JP2006089460A - Ophthalmic thickening agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To develop an eye lotion capable of being thickened on a surface of an eyeball when applied to an eye, while having relatively low viscosity before applied to the eye. <P>SOLUTION: This eye lotion contains an ophthalmic thickening agent consisting of a combination of hydroxyethyl cellulose and dextran, wherein the lotion specifically develops a synergistic thickening effect when mucin coexists therewith. Therefore, the eye lotion is thickened on the surface of the eyeball by being brought into contact with the mucin in a lacrimal fluid layer, when applied to the eye, so that the eye lotion sustains desired pharmaceutical efficacy and refreshing feelings. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to an ophthalmic thickening agent comprising a combination of hydroxyethyl cellulose and dextran. The present invention also provides an ophthalmic solution containing an ophthalmic thickening agent comprising a combination of hydroxyethyl cellulose and dextran, which is thickened by contact with mucin in the tear film at the time of instillation. Furthermore, the present invention is a tear film stabilizer and an ophthalmic solution ocular surface retention promoter comprising a combination of hydroxyethyl cellulose and dextran.

  Eye drops stay on the surface of the eye for a long time when the viscosity is high, and the desired medicinal effect and refreshing feeling persist.However, the higher the viscosity of the eye drops, the more difficult it is to instill and the feeling of comfort is also improved. It is known to get worse.

  The surface of the eye is covered with a tear film composed of three layers, an oil layer, an aqueous layer and a mucin layer. The mucin layer located at the lowest layer of the tear film plays a role in adhering the tear film to the surface of the eye so that the tear liquid does not flow down. When stabilized, a dry portion called a dry spot is generated for a short time until blinking, and thus dry eye symptoms accompanied by dryness and discomfort may be exhibited in the eye.

  On the other hand, hydroxyethyl cellulose is a cellulose derivative having a hydroxyethoxyl group and is widely used as a thickening agent and a dispersing agent. Dextran is a polysaccharide obtained by fermenting sucrose, and is used as a thickener or stabilizer for eye drops.

 Patent Document 1 is an invention related to an ophthalmic solution containing a cooling component and a thickening agent. Examples of the thickening agent include ethyl cellulose, hydroxyethyl cellulose, dextran, and the like. Patent Document 2 is an invention relating to an ophthalmic composition having a self-preserving power and having a pH of 1.5 to 3.5. Examples of additives include polyethylene glycol, hydroxypropylmethylcellulose, hydroxyethylcellulose, and dextran. Yes.

However, none of the above documents is a combination of hydroxyethyl cellulose and dextran.
JP 2002-97129 A US Pat. No. 6,572,849

  Regarding the viscosity of the ophthalmic solution, if the viscosity is low, even if it is instilled, it immediately flows down from the ocular surface, so that the desired medicinal effect and refreshing feeling cannot be maintained. On the other hand, if the ophthalmic solution has a high viscosity, it stays on the surface of the eye for a long time. However, the higher the viscosity, the more difficult it is to apply the eyedrop, and the feeling of comfort tends to deteriorate. Therefore, it is desired to develop an ophthalmic solution that maintains a desired medicinal effect and a refreshing feeling by increasing the viscosity on the surface of the eye during instillation while having a relatively low viscosity before instillation. There is also a need for the development of eye drops that stabilize the tear film and eliminate the dryness and discomfort of the eye.

 The present inventor has conducted earnest research focusing on eye drops coming into contact with the tear film on the surface of the eye, particularly mucin in the tear film when the eye drops are instilled, and is composed of a combination of hydroxyethyl cellulose and dextran. The ophthalmic solution containing an ophthalmic thickener has been found to exhibit a specific synergistic thickening effect in the presence of mucin, and has led to the present invention. Further, the ophthalmic solution containing the ophthalmic thickening agent of the present invention has an excellent effect of stabilizing the tear film from the result of the corneal surface irregularity index change test described later. Further, the ophthalmic thickener of the present invention is useful as a liquid, and can also be used as a base for a comfortable eye drop or an eye wash that is easy on the eyes.

 The ophthalmic solution containing the ophthalmic thickening agent of the present invention exerts a synergistic thickening effect specifically in the presence of mucin, which is an ophthalmic thickening agent combining hydroxyethyl cellulose and dextran. It is presumed that this is based on the promotion of binding to mucin on the ocular surface. If the ophthalmic thickener of the present invention is used as a base for ophthalmic solution, it has an excellent ophthalmic solution retention improvement effect on the ocular surface from the results of the ophthalmic solution ocular surface retention evaluation test described later. Application to a drug delivery system in which retention in the anterior segment and intraocular transferability is improved is also possible.

