JP5713791B2 - Ophthalmic agent - Google Patents

Description

  The present invention relates to an ophthalmic agent.

  Glaucoma is an intractable disease in which visual function is impaired due to an increase in intraocular pressure that the eye can withstand, and there are mainly treatment by drugs and surgery. In addition, ocular hypertension refers to a pathological condition that does not involve visual field abnormalities, although high intraocular pressure exceeding a normal value is recognized, and is considered to have a high possibility of developing into glaucoma in the long term. As a treatment method for ocular hypertension, drug treatment is generally recommended.

  As a drug treatment for these diseases, a method using an eye drop containing an αβ blocker, an α blocker, a β blocker, a prostaglandin or the like is common, and in recent years, among these drugs, prostaglandin Although gin drugs are the mainstream, timolol maleate, which is a β-blocker, is also widely used for treatment from the standpoint of high effectiveness.

  In the past, this timolol maleate ophthalmic solution had to be administered twice a day. However, by adding a gelling agent that gels in the eye, such as gellan gum and methylcellulose, A once-daily type of the same component sustained-release eye drop is provided. For example, in Japan, “Lismon TG eye drop” (trade name, Wakamoto Pharmaceutical) and “Timoptol (registered trademark) XE eye drop” (trade name, Manyu Pharmaceutical) are commercially available.

  In these timolol sustained-release preparations, as described above, a technique of gelling a drug solution in the eye is used, but there is a problem that fogging occurs due to gelation.

For example, the package insert of Timoptol (registered trademark) XE (trade name, Manyu Pharmaceutical) stated that “Ophthalmic solution gels due to contact with tears on the surface of the eye as a characteristic of the preparation immediately after instillation. Or, stickiness may last for several minutes, so explain this to the patient and be careful. "
In order to prevent this fogging, the gel strength may be lowered. Generally, however, the gel strength greatly affects the transferability of the active ingredient to the intraocular tissue (for example, Patent Document 1). It was difficult to obtain sufficient component transfer into the eye tissue while avoiding the occurrence of

Japanese Patent No. 3725783

  In view of the above situation, the present invention provides an ophthalmic agent that suppresses the occurrence of fog at the time of instillation and has high transferability (transfer rate) of timolol maleate, which is an active ingredient, into the ocular tissue. With the goal.

The inventors of the present invention sufficiently transferred timolol maleate (hereinafter sometimes referred to as “active ingredient”) into the ocular tissue while avoiding or reducing the occurrence of the above-mentioned problem, that is, the occurrence of fog during eye drops. In order to satisfy both the incompatible factors of increasing the transferability of the active ingredient into the ocular tissue (transfer rate), unexpectedly, the gelling agent and non-gelling agent are unexpectedly used in ophthalmic agents. When an ionic surfactant is added together with timolol maleate, the migration of timolol maleate into the eye tissue is synergistically or additively enhanced, so the active ingredient is high while reducing fog vision during instillation. It was found that it can be transferred into the ocular tissue at a concentration. Due to this high active ingredient intraocular transfer, a high intraocular pressure-lowering action that has not been obtained in the past can be obtained, and the medicinal effect can be maintained, so that various timolol maleate-containing eye drops can be provided. . Specifically, for example, if priority is given to pharmacological action, a high viscosity gelling agent can be used to significantly increase the medicinal effect compared to existing preparations even if some missight occurs. In addition, for example, if priority is given to comfort during use, a low-viscosity gelling agent can be used to obtain a medicinal effect effective for treatment while suppressing the occurrence of misting at the time of instillation, which is a burden on the patient. it can.
The inventors have further researched and completed the present invention.

That is, the present invention relates to the following (1) to (6).
(1) An ophthalmic agent containing timolol maleate, further comprising (A) a gelling agent and (B) a nonionic surfactant.
(2) The ophthalmic agent according to (1), wherein the gelling agent is at least one selected from gellan gum, alginic acid, and hypromellose.
(3) The ophthalmic use according to (1) or (2), wherein the nonionic surfactant is at least one selected from polyoxyethylene sorbitan fatty acid ester, polyethylene glycol fatty acid ester, and polyoxyethylene hydrogenated castor oil. Agent.
(4) The ophthalmic preparation according to any one of (1) to (3) above, wherein the transferability of timolol maleate into ocular tissue is enhanced.
(5) Said (1) characterized in that migration of timolol maleate into ocular tissue is enhanced by containing (A) a gelling agent and (B) a nonionic surfactant. The ophthalmic preparation described in 1.
(6) Increasing the migration of timolol maleic acid into ocular tissue by further blending (A) a gelling agent and (B) a nonionic surfactant with an ophthalmic agent containing timolol maleate Method.

