of No.1 against Shademonas aeruginosa, we added boric acid to No.1.
, 1-2 was similarly tested using Cytomonas aeruginosa as the indicator bacterium, and the results shown in Table 3 were obtained.

(Margins below) That is, all of the two strains of Cytomonas died within 3 days.

The results shown in Table 4 were obtained for formulation No. 002.

(Left below) In other words, for both strains of S. aeruginosa, within 1 day, for Staphylococcus aureus, within 3 days, for Aspergillus niger, within 140 days, and for Escherichia coli and Candida albicans, within 21 days. All bacteria were killed within a few days.

The test results for formulation No. 013 are shown in Table 5.

(Left below) In other words, S. aeruginosa and Aspergillus niger both within 14 days, Staphylokofcus aureus and Aspergillus niger within 21 days, and Candida and Aspergillus niger.
In C. albicans, all bacteria were killed within 28 days.

As for Escherichia coli, the bacterial count decreased to 1/1000 within 28 days.

Subsequently, similar tests were conducted using the aqueous compositions shown in Table 6.

(Left below) In No. 3, the effect against Escherichia coli was not sufficient, so in No. 3-2 to 3-4, the amount of boric acid and methyl paraoxybenzoate was increased, and in No. 5, paraoxyamne and α-fragrance were added. Benzalkonium chloride is added instead of propyl acid.

For No. 3-2 and No. 3-3, tests were conducted using Escherichia coli as an indicator bacteria, and the results shown in Table 7 were obtained.

(The following is a blank space) That is, for No. 3-2, the number of Escherichia coli bacteria decreased only to about 1/1000 of that of the day-to-day inoculation on the 14th. Further, for No. 3-3, the decrease was only about 1/10 per day for 14 days.

For prescriptions No. 3-4, the results shown in Table 8 were obtained.

(Left below) In other words, with the three types of test bacteria, all the bacteria died within 14 days, and with the other three types of test bacteria, the number of bacteria was 1/100 at the time of inoculation.
It decreased to below 0.

For No. 5, the results shown in Table 9 were obtained.

(Margin below) That is, all bacteria were killed within 7 days.

Reference Example 2 and H 8 A solution in which interferon was dissolved was prepared aseptically in the same manner as in the previous preservative test of the aqueous compositions of Formulation No. 1-2.2 and 3 in Table 1. The samples were stored at 30°C, 30°C, or 40°C, and the appearance and pH were observed over time.

The results are shown in Tables 10 and 11. As a control in Table 0, a solution prepared by dissolving the interferon composition described in the previous example in physiological saline 51 was used.

(Left below) As is clear from the above table, turbidity or suspended matter was formed at 30℃ and 40℃ for No. 1-2.2 and the control from around the 7th day, respectively. but,
In No. 3, even after 14 days at 40°C, there was very little generation of floating matter. Furthermore, there was almost no change in pH between each formulation and the control.

Subsequently, changes in appearance at 40° C. were observed in the same manner as above using the aqueous compositions shown in Table 6.

In No. 5, polysorbate 80, which is a nonionic surfactant, is added to suppress the formation of floating substances due to benzalkonium chloride.

The results of the observation are shown in Table 12.

(The following is a blank space) That is, the appearance changes of prescription Nos. 3-2, 3-3 and 3-4 are the same as those of No. 3;

In No. 5, despite the addition of benzalkonium chloride, almost no suspended matter such as that produced in No. 1-2 was observed.

In addition, each of the aqueous compositions in Tables 1 and 5 above (No.
The storage stability of the titer of interferon was investigated when it was dissolved in 100 mg (excluding 1) and stored at temperatures of 4°C, 25°C, and 40°C, but the titer hardly changed over a 21-day test.

From the results of the above tests, it was found that when interferon is used as eye drops, an aqueous solution containing a quaternary ammonium salt, a boron oxybenzoate, boric acid, and a nonionic surfactant and adjusted to a nearly neutral pH is used as an eye drop. It has become clear that this aqueous solution is suitable as a solution for interferon, and that when interferon is dissolved in this aqueous solution, interferon can be stably maintained for a certain period of time, making it possible to apply interferon to the ophthalmological field.