That is, the present invention
(1) an ophthalmic thickening agent comprising a combination of hydroxyethyl cellulose and dextran,
(2) an ophthalmic solution containing an ophthalmic thickening agent comprising a combination of hydroxyethyl cellulose and dextran;
(3) The ophthalmic solution according to (2) before having a pH of 4 to 8,
(4) The ophthalmic solution according to (2) above, wherein the concentration of hydroxyethyl cellulose is 0.001 to 10% (w / v) and the concentration of dextran is 0.001 to 10% (w / v),
(5) The pH is 4 to 8, the concentration of hydroxyethyl cellulose is 0.001 to 10% (w / v), and the concentration of dextran is 0.001 to 10% (w / v). Ophthalmic solution as described in (2) above,
(6) A thickening agent comprising a combination of hydroxyethyl cellulose and dextran, which is thickened in the presence of mucin,
(7) an ophthalmic solution containing an ophthalmic thickening agent comprising a combination of hydroxyethylcellulose and dextran, which is thickened by contact with mucin in the tear film at the time of instillation;
(8) A tear film stabilizer comprising a combination of hydroxyethyl cellulose and dextran,
(9) a system for stabilizing the tear film on the surface of the eye by instilling an eye drop containing a tear film stabilizer comprising a combination of hydroxyethyl cellulose and dextran;
(10) An ophthalmic solution ocular surface retention promoter comprising a combination of hydroxyethyl cellulose and dextran,
(11) The present invention relates to a system that improves the retention of a drug in the anterior ocular segment by instilling an ophthalmic solution containing an ophthalmic solution ocular surface retention accelerator comprising a combination of hydroxyethyl cellulose and dextran.

 An ophthalmic solution containing an ophthalmic thickening agent comprising a combination of hydroxyethyl cellulose and dextran according to the present invention exhibits a synergistic thickening effect in the presence of mucin. By contacting with the mucin in the inside, it is possible to maintain the desired medicinal effect and refreshing feeling by increasing the viscosity on the surface of the eye. Moreover, since the ophthalmic solution of the present invention stabilizes the tear film, it also helps to eliminate dryness and discomfort in the eye part, leading to improvement of dry eye symptoms. As will be described in detail in the section “Viscosity measurement test in the presence of mucin” described later, a thickener combining hydroxyethyl cellulose and dextran exhibits a specific synergistic thickening action in the presence of mucin. In contrast, the combination of hydroxypropylmethylcellulose and dextran, which are other cellulosic thickeners, did not show a synergistic thickening action and was found to be based on the unique properties of hydroxyethylcellulose.

 In the thickening agent, tear film stabilizer and ophthalmic solution ocular surface retention promoter comprising a combination of hydroxyethyl cellulose and dextran according to the present invention, the weight ratio of hydroxyethyl cellulose and dextran is preferably 0.001 to 0.001. Dextran 0.001 to 10 with respect to 10, more preferably 0.005 to 3 with respect to 0.01 to 5 hydroxyethylcellulose.

 Hydroxyethyl cellulose used in the present invention is a cellulosic polymer having various viscosities, but any may be used. The concentration of hydroxyethyl cellulose in the ophthalmic solution is not particularly limited, but from the viewpoint of the characteristics and effects of the ophthalmic solution, the concentration of hydroxyethyl cellulose is 0.001 to 10% (w / v), more preferably 0.01 to 5% (w / v).

 Dextran used in the present invention is a polysaccharide obtained by fermenting sucrose, and there are various average molecular weights, but any may be used. Preferable examples include dextran 40 (average molecular weight of about 40,000) and dextran 70 (average molecular weight of about 70,000). The concentration of dextran in the ophthalmic solution is not particularly limited, but the concentration of dextran is 0.001 to 10% (w / v), more preferably 0.005 to 3% from the viewpoint of the characteristics and effects of the ophthalmic solution. (W / v).

 An ophthalmic solution containing an ophthalmic thickening agent, a tear film stabilizer, and an ophthalmic solution ocular surface retention accelerator comprising a combination of hydroxyethyl cellulose and dextran according to the present invention is formulated using a widely used technique. It is more preferable to formulate as an ophthalmic solution.

 A drug can be blended in the ophthalmic solution of the present invention. Examples of the drug include antibacterial agents, anti-inflammatory agents, antihistamines, antiglaucoma agents, antiallergic agents, immunosuppressive agents, and antimetabolites.

 An isotonic agent, a buffer, a pH adjuster, a solubilizer, a stabilizer, a preservative and the like can be appropriately blended in the ophthalmic solution of the present invention.

 Examples of isotonic agents include glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol and the like.

 Examples of the buffer include phosphoric acid, citric acid, acetic acid, ε-aminocaproic acid, boric acid, borax, trometamol, and the like.

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

 Examples of solubilizers added when the drug or other additives are poorly water soluble include polysorbate 80, polyoxyethylene hydrogenated castor oil 60, macrogol 4000, and the like.

