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WO2010119942A1 - Lotion ophtalmique de type suspension de levocabastine - Google Patents

Lotion ophtalmique de type suspension de levocabastine Download PDF

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Publication number
WO2010119942A1
WO2010119942A1 PCT/JP2010/056827 JP2010056827W WO2010119942A1 WO 2010119942 A1 WO2010119942 A1 WO 2010119942A1 JP 2010056827 W JP2010056827 W JP 2010056827W WO 2010119942 A1 WO2010119942 A1 WO 2010119942A1
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Prior art keywords
chloride
suspension
levocabastine
type eye
eye drop
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PCT/JP2010/056827
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English (en)
Japanese (ja)
Inventor
洋子 遠藤
章男 木村
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Santen Pharmaceutical Co Ltd
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Santen Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics

Definitions

  • the present invention relates to an improved composition of a suspension-type eye drop containing, as an active ingredient, levocabastine, which is an H 1 blocker eye drop, or a salt thereof.
  • Levocabastine has antihistaminic activity and is widely used as a preventive or therapeutic agent for allergic conjunctivitis.
  • Levocabastine eye drop is a multi-use type eye drop using propylene glycol as an isotonic agent, and needs to have antiseptic effect to prevent secondary contamination.
  • levocabastine eye drops marketed on the market have a sufficient antiseptic effect by adding 0.015% (W / V) of benzalkonium chloride as a preservative (Physicians' desk reference for ophthalmic) medicines, 31 edition (2003)).
  • benzalkonium chloride is known to cause corneal damage when used at high concentrations, so if sufficient antiseptic effect can be maintained, the amount of benzalkonium chloride can be added The lower is desirable.
  • levocabastine suspension type eye drops are widely used as therapeutic agents for allergic conjunctivitis, and are frequently administered drugs such as eye drops multiple times a day. It is rare.
  • levocabastine is a drug that is sparingly soluble in water, and thus is practically used in the form of a suspension-type eye drop. Since the suspension type eye drop does not dissolve the drug, the drug dispersed in the eye drop gradually settles when stored at rest, and the drug concentration in the eye drop becomes non-uniform. Therefore, it is necessary to uniformly disperse the drug by shaking the eye drop container before use. Therefore, if the redispersibility of the suspension-type eye drops can be improved, the usability and convenience are improved, and further, the compliance of the user is improved.
  • Suspension eye drops may form agglomerates during storage even when the drug is uniformly dispersed at the time of preparation, and may not return to the original uniform dispersion state even if shaken before use. is there. Therefore, if the formation of the aggregates can be suppressed, the usability and convenience of the suspension-type eye drops are improved, and further, the compliance of the user is improved.
  • Patent Document 1 describes a dissolved levocabastine ophthalmic solution.
  • This document describes a levocabastine-containing ophthalmic solution that is dissolved by using hydroxypropyl- ⁇ -cyclodextrin as a solubilizing agent, but no suspension type ophthalmic solution has been studied.
  • Patent Document 2 and Patent Document 3 describe a composition containing levocabastine as an antihistamine and an antiallergic agent. In these references, effective combinations of antihistamines and antiallergic agents have been studied for the prevention or treatment of allergic ophthalmic diseases, but the usability and convenience of suspension eye drops containing levocabastine Has not been considered at all.
  • the present inventors have found that a) 0.025% (W / V) levocabastine, b) 0.002 to 0.005% (W / V) benzalkonium chloride, and c ) 0.001 to 0.01% (W / V) of various water-soluble polymers, d) 0.8 to 2.3% (W / V) of isotonic agents (sodium chloride, glycerin)
  • the suspension type ophthalmic solution having an osmotic pressure ratio of 0.5 to 2.0 has an existing anti-revocabastine suspension in spite of the fact that the amount of the preservative is reduced as compared with the existing levocabastine suspension type ophthalmic solution. It has the same preservative effect as a cloudy eye drop, is superior in redispersibility than existing levocabastine suspension type eye drops, has less irritation to the eye tissue, and is excellent in comfort.
  • the headline the present invention has been reached.
  • the present invention reduces the blending amount of benzalkonium chloride, which is a preservative, in levocabastine suspension type eye drops, and blends other components in combination, and limits the concentration of each blending component to a certain range. This not only improved the decline in the preservative effect associated with the reduction in the amount of benzalkonium chloride, but also achieved the purpose of improving the usability and convenience of the levocabastine suspension type eye drops.
