HK1170685B - Eye drops - Google Patents

Description

Eye drops

Technical Field

The present invention relates to an eye drop having good liquid-cutting properties (that is, the amount of liquid remaining near the mouth of an eye drop container during eye dropping is small), and a method for improving the liquid-cutting properties of an eye drop.

Background

The high-viscosity ophthalmic composition is useful because it has an effect of prolonging the residence time of the composition on the surface of the eyeball to thereby maintain the drug effect and prevent dryness of the eye. As a thickener to be incorporated into such a high-viscosity ophthalmic composition, there are known acrylic polymers such as carboxyvinyl polymers, in addition to cellulose polymers such as hypromellose, hydroxyethylcellulose, and methylcellulose, vinyl polymers such as polyvinylpyrrolidone and polyvinyl alcohol, and the like. In particular, carboxyvinyl polymers are useful thickeners because they have a higher thickening effect than cellulose polymers which are generally used as components of eye drops and can achieve a viscosity of several thousand to several tens of thousands mPa · s even when incorporated in a small amount.

On the other hand, an ophthalmic composition such as an eye drop is generally contained in a container configured to allow a drop to be dropped from a spout (nozzle) by pressing the container. For this reason, a method of dropping an eye drop from a nozzle is considered.

For example, as a method for improving the liquid cutting of an eye drop, patent document 1 describes a method for improving the material and shape of a nozzle, but this method is expensive and may limit the shape of a container by defining the shape of the nozzle.

Further, as a method for dealing with a case where the liquid cutting between the eye drops and the nozzle is not good, a method of wiping the nozzle with a clean wipe every time the eye drops are dropped in order to prevent the deposition of the content is conceivable, but this method does not improve the liquid cutting property itself and also causes inconvenience to the user. Patent document 2 discloses a method of mixing a specific component in a liquid composition to suppress precipitation of a component contained therein, but this method is not a method of improving the liquid-cutting property itself.

On the other hand, it is known to add a cooling agent such as menthol, camphor, borneol or the like to an ophthalmic composition. These cooling agents are known to exert effects such as an effect of reducing eye pain caused by the contained components (patent document 3), an effect of optimizing wettability of contact lenses (patent document 4), and the like, in addition to a cooling feeling.

It is also known to add a water-soluble polymer to an ophthalmic composition together with a cooling agent such as menthol, camphor, or borneol. Such ophthalmic compositions are known to have effects of optimizing wettability of contact lenses (patent documents 5 and 6), suppressing adsorption of composition components onto contact lenses (patent documents 7 and 8), sustaining a refreshing feeling (patent document 9), and alleviating irritation at the time of eye drop (patent document 10).

Patent document

Patent document 1: japanese laid-open patent publication No. 2004-196417

Patent document 2: japanese patent laid-open publication No. 2006-219484

Patent document 3: japanese laid-open patent publication No. 2002-201126

Patent document 4: japanese laid-open patent publication No. 11-130667

Patent document 5: japanese patent laid-open publication No. 2006-

Patent document 6: WO97/28827 publication

Patent document 7: WO2005/025539 publication

Patent document 8: japanese laid-open patent publication No. 2002-322048

Patent document 9: japanese laid-open patent publication No. 2002-97129

Patent document 10: japanese patent laid-open publication No. 2005-8596

Disclosure of Invention

Technical problem to be solved by the invention

However, in the case of a highly viscous ophthalmic composition (particularly, an eye drop), the liquid is not cut at the pouring outlet (nozzle in the case of an eye drop container) portion when the composition is poured from the container, and a large amount of liquid remains attached to the vicinity of the pouring outlet (outside the nozzle in the case of an eye drop container) after the liquid is dropped. In addition, since it is practically difficult to always drip an eye drop at a certain angle, the orientation of a container at the time of dripping varies depending on users. In particular, when the container is close to the lateral direction (the direction parallel to the eye surface, i.e., the direction perpendicular to the eye surface in the direction of the container opening), the amount of adhesion and residue on the nozzle tends to increase. In this way, when the eye drops remain on the outer surface of the nozzle after the dropping, there is a possibility that the remaining liquid causes contamination such as adhesion of foreign matter, and as a result, it is considered that the ophthalmic liquid composition is likely to be dropped through the contaminated nozzle at the next use, and therefore, this is not preferable. Further, there is a possibility that the remaining components of the ophthalmic liquid composition are deposited on the outer surface of the nozzle or the ophthalmic liquid composition is dropped from the nozzle onto the surface of the container, which may cause a product impression or a loss of reliability to the user. Further, in the case of poor liquid contact with the nozzle, a part or precipitate of the ophthalmic liquid composition exposed to the environment outside the container at the time of dripping flows back into the container, thereby increasing the risk of mixing foreign matter into the ophthalmic liquid composition in the container. In addition, in the case of eye drops, there is a problem that when the liquid cut is poor, the amount of each drop varies during eye dropping, and the amount of the drug used fluctuates.

Accordingly, a main object of the present invention is to provide a high-viscosity eye drop having excellent liquid-cutting properties at an eye drop container mouth, and a method for improving the liquid-cutting properties of the high-viscosity eye drop at the eye drop container mouth.