  ADVANTAGE OF THE INVENTION According to this invention, generation | occurrence | production of the foggy at the time of instillation can be suppressed, and the ophthalmic agent in which the transferability of the timolol maleate into the ocular tissue can be improved synergistically or additively can be obtained. In addition, the high active ingredient intraocular transfer provides a high intraocular pressure-lowering action that has not been obtained in the past, and the medicinal effects can be maintained. Therefore, various eye drops containing timolol maleate depending on the purpose can be used. Can be provided.

The ophthalmic agent of the present invention is an ophthalmic agent containing timolol maleate, and further contains (A) a gelling agent and (B) a nonionic surfactant.
The ophthalmic preparation of the present invention is usually one in which the transferability of timolol maleate into ocular tissue is enhanced. Specifically, it is preferable that the transferability of timolol maleate to ocular tissues such as aqueous humor, cornea, iris / ciliary body is enhanced.
Furthermore, when an active ingredient other than timolol maleate is contained, there is a risk of affecting the transfer of other active ingredients into the eye tissue, so the transfer of other active ingredients into the eye tissue has not been confirmed. In some cases, an ophthalmic agent containing timolol maleate as the only active ingredient is preferred.

  The ophthalmic preparation of the present invention contains (A) a gelling agent and (B) a nonionic surfactant, so that the transferability of timolol maleate into ocular tissue is enhanced. Is preferred.

  In the present invention, any gelling agent can be used, and specific examples include gellan gum, alginic acid or a salt thereof, hypromellose, carrageenan, agar, xanthan gum, pectin, gelatin, carboxyvinyl polymer, polyvinylpyrrolidone and the like. Among them, a component that does not gel in the preparation before administration and gels in the eye due to a change in conditions during administration is preferable because the container pressing force during administration is small. Specifically, gellan gum, alginic acid, hypromellose and the like are preferable, among which gellan gum and alginic acid are more preferable, and gellan gum is particularly preferable.

As the gelling agent, one or more of the above compounds can be used in any combination. The blending amount of the gelling agent can be appropriately selected depending on the components, but is usually 0.001 to 10 w / v% in the ophthalmic preparation, preferably 0.01 to 5 w / v%, more preferably. Is 0.1 to 3 w / v%.
When the blending amount of the gelling agent is within the above range, good gelling performance can be exhibited, so that the ophthalmic agent has good sustained release performance. Moreover, since it can suppress effectively the generation | occurrence | production of the fog at the time of instillation which becomes a burden of a patient as it is in the said range, the usability | use_condition at the time of ophthalmic preparation administration will become comfortable.

  In the present invention, any nonionic surfactant can be used. For example, polyoxyethylene sorbitan laurate (polysorbate 20), polyoxyethylene sorbitan palmitate (polysorbate 40), polyoxyethylene sorbitan stearate (polysorbate 60). ), Polyoxyethylene sorbitan tristearate (polysorbate 65), polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene sorbitan oleate (polysorbate 80); polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, poly Polyoxyethylene hydrogenated castor oil such as oxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60; polyoxyethylene (160) polyoxypropylene 30) Glycol (Pluronic F68), Polyoxyethylene (42) Polyoxypropylene (67) Glycol (Pluronic P123), Polyoxyethylene (54) Polyoxypropylene (39) Glycol (Pluronic P85), Polyoxyethylene (196) Polyoxyethylene polyoxypropylene glycol such as polyoxypropylene (67) glycol (Pluronic F127), polyoxyethylene (20) polyoxypropylene (20) glycol (Pluronic L-44); polyethylene glycol monolaurate, ethylene monostearate Glycol, polyethylene glycol monostearate such as polyoxyl 40 stearate, polyethylene glycol monooleate, ethylene glycol monostearate Call, ethylene glycol distearate, polyethylene glycol distearate, polyethylene glycol fatty acid esters such diisostearate polyethylene glycol. Of these, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid ester, and the like are particularly preferable. Among them, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyoxyl 40 stearate, and the like are more preferable. 80 is most preferred.

