Eye drop composition comprising imatinib

Abstract

The present invention relates to an eye drop composition comprising imatinib. The present invention relates to an eye drop composition and a method for preparing same, in which the eye drop composition is prepared at a pH level suitable as an eye drop while an appropriate amount of an imatinib derivative is dissolved even within a relatively high pH range, compared to conventional compositions prepared under pH conditions (< pH 5.5) unsuitable for eye drop, in order to dissolve imatinib, and has improved phase stability, long-term stability, bioavailability, and eye irritation.

Description

Ophthalmic composition comprising imatinib

[0001] The present invention relates to an ophthalmic composition comprising imatinib.

[0002]

[0003] Our eyes, responsible for vision, are a vital sensory organ, receiving most of the information necessary for daily life. The front surface of the eye is composed of the cornea and conjunctiva. The sclera, surrounding the eyeball, contains the iris, ciliary body, lens, and vitreous humor, which maintains the eye's spherical shape. The retina is located at the back. The lens, vitreous humor, and aqueous humor constitute the refractive media. Vision impairment or loss due to disease is one of the most significant factors affecting quality of life.

[0004] Dry eye disease (DED), also known as dry eye or keratoconjunctivitis sicca, is a disease in which the ocular surface, namely the cornea and conjunctiva, becomes dry due to a lack of tears or excessive evaporation of tears. It is known as a disorder of the tear film. According to the International Dry Eye WorkShop (DEWS) and the National Eye Institute (NEI), dry eye is a disease of the tears and ocular surface that causes eye discomfort, tear film instability, and decreased vision. Dryness of the ocular surface affects the corneal epithelium, which is protected by the tear film, and causes inflammation. When the amount of tear film is insufficient due to increased tear film evaporation or decreased secretion from the tear glands, the osmotic pressure of the tear film increases, and the friction on the ocular surface due to the lack of tears damages the corneal epithelium, causing inflammation. Dry eye can be divided into aqueous tear-deficient dry eye and evaporative dry eye.

[0005] Aqueous tear-deficiency dry eye is caused by a lack of tears secreted by the lacrimal glands. Evaporative dry eye occurs when the lacrimal glands function normally, but the secretory capacity of the goblet cells in the conjunctiva and the meibomian glands in the eyelids is impaired, resulting in a lack of viscous substances in the tears, leading to excessive moisture loss from the ocular surface. These causes can be endogenous, resulting from underlying diseases affecting the structure or dynamics of the eyelid, or exogenous, resulting from the rapid destruction of the tear film on the ocular surface due to certain external exposures.

[0006] There are many factors that cause dry eye, including decreased tear production, excessive tear evaporation, inflammation of the tear-producing organ, systemic diseases such as Sjogren's syndrome or Stevens-Johnson syndrome, long-term use of smartphones or tablet PCs, and rapid hormonal changes.

[0007] Currently, artificial tears and chondroitin sulfate, glutathione, hyaluronic acid, fibronectin, and serum eye drops are administered to treat dry eye syndrome, but their effectiveness is not yet sufficient. Therefore, the development of effective treatments for dry eye syndrome has been necessary. These treatments are only palliative, and products approved by the US FDA include Restasis®, Xiidra®, CEQUA®, Tyrvaya®, and Eysuvis®. Restasis® (cyclosporine ophthalmic emulsion, 0.05%), an immunosuppressant that inhibits calcineurin, and Xiidra® (lifitegrast ophthalmic solution, 5%), which binds to adhesion molecules on the surface of T cells and blocks T cell activation, are widely used. However, most of these drugs cause side effects including ocular irritation, taste abnormalities, pain at the site of eye instillation, and conjunctival congestion. Therefore, there is a need for therapeutic agents with minimal or no side effects and high patient compliance to treat ocular inflammatory conditions such as DED, and for this purpose, there has been a need for the development of ophthalmic agents that include aspects such as pH and osmotic pressure.