Means for solving the problems

The present inventors have made extensive studies to solve the above problems and have obtained the following findings.

(i) When monoterpene is added to a carboxyvinyl polymer to prepare an eye drop having a viscosity of 200 to 100000 mPas, the amount of liquid adhering to the vicinity of the mouth of the eye drop container during dropping is remarkably reduced, that is, the liquid cut is improved, although the viscosity is high.

(ii) Generally, although high-viscosity eye drops containing a carboxyvinyl polymer have a reduced viscosity by light irradiation, the reduction of viscosity by light irradiation can be suppressed by blending a monoterpene to the carboxyvinyl polymer to form eye drops having a viscosity of 200 to 100000 mPas.

(iii) Although high-viscosity eye drops cause blurring of visual field after instillation, the duration of blurring of visual field is shortened by blending monoterpene into carboxyvinyl polymer to prepare eye drops having a viscosity of 200 to 100000 mPas.

The present invention has been made in view of the above-mentioned findings, and provides an eye drop, a method for improving the liquid-cutting property of an eye drop, a method for suppressing a decrease in viscosity under light irradiation, a method for improving the performance of restoring a blurred visual field after dropping, and the like.

Item 1. an eye drop comprising a carboxyvinyl polymer and a monoterpene and having a viscosity of 200 to 100000 mPas.

Item 2 the eye drop according to item 1, wherein the monoterpene is at least 1 monoterpene selected from menthol, camphor and borneol.

Item 3 the eye drop according to item 1 or 2, wherein the content of the carboxyvinyl polymer is 0.001 to 10 w/v% based on the total amount of the eye drop.

Item 4 the eye drop according to any one of items 1 to 3, wherein the content of monoterpene is 0.0001 to 1 w/v% with respect to the total amount of the eye drop

Item 5 the eye drop according to any one of items 1 to 4, which is filled in an eye drop container.

Item 6 the eye drop according to item 5, wherein the eye drop container is a transparent container.

Item 7. a method for improving the liquid-cutting performance of an eye drop at the mouth of an eye drop container, which comprises adding monoterpene to an eye drop containing a carboxyvinyl polymer to prepare an eye drop having a viscosity of 200 to 100000mPa · s.

Item 8. a method for suppressing a decrease in viscosity of an eye drop upon irradiation with light, which comprises adding monoterpene to an eye drop containing a carboxyvinyl polymer to prepare an eye drop having a viscosity of 200 to 100000mPa · s.

Item 9. a method for improving the ability of a blurred visual field to recover from a blurred visual field after dropping an eye drop, which comprises adding monoterpene to an eye drop containing a carboxyvinyl polymer to prepare an eye drop having a viscosity of 200 to 100000mPa · s.

Item 10. use of a composition, which contains a carboxyvinyl polymer and a monoterpene and has a viscosity of 200 to 100000mPa · s, in the production of an eye drop.

Item 11. a composition for eye drop, which contains a carboxyvinyl polymer and a monoterpene and has a viscosity of 200 to 100000mPa · s.

Item 12. an eye-dropping method comprising a step of dropping a composition containing a carboxyvinyl polymer and a monoterpene and having a viscosity of 200 to 100000mPa · s into the eye.

The eye drop of the present invention has a high viscosity, but the amount of liquid adhering to the eye drop container and remaining near the mouth thereof during dropping is small, i.e., the liquid cut is good. This makes it possible to avoid troubles such as contamination of the container by deposition of the eye drop component near the container opening, and eye diseases caused by entry of the contaminated liquid or deposited component into the eye near the container opening. Further, since the liquid cut is good, fluctuation in the amount of liquid to be dropped can be suppressed, and a constant amount of liquid can be stably dropped.

In addition, many of the eye drops are filled in a container having high transparency, which is easy to control quality. Generally, high-viscosity eye drops containing a polymeric thickener have a reduced viscosity when exposed to light for a long period of time, and thus the effects of the high-viscosity eye drops, such as the persistence of the medicinal effects and the prevention of dryness of the eyes, are impaired. In addition, when a carboxyvinyl polymer is used among the high molecular thickeners, the viscosity tends to decrease strongly. The eye drops of the present invention are high-viscosity eye drops containing the carboxyvinyl polymer which is likely to cause a decrease in viscosity as described above, but since a decrease in viscosity under light irradiation can be suppressed, the effects of the high-viscosity eye drops, such as the persistence of the drug effect and the prevention of dryness of the eyes, can be ensured even after storage.

In general, when the viscosity of an eye drop is high, a blurred visual field, which may be referred to as "fogging", is likely to occur after the eye drop is dropped, and if the blurred visual field continues for a long time, discomfort is caused. The eye drops of the present invention, although viscous due to the inclusion of the carboxyvinyl polymer, quickly recover from blurred vision after dropping and are excellent in feeling of use.

Under these circumstances, the eye drop of the present invention has both high safety and high practicability.

Drawings

FIG. 1 is a view showing a schematic configuration of a single cylindrical rotary viscometer used for viscosity measurement in examples.