 Examples of the stabilizer include edetic acid and sodium edetate.

 Examples of the preservative include sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, and the like, and these preservatives can be used in combination.

 In the ophthalmic solution of the present invention, the pH is desirably set to 4.0 to 8.0, and the osmotic pressure ratio is desirably set to around 1.0.

 The number of instillations of the ophthalmic solution of the present invention can be appropriately selected according to symptoms, age, dosage form, etc., but may be instilled once to about 6 times a day.

 The ophthalmic solution containing the ophthalmic thickener comprising the combination of hydroxyethylcellulose and dextran of the present invention is specific in the presence of mucin, as described in detail in the section on viscosity measurement test in the presence of mucin described later. Shows a synergistic thickening effect. Therefore, the ophthalmic solution of the present invention can maintain a desired medicinal effect, a refreshing feeling, and the like by increasing the viscosity of the ophthalmic solution on the ocular surface by contacting mucin in the tear film at the time of instillation. Further, as is apparent from the results of the ophthalmic solution ocular surface retention evaluation test and the corneal surface irregularity index change test, the ophthalmic solution containing the ophthalmic thickening agent of the present invention is excellent in drug retention in the anterior ocular segment. In addition, it has the effect of stabilizing the tear film and eliminates the dryness of the eye, so the dryness of the eye as an ophthalmic liquid ocular surface retention promoter, tear film stabilizer, dry eye treatment or artificial tears In addition, it is useful for relieving discomfort and also as a base for comfortable eye drops and eye-friendly eyewash solutions.

  The present invention will be described in detail below with reference to examples, but this is for better understanding of the present invention and does not limit the scope of the present invention.

[1] Viscosity measurement test in the presence of mucin This test was conducted in the presence of each test solution and mucin solution according to the test method described in Pharmaceutical Research, 491-495, Vol. 7, No. 5, 1990. The synergistic thickening effect when each test solution comes into contact with the mucin solution is evaluated by measuring the viscosity of the solution.

(experimental method)
As shown in Table 1, test solutions 1 to 6 were prepared by dissolving each thickening agent in physiological saline and physiological saline. Further, a 4% mucin solution (pH 7.0) was prepared by dissolving mucin (manufactured by SIGMA) in a 0.1 M phosphate buffer so as to have a pH similar to that of the tear (neutral).

Next, using a rotational viscometer (Rheostress RS100 HAAKE), mixed solution of each test solution (2 mL) and 4% mucin solution (6 mL), each test solution (2 mL) and 0.1 M phosphate buffer solution (6 mL) ), And each solution of water (2 mL) and 4% mucin solution (6 mL), the viscosity of 100S ^-1 (η1 when the shear rate is increased from 0.1 to 150 S ^{-1 in} 2.5 minutes) , Η2 and η3).

η1: Viscosity of mixed solution of each test solution (2 mL) and 4% mucin solution (6 mL) η2: Viscosity of mixed solution of each test solution (2 mL) and 0.1 M phosphate buffer solution (6 mL) η3: Water (2 mL) Of viscose and 4% mucin solution (6 mL) (result)
The viscosity increase rate of each mixed solution was calculated according to the following formula. These results are shown in Table 2.

Viscosity increase rate = (η1−η2−η3) / η2 × 100
When η1 is about the same as η2 and η3, that is, when there is almost no change in viscosity, the viscosity increase rate calculated by the above equation is about −100%. Further, when η1 clearly increases from η2 and η3, that is, when η1 increases synergistically, the viscosity increase rate calculated by the above equation becomes a positive value.

(Discussion)
When a thickening agent combining hydroxyethyl cellulose and dextran was allowed to coexist with mucin, a specific synergistic thickening effect was shown (test solution 6). However, there is no synergistic thickening effect even when physiological saline, hydroxyethylcellulose, hydroxypropylmethylcellulose, and dextran coexist with mucin (test solutions 1 to 4), and a mixture of hydroxypropylmethylcellulose and dextran with mucin No synergistic thickening effect was shown even when coexisting (test solution 5).

[2] Corneal surface irregularity index change test In this test, each test liquid was measured by measuring the irregularity of the corneal surface after the test liquid was instilled (the irregularity of the tear film) using a cornea shape measuring device. This evaluates the stabilizing effect of the tear film.

(experimental method)
After applying 20 μl each of Test Solution 1 and Test Solution 6 to the eyes of male Japanese white rabbits under general anesthesia, 0 (immediately after instillation) and 10 minutes after corneal shape measurement (Tome It was measured using TMS-2N).

(result)
Based on the measured spherical irregularity index (the spherical irregularity index increases as the shape of the tear film on the cornea becomes invalid), the spherical irregularity index changes (the spherical irregularity index immediately after instillation is 10 minutes later) The value subtracted from the index.) Was calculated. These results are shown in Table 3. In addition, the spherical irregularity index change of each test liquid shows the average value of 3 cases or 5 cases.

