JP5710087B2 - Preparations for eye drops - Google Patents

Description

The present invention relates to ophthalmic solutions prepared with suitable ophthalmic solution for preparations and 該調formulation for preparing a multidose type ophthalmic solution.

  In addition, the molar concentration of “phosphate ion” and “borate ion” in the present specification means a converted value when it is assumed that the electrolyte that generates them is completely ionized.

Conventionally, in a so-called multi-dose type ophthalmic solution that is used repeatedly after opening, it is usually necessary to add a preservative (also referred to as a preservative) in order to maintain aseptic conditions. Many typical antiseptics such as benzalkonium chloride are irritating to the ocular mucosa. For this reason, the following preparations for ophthalmic solutions (ophthalmic compositions) free of preservatives that irritate the ocular mucosa (hereinafter referred to as “irritating preservatives”) are proposed. (See Patent Document 1 claim 1).

“(A) Trometamol 0.5 to 5.0 wt / mass% (mass / volume%)
(B) One or more selected from boric acid, phosphoric acid, acetic acid, maleic acid, phthalic acid, and ε-aminocaproic acid (A) / (B) = 1/5 to 5/1 (mass ratio) An ophthalmic composition having an irritating preservative content of 0.0005% by weight / mass% (mass / volume%) or less, or a non-formulation, characterized in that "
JP 2004-2364 A

An object of the present invention (object) is not added irritant preservative, and preparations for a suitable ophthalmic solution to prepare an ophthalmic solution containing an ophthalmic medicinal ingredients that can inhibit microbial growth 該調The object is to provide an ophthalmic solution prepared using the formulation .

  In order to solve the above-mentioned problems, the present inventors have reached the following new findings in the process of making intensive development.

Here, Pseudomonas aeruginosa low concentration means that the Pseudomonas aeruginosa count concentration is 10 ⁴ CFU / mL or less. When the antiseptic action test was performed in the upper limit range (10 ³ to 10 ⁴ CFU / mL) of Pseudomonas aeruginosa, the low concentration of Pseudomonas aeruginosa (10 ³ to 10 ⁴ CFU / mL) Below, after contact with phosphate ions, less than 24 hours, the bacteria will decrease, but after 24 hours, the bacteria will grow. However, Pseudomonas aeruginosa reduced by phosphate ions exhibits a remarkable sterilization effect by allowing a borate buffer solution (borate ion) exhibiting a bacteriostatic action to coexist with phosphate ions. (See Figure 1)
Although the sterilization effect of Pseudomonas aeruginosa by phosphate ions increases with increasing phosphate ion concentration, it is not necessarily proportional (see FIG. 2), and the osmotic pressure based on the increase in electrolyte concentration containing phosphate ions is sterilizing. It was not possible to obtain the knowledge that it greatly contributed to (see Table 2). In addition, the coexisting molar ratio of borate ion (borate buffer) and phosphate ion (phosphate ion buffer) is 1: 1. The sterilization effect could not be observed (see FIG. 3).

  As for the pH of the eye drop, it is appropriate to adopt a pH close to that of body fluid or tears when irritation to the eyes is assumed. Therefore, the effect of the pH of the coexisting solution (mixed buffer solution) of borate ions and phosphate ions was examined. It was found that a higher pH has a bactericidal action against Pseudomonas aeruginosa (see FIG. 4).

  However, such an ophthalmic solution with a high pH is not practical, and it has been found that adopting a pH as high as possible within the pH range close to tears is advantageous for sterilization against Pseudomonas aeruginosa. It was.

Based on the above findings, the present inventors have conceived an ophthalmic solution preparation having the following constitution.

Boric acid ions (including ortho, meta, tetraboric acid and their salts, and diboron trioxide) and phosphate ions (including neutral and acidic salts of phosphoric acid and phosphoric acid, and phosphorus oxide) And ophthalmic solution containing an ophthalmic medicinal component, which is adjusted to pH 6.5 to 8.0 ,
The boric acid ion substance concentration is 0.050 to 0.250 mol / L,
The substance amount concentration of the phosphate ion is 0.040 to 0.250 mol / L, and
While borate ion / phosphate ion (coexistence molar ratio) = 1/2 to 2/1,
The composition is characterized in that it has an antiseptic action at a low concentration of Pseudomonas aeruginosa (10 ⁴ CFU / mL or less) and does not substantially contain an irritating preservative that gives irritation to the ocular mucosa .

The above preparation for ophthalmic solution is preferably adjusted to pH 6.8 to 7.8 when the ophthalmic solution is made close to the pH of tears.

The preparation for ophthalmic solution having the above-mentioned constitutions contains ophthalmic medicinal ingredients in a predetermined amount to form an ophthalmic solution .