Fig. 2 is a view showing a schematic configuration of a cone-plate rotational viscometer.

Detailed Description

The present invention will be described in detail below.

The eye drop of the present invention contains a carboxyvinyl polymer and a monoterpene, and has a viscosity of 200 to 100000 mPas.

Carboxyvinyl polymer

The Carboxyvinyl polymer (herein, abbreviated as "CVP") is a hydrophilic polymer obtained by polymerizing acrylic acid as a main component, and may be any of polyacrylic acid and polyacrylate.

When polyacrylic acid is used for mixing the components, if the pH is adjusted, a part or all of the components may be changed to polyacrylate in the obtained composition. When the carboxyvinyl polymer is mixed with other components, polyacrylic acid having low viscosity is preferably used, and a part or all of the polyacrylic acid is converted into polyacrylate by pH adjustment, so that the viscosity of the composition for eye drops can be increased. In addition, it is also preferable to use the polyacrylate from the time of mixing.

As the polyacrylate, alkali metal salts such as sodium salt and potassium salt of polyacrylic acid; amine salts such as monoethanolamine, diethanolamine, triethanolamine salts of polyacrylic acid; ammonium salts of polyacrylic acids, and the like. Alkali metal salts are particularly preferred.

In addition, although polyacrylic acid or a salt thereof may be either a crosslinked type or a non-crosslinked type, a crosslinked type polymer is preferable in terms of high thickening effect and easiness to further exhibit the effect of the present invention.

As the carboxyvinyl polymer, commercially available products can be used. As commercially available products, Carbopol (trade name) (Noveon, Lubrizol), Synthalen (trade name), HIVISWAKO (trade name) (both of yugaku corporation), Aqupec (trade name) (sumiton refinement), Junron (trade name) (japanese purified drug) and the like can be used.

The carboxyvinyl polymer may be used alone in 1 kind, or in combination of 2 or more kinds.

The content ratio of the carboxyvinyl polymer is not particularly limited as long as it is necessary to set the viscosity of the eye drops to a desired range, but the total amount of the carboxyvinyl polymer is preferably about 0.001 to 10 w/v%, more preferably about 0.05 to 5 w/v%, and still more preferably about 0.1 to 1 w/v% with respect to the total amount of the eye drops. When the content ratio is within the above range, a desired thickening effect can be obtained. In addition, if the content ratio is within the above range, a good viscosity reduction suppressing effect, a good liquid-cutting improving effect, a good fluctuation suppressing effect of the amount of dropped liquid, and a good feeling of use can be obtained.

Monoterpene

Examples of the monoterpenes include acyclic monoterpenes such as geraniol, nerol, myrcenol, linalool acetate, and lavandil; monocyclic monoterpenes such as menthol, limonene, anethole, eugenol; and bicyclic monoterpenes such as camphor, borneol, isoborneol, eucalyptol, and pinene. Particularly preferred are monocyclic monoterpenes and bicyclic monoterpenes, and more preferred are menthol, camphor and borneol. The monoterpene may be any of d-, l-or dl-isomer. The monoterpenes may be used alone in 1 kind, or in combination of 2 or more kinds.

As monoterpenes, essential oils containing it may also be used. Examples of such essential oils include peppermint oil, eucalyptus oil, peppermint oil, bergamot oil, spearmint oil, rose oil, and the like. These essential oils can be extracted from plants by known methods. Examples of such known methods for extracting essential oils include steam distillation; a fat adsorption method in which a plant is added to deodorized animal fat to adsorb essential oil, and the essential oil is extracted with ethanol; solvent extraction method comprises extracting plant with organic solvent such as hexane or benzene or supercritical fluid, dissolving the extraction solvent in ethanol, and evaporating ethanol to collect residue; pressing, and the like. Monoterpenes can also be recovered from essential oils using various chromatographies.

The content ratio of monoterpene is preferably about 0.0001 to 1 w/v%, more preferably about 0.001 to 0.05 w/v%, even more preferably about 0.002 to 0.05 w/v%, and even more preferably about 0.003 to 0.02 w/v% with respect to the total amount of the eye drops. If the content ratio is within the above range, an eye drop having a good feeling of use can be formed in which the action of monoterpene can be effectively obtained and the irritation is not excessively strong.

Preferred monoterpenes will be described in detail below.

<Menthol>

Menthol generally used may be l-menthol or dl-menthol. Menthol is commercially available from, for example, Kaisha perfumery industries.

The content ratio of menthol is preferably about 0.0001 to 1 w/v%, more preferably about 0.001 to 0.05 w/v%, still more preferably about 0.002 to 0.05 w/v%, and yet more preferably about 0.003 to 0.02 w/v%, relative to the total amount of the eye drops. If the content ratio is within the above range, an eye drop having a good feeling of use can be formed in which the action of monoterpene can be effectively obtained and the irritation is not excessively strong.

<Camphor>

D-camphor or dl-camphor can be usually used as camphor. As the camphor, commercially available products such as those manufactured by Kaisha perfumery industries, etc. can be used.

