KR20230031457A - Eye drop composition with low viscosity - Google Patents

Abstract

The present invention discloses a low-viscosity eye drop composition capable of preventing temporary blurred vision and improving the sensation of eye drop by using hyaluronic acid having a low intrinsic viscosity to easily control the concentration of hyaluronic acid in the composition and lower the dynamic viscosity. In order to achieve the above object, the present invention provides the low-viscosity eye drop composition containing hyaluronic acid or a salt thereof, and water and an additive as a solvent.

Description

Low viscosity eye drop composition {Eye drop composition with low viscosity}

The present invention relates to a low-viscosity eye drop composition.

Hyaluronic acid (hyaluronic acid) is a biosynthetic natural substance that exists in our body, such as skin, and is applied to various fields due to its hydrophilicity.

Among them, hyaluronic acid is used as a main component of eye drops for the treatment of dry eye syndrome.

Dry eye syndrome is caused by insufficient production of tears, excessive evaporation, an imbalance in tear composition, or inflammation of the eye or damage to the epithelial cells within the eye. Due to the dry eye syndrome, the eyes are easily tired and cannot be opened well, and it is comfortable to close the eyes, and the symptoms become worse when the eyes are opened.

Treatment methods for dry eye syndrome vary depending on the cause and severity, but the common basic treatment is mainly using 'artificial tears', that is, eye drops containing hyaluronic acid, to replace tears.

Hyaluronic acid eye drops are most similar to tears, have little irritation, and have an excellent moisturizing effect, so when administered to the eye, they serve to reinforce the intraocular moisture layer.

Commercially available hyaluronic acid eye drops contain 0.1%, 0.15%, 0.18%, and 0.2% concentrations, and generally low-concentration products are commercially available. The use of the hyaluronic acid ophthalmic solution starts from 0.1%, and if there is no improvement, the concentration is gradually increased.

On the other hand, it is known through the literature that the effect of water retention is enhanced as the concentration of hyaluronic acid in eye drops increases. Accordingly, KR Registered Patent No. 10-2051356 proposes a high-concentration eye drop having a hyaluronic acid concentration of 0.3 to 0.8% and mentions that the feeling of use, water retention, corneal affinity, and dispersion in the mucin layer are improved.

However, eye drops containing high-concentration hyaluronic acid have excellent effects, but the dynamic viscosity of the eye drops themselves is high, so the viscosity is high. Such high-viscosity eye drops cause discomfort and temporary blurred vision after administration to the eye. Accordingly, when a low-viscosity eye drop is prepared using a low concentration of hyaluronic acid, the above problem can be solved, but the use of a low concentration of hyaluronic acid cannot prevent deterioration of function as an eye drop.

KR Registration Patent No. 10-2051356 (2019.12.03 announcement)

The present invention applies hyaluronic acid of low concentration as well as high concentration, but as a result of research to prepare a low-viscosity eye drop composition with low dynamic viscosity of the eye drop, when adjusting the limiting viscosity parameter among the physical properties of hyaluronic acid, various A low-viscosity eye drop composition containing a high concentration of hyaluronic acid could be prepared.

An object of the present invention is to provide a low-viscosity eye drop composition.

In order to achieve the above object, the present invention hyaluronic acid or a salt thereof; and a low-viscosity eye drop composition containing water and an additive as a solvent.

At this time, the hyaluronic acid or salt thereof has an intrinsic viscosity of 0.01 to 1.0 m 2 / kg, the concentration of hyaluronic acid in the composition is 0.1 to 0.3% (w / v), and the dynamic viscosity measured at 20 ± 0.1 ° C is 1.0 to 10 cPs.

The low-viscosity eye drop composition according to the present invention uses hyaluronic acid having a low intrinsic viscosity to reduce the dynamic viscosity while applying various concentrations of hyaluronic acid in the composition, thereby preventing temporary blurred vision and improving the feeling of eye drop.

The low-viscosity eye drop composition according to the present invention is an eye drop composition having a low dynamic viscosity by using hyaluronic acid having a low intrinsic viscosity.

In the present invention, "hyaluronic acid" refers to a polysaccharide having one or more repeating structural units formed from glucosan and N-acetylglucosamine. In addition, the "hyaluronic acid salt" is not particularly limited, but is preferably a pharmaceutically acceptable salt, and includes, for example, sodium salt, potassium salt, calcium salt, zinc salt, magnesium salt, ammonium salt and the like. . Unless specifically stated herein, the expression of hyaluronic acid is defined as a term including hyaluronic acid and its salts. According to one embodiment, hyaluronic acid may be sodium hyaluronate.