  • an ionic tonicity agent such as sodium chloride as an isotonic agent can improve the cohesiveness of the active ingredient levocabastine particles, and a specific viscosity grade hydroxypropyl methylcellulose is added.
  • an ionic tonicity agent such as sodium chloride
  • a specific viscosity grade hydroxypropyl methylcellulose is added.
  • it has been found that the cohesiveness of levocabastine particles as an active ingredient can be improved.
  • the present invention relates to a) 0.01 to 0.1% (W / V) levocabastine or a salt thereof, b) 0.0005-0.01% (W / V) benzalkonium chloride, c) 0.00001-2% (W / V) water-soluble polymer, and d) sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glycerin, propylene glycol, polyethylene glycol, trehalose, sucrose, sorbitol and mannitol.
  • a suspension type ophthalmic solution containing 0.1 to 5% (W / V) isotonic agent which is at least one selected from the group consisting of osmotic pressure ratios of 0.5 to 2.0.
  • the present invention also provides: a) 0.01 to 0.1% (W / V) levocabastine or a salt thereof, b) 0.0005-0.01% (W / V) benzalkonium chloride, c) 0.00001-2% (W / V) water-soluble polymer, d) 0.1 to 5% (W / V) isotonic agent which is at least one selected from sodium chloride, potassium chloride, calcium chloride and magnesium chloride, and e) 0.0001 to 0.5%
  • This is a suspension-type eye drop containing a (W / V) nonionic surfactant and having an osmotic pressure ratio of 0.5 to 2.0.
  • the amount of levocabastine compounded in the suspension type eye drop of the present invention is preferably 0.01 to 0.1% (W / V), more preferably 0.02 to 0.05% (W / V). V), and more preferably 0.02 to 0.03% (W / V).
  • the amount of the salt of levocabastine is preferably from 0.01 to 0.1% (W / V), more preferably from 0.02 to 0.06% (W / V), even more preferably in terms of levocabastine. Is 0.02 to 0.03% (W / V).
  • the salt of levocabastine is not particularly limited as long as it is a pharmaceutically acceptable salt, and includes sodium salt, potassium salt, lithium salt, calcium salt, magnesium salt, zinc salt, iron salt, manganese salt, hydrochloric acid, nitric acid. And salts with inorganic acids such as sulfuric acid, and salts with organic acids such as acetic acid, fumaric acid, maleic acid, succinic acid and tartaric acid, and the like, preferably hydrochloride.
  • the benzalkonium chloride compounded in the suspension type eye drop of the present invention may be used as a preservative in ophthalmic preparations.
  • [C 6 H 5 CH 2 N (CH 3 ) 2 R] Cl In which the alkyl group (indicated by R) is C 8 H 17 to C 18 H 37 .
  • the blending amount of benzalkonium chloride is an amount having a sufficient antiseptic effect, and is 0.01% (W / V) or less. Specifically, it is 0.0005 to 0.01% (W / V), more preferably 0.001 to 0.008% (W / V), and still more preferably 0.002 to 0.005%. (W / V).
  • Examples of the water-soluble polymer blended in the suspension type eye drop of the present invention include polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, hydroxypropylmethylcellulose (hypromellose), hydroxypropylethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, and ethyl. Mention may be made of cellulose-based polymers such as methylcellulose, ethylpropylcellulose, carboxymethylcellulose or salts thereof, carboxypropylcellulose or salts thereof, sodium polyacrylate, sodium chondroitin sulfate and the like.
  • the blending amount of the water-soluble polymer is preferably 0.00001 to 2% (W / V), more preferably 0.0001 to 1% (W / V), and 0.0001 to 0.5% (W / V). Is most preferred.
  • the suspension type eye drop of the present invention can further improve the aggregation properties of levocabastine by using hydroxypropylmethylcellulose having a specific viscosity grade as a water-soluble polymer.
  • Viscosity grade of hydroxypropyl methylcellulose may be a 2% (W / V) aqueous solution viscosity of 1 ⁇ 2000mm 2 / s of the 20 ° C., preferably 1 ⁇ 200mm 2 / s, 1 ⁇ 20mm 2 / s Gayori preferable.
  • the amount of the hydroxypropyl methylcellulose is preferably 0.00001 to 2% (W / V), more preferably 0.0001 to 1% (W / V), and 0.0001 to 0.5% (W / V). Is most preferred.
  • the osmotic pressure ratio of the suspension type eye drop of the present invention is 0.5 to 2.0, preferably 0.8 to 1.2, more preferably 0.9 to 1.1, still more preferably 1. 0.