The content ratio of camphor is preferably about 0.0001 to 1 w/v%, more preferably about 0.001 to 0.05 w/v%, even more preferably about 0.002 to 0.05 w/v%, and even more preferably about 0.003 to 0.02 w/v%, relative to the total amount of the eye drops. If the content ratio is within the above range, an eye drop having a good feeling of use can be formed in which the action of monoterpene can be effectively obtained and the irritation is not excessively strong.

<Borneol (borneol)>

As the borneol, d-borneol or dl-borneol can be usually used. As the ice flakes, commercially available products such as those manufactured by Kaisha perfumery industries, etc. can be used.

The content ratio of borneol is preferably about 0.0001-1 w/v%, more preferably about 0.001-0.05 w/v%, even more preferably about 0.002-0.05 w/v%, and even more preferably about 0.003-0.02 w/v% relative to the total amount of the eye drops. If the content ratio is within the above range, an eye drop having a good feeling of use can be formed in which the action of monoterpene can be effectively obtained and the irritation is not excessively strong.

Boric acid buffers

The eye drops of the present invention may further contain a boric acid buffer. Examples of the boric acid buffer include boric acid, and borates such as sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, and borax. Boric acid or borax is particularly preferred, and boric acid and borax are more preferably used in combination.

The content ratio of the boric acid buffer is preferably about 0.05 to 3 w/v%, more preferably about 0.2 to 2.5 w/v%, and still more preferably about 0.7 to 2 w/v% with respect to the total amount of the eye drops.

Optional ingredients

The eye drops of the present invention may contain, in addition to the above-mentioned components, active ingredients (pharmacologically active ingredients, physiologically active ingredients, etc.) widely used in ophthalmic compositions. The blending ratio of various pharmacologically active ingredients or physiologically active ingredients is known in the field of eye drops, and in the eye drop of the present invention, the blending ratio of the pharmacologically active ingredient or physiologically active ingredient can be appropriately set depending on the kind thereof or the like. For example, the blending ratio of the pharmacologically active ingredient or physiologically active ingredient to the total amount of the eye drops may be selected from the range of about 0.0001 to 30% by weight, preferably about 0.001 to 10% by weight.

In the eye drop of the present invention, various carriers and additives may be appropriately selected depending on the use and form thereof, and may contain one or more kinds in combination according to the usual method as long as the effect of the present invention is not impaired.

Any of the components may be used alone in 1 kind, or in combination of 2 or more kinds.

Viscosity of the oil

The viscosity of the eye drops of the present invention is usually about 200 to 100000 mPas, preferably about 500 to 20000 mPas, more preferably about 700 to 10000 mPas, particularly preferably about 1200 to 5000 mPas, and further particularly preferably about 1500 to 4000 mPas. The eye drops having the above viscosity can be obtained by mainly selecting the kind and the amount of the carboxyvinyl polymer appropriately.

In the present invention, the measurement of the viscosity is carried out by (2) a single cylindrical rotational viscometer (Brookfield type viscometer) according to the method for measuring the viscosity described in the general test method of Japanese pharmacopoeia (Japanese: 15 th corrected Japanese medicine) 15 th edition. In the present application, RB-80L (Toyobo industries) was used, and the viscosity at 25 ℃ was measured by selecting conditions such as the rotor and the number of revolutions in accordance with the instructions of the apparatus.

The description about the single cylinder type rotational viscometer is described below. The single cylinder rotational viscometer is a viscometer that measures a torque when a cylinder in a liquid is rotated at a constant angular velocity. Fig. 1 schematically shows the apparatus. K was determined experimentally by calibrating the standard solution beforehand using a viscometer_BThen, the viscosity η of the liquid is calculated by the following equation.

η＝K_B×T/ω

Eta: viscosity of liquid (mPa. s)

K_B: device constant (rad/cm)³)

ω: angular velocity (rad/s)

T: torque (10) acting on the cylindrical surface^-7N·m)

The method of measuring the viscosity of a composition having a viscosity of less than about 100 mPas at 25 ℃ such as the comparative example composition of the present invention is described below for reference. In this case, the viscosity is measured by (3) a cone-plate rotational viscometer (cone and plate viscometer) according to the viscosity measurement method described in the general test method of japanese pharmacopoeia 15 th edition. In the present application, the viscosity at 25 ℃ was measured using TV-20 (east China machine industry), and selecting conditions such as rotor and rotational speed in accordance with the instructions of the machine.

The description of the cone-plate rotational viscometer is as follows. The cone-plate rotational viscometer is a viscometer in which a liquid is held between a flat disk having the same rotation axis and a cone having a large apex angle, one of the disks is rotated, and the torque and the angular velocity corresponding to the torque received by the other disk are measured. A schematic diagram of the apparatus is shown in fig. 2. The viscosity η of the liquid is calculated by the following equation by adding the liquid to the gap of the angle α between the cone and the flat disc, rotating the cone or the flat disc at a constant angular velocity or a constant torque, and measuring the torque applied to the flat disc or the cone when the cone or the flat disc reaches a steady state and the angular velocity corresponding thereto.

