JP4892291B2 - Ophthalmic preservative composition - Google Patents

Description

  The present invention relates to an ophthalmic antiseptic composition comprising a chlorite and a stabilizer thereof, and an ophthalmic solution containing the composition.

 Eye drops are administered directly to the sensitive organs of the human body, the eye, and contact lenses are also used in environments where the eyes are in direct contact. Therefore, it is necessary to pay attention to the components of the ophthalmic solution and the contact lens preservation solution from the viewpoint of safety, and in particular, it is necessary to consider eye irritation and side effects.

 Examples of antiseptic components for ophthalmic solutions include benzalkonium chloride, benzethonium chloride, and sorbic acid. Examples of antiseptic components for contact lens preservation solutions include polyhexamethylene biguanide (PHMB), polyquad, hydrogen peroxide, and purite. (Stabilized chlorine dioxide) has been put to practical use.

 However, although benzalkonium chloride and benzethonium chloride are excellent in antiseptic effect, they may cause corneal damage when the concentration is high, and the use concentration is accompanied by certain restrictions. Moreover, these preservatives may cause a compounding change (chemical reaction) with acidic additives, and also have the property of being easily adsorbed by eye drops containers and filtration filters. Although sorbic acid is hardly adsorbed to the eye drop container, it does not have a sufficient antiseptic effect, and its stability is lowered depending on the pH. On the other hand, peroxide-based preservatives such as hydrogen peroxide exhibit excellent sterilization / cleaning action when added to a contact lens preservation solution, but they are irritating and therefore must be neutralized.

Chlorite is a compound having a ClO ₂ ⁻ ion, and sodium chlorite is used as a disinfectant for tap water. However, it is known that when chlorite is decomposed, chlorine dioxide having a strong oxidizing action is generated and is irritating to eyes, skin, respiratory tract and the like. On the other hand, Patent Document 1 is an invention relating to a method for producing chlorine dioxide and a composition for sterilization, and by generating chlorine dioxide from a chlorine dioxide precursor such as chlorite using a transition metal, An invention is disclosed in which contact lenses and the like are sterilized and washed using the strong bactericidal action of chlorine dioxide.
JP-A-3-164402

  Chlorine dioxide is a strong oxidizing agent like hydrogen peroxide, and is known to have strong irritation to the eyes and skin, so when using chlorite as an ophthalmic antiseptic component Therefore, it is important to increase the safety by suppressing the generation of chlorine dioxide.

The present inventors have made various studies stabilizer suppressing the generation of chlorine dioxide, chlorite and creatinine is a preservative component, geraniol, tocopherol acetic acid, oxyquinoline sulfate, a sugar alcohol and polyoxyethylene sorbitan An ophthalmic solution containing an ophthalmic antiseptic composition comprising at least one stabilizer selected from fatty acid esters is superior in safety by significantly suppressing the generation of chlorine dioxide, and further has an antiseptic effect over a long period of time. Found to last.

That is, the present invention
(1) an ophthalmic antiseptic composition comprising chlorite and at least one stabilizer selected from the following 1) to 6 ):
1) Creatinine 2) Geraniol
3 ) Tocopherol acetate
4 ) Oxyquinoline sulfate
5 ) sugar alcohol, and
6 ) Polyoxyethylene sorbitan fatty acid ester (2) The ophthalmic antiseptic composition according to the above (1), wherein the chlorite is sodium chlorite,
(3) The ophthalmic antiseptic composition according to the above (1), wherein the sugar alcohol is mannitol, sorbitol or xylitol,
(4) The ophthalmic antiseptic composition according to (1), wherein the polyoxyethylene sorbitan fatty acid ester is polysorbate 80, and (5) the ophthalmic antiseptic composition according to any one of (1) to (4) above Ophthalmic solution containing,
(6) an ophthalmic solution comprising 0.00001 to 1% (W / V) chlorite and at least one stabilizer selected from the following 1) to 6 ):
1) 0.0001-5% (W / V) creatinine 2) 0.00001-0.05% (W / V) geraniol
3 ) 0.0001 to 1% (W / V) tocopherol acetate
4 ) 0.00001 to 1% (W / V) of oxyquinoline sulfate
5 ) 0.001-10% (W / V) sugar alcohol, and
6 ) 0.0001-10% (W / V) polyoxyethylene sorbitan fatty acid ester.