[0008] Meanwhile, imatinib, better known as Gleevec, is a leukemia treatment drug and is used to treat chronic myeloid leukemia (CML). It was developed by Novartis in Switzerland. Imatinib selectively inhibits the activity of tyrosine kinase, which is produced by the Philadelphia gene (an oncogene created by a chromosomal translocation of the Bcr and Abl genes), a primary cause of chronic myeloid leukemia. Furthermore, imatinib is known to be effective not only against chronic myeloid leukemia but also against gastrointestinal stromal tumors (GIST), a type of gastric cancer. Imatinib also has derivatives, such as imatinib mesylate, which are only soluble at pH levels below 5.5, making them unsuitable for use as eye drops administered directly into the eye.

[0009] Imatinib also binds to the discoidin domain receptor (DDR), a tyrosine kinase, and DDR1 is expressed on activated T cells and the corneal epithelium. In a rat dry eye model, topical application of imatinib mesylate inhibited inflammatory cell recruitment to dry eye lesions and ocular surface damage. Furthermore, in a rabbit model of dry eye, imatinib mesylate exhibited anti-inflammatory effects in the cornea and suppressed goblet cell damage caused by dry eye, demonstrating a therapeutic effect in dry eye.

[0010] Accordingly, the inventors of the present invention have completed the present invention by confirming that when sulfobutyl ether beta cyclodextrin is combined with an imatinib derivative, the properties and long-term stability are maintained without long-term precipitation formation within a biocompatible pH range, and the bioavailability and ophthalmic sensation are improved.

[0011]

[0012] One aspect of the present invention is to provide an ophthalmic composition having improved stability, bioavailability and eye irritation, including an imatinib derivative and sulfobutylether beta cyclodextrin (SBE-β-CD), and a method for preparing the same.

[0013]

[0014] One aspect of the present invention provides an ophthalmic composition comprising an imatinib derivative and sulfobutylether beta cyclodextrin (SBE-β-CD).

[0015] In one specific example of the present invention, the imatinib derivative may be at least one of imatinib, imatinib mesylate, N-desmethyl imatinib, imatinib hydrochloride, imatinib acid, imatinib caffeic acid, imatinib ferulic acid, imatinib p-coumaric acid, imatinib 4-benzoic acid, imatinib acetate, imatinib dichloroacetate, imatinib regioisomer, and imatinib carbaldehyde.

[0016] In one specific example of the present invention, the imatinib derivative may be contained in an amount of 0.3 to 4.0 mg / mL and the sulfobutyl ether beta cyclodextrin may be contained in an amount of 5 to 20 mg / mL.

[0017] In one specific example of the present invention, the ophthalmic composition may have a pH of 5.5 to 7.0.

[0018] In one specific example of the present invention, the ophthalmic composition may be used for the prevention or treatment of dry eye or ophthalmic diseases related to dry eye.

[0019] Another aspect of the present invention provides a method for treating dry eye or an ophthalmic disease associated with dry eye, comprising administering the composition to a patient with dry eye or an ophthalmic disease associated with dry eye.

[0020] Another aspect of the present invention provides a use of the composition for preparing a composition for preventing or treating dry eye or an ophthalmic disease associated with dry eye.

[0021]

[0022] The present invention provides a formulation that is more suitable for ophthalmic administration because it can be prepared at a pH level suitable for ophthalmic administration while dissolving an appropriate amount of an imatinib derivative even in a relatively high pH range, and has excellent long-term stability, compared to conventional compositions that are prepared under pH conditions (< pH 5.5) that are unsuitable for ophthalmic administration to dissolve imatinib.

[0023] The composition of the present invention has a transparent appearance, excellent long-term stability, maintains excellent eye drop sensation when applied to the eye, and has excellent bioavailability such as ocular tissue residence time and residual amount of imatinib methylate, and has no side effects such as eye irritation, foreign body sensation, and blurred vision, so that it can be usefully used for the prevention or treatment of dry eye or symptoms related thereto.