  • the isotonic agent incorporated in the suspension type eye drop of the present invention has an isotonic effect capable of adjusting the osmotic pressure ratio of the suspension type eye drop of the present invention to 0.5 to 2.0. If it is.
  • the ionic tonicity agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like
  • examples of the nonionic tonicity agent include glycerin, propylene glycol, polyethylene glycol, trehalose, sucrose. Claus, sorbitol, mannitol and the like can be mentioned.
  • the amount of isotonic agent is not particularly limited as long as the osmotic pressure ratio of the suspension type eye drop of the present invention can be adjusted to 0.5 to 2.0, but is 0.1 to 5% (W / V). Is more preferable, and 0.3 to 3% (W / V) is more preferable.
  • the suspension type eye drop of the present invention can further improve the aggregation properties of levocabastine by adding an ionic tonicity agent as an isotonic agent.
  • the ionic tonicity agent is preferably at least one selected from sodium chloride, potassium chloride, calcium chloride and magnesium chloride, more preferably sodium chloride.
  • Nonionic surfactants blended in the suspension type eye drop of the present invention include polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, polysorbate 65, and other polyoxy Polyethylene ethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil Polyoxyethylene castor oil derivatives such as polyoxyl 35 castor oil, polyoxyl 40 castor oil; polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) poly Such as oxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol, etc.
  • Polyoxyethylene polyoxypropylene glycol at least one selected from polyoxyl stearate 40 and sucrose fatty acid ester, etc., preferably polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyoxy35 castor oil and polyoxyl monostearate 40, more preferably polysorbate 80.
  • the total amount of the nonionic surfactant is 0.0001 to 0.5% (W / V), preferably 0.001 to 0.1% (W / V), and more.
  • the content is 0.003 to 0.05% (W / V).
  • Buffers blended in the suspension type eye drops of the present invention are phosphoric acid, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate Phosphates such as boric acid, borax such as sodium borate, potassium borate, etc .; citrates such as sodium citrate and disodium citrate; acetates such as sodium acetate and potassium acetate, carbonic acid At least one selected from carbonates such as sodium and sodium bicarbonate, ⁇ -aminocaproic acid and trometamol, preferably phosphoric acid, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, phosphoric acid At least one selected from potassium, potassium dihydrogen phosphate and dipotassium hydrogen phosphate; Ri is preferably sodium dihydrogen phosphate and disodium hydrogen phosphate.
  • the total amount of the buffering agent is preferably 0.001 to 5.0% (W / V), more preferably 0.01 to 1.0% (W / V), and 0.1 to 0.00%. 5% (W / V) is more preferable, and 0.2 to 0.4% (W / V) is most preferable.
  • the suspension type eye drop of the present invention can be prepared by a widely used method, and a pH adjuster, a stabilizer and the like can be blended as necessary.
  • pH regulators examples include hydrochloric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, and the like.
  • stabilizers examples include edetic acid and sodium edetate.
  • the pH of the suspension type eye drop of the present invention is desirably set to 3.0 to 8.5.
  • the eye diseases in which the suspension type eye drop of the present invention is used are allergic or inflammation-related diseases, such as allergic conjunctivitis, spring catarrh, atopic keratoconjunctivitis, infectious keratoconjunctivitis, blepharitis, cataract surgery eye Itching and the like can be mentioned.
  • the number of instillations of the suspension type ophthalmic solution of the present invention is appropriately selected depending on the symptom, age, dosage form, and the like, but 1 to several drops at a time, 1 to several times a day (for example, 1 to 6 times) That's fine.
  • the test preparation of the present invention has the existing levocabastine suspension type ophthalmic solution in spite of the fact that the preservative content is reduced as compared with the existing levocabastine suspension type ophthalmic solution. It has an excellent preservative effect equivalent to the agent.
  • the suspension type ophthalmic solution of the present invention is superior in redispersibility and less irritating to the eye tissue than the existing levocabastine suspension type eyedrop, and is a comfortable formulation.
  • Preservative Efficacy Test A preservative efficacy test was carried out using the suspension type eye drop of the present invention.
  • test preparation 1 Benzalkonium chloride (0.005 g), hydroxypropyl methylcellulose 2910 (2% (W / V) aqueous solution at 20 ° C. has a viscosity of 6 mm 2 / s: manufactured by Shin-Etsu Chemical Co., Ltd.) (0.001 g), sodium chloride (0. 8 g), polysorbate 80 (0.005 g), sodium edetate (appropriate amount), disodium hydrogen phosphate and sodium dihydrogen phosphate (appropriate amount) as a buffer were placed in a 100 mL beaker, purified water was added and dissolved by stirring.