  In the present invention, the chlorite as the antiseptic component is not particularly limited as long as it is a salt of chlorite, but for example, an alkali metal chlorite such as sodium chlorite and potassium chlorite, calcium chlorite , Alkaline earth metal salts of chlorite such as magnesium and barium, copper chlorite, lead chlorite, ammonium chlorite and the like, more preferably sodium chlorite.

  The concentration of chlorite in the ophthalmic solution is preferably 0.00001 to 1% (W / V), more preferably 0.0001% to 0.1% (W / V).

 In the present invention, examples of the stabilizer capable of stabilizing the chlorite, which is an antiseptic component, and suppressing the generation of chlorine dioxide include the following seven.

1) Creatinine 2) Geraniol
3 ) Tocopherol acetate
4 ) Oxyquinoline sulfate
5 ) Sugar alcohol
6 ) Polyoxyethylene sorbitan fatty acid ester Here, as sugar alcohol, mannitol, sorbitol, xylitol, sucrose, etc. are mentioned, More preferably, it is mannitol. Examples of the polyoxyethylene sorbitan fatty acid ester include polysorbate 80 [polyoxyethylene sorbitan monooleate], polysorbate 60 [polyoxyethylene sorbitan monostearate], polysorbate 40 [polyoxyethylene sorbitan monopalmitate], and polyoxyethylene sorbitan. Examples thereof include monolaurate, polyoxyethylene sorbitan trioleate, polysorbate 65 [polyoxyethylene sorbitan tristearate], and more preferably polysorbate 80.

The concentration of stabilizer in ophthalmic solutions, from 0.0001 to 5% for creatinine (W / V), 0.00001~0.05% for geraniol (W / V), tocopherol acetic acid (alpha, beta , Γ, δ) is 0.0001 to 1% (W / V), oxyquinoline sulfate is 0.00001 to 1% (W / V), and sugar alcohol is 0.001 to 10% (W / V). ), Polyoxyethylene sorbitan fatty acid ester is preferably 0.0001 to 10% (W / V).

 The seven stabilizers may be used alone or in combination.

 The ophthalmic solution of the present invention is preferably used, for example, as an ophthalmic solution or a contact lens preservation solution, and can be prepared by a widely used method.

 In addition, the ophthalmic solution of the present invention can be appropriately mixed with a drug, an isotonic agent, a buffering agent, a pH adjusting agent, a thickening agent and the like as necessary.

 The drug to be added to the ophthalmic solution of the present invention is not particularly limited. For example, anti-glaucoma agents (such as timolol, prostaglandin derivatives, carbonic anhydrase inhibitors), various vitamins (vitamin B2, vitamin B6, vitamin B12) , Vitamin E, panthenol), decongestants (tetrahydrozoline hydrochloride, naphazoline hydrochloride, etc.), anti-inflammatory agents (diclofenac, indomethacin, fluorometholone, pranoprofen, dipotassium glycyrrhizinate, epsilon-aminocaproic acid, etc.), antihistamines ( Chlorpheniramine maleate, diphenhydramine hydrochloride, etc.), antiallergic agents (such as cromoglycate sodium), antibacterial agents (quinolone antibacterial agents, cephalosporins, sulfacetamide sodium, sulfamethoxazole, etc.), amino acids (L-asparagine Potassium, aminoethyl sulfonic acid, sodium chondroitin sulfate, etc.), etc. Diagnostic reagents (sodium fluorescein), sodium hyaluronate, may be mentioned neostigmine methylsulfate and the like.

 Examples of the isotonizing agent include glycerin, propylene glycol, polyethylene glycol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like.

  Examples of the buffer include phosphates such as sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate; sodium borate, potassium borate Citrates such as sodium citrate and disodium citrate; acetates such as sodium acetate and potassium acetate; carbonates such as sodium carbonate, sodium hydrogen carbonate, trometamol, and epsilon aminocaproic acid Can do.

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

  Examples of the thickener include hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, carboxyvinyl polymer, polyvinylpyrrolidone and the like.

 The pH of the ophthalmic solution of the present invention is preferably 3 to 9, particularly 5 to 8.

And chlorite, creatinine, geraniol, tocopherol acetic acid, ophthalmic containing ophthalmic preservative composition comprising at least one stabilizer selected oxyquinoline sulfate, a sugar alcohol and polyoxyethylene sorbitan fatty acid esters Since the liquid agent suppresses the generation of chlorine dioxide, it is excellent in safety and maintains the antiseptic effect for a long time.