η＝3α/2πR³×100T/ω

Eta: viscosity of liquid (mPa. s)

Pi: circumferential ratio

R: radius of the cone (cm)

α: angle between flat circular plate and cone (rad)

ω: angular velocity (rad/s)

T: torque (10) acting on a flat circular plate or a conical surface^-7N·m)

Others

The dosage form of the eye drop of the present invention is not particularly limited. Preferably a liquid formulation.

The pH of the eye drop of the present invention may be about 3 to 10, preferably about 4 to 9, more preferably about 5 to 8.5, and particularly preferably about 7 to 8.5.

As the container for filling the eye drop of the present invention, a known eye drop container can be used without limitation. As the eye drop container, a container having a shape capable of dropping eye drops into eyes, for example, a container having a nozzle and a container port at the tip end of the nozzle can be generally used. The eye drop container for containing the eye drops of the present invention may be any of a container having a structure in which a nozzle formed separately from the container is attached to the container and a container having a structure in which the nozzle (liquid pouring section) is integrally formed with the container main body (for example, disposable eye drops).

The container for containing the eye drop of the present invention is usually made of plastic. The material for forming the plastic container is not particularly limited, but examples thereof include any one of polyethylene terephthalate, polyacrylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene and polyimide, a copolymer thereof, and a mixture of 2 or more kinds thereof. In particular, polyethylene terephthalate, polyacrylate, polyethylene naphthalate, a copolymer thereof, or a mixture of 2 or more of them is preferable in terms of the ease of use of extrusion and the like to exhibit the effects of the present invention.

The eye drop of the present invention may be filled in a transparent container (a container having transparency to such an extent that it does not hinder observation of foreign matter) mainly made of such a material, or may be filled in a container shielded from light. For example, the light-shielding can be performed by adding a colorant to the above-mentioned transparent container material, or the light-shielding can be performed by covering the container with a shrink film, an outer package, or the like.

In addition, the volume of the container is preferably about 0.5 to 20mL, more preferably about 3 to 18mL, and even more preferably about 5 to 15mL, in order to make it easier to utilize the degree of extrusion and the like to further exert the effect of the present invention.

The nozzle provided in the container for containing the eye drop of the present invention is not particularly limited in its structure or its constituent material. The structure of the nozzle may be any structure commonly used as a nozzle of an eye drop container, and the same example as the above-described plastic container can be given as a constituent material of the nozzle. From the viewpoint of improving the liquid-cutting property of the eye drop of the present invention and suppressing fluctuation of the amount of dropping, a nozzle containing polyethylene or polypropylene as a constituent material is preferable. Examples of the polyethylene include high-density polyethylene and low-density polyethylene, and a nozzle containing low-density polyethylene as a constituent material is particularly preferable.

Manufacturing method

The eye drops of the present invention can be prepared by a known method (Japanese examined patent publication No. Sho 60-56684, etc.) in addition to the conventional methods. For example, the composition can be prepared by dispersing each component (carboxyvinyl polymer, monoterpene, and optionally other pharmacologically active ingredients or physiologically active ingredients, additives, etc.) in a carrier such as water, homogenizing, dissolving, or emulsifying the dispersion using a homogenizer, etc., and adjusting the pH with a pH adjuster.

Further, as a method for blending monoterpene, a method of adding monoterpene to an aqueous solvent, heating it as necessary, and stirring it to dissolve it; the monoterpene may be added to the aqueous solvent after being solubilized in a surfactant or a dissolution assistant, which may be added as needed, or in a polyhydric alcohol such as glycerin or propylene glycol, which may be added as needed. Further, as a method for sterilizing the preparation, a method such as autoclave sterilization, filtration sterilization, or the like can be selected.

Application and method of use

The eye drops of the present invention include eye drops that can be used while wearing contact lenses. In the present specification, the contact lenses include all types of contact lenses, such as hard contact lenses (including oxygen permeable hard contact lenses) and soft contact lenses (including silicone hydrogel contact lenses).

The administration and dosage of the eye drops of the present invention vary depending on the symptoms, age, etc. of the patient, but generally about 1 to 6 drops are given for 1 day, and about 1 to 2 drops are given for 1 time.

The object of the eye drop of the present invention is not particularly limited, but a patient suffering from dry eye (including a person whose eyes have dry symptoms), a patient suffering from asthenopia, and the like can be mentioned. In particular, dry eye patients, especially those with hyperevaporative dry eye, are suitable subjects.

Other modes of the invention

By blending monoterpene into a high-viscosity eye drop containing a carboxyvinyl polymer, the drop in viscosity can be suppressed and the liquid-cutting at the container mouth during the dropping can be improved. Accordingly, the present invention includes a method for improving the liquid-cutting performance of an eye drop at the mouth of an eye drop container, wherein monoterpene is added to an eye drop containing a carboxyvinyl polymer to prepare an eye drop having a viscosity of 200 to 100000mPa · s.

The present invention also provides a method for suppressing a decrease in viscosity of an eye drop upon irradiation with light, wherein a monoterpene is added to an eye drop containing a carboxyvinyl polymer to prepare an eye drop having a viscosity of 200 to 100000 mPas.