In the present invention, 'low viscosity' means that the dynamic viscosity of the eye drop composition is low.

An eye drop composition according to one embodiment of the present invention includes hyaluronic acid or a salt thereof; and water as a solvent and additives.

In this case, hyaluronic acid having a low intrinsic viscosity is used in the present invention, but it is easy to adjust the hyaluronic acid occupied in the entire eye drop composition from a low concentration to a high concentration in various ways, and the viscosity, that is, the dynamic viscosity, of the final eye drop composition can be lowered.

The concentration of hyaluronic acid in the eye drop composition is to secure the effect of the water retention ability of the hyaluronic acid, and the water retention ability is usually enhanced as the concentration of hyaluronic acid increases. However, as the concentration of the hyaluronic acid increases, the viscosity increases, causing irritation when administered to the eyeball, or giving a sticky or stiff feeling during eyelid movement even if there is no stimulation, resulting in a very poor eye drop feeling. Therefore, it can be said that the higher the concentration of hyaluronic acid is, the more favorable it is for wetting, and the lower the dynamic viscosity, the better the instillation feeling.

The concentration of hyaluronic acid according to the present invention can be prepared in various ways from a low concentration range to a high concentration range that can be used as an eye drop composition, and is preferably 0.1 to 0.3% (w/v), 0.15 to 0.3% (w/v). am. According to one embodiment, it may have a range of 0.1 to 0.25% (w/v), 0.15 to 0.2% (w/v) in the case of a low concentration, and greater than 0.25 to 0.3% (w/v) in the case of a high concentration.

The viscosity of an eye drop composition is defined as dynamic viscosity.

Dynamic viscosity is called absolute viscosity, and it means that the degree of stickiness that resists against the direction of flow, that is, the direction of motion of the fluid in the flowing state, is expressed in absolute magnitude. The unit of the dynamic viscosity is cP, and it is necessary to describe the measurement temperature. For example, the dynamic viscosity of water measured at 20 °C is 1cp, and the dynamic viscosity of water measured at 25 °C is 0.894cp.

The dynamic viscosity in the present invention is a value measured according to USP physical tests Viscosity-Rotational methods, method I ubbelohde-type capillary viscometer, and the dynamic viscosity measured at 20 ± 0.1 ° C has a range of 1.0 to 10 cPs.

Eye drops having a value of 20 to 33 cPs based on the dynamic viscosity are generally used, but it is preferable to have a lower dynamic viscosity than this in terms of feeling of use. However, in the case of conventional eye drops, the concentration of hyaluronic acid has to be lowered in order to match the dynamic viscosity, and when the concentration is further lowered for a feeling of use, the amount of hyaluronic acid is small during eye drops, so the water retention ability may be significantly reduced.

The dynamic viscosities of 1 cPs or more, 10 cPs or less, 9 cPs or less, 7 cPs or less, 5 cPs or less, 1 to 5 cPs, 1 to 3 cPs, or 1 to 2 cPs presented in the present invention are at a lower level than conventionally known eye drops, and users when administering the eye drop composition can increase the usability of In addition, it is advantageous that the eye drop is applied evenly on the surface of the eyeball, and due to the low dynamic viscosity, when administered to the eyeball, it is more dispersed in the eyeball within a short time, so that the eyeball wetting ability of hyaluronic acid can be increased. When the dynamic viscosity is high, that is, the high-viscosity eye drop composition may not feel good after eye drop due to the high viscosity and may cause temporary blurred vision.

According to one embodiment of the present invention, when a high-concentration eye drop composition of 0.3% is prepared, an eye drop composition having a very low dynamic viscosity of 2 cPs or less, specifically 1.0 to 1.7 cPs, is prepared by using hyaluronic acid having a low intrinsic viscosity. did

In addition, according to another embodiment, when preparing a low-concentration eye drop composition of 0.18%, an eye drop composition having a very low dynamic viscosity of 3 cPs or less, specifically 1.0 to 2.9 cPs, was prepared by using hyaluronic acid having a low intrinsic viscosity. .

The above result means that the concentration of hyaluronic acid in the eye drop composition can be prepared in various ways through the use of hyaluronic acid having a low intrinsic viscosity, and it can be seen that the dynamic viscosity of the eye drop composition can be greatly reduced at all of these various concentrations. .

