JP4466875B2 - Eye drops for soft contact lenses - Google Patents

Description

  The present invention relates to an eye drop for a contact lens that contains a preservative having a cationic group and can be instilled in a state in which the contact lens is mounted. More specifically, the preservative having a cationic group contained in the eye drop is a contact. The present invention relates to an eye drop for a contact lens that suppresses adsorption to a lens and has excellent antiseptic power.

  Conventionally, as preservatives for eye drops, compounds having a cationic group such as benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, p-aminobenzoic acid ester and sorbic acid are used alone or in combination. It is used.

  Among these preservatives, especially preservatives having a cationic group have been widely used as preservatives for eye drops because of their excellent antiseptic power, but these preservatives have an affinity for contact lenses, particularly soft contact lenses. For this reason, when eye drops containing these preservatives are applied by eye drops while wearing the contact lenses, the preservatives in the eye drops are adsorbed on the contact lenses and sequentially accumulated in the contact lenses. Such adsorption and accumulation of preservatives may cause deterioration and physical changes in contact lenses, and may cause eye damage when wearing contact lenses that accumulate the above preservatives. There is also.

  Therefore, in order to develop an eye drop that can be applied with eye drops while wearing a contact lens, particularly a soft contact lens, and is excellent in storage stability of the eye drop itself, a cationic group contained in the eye drop is used. There is a need for a means for preventing the preservative contained in the contact lens from being absorbed. In recent years, various proposals have been made as the above means. For example, Japanese Patent Publication No. 55-15008 proposes a method of adding a nonionic surfactant to an eye drop containing a preservative having a cationic group. However, in this method, the effect of suppressing the adsorption of the preservative to the contact lens is not sufficient, and in other proposals, no means for exhibiting a sufficiently effective adsorption suppression effect has been developed yet.

Japanese Patent Publication No.55-15008

  The present invention has been made in view of the above circumstances, contains a preservative having a cationic group, not only has an excellent antiseptic power, it is sufficient that the preservative in the eye drop is adsorbed to the contact lens It is an object of the present invention to provide an eye drop for a contact lens that is suppressed and can be applied to eye drops even with the contact lens attached.

  As a result of intensive studies to achieve the above object, the present inventor found that the preservative of the above preservative can be obtained by combining cyclodextrin and ethylenediaminetetraacetic acid or a salt thereof in combination with a preservative having a cationic group. Adhesion of preservatives to contact lenses, particularly soft contact lenses, can be sufficiently effectively suppressed without sacrificing force, and by using boric acid and / or borax in combination with the above preservatives, the preservative power can be further increased. It was found that it was enhanced, and the present invention was made.

That is, the present invention provides the following eye drops for soft contact lenses.
[1]. Cyclodextrins selected from cyclodextrin and cyclodextrin derivatives having a saccharide ring structure of cyclodextrin in eye drops containing 0.001 to 0.1% by weight / volume% of a preservative having a cationic group. Eyedrops for soft contact lenses that can be instilled in a state where a soft contact lens is mounted, comprising 5 wt / vol% and ethylenediaminetetraacetic acid or a salt thereof 0.006 to 0.1 wt / vol% Agent.
[2]. The eye drop for soft contact lenses according to [1], wherein the cyclodextrins are α-cyclodextrin.

  According to the present invention, a contact lens, in particular a soft contact lens, can be obtained without impairing the preservative power of the preservative by using cyclodextrin and EDTA or a salt thereof in combination with an eye drop containing a preservative having a cationic group. Since the adsorption of the preservative to the skin can be suppressed sufficiently effectively, the eye drop of the present invention can be applied to eye drops while wearing a contact lens, particularly a soft contact lens, and is particularly useful as an eye drop for contact lenses. .

  In addition, by adding boric acid and / or borax as the eye drop of the present invention, the eye drop not only has a preservative power superior to conventional eye drops containing a preservative having a cationic group, but also a contact lens. It is possible to obtain an ophthalmic solution in which the adsorption of the preservative is sufficiently effectively suppressed.