As the nonionic surfactant, one or more of the above compounds can be used in any combination. The compounding quantity of a nonionic surfactant is 0.001-10 w / v% normally in an ophthalmic preparation, Preferably it is 0.005-5 w / v%, More preferably, it is 0.01-0.5 w. / V%.
It is preferable that the blending amount of the nonionic surfactant is within the above range because sufficient migration of the active ingredient into the ocular tissue can be obtained. Furthermore, it is preferable for it to be in the above-mentioned range since it has little eye irritation and less cytotoxicity.

The combination of (A) the gelling agent and (B) the nonionic surfactant in the present invention is not particularly limited as long as the effects of the present invention are exhibited. For example, gellan gum is used as the (A) gelling agent. In this case, it is preferable to use polyoxyethylene sorbitan fatty acid ester, polyethylene glycol fatty acid ester or the like as (B) nonionic surfactant. As the polyoxyethylene sorbitan fatty acid ester, polysorbate 80 or the like is preferable. As the polyethylene glycol fatty acid ester, polyethylene glycol monostearate is preferable, and among them, polyoxyl 40 stearate is more preferable.
For example, when alginic acid is used as the gelling agent (A), it is preferable to use polyoxyethylene sorbitan fatty acid ester or the like as the nonionic surfactant (B). As polyoxyethylene sorbitan fatty acid ester, polysorbate 80 or the like is more preferable.

  The ophthalmic agent of the present invention includes other drugs and various pharmaceutically acceptable additives (stabilizers, pH adjusters / buffers, preservatives, as long as the effects of the present invention are not impaired in addition to the above components. , Solubilizers, antioxidants, solvents, solubilizers, suspending agents, flavoring agents / fragrances, cooling agents, coloring agents, buffering agents, etc.) can be added. In addition, the addition amount of these arbitrary components can be mix | blended normal amount in the range which does not prevent the effect of this invention.

  The ophthalmic agent of the present invention can be prepared by a conventional method, and the method is not particularly limited. For example, each component can be obtained by mixing and stirring with purified water of a specified amount or less, then adjusting the volume to a specified amount with purified water, and performing filtration, sterilization treatment, or the like as necessary. The ophthalmic preparation of the present invention is preferably used after being adjusted within the pH range normally used for eye drops, and the pH is usually from 5 to 9, and preferably from 6 to 8.

  The ophthalmic preparation of the present invention is preferably used in a form for topical ocular administration, and specifically includes eye drops, ointments and the like.

  The compounding amount of timolol maleate which is an active ingredient in the ophthalmic preparation of the present invention is not particularly limited, but is usually 0.01 to 5 w / v% as timolol in the ophthalmic preparation, preferably 0.1 to 1 w. / V%. The dosage and frequency of administration of the ophthalmic preparation of the present invention vary depending on the age, body weight, dosage form, etc. of the subject of administration, but when used as an eye drop for adults, it is usually several times a day, preferably Is administered 1 to 6 times, usually several drops per dose, preferably 1 to 3 drops.

  As an administration target of the ophthalmic agent of the present invention, a mammal that has developed or is likely to develop glaucoma or ocular hypertension is preferable, and among them, a human is more preferable.

  In the ophthalmic preparation, the transferability of timolol maleate into the eye tissue can be improved by blending (A) a gelling agent and (B) a nonionic surfactant together with timolol maleate. Moreover, generation | occurrence | production of the foggy at the time of instillation can also be suppressed.

  In addition to the ophthalmic agent containing timolol maleate, a method of increasing the migration of timolol maleic acid into the ocular tissue by further blending (A) a gelling agent and (B) a nonionic surfactant, Included in the present invention.