The preparation for ophthalmic solution of the present invention basically has a preservative action by coexisting borate ions and phosphate ions and adjusting the pH to 6.5 to 8.0. The composition is substantially free of preservatives.

Here, boric acid ions include ortho-meta-tetraboric acid and salts thereof, and diboron trioxide. Specifically, as a borate ion generator, boric acid used in borate buffer, alkali borate such as Na ₂ B ₄ O ₇ (xM ₂ O · yB ₂ O ₃ · zH ₂ O) In addition, boron oxide can be used. Here, M is Na or K.

Moreover, as a phosphate ion, the neutral salt and acidic salt origin of phosphoric acid and phosphoric acid and phosphorus oxide origin are included. Specifically, as a phosphate ion generating agent, phosphoric acid monohydrogen salt (M ¹ ₂ HPO ₄ ), phosphoric acid dihydrogen salt (M ¹ H ₂ PO ₄ ) (water used in a phosphate buffer solution is used. In addition, phosphoric acid, phosphorus oxide, etc. can be used.

  Sodium hydroxide or hydrochloric acid is used as a pH adjuster, and the pH adjuster is used to adjust the pH to 6.5 to 8.0, and preferably to a pH of 6.8 to 7.8.

  The borate ion / phosphate ion substance concentration and the coexisting substance amount ratio are set as follows.

The borate ion concentration is 0.050 to 0.250 mol / L
Phosphate ion substance concentration is 0.040 to 0.250 mol / L
Borate ion / phosphate ion (coexistence molar ratio) = 1/2 to 2/1
The ophthalmic solution is prepared as follows using the preparation for ophthalmic solution having the above structure.

In other words, an ophthalmic medicinal ingredient is added to the ophthalmic solution for preparations, and eye drops. At this time, in addition to the additives, additives such as tonicity agents, stabilizers, antioxidants and surfactants can be used.

  Examples of the isotonic agent include polyols such as mannitol, glycerin, glucose, and sorbitol, amines such as aminoethylsulfonic acid, and inorganic salts such as NaCl.

  As the stabilizer, butylene glycol, dipropylene glycol, propylene glycol, ethanol, isopropanol, xylitol, epsilon aminocaproic acid, glycine, hyaluronic acid, glyceryl stearate, polyethylene glycols, carboxyvinyl polymer, polyvinylpyrrolidone, polyvinyl alcohol, edet Examples thereof include acid, dibutylhydroxytoluene, tocopherol and the like.

Examples of the antioxidant include ascorbic acid, isoascorbic acid, cysteine hydrochloride, and the like.

  Examples of the surfactant include nonionic compounds such as polysorbate, castor oil EO adduct, and hardened castor oil EO adduct. In addition, if it is used for ophthalmic solution, it is not restricted to a nonionic system.

  Examples of the ophthalmic medicinal component include fluorometholone, cyanocobalamin, carteolol hydrochloride, chlorpheniramine maleate, sodium cromoglycate, and the like.

  Furthermore, in the present invention, the ophthalmic solution having the above-described configuration is desirably used as a container-filled ophthalmic solution filled in a sterile ophthalmic container that can ensure aseptic condition even after opening. As the sterile eye drop container, for example, a filter provided with a filter having pores of 0.22 μm or less or a backflow prevention valve in a flow path for discharging eye drop can be used.

  By adopting such a configuration, it is usually formulated for the purpose of preventing bacteria and fungi from contaminating the drug solution in the eye drop container when the nozzle of the eye drop container comes into contact with the eyeball or tears during patient use. Contains corneal epithelial disorder preservatives and surfactants, such as benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, benzyl alcohol, phenylethyl alcohol, etc., and paraoxybenzoic acid esters The prescription (formulation) not to be performed can be secured more reliably.

  As the aseptic eye drop container, one having the following structure previously proposed by the applicant of the present application is desirable (see FIG. 6: Japanese Patent Application Laid-Open No. 2004-51593).

  The sterile eye drop container 1 includes a so-called delaminated bottle 2 formed by laminating and forming an inner layer 22 that can be peeled off from the outer layer 21 on the inner surface of the outer layer 21 and a stopper 3 attached to the mouth of the bottle 2. 21 is provided with a vent hole 4 for introducing outside air between the inner layer 22 and the outer layer 21, and a discharge path for discharging (spouting) ophthalmic solution contained in the inner layer 22 to the plug body 3. 10 is provided, and a filter 7 and a check valve 8 are provided in the discharge passage 10, and the filter 7 is disposed on the discharge downstream side of the reverse support valve 8.

  Furthermore, as a feature of this delamination bottle, when the contents liquid (eye drops) is discharged during instillation, the volume of the contents liquid remaining in the container is reduced by that volume, and the peelable inner layer is peeled off from the outer layer. Since the contents are reduced in accordance with the change, air is not sucked into the content liquid, and more bacteria can be prevented from entering the container.