1. Chlorine dioxide generation suppression test (1) Sample preparation test solution 1
Dissolve 7 mg of chlorite, 500 mg of creatinine and 20 mg of sodium hydrogen phosphate in about 80 mL of purified water, adjust the pH to 7.0 with dilute hydrochloric acid or sodium hydroxide, and adjust the total volume to 100 mL with purified water to obtain Test Solution 1 It was.

Test solutions 2-6
Test solutions 2 to 6 were obtained in the same manner as in test solution 1 except that geraniol 5 mg, glucose 200 mg, mannitol 2 g, polysorbate 80 100 mg, and oxyquinoline sulfate 10 mg were used instead of creatinine 500 mg in test solution 1. It was.

Test solution 7
Mix 140 mg of d-α-tocopherol acetate and 100 mg of polysorbate 80, then add 7 mg of chlorite, 20 mg of sodium hydrogenphosphate and about 80 mL of purified water to dissolve, and adjust the pH to 7.0 with dilute hydrochloric acid or sodium hydroxide. The test solution 7 was obtained by adjusting the total volume to 100 mL with purified water.

Comparative test solution 1
A comparative test solution 1 was obtained by dissolving 7 mg of chlorite and 20 mg of sodium hydrogen phosphate in about 80 mL of purified water, adjusting the pH to 7.0 with dilute hydrochloric acid or sodium hydroxide, and adjusting the total volume to 100 mL with purified water.

(2) Test method and results 1) Determination of chlorine dioxide by DPD method (14 days)
Using test solutions 1 to 5 and comparative test solution 1, the chlorine dioxide generation concentration (ppm) was measured by the DPD method described in the water test method. The test results are shown in Table 1.

Note) * 1: Indicates that ND is 0.02 ppm or less (measurement range of DPD method: 0.02-5 ppm).

2) Confirmation of the presence of chlorine dioxide by detector tube (14 days)
Since the test solutions 6 and 7 are colored and cannot be quantified by the DPD method, the presence of chlorine dioxide was confirmed using a simple test method using a detector tube. That is, after the chlorine dioxide in the test solutions 6 and 7 and the comparative test solution 1 was vaporized under reduced pressure conditions, the presence of chlorine dioxide was confirmed using a detector tube. These test results are shown in Table 2.

Note) * 2: N.D. indicates that chlorine dioxide was not present (detection tube measurement range: 0.05-0.6 ppm).

(3) Discussion As is clear from Tables 1 and 2, an ophthalmology comprising chlorite and each stabilizer (creatinine, geraniol, glucose, mannitol, polysorbate 80, oxyquinoline sulfate, d-α-tocopherol acetate). Since the ophthalmic solution containing the antiseptic composition for use can remarkably suppress the generation of chlorine dioxide, it is excellent in safety and has little irritation to the eyes.

2. Preservative Efficacy Test (1) Preservative Efficacy Test Using P. aeruginosa and C. albicans 1) Sample The test solutions 1-7 were used.

2) Test methods and results Preservation efficacy tests are conducted in accordance with the 14th revised Japanese Pharmacopoeia preservation efficacy test method, using Pseudomonas aeruginosa (P. aeruginosa) and Candida albicans (C. albicans) as test bacteria. The viable cell count was measured after 7 and 14 days. The survival rate (%) of the bacteria was calculated according to the following formula.

Survival rate (%) = number of viable bacteria at sampling / initial number of bacteria x 100
These test results are shown in Table 3.

Note) * 3: N.D. indicates that no bacteria were detected.

(2) Storage efficacy test using A. niger 1) Sample preparation test solution 8
Chlorite 20 mg, geraniol 5 mg and sodium hydrogen phosphate 200 mg were dissolved in purified water, pH was adjusted to 6.5 with dilute hydrochloric acid or sodium hydroxide, and the total amount was adjusted to 100 mL with purified water to obtain test solution 8.

Test solutions 9 and 10
Test solutions 9 and 10 were obtained in the same manner as in test solution 8 except that 50 mg of creatinine and 2 g of mannitol were used instead of 5 mg of geraniol in test solution 8.

Test solutions 11 and 12
Test solutions 11 and 12 were obtained in the same manner as in test solution 8, except that 20 mg of chlorite in test solution 8 was changed to 50 mg and 7 mg, respectively.

2) Test method and results A storage efficacy test was performed using test solutions 8-12. The preservation efficacy test is conducted in accordance with the 14th revised Japanese Pharmacopoeia preservation efficacy test method. Using Aspergillus niger (A.niger) as the test bacteria, the viable cell count is measured after 7, 14 and 28 days. did. The criteria of the Japanese Pharmacopoeia (JP) and the US Pharmacopoeia (USP) of Category IA in which eye drops are classified are shown below.