The present invention also provides a method for improving the ability of the eye to recover from blurring of visual field after instillation of an eye drop, wherein monoterpene is added to an eye drop containing a carboxyvinyl polymer to prepare an eye drop having a viscosity of 200 to 100000 mPas.

The present invention also includes the use of a composition for the production of an eye drop, the composition containing a carboxyvinyl polymer and a monoterpene and having a viscosity of 200 to 100000 mPas.

The present invention also provides a composition for eye drop, which contains a carboxyvinyl polymer and a monoterpene and has a viscosity of 200 to 100000 mPas.

The present invention also provides an eye-drop method comprising the step of dropping a composition containing a carboxyvinyl polymer and a monoterpene and having a viscosity of 200 to 100000 mPas into the eye.

The types, contents, dosage forms, viscosities, pH, methods of use, methods of production, and the like of the components in these methods are the same as those of the above-mentioned eye drops.

Examples

The present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

(1) Preparation of the samples

Eye drops of examples 1 to 25 and comparative examples 1 to 20 having the compositions shown in tables 1 to 9 described below were prepared by the following methods. That is, a carboxyvinyl polymer or hydroxypropylmethylcellulose is added to pure water and dispersed under stirring, and then components other than a pH adjuster (sodium hydroxide or hydrochloric acid) are added and dissolved under stirring for 1 hour or more. Then, after adjusting the pH to 7.3-7.6 with sodium hydroxide or hydrochloric acid, adding a proper amount of pure water to achieve the concentration of each formula.

After each of the prepared eye drops was left to stand overnight at a temperature of 25 ℃ in the light-shielded state, the viscosity, osmotic pressure, amount of liquid adhering to the nozzle or decrease in viscosity under light irradiation, fluctuation in the amount of dripping, and sensory evaluation were performed.

(2) Experimental methods

(2-1) measurement of viscosity

The viscosity of each eye drop was measured by the following method.

Examples 1 to 25 and comparative examples 1, 3, 4, 7 to 20

Viscosity was measured under the following conditions using RB-80L (Tokyo industries) according to the test method of "(2) Single Cylinder rotational viscometer (Brookfield type viscometer)" described in Japanese pharmacopoeia general test methods viscometer method 2, 15 th edition, viscosity measurement method.

The measurement temperature is 25 DEG C

Speed of rotation and rotor No.

Viscosity of 100 mPas or more and less than 350 mPas: rotating speed of 30rpm and rotor No. M2

Viscosity of 350 mPas or more and less than 1500 mPas: rotating speed of 12rpm and rotor No. M2

Viscosity 1500 mPas or more: rotating speed of 12rpm and rotor No. M3

Viscosity after a set time of 1 minute

Comparative examples 2, 5 and 6

Viscosity was measured under the following conditions using TV-20 (eastern industry) according to the test method of "(3) cone-plate rotational viscometer (cone-plate viscometer)" described in japanese pharmacopoeia general test methods viscosity measurement method, 15 th edition, 2 nd method rotational viscometer method.

The measurement temperature is 25 DEG C

Comparative examples 5 and 6 at 2.5rpm

100rpm comparative example 2

Rotor No.01

Viscosity after setting time 3 minutes

(2-2) measurement of decrease in viscosity under light irradiation

Each eye drop was filled in a glass container having a capacity of 30 mL. The containers filled with the eye drops were irradiated with an irradiance of 350W/m using a sunlight tester (SUNTEST XLS +; manufactured by Toyo Seiki Seisaku-sho Ltd.) as a light irradiation device²Light irradiation was performed for 8 hours. At the radiation illuminance of 350W/m²At a time of 8 hours, the light irradiation was equivalent to 10000kJ/m²。

After the irradiation, the sample without irradiation light (non-irradiated sample) and the sample with irradiation light (irradiated sample) were stored in a dark state at 25 ℃ for one night. Then, the viscosity at 25 ℃ was measured immediately as described in the section of "(2-1) viscosity measurement" mentioned above.

The viscosity of the non-irradiated sample was set to 100%, and the viscosity after irradiation was expressed relative to the relative viscosity thereof, and the decrease in viscosity under irradiation with light of each eye drop was evaluated.

Relative viscosity (%)

(viscosity of irradiated sample (25 ℃ C.)/viscosity of non-irradiated sample (25 ℃ C.)) X100

(2-3) measurement of amount of liquid adhering to the nozzle

Each eye drop was filled into a 15 mL-volume polyethylene terephthalate eye drop container, and a low-density polyethylene nozzle was attached to the container. Various eye drop scenes were conceived, and eye drops were dropped in the lateral direction (with the angle of the nozzle approximately horizontal) where it is considered most likely to leave liquid in the nozzle, and the weight of the drops was measured for 1 drop, and the liquid adhering to the outside of the nozzle was sucked off with a filter paper. This operation was repeated 20 times to calculate the average dropping amount. The total weight of 20 drops sucked off by the filter paper was measured for the amount of the adhesive on the outer side of the nozzle, and the average weight was calculated by dividing the measured weight by 20.