  Examples and comparative examples performed for confirming the effects of the present invention will be described.

<Test Example 1>
A phosphate buffer solution inoculated (inoculated) with 10 ³ to 10 ⁴ P. aeruginosa per mL of sample was allowed to stand in a constant temperature room at 25 ° C. for 12 hours, and then the phosphate buffer solution and the like. An amount of borate buffer or phosphate buffer was added. In addition, the thing of the prescription shown in Table 1 was used for each buffer solution.

  And before and after that, the number of viable bacteria in 1 mL of the sample inoculated with the bacteria was measured every predetermined time by the Kantani plate pour method. The number of samples was three, and the arithmetic average value was obtained.

  From FIG. 1 showing these results, a buffer mixed solution (borate ion / phosphate ion coexisting solution) obtained by adding a borate buffer solution to a phosphate buffer solution in the middle has a remarkable sterilizing action against Pseudomonas aeruginosa. I understand that.

＜試験例２＞
図２に示されるモル濃度にて調製したリン酸緩衝液について、試験例１と同様の操作をおこない、１２ｈ後の緑膿菌生存数を求めた。それらの結果を示す図２から、リン酸イオンによる緑膿菌滅菌効果は、リン酸イオン濃度上昇により大きくなるが、必ずしも比例関係にないことが分かる。

<Test Example 2>
For the phosphate buffer prepared at the molar concentration shown in FIG. 2, the same operation as in Test Example 1 was performed to determine the survival number of Pseudomonas aeruginosa after 12 hours. FIG. 2 showing these results shows that the effect of sterilizing Pseudomonas aeruginosa by phosphate ions increases as the phosphate ion concentration increases, but is not necessarily proportional.

<Test Example 3>
Each test solution whose osmotic pressure ratio was adjusted with sodium chloride so as to have the osmotic pressure ratio shown in Table 2 was subjected to the same operation as in Test Example 1, and the number of surviving Pseudomonas aeruginosa after 48 hours was determined. From Table 2 showing these results, the knowledge that osmotic pressure greatly contributes to the sterilization effect based on the increase in the concentration of the electrolyte containing phosphate ions was not obtained.

＜試験例４＞
ホウ酸イオンとリン酸イオンとの共存モル比がそれぞれ異なる表３に示す処方のホウ酸緩衝液／リン酸緩衝液の混合緩衝液（ホウ酸イオン／リン酸イオン共存液）に、１０³〜１０⁴CFU/mLとなるように緑膿菌を播種して各試料を調製した。なお、各試料のｐＨは、ＨＣｌ（１Ｎ）又はＮａＯＨ（１Ｎ）を用いてｐＨ７．４に、浸透圧比（生理食塩水に対する）はＮａＣｌにて１とした。

<Test Example 4>
In a mixed buffer solution (borate ion / phosphate ion coexisting solution) of borate buffer / phosphate buffer having a formulation shown in Table 3 in which the coexisting molar ratios of borate ion and phosphate ion are different from 10 ³ to Each sample was prepared by inoculating Pseudomonas aeruginosa at 10 ⁴ CFU / mL. The pH of each sample was adjusted to pH 7.4 using HCl (1N) or NaOH (1N), and the osmotic pressure ratio (relative to physiological saline) was set to 1 with NaCl.

  And the survival number of Pseudomonas aeruginosa was calculated | required like Test Example 1 after leaving each sample for 48 hours in a 25 degreeC thermostat.

From Figure 3 showing the results, the range mixing molar ratio of borate ion / phosphate ion = about 1 / 5-6 / 1 have a sterile action, in particular in the range of about 1 / 4-5 / 1 However , it can be seen that the sterilization effect is remarkable in the range of about 1/2 to 2/1 .

＜試験例５＞
それぞれ、表４に示す処方のホウ酸緩衝液／リン酸緩衝液の混合緩衝液（ホウ酸イオン／リン酸イオン共存液）について、ＨＣｌ（１Ｎ）又はＮａＯＨ（１Ｎ）を用いて、それぞれ、図４に示す各ｐＨに調節するとともに、ＮａＣｌにて浸透圧比（生理食塩水に対する）１としたものに、１０³〜１０⁴CFU/mLとなるように緑膿菌を播種して各試料を調製した。そして、上記試験例１と同様にして、所定時間毎に、生菌数を測定して、緑膿菌生存数を求めた。なお、ホウ酸緩衝液単独、リン酸緩衝液単独についても同様にして、緑膿菌生存数を求めた。

<Test Example 5>
About the borate buffer / phosphate buffer mixed buffer solution (borate ion / phosphate ion coexisting solution) having the formulation shown in Table 4, respectively, using HCl (1N) or NaOH (1N), Each sample was prepared by adjusting to each pH shown in 4 and inoculating Pseudomonas aeruginosa to 10 ³ to 10 ⁴ CFU / mL in an osmotic pressure ratio (relative to physiological saline) of 1 with NaCl. did. Then, in the same manner as in Test Example 1, the number of viable bacteria was measured every predetermined time to determine the survival number of Pseudomonas aeruginosa. In addition, the survival number of Pseudomonas aeruginosa was calculated | required similarly about the boric-acid buffer single and the phosphate buffer single.