That is, the present invention provides an ophthalmic aqueous composition for dissolving interferon, which is an aqueous solution containing a quaternary ammonium salt, a paraoxybenzoic acid ester, boric acid, and a nonionic surfactant, and whose pH is adjusted to approximately neutral. and an interferon-containing ophthalmic aqueous composition obtained by dissolving interferon in the aqueous solution.

As the quaternary ammonium salt, for example, benzalkonium chloride, benzethonium chloride, etc. are used. Fourth
Grade ammonium salts are generally 0.001-0.003%
, preferably at a concentration of about 0.002%.

As the paraoxybenzoic acid ester, for example, methyl paraoxybenzoate and propyl paraoxybenzoate are used. These esters are usually 0.02 to 0.0
It is used at a concentration of 5%, preferably about 0.03%.

Boric acid is used at a concentration of 0.5-2%, preferably 1-1.5%.

As nonionic surfactants, for example polyoxyethylene ethers of sorbitan partially esterified with oleic acid, such as polysorbate 80, are used. It is 0.03-0.07%, preferably about 0.0
Used at a concentration of 5%.

The pH of the aqueous composition is 6 to 8 from the viewpoint of use as eye drops.
, preferably 6.5 to 7.5, particularly preferably around neutrality, that is, about 7.

In the aqueous composition, sodium sulfate is added as necessary,
pH regulators such as borax, osmotic pressure regulators such as sodium chloride, stabilizers such as sodium edetate can be added.

' Various types of interferon can be used, but α type is preferable for ophthalmological use, and an adsorption inhibitor such as serum albumin may be mixed in to prevent interferon from adsorbing to the container. good. Preferably, the serum albumin is of human origin.

The present invention is used as an ophthalmic aqueous composition for dissolving interferon, and as an aqueous composition in which interferon is dissolved.

(Function) In the present invention, the quaternary ammonium salt, the boron oxybenzoic acid ester, and the boric acid act together as a preservative, and the polysorbate prevents the generation of floating substances due to the addition of the quaternary ammonium salt.

Example 1 Benzalkonium chloride 0.1mg Methyl paraoxybenzoate 1.5mg Boric acid
Borax 12.5 mong Sodium chloride 1.0 pods Sodium etetate 2.5n+g Polysorbate 80
Mix and dissolve an appropriate amount of sterilized purified water to make a total volume of 5 ml, fill it into an ampoule, melt it shut, reduce the opening by heating, and prepare α-type Interflon 5XlO'.
An interferon solution is made of lυ and an appropriate amount of human serum albumin.

Example 2 Interferon mH is obtained by dissolving α-type interferon 5xlO' rU and an appropriate amount of human serum albumin in the solution of 51 prepared according to the recipe of Example 1.

(Effects of the Invention) The ophthalmological aqueous composition of the present invention can stably retain the interferon in the solution for a certain period of time as an eye drop when various types of interferon are dissolved, and is a new method for using interferon as an eye drop. A dosage form can be provided.

Claims (6)

[Claims] (1) An ophthalmological aqueous composition for dissolving interferon, which is an aqueous solution containing a quaternary ammonium salt, paraoxybenzoic acid ester, boric acid, and a nonionic surfactant, and whose pH is adjusted to approximately neutral. . (2) Quaternary ammonium salt is 0.001 to 0.003
%, preferably about 0.002%, paraoxybenzoic acid ester 0.02-0.05%, preferably about 0.03%
%, boric acid 0.5-2%, preferably 1-1.5%,
A composition according to claim 1, containing 0.03 to 0.07% polysorbate, preferably about 0.05%. (3) The composition according to claim 1, wherein the interferon is α-type interferon. (4) An interferon-containing ophthalmic aqueous composition, which is prepared by dissolving interferon in an aqueous solution containing a quaternary ammonium salt, paraoxybenzoic acid ester, boric acid, and polysorbate, the pH of which is adjusted to approximately neutral. (5) Quaternary ammonium salt is 0.001 to 0.003
%, preferably about 0.002%, paraoxybenzoic acid ester 0.02-0.05%, preferably about 0.03%
%, boric acid 0.5-2%, preferably 1-1.5%,
5. A composition according to claim 4, containing 0.03 to 0.07% polysorbate, preferably about 0.05%. (6) The composition according to claim 4, wherein the interferon is α-type interferon.