[0024]

[0025] Figure 1 shows the results of observation of the properties of Formulation 12 of Experimental Example 1 after one week under accelerated harsh storage conditions.

[0026] Figure 2 is a drawing illustrating a manufacturing process of an eye drop composition of the present invention.

[0027] Figure 3 is a representative chromatogram result of content analysis of a formulation prepared using the ophthalmic composition of the present invention.

[0028]

[0029] One aspect of the present invention provides an ophthalmic composition comprising an imatinib derivative and sulfobutylether beta cyclodextrin (SBE-β-CD).

[0030] The above imatinib derivatives include not only imatinib but also pharmaceutically acceptable salts, isomers, etc. of imatinib, and specifically, the above imatinib derivatives include imatinib, imatinib mesylate, N-desmethyl imatinib, imatinib hydrochloride, imatinib acid, imatinib caffeic acid, imatinib ferulic acid, imatinib p-coumaric acid, imatinib 4-benzoic acid, imatinib acetate, imatinib dichloroacetate, imatinib regioisomer, and imatinib carbaldehyde. It can be one or more of carbaldehyde.

[0031] The above “Imatinib” is well known as the leukemia treatment drug Gleevec, and is a treatment for chronic myeloid leukemia (CML) and was developed by Novartis of Switzerland. Imatinib selectively inhibits the activity of tyrosine kinase produced by the Philadelphia gene (an oncogene produced by chromosomal translocation of the Bcr gene and the Abl gene) and its structure is as shown in the following chemical formula 1.

[0032]

[0033] The above sulfobutylether beta cyclodextrin (SBE-β-CD) is a derivative of cyclodextrin. Cyclodextrin is a cyclic oligosaccharide used to improve the solubility and bioavailability of pharmaceuticals. Sulfobutylether beta cyclodextrin is sold by CyDex under the product name Captisol and is registered in the FDA Drug Master Files (DMF) as type IV (captisol CMC) and type V (captisol safety studies), and its structure is as shown in chemical formula 2.

[0034]

[0035] The above sulfobutyl ether beta cyclodextrin is used as a substance for improving the solubility of imatinib derivatives in the present invention. In particular, imatinib, particularly imatinib mesylate, has been known to be highly soluble in water, but this is limited to when the pH is lower than 5.5 (0.0146 mg / mL), and therefore, there was an aspect of it being inappropriate to directly utilize imatinib as an eye drop that is directly administered to the eye. However, the inventor of the present invention confirmed that the solubility of imatinib was improved in a relatively high pH range by adding the above-mentioned sulfobutyl ether beta cyclodextrin, and confirmed that it was an appropriate pH range for utilization as an eye drop (Experimental Example 1).

[0036] In one specific example of the present invention, the imatinib derivative may be 0.3 to 4.0 mg / mL, more specifically 0.5 to 3.0 mg / mL, and the sulfobutyl ether beta cyclodextrin may be 5 to 20 mg / mL, more specifically 10 to 17 mg / mL. As an example, the imatinib derivative may be 0.5, 1.0, or 3.0 mg / mL, and the sulfobutyl ether beta cyclodextrin may be 15.0 mg / mL. If the imatinib derivative is included outside the above range, the ophthalmic composition of the present invention may not achieve the desired effect or may cause toxicity, and if the sulfobutyl ether beta cyclodextrin is included outside the above range, the desired improved solubility may not be achieved or toxicity may occur.

[0037] As described above, the present invention can produce an ophthalmic composition having a relatively high pH by improving the solubility of an imatinib derivative by including sulfobutyl ether beta cyclodextrin, and as one specific example of the present invention, the ophthalmic composition can provide an ophthalmic composition having a pH of 5.5 to 7.0, more specifically, a pH of 6 to 6.5, and as an example, a pH of 6.2.

[0038] This can improve problems caused by the relatively low pH of conventional eye drops.

[0039] As one specific example of the present invention, the ophthalmic composition may be used for the prevention or treatment of dry eye or ophthalmic diseases associated with dry eye.