  FIG. 4 showing these results shows that the higher the pH, the stronger the sterilization effect of Pseudomonas aeruginosa, and even when the pH is lower (pH 6.0, pH 7) than each buffer alone (pH 7.4). 0.0) It can be seen that the sterilization effect is higher in the mixed buffer solution (borate ion / phosphate ion mixed solution).

＜実施例１〜３＞
表５に示す本発明の範囲内にある各処方の点眼液を調製し、防腐剤フリーのマルチドーズ型の点眼容器（図６の無菌点眼容器）にそれぞれ、充填した。内容液を５滴、滴下して清浄化した滴下口に、緑膿菌の菌液（１０³〜１０⁴CFU/mL）を付着させて各試料を調製した。そして、２５℃恒温室内に１２ｈ放置後、それぞれ、２枚の寒天平板上に１滴目、２滴目を滴下した後（滴下により滴下口はある程度除菌される。）、カンテン平板表面塗抹法で培養して、生菌数を測定した。比較のために、ホウ酸緩衝液単独でも同様に行った。

<Examples 1-3>
Eye drops of each formulation within the scope of the present invention shown in Table 5 were prepared and filled into preservative-free multi-dose eye drop containers (sterile eye drop containers in FIG. 6). Each sample was prepared by adhering a bacterial solution of Pseudomonas aeruginosa (10 ³ to 10 ⁴ CFU / mL) to a dropping port cleaned by dropping 5 drops of the content liquid. Then, after standing in a constant temperature room at 25 ° C. for 12 hours, the first and second drops were dropped on two agar plates (the dropping mouth was sterilized to some extent by dropping), and then the plate surface smearing method. And the number of viable bacteria was measured. For comparison, the same procedure was performed with borate buffer alone.

  As shown in FIG. 5 showing the results, viable bacteria were observed in both the first and second drops only with the borate buffer solution (borate ion alone solution) and the phosphate buffer solution (phosphate ion alone solution) alone. However, in the borate ion / phosphate ion coexisting liquid of the example, no viable bacteria were observed in the first and second drops, and it was found that the bacteria died.

It is a graph which shows the test result of the Pseudomonas aeruginosa sterilization effect at the time of adding the borate ion with respect to a phosphate ion on the way. It is a graph which shows the test result of the influence which has on the sterilization effect of phosphate ion concentration. It is a graph which shows the result of the influence test which has on the sterilization effect of the borate ion / phosphate ion coexisting molar ratio in the coexisting liquid of a phosphate ion and a borate ion. It is a graph which shows the result of the influence test which gives the sterilization effect of pH in the coexisting liquid of a phosphate ion and a borate ion. It is a graph which shows the test result of the sterilization effect at the time of filling an aseptic eye drop container with an Example, a boric acid buffer solution, and a phosphate buffer solution, and making a dripping port contaminate bacteria. It is a schematic sectional drawing which shows an example of the sterile eyedrop container suitable for filling the eyedrops of this invention.

DESCRIPTION OF SYMBOLS 1 Aseptic eyedrop container 2 Laminated peeling bottle 3 Plug body 21 Outer layer 22 Inner layer

Claims (3)

Boric acid ions (including ortho, meta, tetraboric acid and their salts, and diboron trioxide) and phosphate ions (including neutral and acidic salts of phosphoric acid and phosphoric acid, and phosphorus oxide) And ophthalmic solution containing an ophthalmic medicinal component, which is adjusted to pH 6.5 to 8.0,
The boric acid ion substance concentration is 0.050 to 0.250 mol / L,
The substance amount concentration of the phosphate ion is 0.040 to 0.250 mol / L, and
Borate ion / phosphate ion (coexistence molar ratio) = 1/2 to 2/1 ,
An ophthalmic solution characterized by having an antiseptic action at a low concentration of Pseudomonas aeruginosa (10 ⁴ CFU / mL or less) as a composition and substantially free of an irritating preservative that irritate the ocular mucosa. Preparations. The preparation for ophthalmic solution according to claim 1, wherein the preparation is adjusted to pH 6.8 to 7.8. Eye drops claim 1 or 2 wherein the ophthalmic medicinal ingredient in eye drop for preparations according to characterized by comprising the predetermined amount.

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