  The (A) gelling agent and (B) nonionic surfactant in the method of the present invention, and preferred embodiments thereof are the same as those in the ophthalmic agent described above. By improving the transferability of timolol maleic acid into the ocular tissue, medicinal effects such as an intraocular pressure lowering effect of timolol maleic acid are efficiently exhibited. Moreover, the effect of improving the sustainability of medicinal effects can be obtained by increasing the migration of timolol maleic acid into the ocular tissue. The method of the present invention is suitably used for enhancing the migration of timolol maleate into ocular tissues such as aqueous humor, cornea, iris / ciliary body and the like.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in more detail, these do not limit this invention at all.

Example 1
Gellan gum and D-mannitol are dissolved in about 60 mL of warm purified water and cooled, and then timolol maleate and trometamol are added, and benzalkonium chloride and polysorbate previously mixed therein are added. 80 was added, and the total amount was adjusted to 100 mL with purified water to prepare an ophthalmic preparation. The compounding amount of each component in the ophthalmic preparation was such that each component had the concentration (w / v%) shown in Table 1.

Example 2 and Comparative Examples 1-2
Example 2 and Comparative Examples 1 and 2 were also prepared in the same procedure as Example 1 with the formulation shown in Table 1 except for the components not added.
In addition, the unit of the compounding quantity of each component in Table 1 is w / v%.

Comparative Examples 3-4
After dissolving D-mannitol, timolol maleate, and trometamol in about 60 mL of purified water, benzalkonium chloride and polysorbate 80 previously mixed are added thereto, and the total amount is 100 mL with purified water. The ophthalmic preparations having the formulations shown in Table 1 were prepared. Comparative Example 4 was prepared in the same manner as Comparative Example 3 with the formulation shown in Table 1 except for the components not added.

  The pH and osmotic pressure ratio of each ophthalmic solvent prepared in the examples and comparative examples were determined according to `` pH METER F-52 '' (product name, manufactured by Horiba, Ltd.) and `` Model 3250 Osmometer '' (product name, manufactured by Advance). It is measured.

Example 3
Gellan gum and D-mannitol are dissolved in about 60 mL of warm purified water and cooled, and then timolol maleate and trometamol are added, and benzalkonium chloride and stearin previously mixed therein are added. The acid polyoxyl 40 was added, the whole quantity was adjusted to 100 mL with purified water, and the ophthalmic preparation was prepared. The compounding amount of each component in the ophthalmic preparation was such that each component had a concentration (w / v%) shown in Table 2.

Comparative Example 5
After dissolving D-mannitol, timolol maleate, and trometamol in about 60 mL of purified water, benzalkonium chloride and polyoxyl 40 stearate mixed in advance are added thereto, and the whole amount is added with purified water. Was adjusted to 100 mL, and ophthalmic preparations having the formulations shown in Table 2 were prepared.
In addition, the unit of the compounding quantity of each component in Table 2 is w / v%.

Example 4
Add alginic acid, sodium chloride, timolol maleate, and trometamol to approximately 60 mL of purified water, add benzalkonium chloride and polysorbate 80, which have been mixed in advance, to a total volume of 100 mL with purified water. An ophthalmic preparation was prepared by adjusting. The compounding amount of each component in the ophthalmic preparation was such that each component had a concentration (w / v%) shown in Table 3.

Comparative Example 6
Also for Comparative Example 6, an ophthalmic agent was prepared by the same procedure as Example 4 with the formulation shown in Table 3 except for the components not added.
In addition, the unit of the compounding quantity of each component in Table 3 is w / v%.

Reference example 1
As Reference Formulation 1, a commercially available formulation (trade name: Timoptol (registered trademark) ophthalmic solution, Santen Pharmaceutical Co., Ltd.) containing timolol maleate (0.5 w / v%) as an active ingredient was used. Timoptol (registered trademark) ophthalmic solution contains benzalkonium chloride solution (preservative), sodium dihydrogen phosphate, sodium hydrogen phosphate hydrate (buffer), sodium hydroxide (pH adjuster) as additives. It contains. The pH of Timoptol (registered trademark) ophthalmic solution was 7.0.