(2-4) evaluation of fluctuation in dripping amount

Each eye drop was filled into a 15 mL-volume polyethylene terephthalate eye drop container, and a low-density polyethylene nozzle was attached to the container. The eye drops were dropped in the horizontal direction (the angle of the nozzle was made substantially horizontal), and the dropping weight was measured for 1 drop. This operation was repeated 20 times to calculate the average dropping Amount (AVG), Standard Deviation (SD), and Coefficient of Variation (CV).

(2-5) measurement of osmotic pressure

The osmotic pressure of each eye drop was measured by an osmotic pressure measurement method (freezing point depression method) described in japanese pharmacopoeia, fifteenth edition.

(2-6) measurement of time from blurring to restoration of visual field after dropping

For 3 subjects, the test eye drop was dropped into one eye, the control eye drop having the same composition as the test eye drop except that it contained no monoterpene was dropped into the other eye, and the time from blurring to restoration of the visual field after dropping of both eye drops was measured.

(3) Results

(3-1) amount of liquid adhering to the nozzle

Table 1 below shows the composition, pH, osmotic pressure, viscosity, amount of liquid deposited per 1 drop, and nozzle adhesion of each eye drop using l-menthol as monoterpene.

[ Table 1]

(unit of concentration of each component: g/100ml)

In Table 1, AQUPEC HV-505E of carboxyvinyl polymer is manufactured by Sumitomo Seiki and METOLOSE 65SH-4000 of hydroxypropyl methylcellulose is manufactured by shin-Etsu chemical Co.

In table 1, as is clear from comparison between example 1 and comparative example 1, by blending menthol to a carboxyvinyl polymer, the amount of adhesion to the nozzle can be reduced while maintaining high viscosity. Further, as is clear from comparison between comparative example 3 and comparative example 4, the above-mentioned effect by the blending of menthol is obtained by the combination with the carboxyvinyl polymer, and cannot be obtained by the combination with hydroxypropylmethylcellulose even with the same thickener.

In addition, comparative example 2 does not contain a carboxyvinyl polymer, and comparative examples 5 and 6 contain sodium chloride, and therefore, the viscosity is lower than that of the eye drops of the present invention. Therefore, there is no problem of improving the liquid-cutting.

(3-2) fluctuation in dripping amount (one)

In addition, the fluctuation in the dropping amount was compared between example 1 and comparative example 1, and between comparative example 3 and comparative example 4. Fluctuation in the amount of dripping was calculated by using an F test (test using dispersion of 2 specimens, significance level of 0.05) of Microsoft Excel 97. The results are shown in table 2 below.

[ Table 2]

From comparison between example 1 and comparative example 1, it is understood that the P value is not more than a significant level, and the fluctuation of the two is significantly different, and the fluctuation of the dropping amount is significantly reduced by blending menthol to the carboxyvinyl polymer. It is also found that, since the P value is a significant level or more, no significant difference is observed in fluctuation of the dropping amount between comparative examples 3 and 4 in which hydroxypropylmethylcellulose is used as a thickener, the effect of reducing fluctuation of the dropping amount by blending menthol is observed in combination with a carboxyvinyl polymer.

(3-3) fluctuation of dropping amount (second)

The composition, pH, osmotic pressure, viscosity, and fluctuation (standard deviation (SD), Coefficient of Variation (CV)) of each eye drop using l-menthol, d-camphor, or d-borneol as monoterpene are shown in tables 3 to 6 below.

TABLE 3

(unit of concentration of each component: g/100ml)

The Carbopol 980 of the carboxyvinyl polymer in Table 3 is available from Lubrizol corporation.

[ Table 4]

[ Table 4]

(unit of concentration of each component: g/100ml)

	Example 8	Comparative example 9
			Boric acid	0.7	0.7
Borax	1	1
			Menthol	0.015	-
CVP(Carbopol 980)	0.32	0.32
			Sodium chloride	0.08	0.08
HCl or NaOH	Proper amount of	Proper amount of
			pH	7.38	7.37
Osmotic pressure	254	252
			Viscosity of the oil	745	802.5
SD	0.002782	0.003882
			CV(％)	8.6	11.1

[ Table 5]

(unit of concentration of each component: g/100ml)

[ Table 6]

(unit of concentration of each component: g/100ml)

As is clear from tables 3 to 6, in the eye drops of the examples of the present invention containing both a carboxyvinyl polymer and a monoterpene, the Standard Deviation (SD) value and the Coefficient of Variation (CV) value of the amount of dripping were smaller and the fluctuation of the amount of dripping was suppressed as compared with the eye drops of the comparative examples containing no monoterpene.

(3-4) viscosity reduction under light irradiation

The composition, viscosity before and after light irradiation, and relative viscosity of each eye drop using l-menthol, d-camphor, or d-borneol as monoterpene are shown in tables 7 to 9 below.

[ Table 7]

(unit of concentration of each component: g/100ml)

[ Table 8]

(unit of concentration of each component: g/100ml)

	Example 22	Comparative example 17
			Boric acid	0.7	0.7
Borax	1	1
			Menthol	0.015	-
CVP(AQUPECHV-505E)	0.255	0.255
			HCl or NaOH	Proper amount of	Proper amount of
pH	7.41	7.31
			Viscosity before light irradiation (mPa. s)	960.0	902.5
Viscosity after light irradiation (mPa. multidot.s)	507.5	138.0
			Relative viscosity	53％	15％

As is clear from tables 7 to 9, in the eye drops of the examples of the present invention containing both a carboxyvinyl polymer and a monoterpene, the decrease in viscosity under light irradiation was suppressed, and the decrease in viscosity was suppressed depending on the concentration of the monoterpene, as compared with the eye drops of the comparative examples not containing the monoterpene.