  Hereinafter, the present invention will be described in further detail. The eye drop of the present invention contains a preservative having a cationic group, cyclodextrins and ethylenediaminetetraacetic acid or a salt thereof as essential components. In this case, as the preservative having a cationic group in the present invention, known ones can be used. For example, benzalkonium chloride, benzethonium chloride, cetyldimethylbenzylammonium chloride, domifene bromide, 3- (trimethoxysilyl) ) Quaternary such as propyldimethyloctadecylammonium chloride, stearyldimethylbenzylammonium chloride, stearyltrimethylammonium chloride, distearyldimethylammonium chloride, stearylpentaethoxyammonium chloride, cetylpyridinium chloride, cetylpyridinium bromide, lauroylisoquinolium bromide Ammonium salt type; chlorhexidine hydrochloride, chlorhexidine gluconate, dodecylguanidine hydrochloride, polyhexamethylenebiguanidine hydrochloride, 6-acetoxy- , 4-dimethylmetadioxane and other guanidine-based antiseptics can be mentioned, but in view of suitability for eye drops, antiseptic power, etc., quaternary ammonium salt type is preferable, and these are one kind You may use individually or in combination of 2 or more types.

  The blending amount of the preservative in the eye drop of the present invention is not particularly limited, but is usually 0.001 to 0.1% (weight / volume%, the same applies hereinafter) of the whole eye drop, preferably 0.005 to 0 0.02%. If it is less than 0.001%, the preservative action by the preservative becomes insufficient, and if it exceeds 0.1%, eye irritation may occur when the eye drops are applied, and the feeling of use may be impaired.

  Examples of the cyclodextrins of the present invention include cyclodextrin and cyclodextrin derivatives having a saccharide cyclic structure of cyclodextrin necessary for inclusion. Examples of cyclodextrins include α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin. Dextrin and δ-cyclodextrin may be mentioned, and as cyclodextrin derivatives, for example, methylated cyclodextrin, hydroxyethylated cyclodextrin, maltosyl-α-cyclodextrin, hydroxyethyl-β-cyclodextrin, triacetyl-β -Cyclodextrin, etc., among which α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, δ-cyclodextrin, methylated cyclodextrin Phosphorus and hydroxyethylated cyclodextrin are preferably used, and these may be used alone or in combination of two or more.

  The eye drop of the present invention suppresses the adsorption of the preservative to the contact lens by adding the cyclodextrin to the preservative-containing eye drop having a cationic group. The amount of the cyclodextrin in the eye drop Although it does not restrict | limit in particular, Preferably it is 0.03-1% of the whole eyedrop, More preferably, it is 0.03-0.5%. If it is less than 0.03%, the effect of suppressing the preservative adsorption by cyclodextrin may be insufficient, and if it exceeds 1%, there may be a problem in the storage stability of the eye drop under low temperature conditions.

  As the salt of ethylenediaminetetraacetic acid (EDTA) of the present invention, known salts can be used, such as EDTA potassium, EDTA tripotassium, EDTA sodium zinc, EDTA disodium, EDTA trisodium, EDTA tetrasodium, EDTA sodium. Alkali metal salts such as calcium, EDTA sodium cobalt, EDTA sodium iron, EDTA sodium copper, EDTA sodium nickel, EDTA sodium magnesium, and EDTA sodium manganese; Are preferably used, and these may be used alone or in combination of two or more, or may be used in combination with EDTA.

  The eye drop of the present invention is a combination of the cyclodextrin and EDTA or a salt of the EDTA, thereby preventing a drop in the preservative power of the eye drop due to the addition of the cyclodextrin. Although the compounding quantity of a salt is not restrict | limited in particular, Preferably it is 0.006% or more of the whole eyedrop, More preferably, it is 0.006-0.1%, Especially 0.006-0.06%. If the amount is less than 0.006%, the effect of preventing the reduction of the antiseptic power of the eye drop by adding EDTA or a salt thereof may be insufficient. If the amount exceeds 0.1%, the eye irritation when the eye drop is applied May occur and the feeling of use may be impaired.

  In the eye drop of the present invention, it is more preferable to add boric acid and / or borax in addition to the above components, since the antiseptic power of the eye drop is further enhanced. The boric acid and borax are not necessarily used in combination, but the combined use is more effective. The amount of boric acid and borax in the eye drop of the present invention is not particularly limited, but preferably boric acid is 0.1% or more of the whole eye drop, borax is 0.01% or more of the whole eye drop, Below these concentrations, the effect of enhancing the preservative power by boric acid and borax may be insufficient. Also, considering the safety to the living body, the smaller the blending amount, the better. Therefore, it is more preferable that boric acid is 0.1 to 0.5% and borax is 0.01 to 0.08%. is there.