Reference example 2
As Reference Formulation 2, a commercially available formulation (trade name: Timoptol (registered trademark) XE ophthalmic solution, Manyu Pharmaceutical Co., Ltd.) containing timolol maleate (0.5 w / v%) as an active ingredient was used. Timoptol (registered trademark) XE ophthalmic solution contains gellan gum (gelling agent), trometamol (buffering agent), benzododecinium bromide (preservative), D-mannitol (isotonic agent) as additives. is there. The pH of Timoptol (registered trademark) EX ophthalmic solution was 7.0.

Test example 1
Active ingredient tissue concentration measurement test The preparations prepared in Examples 1 and 2 and Comparative Examples 1 to 4, respectively, and the preparations of Reference Examples 1 and 2 were each instilled into animals, and aqueous humor, cornea, iris and ciliary body In each tissue, the concentration of the active ingredient in the tissue was measured. The detailed procedure is as follows.

1. Test procedure Rabbits (male Japanese white species, 2 kg to 3 kg) were administered with 50 μL of the preparations of Examples, Comparative Examples and Reference Examples (0.5% timolol ophthalmic solution) in both eyes (two eyes × 3 animals each). : N = 6), the eye was forcibly closed for 30 seconds. Two hours after the instillation, anesthesia was killed with sodium pentobarbital, the eyeball was removed, washed with physiological saline, and the aqueous humor, cornea and iris / ciliary body were collected. Each tissue was stored frozen at −20 ° C. until analysis.

2. Quantitation procedure (aqueous humor)
100 μL of collected aqueous humor was accurately weighed, 100 μL of mobile phase was accurately added and mixed, and then stored at 4 ° C. or lower, and centrifuged at 14800 rpm for 10 minutes, and the supernatant was used as a sample solution. The sample solution was stored at 4 ° C. or lower until immediately before measurement.

Test condition detector: ultraviolet absorption photometer (measurement wavelength: 294 nm)
Column: A stainless tube having an inner diameter of 3.0 mm and a length of 15 cm was filled with 5 μm of octadecylsilylated silica gel for liquid chromatography.
Column temperature: Constant temperature around 40 ° C. Mobile phase: 1 g of sodium lauryl sulfate was dissolved in 600 mL of water, and 400 mL of acetonitrile and 1 mL of phosphoric acid were added.
Flow rate: Adjusted so that the holding time of timolol was about 10 minutes.

(Cornea, iris, ciliary body)
Take one collected cornea or iris / ciliary body, cut it finely with scissors, add exactly 3 mL of 0.1 mol / L hydrochloric acid-containing ethanol, homogenize for 1 minute under ice-cooling, and store at 4 ° C or lower While centrifuging at 2500 rpm for 10 minutes. After 2.5 mL of the supernatant was accurately weighed and concentrated to dryness under reduced pressure, 0.25 mL of water was accurately added to the residue to dissolve it, and centrifuged at 14800 rpm for 10 minutes while storing at 4 ° C. or lower. Further, the supernatant was centrifuged at 14800 rpm for 30 minutes using a filter having a fractional molecular weight of 10,000, and the filtrate was used as a sample solution. The sample solution was stored at 4 ° C. or lower until immediately before measurement.

Test condition detector: ultraviolet absorption photometer (measurement wavelength: 294 nm)
Column: A stainless tube having an inner diameter of 3.0 mm and a length of 15 cm was filled with 5 μm of octadecylsilylated silica gel for liquid chromatography.
Column temperature: Constant temperature around 40 ° C. Mobile phase: 1 g of sodium lauryl sulfate was dissolved in 600 mL of water, and 400 mL of acetonitrile and 1 mL of phosphoric acid were added.
Flow rate: Adjusted so that the holding time of timolol was about 10 minutes.

  Tables 4 and 5 show the results of this test (concentration of timolol in the aqueous humor, cornea, and iris / ciliary body at 2 hours after administration of the preparation). The numerical values shown in Tables 4 and 5 are average values (n = 6).