(3-5) time taken for visual field to recover from blurring after dropping

For the eye drops of example 5 (containing a carboxyvinyl polymer and menthol) and the eye drops of comparative example 8 (the eye drops of the same composition as in example 5 except that they did not contain menthol) having the compositions shown in table 3, the time from blurring to restoration of the visual field after the dropping was measured. The results are shown in table 10 below.

[ Table 10]

Example 5 faster recovery from blur	There is no difference	Comparative example 8 from blur to recovery faster
			3 persons	0 person	0 person

As is clear from table 10, by blending a carboxyvinyl polymer and menthol, the visual field after dropping was blurred to be restored more quickly.

As described above, it is generally known that an eye drop tends to cause "blur" which is sometimes called fogging after dropping as the viscosity increases, and that the discomfort increases if the blur is not completed for a long time. The eye drops of example 5 and comparative example 8 used in this test were those with a relatively high viscosity of approximately 2600mPa · s.

The eye drops of comparative example 8 containing no menthol were pasty and therefore had very poor feeling of use, and the subjects were evaluated that the lower eyelid remained in the eye drops for a long time and had a feeling of use that both eyelids were sticky when blinking, and that the visual field was always blurred when the eye drops were blinked. On the other hand, the eye drop of example 5 containing menthol was combined, and the eye drop had sticky slimy feel, sticky sensation in use with both eyelids upon blinking, and blurred vision, as in comparative example 8, but was evaluated to have a high degree of disappearance and a rapid improvement in the visual field.

For the eye drops of example 9 (containing a carboxyvinyl polymer and menthol) and the eye drops of comparative example 10 (the same composition as in example 9 except that they contained no menthol) whose compositions are shown in table 5, the time from blurring to restoration of the visual field after dropping was evaluated. The results are shown in table 11 below.

[ Table 11]

Example 9 faster recovery from blur	There is no difference	Comparative example 10 faster recovery from blur
			3 persons	0 person	0 person

The eye drops of example 9 and comparative example 10 are also relatively high-viscosity eye drops having a viscosity of about 2100 to 2400mPa · s. As is clear from comparison of the eye drop of example 9 with the eye drop of comparative example 10, by blending menthol in combination with the carboxyvinyl polymer, the visual field after the dropping is more rapid from blurring to recovery, and the unpleasant feeling is suppressed.

Industrial applicability of the invention

The eye drop of the present invention has good liquid-cutting property during dropping despite its high viscosity, and is suppressed in fluctuation of the dropping amount, and reduced in viscosity under light irradiation, and yet has a high viscosity, and the visual field after dropping is rapidly restored from blurred vision to high-viscosity vision. Therefore, the eye drop of the present invention is highly practical and has a good feeling of use.

Claims (6)

1. A method for improving the liquid cutting performance of eye drops at the mouth of an eye drop container is characterized in that,

adding a carboxyvinyl polymer and a monoterpene to an eye drop to prepare an eye drop having a viscosity of 200 to 4000mPa s,

the content of monoterpene is 0.001-0.05 w/v% relative to the total amount of the eye drops.

2. A method for suppressing a decrease in the viscosity of an eye drop upon irradiation with light,

adding a carboxyvinyl polymer and a monoterpene to an eye drop to prepare an eye drop having a viscosity of 200 to 4000mPa s,

the content of monoterpene is 0.001-0.05 w/v% relative to the total amount of the eye drops.

3. A method for improving the ability of visual field from blurring to restoration after dropping eye drops, characterized in that,

adding a carboxyvinyl polymer and a monoterpene to an eye drop to prepare an eye drop having a viscosity of 200 to 4000mPa s,

the content of monoterpene is 0.001-0.05 w/v% relative to the total amount of the eye drops.

4. An eye drop containing a carboxyvinyl polymer and a monoterpene and having a viscosity of 200 to 4000 mPas is used for the production of an eye drop having improved liquid-cutting performance at the mouth of an eye drop container,

wherein the content of monoterpene is 0.001-0.05 w/v% relative to the total amount of the eye drops.

5. Use of an eye drop containing a carboxyvinyl polymer and a monoterpene and having a viscosity of 200 to 4000 mPas for the production of an eye drop which suppresses a decrease in viscosity of the eye drop after production under irradiation with light,

wherein the content of monoterpene is 0.001-0.05 w/v% relative to the total amount of the eye drops.

6. An eye drop containing a carboxyvinyl polymer and a monoterpene and having a viscosity of 200 to 4000 mPas is used for the production of an eye drop having an improved ability to restore a blurred visual field after the eye drop is applied,

wherein the content of monoterpene is 0.001-0.05 w/v% relative to the total amount of the eye drops.