  The eye drop of the present invention is particularly useful as an eye drop for a contact lens that can be instilled with a contact lens, particularly a soft contact lens, since the preservative is prevented from adsorbing to the contact lens.

  In addition to the above-mentioned components, the eye drop of the present invention can be blended with various components that are usually used for the preparation of eye drops, if necessary, in their normal usage. For example, active ingredients such as anti-inflammatory agents, vitamin agents, antihistamines, and additives such as pH regulators, buffers, tonicity agents, solubilizers, preservatives can be blended. Can be prepared.

  EXAMPLES Hereinafter, although an experiment example and an Example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example.

[Experimental Example 1]
First, an adsorption suppression test of benzalkonium chloride on a soft contact lens was performed.

  A solution having the following composition was prepared by a conventional method of eye drops, and the adsorption inhibition rate of benzalkonium chloride on a commercially available soft contact lens was measured by the following test method. The results are shown in Table 1.

<Composition>
%
Taurine 1
Sodium dihydrogen phosphate 0.7
Disodium hydrogen phosphate 0.06
α-cyclodextrin 0.01-0.3
Benzalkonium chloride 0.01
Purified water remaining
100.0

<Adsorption suppression test method for benzalkonium chloride>
Take 10 ml of the above composition in a 30 ml vial, soak one soft contact lens, and shake in a thermostatic bath at 25 ° C. for 24 hours. Thereafter, the contact lens was taken out, the concentration of benzalkonium chloride present in this solution was quantified by HPLC, and the absorption inhibition rate was calculated by the following formula.

  In addition, the same operation as described above was carried out for those to which no contact lens was added and this was used as a control.

  From the results in Table 1, it is recognized that the addition of α-cyclodextrin to a solution containing benzalkonium chloride suppresses the adsorption of benzalkonium chloride to the soft contact lens, and the inhibitory effect is α-cyclodextrin. It was found that the addition of to a concentration in the solution of 0.03% or more becomes remarkable.

  For β-cyclodextrin, γ-cyclodextrin, δ-cyclodextrin, methylated cyclodextrin and hydroxyethylated cyclodextrin, the same results as in Table 1 were obtained.

[Experiment 2]
Next, in order to test the low temperature stability of the above solution, the solution was prepared by setting the blending amount of α-cyclodextrin in the composition of Experimental Example 1 in the range of 0.03 to 2%, and at 5 ° C., respectively. The stability (appearance) of the solution after storage for 6 months was observed according to the following evaluation criteria. The results are shown in Table 2.

<Evaluation criteria>
○: No change △: Slight turbidity ×: Precipitate formation

  From the results of Table 1 and Table 2, when α-cyclodextrin is added to a solution containing benzalkonium chloride to suppress adsorption of benzalkonium chloride to the soft contact lens, the low temperature stability of the solution is considered. It was observed that the concentration of α-cyclodextrin is preferably 1% or less, more preferably 0.5% or less. Similar results were obtained for the other cyclodextrins described above.

[Experiment 3]
The following antiseptic test was conducted for each solution of Experimental Example 1 described above.

<Preservation test method>
Escherichia coli (E. coli)
Psedomonas aeruginosa (P. aeru)
Stapyrococcus aureus (S. aureus)
Bacteria and Aspergillus nigar (A. nigar)
Candida albicans (Candida)
The fungi were tested according to the storage drag test described in Pharmacopeia of the United States.

  The results of the above test were evaluated according to the following criteria. The results are shown in Table 3.

◎: Time required for killing fungi within 5 days ○: Fungi killed in 6-10 days ×: 11-15 days, or fungi killed in 15 days or more

  From the results in Tables 1 and 3, when α-cyclodextrin is added to a solution containing benzalkonium chloride so that the concentration becomes 0.03% or more, adsorption of benzalkonium chloride to the soft contact lens is suppressed. However, it was observed that the preservative power of the solution was significantly reduced.

[Experimental Example 4]
In the composition of Experimental Example 1, EDTA disodium salt (EDTA-2Na) was further added to the solution so that the concentration in the solution would be 0.002 to 0.3% by a conventional method of eye drops. The solution was subjected to the preservative strength test of Experimental Example 3 above, and the preservative strength of each solution was evaluated according to the same criteria as described above. The results are shown in Table 4. In addition, since the said result was the same result with any fungi irrespective of the kind of fungi, the kind of fungi is not described in Table 4.