  • test preparation 1 levocabastine hydrochloride (0.027 g) was added and dispersed, then the pH was adjusted to 7 using sodium hydroxide or dilute hydrochloric acid, and purified water was added to make a total volume of 100 mL. Pressure ratio: 1.0) was obtained. Hereinafter, this is designated as test preparation 1.
  • Test preparation 2 Suspension type eye drops (osmotic pressure ratio: 1), except that concentrated glycerin (2.3 g) is used instead of sodium chloride (0.8 g) of test preparation 1, except that concentrated glycerin (2.3 g) is used. 0.0). Hereinafter, this is designated as test preparation 2.
  • Test preparation 3 Benzalkonium chloride (0.002 g), hydroxypropylmethylcellulose 2910 (2% (W / V) aqueous solution at 20 ° C. has a viscosity of 6 mm 2 / s: manufactured by Shin-Etsu Chemical Co., Ltd.) (0.001 g), sodium chloride (0. 8 g), polysorbate 80 (0.05 g), sodium edetate (appropriate amount), and disodium hydrogen phosphate and sodium dihydrogen phosphate (appropriate amount) as a buffer were placed in a 100 mL beaker, purified water was added and dissolved by stirring.
  • test preparation 3 levocabastine hydrochloride (0.027 g) was added and dispersed, then the pH was adjusted to 6 using sodium hydroxide or dilute hydrochloric acid, and purified water was added to make a total volume of 100 mL. Pressure ratio: 1.0) was obtained. Hereinafter, this is designated as test preparation 3.
  • Test preparation 4 A suspension type eye drop (osmotic pressure ratio: 1.0) was obtained by performing the same operation as in the case of the test preparation 3 except that the pH of the test preparation 3 was changed from 6 to 8. Hereinafter, this is designated as test preparation 4.
  • Test preparation 5 Benzalkonium chloride (0.003 g), hydroxypropylmethylcellulose 2910 (2% (W / V) aqueous solution at 20 ° C. has a viscosity of 6 mm 2 / s: manufactured by Shin-Etsu Chemical Co., Ltd.) (0.001 g), sodium chloride (0. 8 g), polysorbate 80 (0.005 g), sodium edetate (appropriate amount), disodium hydrogen phosphate and sodium dihydrogen phosphate (appropriate amount) as a buffer were placed in a 100 mL beaker, purified water was added and dissolved by stirring.
  • test preparation 5 levocabastine hydrochloride (0.027 g) was added and dispersed, then the pH was adjusted to 7 using sodium hydroxide or dilute hydrochloric acid, and purified water was added to make a total volume of 100 mL. Pressure ratio: 1.0) was obtained. Hereinafter, this is designated as test preparation 5.
  • Test preparation 6 Except for changing the blending amount of hydroxypropylmethylcellulose 2910 in test preparation 5 from 0.001 g to 0.005 g, the same operation as in test preparation 5 was performed, and suspension type eye drop (penetration) of test preparation 6 Pressure ratio: 1.0) was obtained.
  • Test preparation 7 Except for changing the blending amount of hydroxypropylmethylcellulose 2910 in test preparation 5 from 0.001 g to 0.01 g, the same operation as in test preparation 5 was performed to obtain suspension type eye drop (penetration) of test preparation 7 Pressure ratio: 1.0) was obtained.
  • Test preparation 8 Except for changing the blending amount of hydroxypropylmethylcellulose 2910 in test preparation 5 from 0.001 g to 0.1 g, the same operation as in test preparation 5 was performed to prepare suspension type eye drop (penetration) of test preparation 8. Pressure ratio: 1.0) was obtained.
  • Test preparation 9 Except for changing the blending amount of hydroxypropylmethylcellulose 2910 in test preparation 5 from 0.001 g to 0.5 g, the same operation as in test preparation 5 was performed to obtain suspension type eye drop (penetration) of test preparation 9 Pressure ratio: 1.0) was obtained.
  • Test Method Preservative efficacy tests were conducted on test preparations 1 to 9. Preservative efficacy test of Test preparation 1 and 2, the European Pharmacopoeia performed in compliance with (EUROPEAN PHARMACOPOEIA 5 th Edition) for preservative effectiveness test method, Escherichia coli as the test bacterium (E.coli), Pseudomonas aeruginosa (P.aeruginosa ) And the viable cell count was measured after 24 hours and 28 days using Staphylococcus aureus (S. aureus). In addition, the viable cell count was measured after 7 and 28 days using Candida albicans (C. albicans) and Aspergillus niger (A. niger).