(Discussion)
As is apparent from Table 3, the test liquid 6 containing a thickening agent in which hydroxyethyl cellulose and dextran are combined exhibits a remarkable tear film stabilizing effect as compared with physiological saline (test liquid 1). It was.

[3] Eye drop ocular surface residence evaluation test In this test, the eye of each test ophthalmic solution was measured by measuring the fluorescence intensity of the tear film after instilling the test ophthalmic solution using an anterior ocular fluorescence measurement device. The surface retention action is evaluated.

(experimental method)
After applying 20 μl each of Test Solution 1 and Test Solution 6 containing 0.002% sodium fluorescein to the eyes of male Japanese white rabbits under general anesthesia, 0 (immediately after instillation) to 5 minutes after forced incision 30 Using the anterior ocular fluorescence measurement device (Kowa, FL-500) every second, every minute from 5 minutes to 10 minutes, and every 10 minutes to 30 minutes, The fluorescence intensity was measured.

(result)
Based on the measured fluorescence intensity of the lacrimal fluid layer, the average value of the fluorescence intensity residual ratio (refers to the ratio of the fluorescence intensity at each measurement time when the fluorescence intensity immediately after instillation is 100%) was calculated (each 4 Example average). Further, non-compartmental analysis was performed using the calculated average value, and λz (indicating disappearance rate, the smaller the value, the higher the retention) immediately after instillation and 30 minutes after instillation. AUC (indicating the area under the fluorescence intensity-time curve, the greater the value, the higher the retention) was calculated. The fluorescence intensity measurement results are shown in FIG. 1 and the analysis results are shown in Table 4.

(Discussion)
As is apparent from FIG. 1 and Table 4, the test liquid 6 containing a thickening agent combining hydroxyethyl cellulose and dextran showed higher ocular surface retention compared to physiological saline (test liquid 1). .

[Formulation example]
A typical formulation example in which an ophthalmic thickening agent comprising a combination of hydroxyethyl cellulose and dextran is blended is shown below.

Formulation Example 1 (ophthalmic solution)
Hydroxyethylcellulose 500mg in 100ml
Dextran 300mg
Sodium dihydrogen phosphate dihydrate appropriate amount 1N sodium hydroxide appropriate amount hydrochloric acid appropriate amount sterilized purified water appropriate amount

 In the same manner as in the above formulation example, an ophthalmic solution containing 100 mg, 1 g, 3 g, and 5 g of hydroxyethyl cellulose in 100 ml can be prepared.

Formulation Example 2 (ophthalmic solution)
Hydroxyethylcellulose 300mg in 100ml
Dextran 300mg
Sodium dihydrogen phosphate dihydrate appropriate amount 1N sodium hydroxide appropriate amount hydrochloric acid appropriate amount sterilized purified water appropriate amount

  In the same manner as in the above formulation example, an ophthalmic solution containing 50 mg, 100 mg, 500 mg, and 1 g of dextran in 100 ml can be prepared.

FIG. 1 is a graph showing the relationship between the fluorescence intensity remaining rate on the ocular surface (tear fluid layer) and time when the test solution 1 and the test solution 6 are used.

Claims (11)

An ophthalmic thickening agent comprising a combination of hydroxyethyl cellulose and dextran. An ophthalmic solution containing an ophthalmic thickening agent comprising a combination of hydroxyethyl cellulose and dextran. The ophthalmic solution according to claim 2, having a pH of 4-8. The ophthalmic solution according to claim 2, wherein the concentration of hydroxyethyl cellulose is 0.001 to 10% (w / v) and the concentration of dextran is 0.001 to 10% (w / v). The pH is 4 to 8, the concentration of hydroxyethyl cellulose is 0.001 to 10% (w / v), and the concentration of dextran is 0.001 to 10% (w / v). The ophthalmic solution described. A thickening agent comprising a combination of hydroxyethyl cellulose and dextran, which is thickened in the presence of mucin. An ophthalmic solution containing an ophthalmic thickening agent comprising a combination of hydroxyethylcellulose and dextran, which is thickened by contact with mucin in the tear film at the time of instillation. A tear film stabilizer comprising a combination of hydroxyethyl cellulose and dextran. A system for stabilizing a tear film on the surface of an eye by instilling an eye drop containing a tear film stabilizer comprising a combination of hydroxyethyl cellulose and dextran. An ophthalmic solution ocular surface retention accelerator comprising a combination of hydroxyethyl cellulose and dextran. A system for improving the retention of a drug in the anterior ocular segment by instilling an ophthalmic solution containing an ophthalmic solution ocular surface retention accelerator comprising a combination of hydroxyethyl cellulose and dextran.

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