  From the results in Table 4, the decrease in the antiseptic power of the solution due to the addition of 0.01 to 1.0% α-cyclodextrin to the solution containing benzalkonium chloride was prevented by the addition of EDTA-2Na, and the effect was It was observed that the addition of EDTA-2Na becomes remarkable when the concentration in the solution is 0.006% or more.

[Experimental Example 5]
Solutions having the following compositions were prepared by a conventional method of eye drops, and the antiseptic power test of Experimental Example 3 was conducted for each solution, and the antiseptic power of each solution was evaluated according to the same criteria as described above. The results are shown in Table 5. In addition, since the said result was the same result also in any microbe irrespective of the kind of fungi, in Table 5, the kind of fungi is not described.

<Composition>
%
Taurine 1.0
EDTA-2Na 0.006
α-cyclodextrin 0.03
Benzalkonium chloride 0.01
Boric acid 0-1.0
Borax 0-0.15
Sodium dihydrogen phosphate appropriate amount Disodium hydrogen phosphate appropriate amount
Purified water remaining
100.0
(Sodium dihydrogen phosphate and disodium hydrogen phosphate were added in appropriate amounts to adjust the pH of the eye drop to about 7.2.)

  From the results of Table 5, it can be seen that boric acid and borax can improve the antiseptic power of a solution containing benzalkonium chloride, α-cyclodextrin and EDTA-2Na, either alone or in combination. It was confirmed that the effect of improving the antiseptic power of the solution becomes remarkable by adding so that the concentration becomes 0.1% or more and 0.01% or more in the case of borax.

  However, in general, boric acid / borax is often used in the concentration range of 0.5 to 1.0% in the eye drop, but according to the eye drop of the present invention, boric acid / borax is more diluted. Since the effect of improving the antiseptic power can be exhibited at a low concentration (for example, 0.1%), the eye drop of the present invention is much more preferable than the above-described general eye drops in view of the safety of the living body.

[Examples 1 and 2 and Comparative Example 1]
About the composition shown in Table 6, it prepared so that the total amount of a composition might be set to 1000g by the conventional method of eyedrops, and the eyedrops based on Example 1, 2 or the comparative example 1 were obtained. For each eye drop, the same test as in Experimental Example 1 and Experimental Example 3 was performed, and for the test in Experimental Example 3, the antiseptic power of each eye drop was evaluated according to the same criteria as described above. The results are also shown in Table 6.

  From the results of Table 6, the ophthalmic solution of the present invention contains α-cyclodextrin and EDTA-2Na in an ophthalmic solution containing benzalkonium chloride (Example 1). In particular, when boric acid and borax are added (Example 2), it is recognized that the antiseptic power of the eye drops is more excellent.

  On the other hand, when only α-cyclodextrin is used in combination with the ophthalmic solution containing benzalkonium chloride (Comparative Example 1), it is recognized that the preservative adsorption inhibition rate is excellent, but the ophthalmic solution is inferior in antiseptic power. .

[Examples 3 to 14]
About the composition shown in Table 7, it prepared so that the total amount of a composition might be set to 1000g by the conventional method of eyedrops, and the eyedrops which concern on Examples 3-14 were obtained. For each eye drop, the same test as in Experimental Example 1 and Experimental Example 3 was performed, and for the test in Experimental Example 3, the antiseptic power of each eye drop was evaluated according to the same criteria as described above. The results are also shown in Table 7. In Table 7, each component is abbreviated as follows.

CS: chondroitin sodium sulfate,
Vesium chloride: benzalkonium chloride,
Gluconic acid C: Chlorhexidine gluconate,
Benzeth chloride: benzethonium chloride,
α-CD: α-cyclodextrin,
β-CD: β-cyclodextrin,
γ-CD: γ-cyclodextrin,
Methylated α-CD: methylated α-cyclodextrin,
HE-β-CD: hydroxyethylated β-cyclodextrin,
EDTA-2K: Diethyl potassium ethylenediaminetetraacetate

Claims (2)

  Cyclodextrins selected from cyclodextrins and cyclodextrin derivatives having a saccharide ring structure of cyclodextrins in eye drops containing 0.001 to 0.1% by weight / volume% of a preservative having a cationic group. Instillation for soft contact lenses that can be instilled in a state of wearing a soft contact lens, comprising 5% weight / volume% and ethylenediaminetetraacetic acid or a salt thereof 0.006 to 0.1% weight / volume% Agent.   The eye drop for soft contact lenses according to claim 1, wherein the cyclodextrins are α-cyclodextrins.