  • E.coli test bacterium
  • Pseudomonas aeruginosa P.aeruginosa
  • S. aureus Staphylococcus aureus
  • viable cell count was measured after 7 and 28 days using Candida albicans (C. albi
  • test preparations 3 and 4 were conducted in accordance with the Japanese Pharmacopoeia (15th revision) and the US Pharmacopoeia preservative efficacy test methods, and Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (C. albicans) and Aspergillus niger (A. niger), the viable cell count was measured after 7 and 28 days.
  • E. coli Escherichia coli
  • Pseudomonas aeruginosa P. aeruginosa
  • Staphylococcus aureus S. aureus
  • Candida albicans C. albicans
  • A. niger Aspergillus niger
  • the preservative efficacy test of the test preparations 5 to 9 is performed in accordance with the Japanese Pharmacopoeia (15th revision) and the US Pharmacopoeia preservative efficacy test method, and Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (C. albicans) and Aspergillus niger (A. niger), and the viable cell count after 7 days was measured.
  • Escherichia coli E. coli
  • Pseudomonas aeruginosa P. aeruginosa
  • Staphylococcus aureus S. aureus
  • Candida albicans C. albicans
  • A. niger Aspergillus niger
  • the survival rate (%) of the bacteria was calculated from the numerical values obtained in each test according to the following formula.
  • Tables 1-4 Test results and discussion These test results are shown in Tables 1-4. In Tables 1 to 3, ND indicates that no bacteria were detected, and NI in Table 4 indicates that the bacteria did not increase.
  • the suspension type ophthalmic solution of the present invention satisfied the standards defined in the European Pharmacopoeia Standard “A”, the Japanese Pharmacopoeia or the US Pharmacopoeia preservation efficacy test. That is, the suspension type ophthalmic solution of the present invention has an excellent preservative effect equivalent to that of the existing levocabastine suspension type eyedrops, although the amount of the preservative is smaller than that of the existing levocabastine suspension type eyedrops. .
  • the European Pharmacopoeia Standard “A” preservative efficacy test stipulates more stringent requirements than the Japanese Pharmacopoeia and US Pharmacopoeia tests.
  • Test preparation 1 and commercially available levocabastine hydrochloride ophthalmic solution [“Ribostine ophthalmic solution 0.025%” (Seller: Santen Pharmaceutical Co., Ltd.): Levocabastine compounding amount 0.25 mg / ml] (hereinafter referred to as “Comparative formulation 1”), 30 10 times a day at a minute interval, the eye was instilled on the cornea of the eye of a rabbit (white rabbit; male 20 weeks old), and the number of blinks per minute was measured after the 10th instillation (4 cases, 4 eyes each). .
  • the suspension-type eye drop of the present invention is a gentler and more comfortable formulation for the eye tissue than the existing levocabastine suspension-type eye drop.
  • Redispersibility evaluation test 1 The redispersibility was examined using the suspension-type eye drop of the present invention.
  • test preparation 10 Concentrated glycerin (2.3 g) was used instead of sodium chloride (0.8 g) of test preparation 1, and hydroxypropyl methylcellulose 2910 (2% (W / V) aqueous solution at 20 ° C. had a viscosity of 6 mm 2 / s: Shin-Etsu Except that hydroxypropylmethylcellulose 2910 (the viscosity of a 2% (W / V) aqueous solution at 20 ° C. is 4000 mm 2 / s: manufactured by Shin-Etsu Chemical Co., Ltd.) (0.001 g) is used instead of (0.001 g). In the same manner as in the case of the test preparation 1, a suspension type eye drop (osmotic pressure ratio: 1.0) was obtained. Hereinafter, this is designated as test preparation 10.
  • Test method The redispersibility of the levocabastine particles of the test preparations 1 and 10 was examined. Each test preparation is filled into a 5 mL eye drop container and stored in an upright state for a certain period (4 weeks or 3 months) under the conditions shown in Table 5 (50 ° C., 40 ° C./75% RH or 25 ° C./40% RH). did. Immediately after storage, the eye dropper was placed in a box and allowed to fall in a certain direction, and the number of falls until the levocabastine particles settled on the bottom of the container completely peeled off from the container and redispersed was measured.
  • the test preparations 1 and 10 of the present invention were easily redispersed. That is, the suspension type ophthalmic solution of the present invention can easily disperse levocabastine particles by shaking, and is superior in redispersibility to existing levocabastine suspension type eye drops.