In particular, since the eye drop composition of the present invention does not lower the concentration of hyaluronic acid in order to secure a low dynamic viscosity, the deterioration of the eye drop and temporary blurred vision can be suppressed, and the wetting ability of the hyaluronic acid can be sufficiently obtained.

As described above, the effect of increasing the dynamic viscosity of the eye drop composition without lowering the concentration of hyaluronic acid in the eye drop composition can be achieved by using hyaluronic acid whose intrinsic viscosity is adjusted.

Intrinsic viscosity (η) means the degree to which one molecule contributes to viscosity when the interaction between solute molecules is negligible, and is related to molecular weight. That is, the average molecular weight of the polymer can be calculated by measuring the intrinsic viscosity of the sample.

Intrinsic viscosity can measure molecular weight using the Mark-Houwink equation ([η]=KMα). At this time, the K and α are constants determined by the type of polymer, the type of solvent, and the temperature published in the polymer handbook. Looking at the Mark-Houwink equation, it can be seen that the limiting viscosity is proportional to the molecular weight (M).

The limiting viscosity in the present invention is 0.01 to 1.0 m2/kg, 0.01 to 0.8 m2/kg, 0.01 to 0.3 m2/kg, 0.01 to 0.28 m2/kg, 0.04 to 0.28 m2/kg, 0.04 to 0.2 m2/kg, 0.04 to 0.19 m2/kg, 0.15 to 0.28 m2/kg, or 0.19 to 0.28 m2/kg. When the molecular weight of sodium hyaluronate is converted using this limiting viscosity, it has a low molecular weight range of 2 kDa to 100 kDa.

The low molecular weight hyaluronic acid having such a low limiting viscosity has high wetting ability when present in an eye drop composition at the same concentration as the high molecular weight hyaluronic acid due to a large number of -OH groups in the molecular chain.

In addition, in the case of hyaluronic acid having a low limiting viscosity, the fluidity is higher than that of hyaluronic acid having a high limiting viscosity, and thus the dynamic viscosity of the eye drop composition can be greatly reduced. That is, in the case of high molecular weight hyaluronic acid having a high limiting viscosity, there is a limit to lowering the viscosity of the eye drop composition by causing entanglement between chains due to its long chain structure. dynamic viscosity increases. Due to the increased dynamic viscosity, the fluidity on the surface of the eyeball is lowered, and thus the wettability may eventually be lowered.

As described above, the eye drop composition of the present invention can lower the dynamic viscosity while controlling the concentration of hyaluronic acid in the eye drop composition by using hyaluronic acid having a low intrinsic viscosity. As a result, it is possible to prevent temporary blurred vision caused by the use of the high-viscosity eye drop composition and to improve eye drop sensation.

On the other hand, the eye drop composition of the present invention may include hyaluronic acid or a salt thereof as described above; and water and an additive as a solvent, and the additive includes at least one selected from the group consisting of sodium edetate, a viscosity regulator, a pH regulator, a buffer, and an isotonic agent.

Sodium edetate (sodium salt of ethylenediaminetetraacetic acid) functions as a metal ion sequestering agent to stabilize hyaluronic acid from metal ions, and may be in the form of a hydrate. Examples of sodium edetate include monosodium edetate, disodium edetate and tetrasodium edetate, and examples of hydrates include dihydrate of disodium edetate and the like.

The concentration of ethylenediamine tetraacetates in the present ophthalmic composition may be 0.001 to 0.2% (w/v), preferably 0.005 to 0.15% (w/v). At this concentration, the main component can be stabilized by effectively blocking metal ions. In addition, the eye drop composition of the present embodiment may not contain ethylenediaminetetraacetates at all.

The pH of the eye drop composition according to one embodiment of the present invention is preferably 5.5 as a lower limit, more preferably 6, more preferably more than 6, and more preferably 8 as an upper limit, more preferably 7.5, and still more preferably 7. do. Within this pH range, the hyaluronic acid in the eye drop composition is stabilized and is hypoallergenic, so it can be suitably used for patients with dry eye syndrome.

The pH adjusting agent is not particularly limited as long as it can adjust the pH of the present ophthalmic composition, and specific examples thereof include dilute hydrochloric acid and sodium hydroxide.