Moreover, about the same data as Table 4, what was rearranged from the viewpoint of the presence or absence of a surfactant and the presence or absence of a gelling agent is shown in Tables 6, 8 and 10. In addition, Tables 7, 9 and 11 show the addition effect of each component, the effect at the time of combined use, and the synergistic effect rate at the time of combined use. The addition effect of each component shown in Tables 7, 9 and 11 and the effect at the time of combination were calculated from the timolol concentration in each eye tissue at 2 hours after administration of the preparation.
The synergistic effect rate is calculated by the following equation.
Synergistic effect rate = effect when used in combination / (effect of nonionic surfactant + effect of gelling agent)

Table 6 shows timolol concentration (μg / g) in the aqueous humor at 2 hours after administration of the preparation. Table 7 shows the synergistic effect rate calculated from the effects of addition of each component on the transfer of timolol to the aqueous humor and the combined effect, and the timolol concentration (μg / g) in the aqueous humor at 2 hours after administration of the preparation. It is.
Table 8 shows the timolol concentration (μg / g) in the cornea at 2 hours after administration of the preparation. Table 9 shows the synergistic effect rate calculated from the effect of addition of each component on the transfer of timolol to the cornea and the effect at the time of combination, and the timolol concentration (μg / g) in the cornea at 2 hours after administration of the preparation. is there.
Table 10 shows the timolol concentration (μg / g) in the iris / ciliary body at 2 hours after administration of the preparation. Table 11 shows the effect of addition of each component on the transfer of timolol to the iris / ciliary body and the effect at the time of combination, and the concentration of timolol in the iris / ciliary body at 2 hours after administration of the preparation (μg / g). It is a synergy rate calculated from
The gellan gum concentration (%) in Tables 6 to 11 means w / v%.

  For example, when Table 7 is described as an example, when polysorbate 80 is added to an ophthalmic preparation (Comparative Example 4) that does not contain gellan gum and polysorbate (Comparative Example 3), it is compared with the case where it is not added (Comparative Example 4). The timolol concentration in the aqueous humor increased by 0.18 μg / g (effect by adding polysorbate 80). When the aqueous timolol concentration in the aqueous humor when the ophthalmic agent of Comparative Example 4 is used is 100%, the aqueous humor timolol concentration in the aqueous humor when the polysorbate 80 is added (Comparative Example 3) is 142%. Met. When 0.6% w / v gellan gum is added to the ophthalmic preparation of Comparative Example 4 (Comparative Example 1), the concentration of timolol in the aqueous humor is increased by 1.34 μg / g compared to the case where it is not added (Comparative Example 4). (Effect by adding gellan gum). Furthermore, when polysorbate 80 and 0.6 w / v% gellan gum were added to the ophthalmic preparation of Comparative Example 4 (Example 1), the concentration of timolol in the aqueous humor was 4 compared to the case where these were not added (Comparative Example 4). 0.05 μg / g increased (effect when combined).

Test example 2
Active ingredient tissue concentration measurement test Test procedure Rabbits (male Japanese white species, 2 kg to 3 kg) were instilled into both eyes with 50 μL of each preparation (0.5% timolol ophthalmic solution) prepared in Example 3 and Comparative Examples 2, 4 and 5, respectively. (Each 2 eyes × 3 animals: n = 6) was forcibly closed for 30 seconds. One hour after instillation, anesthesia was killed with sodium pentobarbital, the eyeball was removed, washed with physiological saline, and aqueous humor was collected. Each tissue was stored frozen at −20 ° C. until analysis.

2. Quantitative Procedure In the same manner as in Test Example 1, the concentration of the active ingredient in the aqueous humor was measured.
Table 12 shows the results of this test (concentration of timolol (μg / g) in the aqueous humor at 1 hour after administration of the preparation). The numerical values shown in Table 12 are average values (n = 6).

  Moreover, about the same data as Table 12, what rearranged from the viewpoint of the presence or absence of a surfactant and the presence or absence of a gelling agent is shown in Table 13. Table 14 shows the effect of addition of each component and the effect at the time of combined use on the transfer of timolol to aqueous humor.

  From Table 14, when polyoxyl 40 stearate was added to the ophthalmic preparation of Comparative Example 4 (Comparative Example 5), the concentration of timolol in the aqueous humor increased by 0.53 μg / g compared to the case where it was not added (Comparative Example 4). (Effect of adding polyoxyl stearate 40). Moreover, when gellan gum was added to the ophthalmic preparation of Comparative Example 4 (Comparative Example 2), the concentration of timolol in the aqueous humor increased by 0.45 μg / g as compared with the case where it was not added (Comparative Example 4). ). Furthermore, when polyoxyl 40 stearate and gellan gum were added to the ophthalmic preparation of Comparative Example 4 (Example 3), the concentration of timolol in aqueous humor was 0.62 μg / g compared to the case where these were not added (Comparative Example 4). Increased (effect when combined).