  • test preparations 11-17 instead of hydroxypropylmethylcellulose 2910 (the viscosity of a 2% (W / V) aqueous solution at 20 ° C. is 6 mm 2 / s: manufactured by Shin-Etsu Chemical Co., Ltd.) of Test Preparation 1, hydroxyethylcellulose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer
  • Each suspension type ophthalmic solution (osmotic pressure ratio: 1.0) was obtained by using 0.01 g each of polyethylene glycol and sodium chondroitin sulfate, and performing the same operation as in the case of the test preparation 1. These are hereinafter referred to as test preparations 11 to 17.
  • test Method The redispersibility of the levocabastine particles of the test preparations 11 to 17 was examined. Each test preparation was filled in a 5 mL eye drop container and stored in an upright state under the conditions shown in Table 6 (50 ° C., 4 weeks). Immediately after storage, the eye dropper was placed in a box and allowed to fall in a certain direction, and the number of falls until the levocabastine particles settled on the bottom of the container completely peeled off from the container and redispersed was measured.
  • test preparation 18 Suspension type eye drops (osmotic pressure ratio: 1.0) by performing the same operation as in the case of the test preparation 1 except that the blending amount of the polysorbate 80 of the test preparation 1 is changed from 0.005 g to 0.05 g. Got. Hereinafter, this is designated as test preparation 18.
  • Test preparation 19 Hydroxypropylmethylcellulose 2910 (2 at 20 ° C.) instead of hydroxypropylmethylcellulose 2910 (2% (W / V) aqueous solution at 20 ° C .: 6 mm 2 / s: manufactured by Shin-Etsu Chemical Co., Ltd.) (0.001 g) % (W / V) aqueous solution is 4000 mm 2 / s (manufactured by Shin-Etsu Chemical Co., Ltd.) (0.001 g). An osmotic pressure ratio: 1.0) was obtained. Hereinafter, this is designated as test preparation 19.
  • test preparations 1, 2, 10, 18 and 19 were examined. Each test preparation was filled into a 5 mL eye drop container and stored in an upright state for a certain period (3, 6 or 25 months) under the conditions shown in Table 7 (40 ° C./75% RH or 25 ° C./40% RH). After completion of the storage, the eye drop container was inverted and mixed in a certain direction, and redispersed by rotating until the levocabastine particles settled on the bottom surface of the container were completely peeled off from the container. Thereafter, the number of aggregates dispersed in the liquid was visually measured.
  • the test preparation 19 using sodium chloride, which is an ionic tonicity agent is more effective than the test preparation 10 using concentrated glycerin, which is a nonionic tonicity agent. Less aggregates. That is, by adding an ionic tonicity agent such as sodium chloride, the cohesiveness of levocabastine particles, which are the active ingredient of the suspension type eye drop of the present invention, is further improved. In addition, a difference was observed in the formation of agglomerates of levocabastine hydrochloride particles in Test preparation 1 and Test preparation 19 and Test preparation 2 and Test preparation 10 containing a nonionic tonicity agent. That is, the cohesiveness of levocabastine particles, which are the active ingredient of the suspension type eye drop of the present invention, can be further improved by selecting the viscosity grade of hydroxypropylmethylcellulose.
  • Formulation Example The following formulation was obtained according to the preparation method of the example. In addition, in the following formulation example, the compounding quantity of each component is a content in 100 mL.
  • Formulation Example 2 Levocabastine hydrochloride 0.027g Benzalkonium chloride 0.005g Hydroxypropyl methylcellulose 2910 0.001g Concentrated glycerin 2.3g Polysorbate 80 0.05g Disodium hydrogen phosphate Appropriate amount Sodium dihydrogen phosphate Appropriate amount Sodium edetate Appropriate amount Sodium hydroxide Appropriate amount Dilute hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount In the above formula, 0.0005g, 0.001g, 0.002g, The same preparation as Preparation Example 2 can be obtained by changing to 0.003 g, 0.004 g, 0.006 g, 0.008 g and 0.01 g, and the blending amount of polysorbate 80 is 0.001 g and 0.003 g. , 0.005 g, 0.007 g, 0.01 g, 0.03 g, and 0.1 g can be used to obtain a preparation similar
  • Formulation Example 3 Levocabastine hydrochloride 0.027g Benzalkonium chloride 0.005g Hydroxypropylmethylcellulose 2910 0.005g Potassium chloride 1.0g Disodium hydrogen phosphate Appropriate amount Sodium dihydrogen phosphate Appropriate amount Sodium edetate Appropriate amount Sodium hydroxide Appropriate amount Dilute hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount In the above formula, 0.0005g, 0.001g, 0.002g, A preparation similar to Preparation Example 3 can be obtained by changing to 0.003 g, 0.008 g, and 0.01 g.