The viscosity modifier (or thickener) imparts viscosity to the eye drops, and serves to improve proper eye drop feeling and retention. Polyvinylpyrrolidone, sodium carboxymethyl cellulose, polyvinyl acetate, hypromellose, hydroxyethyl cellulose, carbomer, etc. may be added to the viscosity modifier used in pharmaceuticals. It can also be added as a viscosity modifier. The type and amount (concentration) of these viscosity modifiers are not particularly limited as long as they can maintain the appropriate viscosity of eye drops.

The buffer is used together with the pH adjusting agent to maintain the pH of the eye drop composition at, for example, 5.5 to 8.0, specifically sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium acetate, ε-aminocaproic acid , tromethamine, sodium lactate, hydrochloric acid, sodium hydroxide and the like, but ε-aminocaproic acid is preferred. The addition amount (concentration) of the buffer is not particularly limited as long as the pH can be adjusted within the above range.

The isotonic agent adjusts the osmotic pressure of eye drops to be similar to the osmotic pressure in the eyeball to eliminate irritation and pain caused by the difference in osmotic pressure during eye drops. there is.

Meanwhile, the eye drop composition according to the present invention may be used for improvement, prevention or treatment of ophthalmic diseases, and may be preferably used for improvement, prevention or treatment of disorders caused by dry eye.

The "disorders associated with dry eye" include keratoconjunctivitis sicca, corneal conjunctival epithelial disorders, hypolacrimal lacrimal lacrimation, Stevens-Johnson syndrome, dry eye syndrome, Sjogren's syndrome, lacrimal deficiency, ocular congestion, tear film instability, or ocular edema; allergic conjunctivitis, viral conjunctivitis, or dry eye after cataract surgery; and contact lens wearing-related dry eye or VDT work-related dry eye.

In addition, the "conjunctival epithelial disorder" includes dry eye, corneal epithelial defect, conjunctival epithelial defect, corneal epithelial erosion, corneal thickness reduction, corneal infiltration, corneal perforation, or corneal epithelial exfoliation; corneal ulcer, keratitis, conjunctivitis, superficial punctate keratosis, keratoconjunctivitis sicca, limbic keratoconjunctivitis, filamentous keratitis, corneal ulcer and infectious eye disease of the corneal conjunctival epithelium; These may include intraocular trauma, microsurgery, or conjunctival epithelial disorders associated with wearing hard contact lenses.

For treatment and/or prophylaxis of mammalian patients, particularly humans, the dosage of the composition according to the present invention can be routinely determined by a medical practitioner or a person skilled in the art. For example, when the composition according to the present invention is used as an eye drop for an adult dry eye patient, the preferred dosage of the composition is, for example, 1 to 4 drops (about 0.025 to 0.1 mL) per eye drop, 1 to 1 per day. It can be administered up to 10 times, but is not limited thereto, and a medical practitioner or a person skilled in the art can determine the most suitable actual dosage according to the condition to be treated, as well as the age, weight, sex and response of the patient to be treated.

The composition of the present invention may contain additional drugs (also referred to as "therapeutic agents" or "agents") to improve or treat the above-mentioned ophthalmic diseases, such drugs for example, glaucoma drugs (prostaglandin, latano Frost, etc.), muscarinic agents (Pilocarpine, etc.), beta blockers (Betaxolol, etc.), alpha agonists (Brimonidine, etc.), carbonic anhydrase inhibitors (dorzolamide or brinzolamide, etc.), anti-inflammatory drugs (steroids, etc.) , soft steroids, or non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen), pain relievers (such as salicylic acid and acetaminophen), antibiotics (such as beta-lactam antibiotics, macrocyclic antibiotics such as erythromycin, fluoroquinolones, etc.), antiviral agents (such as reverse transcriptase inhibitors or viral protease inhibitors), dry eye syndrome drugs (such as cyclosporine, olapatadine, pain relievers or sodium hyaluronate), and the like, but are not limited thereto.

[Example]

Hereinafter, a preferred embodiment is presented to aid understanding of the present invention. However, the following examples are only provided to more easily understand the present invention, and the content of the present invention is not limited by the examples.

Test Example 1: Preparation of 0.3% high-concentration eye drop composition

As shown in the table below, eye drop compositions containing sodium hyaluronate having different intrinsic viscosities at a concentration of 0.3% (w/v) were prepared, and each physical property was measured.

Specifically, an eye drop composition was prepared by dissolving the mixture in a solvent by stirring with a paddle mixer (about 500 rpm) and then adding the rest of the composition.