Test example 3
Active ingredient tissue concentration measurement test Test procedure Rabbits (male Japanese white species, 2 kg to 3 kg) were instilled into both eyes with 50 μL of each preparation (0.5% timolol ophthalmic solution) prepared in Example 4 and Comparative Examples 3 to 4 and 6, respectively. (Each 2 eyes × 3 animals: n = 6) was forcibly closed for 30 seconds. One hour after instillation, anesthesia was killed with sodium pentobarbital, and the eyeball was removed, washed with physiological saline, and aqueous humor and cornea were collected. Each tissue was stored frozen at −20 ° C. until analysis.

2. Quantitative Procedure In the same manner as in Test Example 1, the concentration of the active ingredient in the aqueous humor and cornea tissues was measured.
Table 15 shows the results of this test (concentration of timolol (μg / g) in the aqueous humor and cornea at 1 hour after administration of the preparation). The numerical values shown in Table 15 are average values (n = 6).

Moreover, about the same data as Table 15, what rearranged from the viewpoint of the presence or absence of a surfactant and the presence or absence of a gelling agent is shown in Table 16 and Table 18.
Table 16 shows the timolol concentration (μg / g) in the aqueous humor at 1 hour after administration of the preparation. Table 17 shows the synergistic effect rate calculated from the addition effect of each component and the combined use effect on the transfer of timolol to the aqueous humor, and the timolol concentration (μg / g) in the aqueous humor at 1 hour after administration of the preparation. It is.
Table 18 shows the timolol concentration (μg / g) in the cornea at 1 hour after administration of the preparation. Table 19 shows the effect of addition of each component and the effect at the time of combined use on the transfer of timolol to the cornea.

  From the above results, nonionic surfactant and gelation together with timolol maleate, compared with the case where a nonionic surfactant is blended with an ophthalmic agent containing timolol maleate and a gelling agent. When the agent was added, the transferability of timolol maleate into the ocular tissue was additively or synergistically increased. As a result, for example, the tissue concentration of Example 2 in which only 0.3% w / v gellan gum was blended was comparable to that in Comparative Example 1 in which 0.6% w / v gellan gum was blended. Further, for example, the tissue concentration of timolol maleate when the ophthalmic preparations of Examples 1 and 2 are used is remarkably high, about the same as that of the commercially available preparations 1 and 2 of Reference Examples, about 8 times. When the preparation is administered to a patient, a stronger intraocular pressure lowering effect is expected. In addition, according to the present invention, it is possible to obtain a high tissue migration property. Therefore, if the drug efficacy is equivalent to that of the commercial preparations 1 and 2 of the reference example, the gel is significantly more than that of the commercial preparation. It is possible to reduce the blending amount of the agent, and there is an effect that the fogging due to the side effect of the gelling agent can be reduced.

  The present invention is useful in the medical field, pharmaceutical field and the like.

Claims (5)

An ophthalmic agent containing timolol maleate, further comprising (A) at least one selected from gellan gum, alginic acid and hypromellose as a gelling agent and (B) a nonionic surfactant. An ophthalmic agent.   The ophthalmic agent according to claim 1, wherein the nonionic surfactant is at least one selected from polyoxyethylene sorbitan fatty acid ester, polyethylene glycol fatty acid ester, and polyoxyethylene hydrogenated castor oil.   The ophthalmic preparation according to claim 1 or 2, wherein the transferability of timolol maleate into ocular tissue is enhanced.   The ophthalmologic according to claim 1, wherein the migration of timolol maleate into ocular tissue is enhanced by containing (A) a gelling agent and (B) a nonionic surfactant. Agent. Timolol maleate for the production of an ophthalmic agent that improves the transferability of timolol maleate into ocular tissues and avoids or reduces the occurrence of fog during eye drops, and (A) gelation Use of at least one selected from gellan gum, alginic acid and hypromellose and (B) a nonionic surfactant as an agent.