  • Formulation Example 4 Levocabastine hydrochloride 0.027g Benzalkonium chloride 0.003g Hydroxypropylmethylcellulose 2910 0.01g Sodium chloride 0.8g Polysorbate 80 0.05g Disodium hydrogen phosphate Appropriate amount Sodium dihydrogen phosphate Appropriate amount Sodium edetate Appropriate amount Sodium hydroxide Appropriate amount Dilute hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount
  • the blending amount of polysorbate 80 is 0.001 g, 0.003 g, 0.005 g,.
  • the same formulation as Formulation Example 4 can be obtained by changing to 007 g, 0.01 g, 0.03 g, and 0.1 g.
  • Formulation Example 5 Levocabastine hydrochloride 0.027g Benzalkonium chloride 0.003g Methylcellulose 0.01g Propylene glycol 2.5g Polysorbate 80 0.05g Disodium hydrogen phosphate Appropriate amount Sodium dihydrogen phosphate Appropriate amount Sodium edetate Appropriate amount Sodium hydroxide Appropriate amount Dilute hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount
  • the blending amount of polysorbate 80 is 0.001 g, 0.003 g, 0.005 g,.
  • the same formulation as Formulation Example 5 can be obtained by changing to 007 g, 0.01 g, 0.03 g, and 0.1 g.
  • Formulation Example 6 Levocabastine hydrochloride 0.027g Benzalkonium chloride 0.006g Polyethylene glycol 1.8g Sodium chloride 1.0g Disodium hydrogen phosphate Appropriate amount Sodium dihydrogen phosphate Appropriate amount Sodium edetate Appropriate amount Sodium hydroxide Appropriate amount Dilute hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount In the above formula, 0.0005g, 0.001g, 0.002g, A preparation similar to Preparation Example 6 can be obtained by changing to 0.003 g, 0.008 g, and 0.01 g.
  • Formulation Example 7 Levocabastine hydrochloride 0.027g Benzalkonium chloride 0.003g Hydroxypropyl methylcellulose 2910 0.1g Sodium chloride 0.8g Polyoxyethylene hydrogenated castor oil 60 0.07g Disodium hydrogen phosphate Appropriate amount Sodium dihydrogen phosphate Appropriate amount Sodium edetate Appropriate amount Sodium hydroxide Appropriate amount Dilute hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount In the above formulation, the compounding amount of polyoxyethylene hydrogenated castor oil 60 is 0.005 g, 0.03 g, 0 A formulation similar to Formulation Example 7 can be obtained by changing to 0.1 g.
  • Formulation Example 8 Levocabastine hydrochloride 0.027g Benzalkonium chloride 0.005g Hydroxypropylmethylcellulose 2910 0.005g Polyvinylpyrrolidone 0.01g Sodium chloride 1.0g Disodium hydrogen phosphate Appropriate amount Sodium dihydrogen phosphate Appropriate amount Sodium edetate Appropriate amount Sodium hydroxide Appropriate amount Dilute hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount A preparation similar to Preparation Example 8 can be obtained by changing to 0.003 g, 0.008 g, and 0.01 g.
  • Formulation Example 9 Levocabastine hydrochloride 0.027g Benzalkonium chloride 0.003g Hydroxyethyl cellulose 0.02g Sodium chloride 0.8g Polysorbate 80 0.03g Polyoxyethylene hydrogenated castor oil 60 0.03g Disodium hydrogen phosphate Appropriate amount Sodium dihydrogen phosphate Appropriate amount Sodium edetate Appropriate amount Sodium hydroxide Appropriate amount Dilute hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount
  • the blending amount of polysorbate 80 is 0.003g, 0.007g, 0.01g
  • the same preparation as Preparation Example 9 can be obtained by changing to 1 g, and the same amount as Preparation Example 9 can be obtained by changing the blending amount of polyoxyethylene hydrogenated castor oil 60 to 0.005 g, 0.01 g and 0.1 g.
  • a formulation can be obtained.