JP criteria (fungus): The number of viable bacteria after 14 and 28 days should be the same level or lower than the number of inoculated bacteria USP criteria (fungus): Viable counts after 7, 14, and 28 days Table 4 shows the test results.

(3) Preservation efficacy test using 5 bacterial species 1) Sample preparation Test solution 13
Dissolve 7 mg of chlorite, 5 mg of geraniol, 400 mg of potassium chloride, 100 mg of sodium chloride and 1 g of boric acid in purified water, adjust the pH to 7.5 with dilute hydrochloric acid or sodium hydroxide, and test the total volume with purified water at 100 mL Solution 13 was obtained.

Test solution 14
Test solution 14 was obtained in the same manner as test solution 13 except that 2 g of mannitol was used instead of 5 mg of geraniol in test solution 13.

Comparative test solution 2
400 mg of potassium chloride, 100 mg of sodium chloride and 1 g of boric acid were dissolved in purified water, the pH was adjusted to 7.5 with dilute hydrochloric acid or sodium hydroxide, and the total amount was adjusted to 100 mL with purified water to obtain a comparative test solution 2.

2) Test method and results A storage efficacy test was performed using test solutions 13 to 14 and comparative test solution 2. The preservation efficacy test is conducted in accordance with the preservation efficacy test method of the 14th revised Japanese Pharmacopoeia, and Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Using Condida albicans (C. albicans) and Aspergillus niger (A. niger), the viable cell count was measured after 14 and 28 days. The survival rate (%) of the bacteria was calculated according to the following formula.

Survival rate (%) = number of viable bacteria at sampling / initial number of bacteria x 100
These test results are shown in Table 5.

(3) Discussion As is clear from Tables 3 to 5, ophthalmic solutions containing an ophthalmic antiseptic composition comprising chlorite and the respective stabilizers are Pseudomonas aeruginosa (Gram-negative bacteria), Candida ( It exhibits excellent antiseptic effects against various fungi such as fungi) and black koji molds (fungi).

3. Formulation Example A typical formulation example is shown below.

Formulation Example 1 (pH 7)
100mg sodium hyaluronate in 100ml
Sodium chlorite 7mg
Creatinine 50mg
Sodium chloride 850mg
Sodium dihydrogen phosphate 200mg
Sodium hydroxide Appropriate amount Dilute hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount

Formulation Example 2 (pH 7)
100mg sodium hyaluronate in 100ml
Sodium chlorite 7mg
Geraniol 5mg
Sodium chloride 900mg
Sodium dihydrogen phosphate 200mg
Sodium hydroxide Appropriate amount Dilute hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount

Formulation Example 3 (pH 7)
100mg sodium hyaluronate in 100ml
Sodium chlorite 7mg
Mannitol 2g
Sodium dihydrogen phosphate 200mg
Sodium hydroxide Appropriate amount Dilute hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount

Formulation Example 4 (pH 7)
100mg of potassium chloride in 100ml
Sodium chloride 400mg
Sodium chlorite 7mg
Geraniol 5mg
1g boric acid
Sodium hydroxide Appropriate amount Dilute hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount

Claims (6)

An ophthalmic antiseptic composition comprising chlorite and at least one stabilizer selected from the following 1) to 6 ).
1) Creatinine 2) Geraniol
3 ) Tocopherol acetate
4 ) Oxyquinoline sulfate
5 ) sugar alcohol, and
6 ) Polyoxyethylene sorbitan fatty acid ester The ophthalmic antiseptic composition according to claim 1, wherein the chlorite is sodium chlorite. The ophthalmic antiseptic composition according to claim 1, wherein the sugar alcohol is mannitol, sorbitol or xylitol. The ophthalmic antiseptic composition according to claim 1, wherein the polyoxyethylene sorbitan fatty acid ester is polysorbate 80. An ophthalmic solution comprising the ophthalmic antiseptic composition according to claim 1. An ophthalmic solution comprising 0.00001 to 1% (W / V) chlorite and at least one stabilizer selected from 1) to 6 ) below.
1) 0.0001-5% (W / V) creatinine 2) 0.00001-0.05% (W / V) geraniol
3 ) 0.0001 to 1% (W / V) tocopherol acetate
4 ) 0.00001 to 1% (W / V) of oxyquinoline sulfate
5 ) 0.001-10% (W / V) sugar alcohol, and
6 ) 0.0001-10% (W / V) polyoxyethylene sorbitan fatty acid ester