- Dynamic viscosity: measured according to USP physical tests Viscosity-Rotational methods, method I ubbelohde-type capillary viscometer

- Sensory evaluation: After instilling 1 drop of each eye drop composition on 12 subjects, the eye drop feeling (1 to 5 points, 5 points is good) and temporary blurred vision (occurrence, +: occurrence) were evaluated.

Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 chief ingredient sodium hyaluronate
(Intrinsic viscosity, m ³ /kg) 3.0
(0.28) 3.0
(0.19) 3.0
(0.04) 3.0
(1.7) 3.0
(1.3) 3.0
(0.8) isotonic agent sodium chloride 7.0 7.0 7.0 7.0 7.0 7.0 potassium chloride 1.5 1.5 1.5 1.5 1.5 1.5 buffer aminocaproic acid 2.0 2.0 2.0 2.0 2.0 2.0 additive Edetate Sodium Hydrate 0.1 0.1 0.1 0.1 0.1 0.1 solvent water Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount total amount 1mL 1mL 1mL 1mL 1mL 1mL Dynamic viscosity (cPs) 1.7 1.3 1.0 23.5 12.6 5.7 Eye drop evaluation (score) 5.0 5.0 5.0 2.1 2.9 3.6 Temporary blurred vision - - - +++ ++ +

Referring to the table, the compositions of Examples 1 to 3 having low intrinsic viscosity have very low dynamic viscosities compared to the compositions of Comparative Examples 1 to 3 containing the same concentration of sodium hyaluronate. In particular, in the case of the eye drop compositions prepared in Example 3 and Comparative Example 1, it can be seen that the dynamic viscosity has a very large difference of up to 23.5 times. From the above table, it can be seen that the compositions of Examples 1 to 3 were excellent in the evaluation of eye drops and did not cause temporary blurred vision.

From these results, it can be seen that when a high-concentration eye drop composition is prepared, the use of hyaluronic acid having a low intrinsic viscosity lowers the dynamic viscosity of the eye drop, thereby preventing a feeling of eye drop and temporary blurred vision.

Test Example 2: Preparation of 0.18% low-concentration eye drop composition

As shown in the table below, eye drop compositions containing sodium hyaluronate having different intrinsic viscosities at concentrations of 0.18% (w/v) and 0.3% (w/v) were prepared, and each physical property was measured. At this time, the preparation and measurement method of the eye drop composition is the same as in Test Example 1.

Example 4 Example 5 Example 6 Comparative Example 4 Comparative Example 5 chief ingredient sodium hyaluronate
(Intrinsic viscosity, m ³ /kg) 1.8
(0.8) 1.8
(0.28) 1.8
(0.04) 1.8
(1.7) 1.8
(1.3) isotonic agent sodium chloride 2.8 2.8 2.8 2.8 2.8 potassium chloride 0.9 0.9 0.9 0.9 0.9 buffer aminocaproic acid 1.0 1.0 1.0 1.0 1.0 sodium hydrogen phosphate 1.0 1.0 1.0 1.0 1.0 additive Edetate Sodium Hydrate 0.3 0.3 0.3 0.3 0.3 solvent water Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount total amount 1mL 1mL 1mL 1mL 1mL Dynamic Viscosity (cPs) 2.9 1.1 1.0 12.0 8.7 Eye drop evaluation (score) 4.8 5.0 5.0 3.0 3.3 Temporary blurred vision - - - ++ +

Referring to the above table, the compositions of Examples 4 to 6 having low intrinsic viscosity have very low dynamic viscosities compared to the compositions of Comparative Examples 4 to 5 containing the same concentration of sodium hyaluronate. From the above table, it can be seen that the compositions of Examples 4 to 6 were excellent in the evaluation of eye drops and did not cause temporary blurred vision.

From these results, it can be seen that when a low-concentration eye drop composition is prepared, the use of hyaluronic acid having a low intrinsic viscosity lowers the dynamic viscosity of the eye drop, thereby preventing a feeling of eye drop and temporary blurred vision.

Claims (1)

hyaluronic acid or a salt thereof; and water as a solvent and additives;
The hyaluronic acid or salt thereof has an intrinsic viscosity of 0.01 to 1.0 m 2 / kg, the concentration of hyaluronic acid in the composition is 0.1 to 0.3% (w / v), and the dynamic viscosity measured at 20 ± 0.1 ° C is 1.0 to 10 An eye drop composition that is cPs.