  • Formulation Example 10 Levocabastine hydrochloride 0.027g Benzalkonium chloride 0.005g Hydroxypropyl methylcellulose 2910 0.5g Sodium chloride 0.8g Concentrated glycerin 1.5g Polysorbate 80 0.03g Disodium hydrogen phosphate Appropriate amount Sodium dihydrogen phosphate Appropriate amount Sodium edetate Appropriate amount Sodium hydroxide Appropriate amount Dilute hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount In the above formula, 0.0005g, 0.001g, 0.002g, A preparation similar to Preparation Example 10 can be obtained by changing to 0.003 g, 0.008 g, and 0.01 g.
  • the present invention reduces the compounding amount of the preservative (benzalkonium chloride) in the preparation containing levocabastine as much as possible, and further improves the usability and convenience required for the suspension type eye drops.
  • the preservative benzalkonium chloride

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Abstract

Composition marquant une amélioration sur les lotions ophtalmiques de type suspension contenant de la levocabastine ou un sel de levocabastine. Lotion ophtalmique de type suspension contenant (a) de 0,01 à 0,1% de levocabastine ou d'un sel de levocabastine, (b) de 0,0005 à 0,01% (en poids/volume) de chlorure de benzalkonium, (c) de 0,00001 à 2% (en poids/volume) d'un polymère hydrosoluble, (d) de 01 à 5% (en poids/volume) d'un agent d'isotonisation représenté par au moins un composé pris parmi : chlorure de sodium, chlorure de potassium, chlorure de calcium, chlorure de magnésium, glycérol, propylène glycol, polyéthylène glycol, tréhalose, sucrose, sorbitol et mannitol, qui présente un rapport de pression osmotique de 05-2,0, dont la teneur en antiseptique est inférieure à celle des lotions ophtalmiques de type suspension de levocabastine existantes et qui, nonobstant, égale lesdites lotions existantes en termes d'efficacité antiseptique. De plus, la lotion ophtalmique de type suspension l'emporte sur les lotions ophtalmiques de type suspension de levocabastine existantes sous l'angle de la redispersabilité.
PCT/JP2010/056827 2009-04-17 2010-04-16 Lotion ophtalmique de type suspension de levocabastine Ceased WO2010119942A1 (fr)

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Cited By (2)

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JP2016500079A (ja) * 2012-12-06 2016-01-07 アルコン リサーチ， リミテッド フィナフロキサシン懸濁組成物
JP2021176825A (ja) * 2020-05-08 2021-11-11 株式会社セラバリューズ クルクミン含有経口摂取用固形製剤

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JP5774898B2 (ja) * 2011-04-22 2015-09-09 杏林製薬株式会社 安定化製剤
KR102433489B1 (ko) 2013-03-14 2022-08-17 팬옵티카, 인크. 눈의 후안부로의 약물 전달을 위한 안구용 제제
JP2022131565A (ja) * 2021-02-26 2022-09-07 ロート製薬株式会社 水性医薬組成物
US20250120910A1 (en) * 2021-08-18 2025-04-17 Guangzhou Ocusun Ophthalmic Biotechnology Co., Ltd. Pharmaceutical composition, preparation method therefor and application thereof

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JP2009013136A (ja) * 2007-07-06 2009-01-22 Rohto Pharmaceut Co Ltd 水性医薬組成物
JP2009029779A (ja) * 2007-06-29 2009-02-12 Rohto Pharmaceut Co Ltd レボカバスチン及び／又はその塩を含有する水性医薬組成物
JP2009051761A (ja) * 2007-08-24 2009-03-12 Rohto Pharmaceut Co Ltd レボカバスチンとリドカインを含有する水性医薬組成物

Patent Citations (3)

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JP2009029779A (ja) * 2007-06-29 2009-02-12 Rohto Pharmaceut Co Ltd レボカバスチン及び／又はその塩を含有する水性医薬組成物
JP2009013136A (ja) * 2007-07-06 2009-01-22 Rohto Pharmaceut Co Ltd 水性医薬組成物
JP2009051761A (ja) * 2007-08-24 2009-03-12 Rohto Pharmaceut Co Ltd レボカバスチンとリドカインを含有する水性医薬組成物

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016500079A (ja) * 2012-12-06 2016-01-07 アルコン リサーチ， リミテッド フィナフロキサシン懸濁組成物
JP2021176825A (ja) * 2020-05-08 2021-11-11 株式会社セラバリューズ クルクミン含有経口摂取用固形製剤
JP7080504B2 (ja) 2020-05-08 2022-06-06 株式会社セラバリューズ クルクミン含有経口摂取用固形製剤

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