[0040] The above "dry eye disease" is also called dry eye or keratoconjunctivitis sicca, and refers to an eye disease in which the surface of the eye is damaged and the eyes feel irritated, sore, and feel a foreign body sensation, and dryness due to insufficient tears, excessive evaporation of tears, or an imbalance in the composition of tears.

[0041] In the present invention, “dry eye-related ophthalmic diseases” may include dry keratoconjunctivitis, corneal ulcer due to dryness, blepharitis (inflammation of the eyelid), eye congestion, and corneal neovascularization.

[0042] In the present invention, dry eye is characterized as aqueous tear-deficient dry eye or evaporative dry eye.

[0043] In the present invention, "aqueous tear-deficiency dry eye" means dry eye in which symptoms are caused by a lack of tears themselves or one component of tears, which causes the ocular surface to dry out, and "evaporative dry eye" means a disease in which symptoms are caused by a phenomenon in which the tear film evaporates excessively, so that the tear film does not sufficiently lubricate the ocular surface, causing the ocular surface to dry out, resulting in discomfort and irritation.

[0044] The ophthalmic composition of the present invention may additionally include a thickener, taking into account the purpose of the eye drop. The thickener in the present invention refers to a pharmaceutical or edible thickener commonly used in the art, and includes, but is not limited to, chitosan, hyaluronic acid, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), polyvinylpyrrolidone (PVP), carboxymethylcellulose (CMC), carbomer, glycerin, polyethylene oxide (PEO), hyaluronic acid, and the like.

[0045] The eye drop of the present invention additionally comprises a carrier comprising an aqueous solution, and is characterized in that it is in a liquid state, and the carrier comprising the aqueous solution is characterized in that it is at least one pharmaceutically acceptable carrier selected from the group consisting of distilled water, a phosphate buffer solution, a balanced salt solution, and physiological saline.

[0046] The ophthalmic composition of the present invention may also include a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not significantly stimulate a living organism and does not inhibit the biological activity and properties of the administered active ingredient. Examples of the pharmaceutically acceptable carrier include isotonic agents, buffers, stabilizers, pH adjusters, and solvents. The solvent may include distilled water, phosphate buffered saline, a balanced salt solution, saline, or a mixture thereof. The content used in this case needs to be adjusted according to the amount required for the total capacity of the ophthalmic composition to be manufactured. That is, in the case of an eye drop, the amount used is adjusted with a solvent in addition to the ophthalmic composition in the total ophthalmic solution. The ophthalmic composition according to the present invention is preferably in the form of a liquid formulation. The ophthalmic drop of the present invention is characterized in that it is used for the treatment of dry eye syndrome or ocular diseases related to dry eye syndrome.

[0047] The ophthalmic composition of the present invention is characterized by being administered topically or by ophthalmic administration.

[0048] In the present invention, the term "administration" means introducing the pharmaceutical composition of the present invention to a patient by any appropriate method, and the administration route of the composition of the present invention may be administered through various routes, such as oral or parenteral, as long as it can reach the target tissue. Preferably, it is administered topically to the eye. The treatment method utilizing the composition of the present invention includes administering imatinib in a pharmaceutically effective amount. It is obvious to a person skilled in the art that an appropriate total daily dosage can be determined by treatment within the scope of sound medical judgment. It is preferable that a specific therapeutically effective amount for a specific patient be applied differently depending on various factors, including the type and degree of the response to be achieved, the specific composition including whether other agents are used in some cases, the patient's age, weight, general health condition, sex, and diet, the time of administration, the route of administration and the secretion rate of the composition, the treatment period, drugs used together or concurrently with the specific composition, and similar factors well known in the medical field.

[0049] Although the present invention is originally intended for use in humans, it may also be used for other mammals such as dogs and cats for veterinary purposes.

[0050] The dosage unit may contain, for example, 1, 2, 3 or 4 times the individual dosage, or 1 / 2, 1 / 3 or 1 / 4 times the individual dosage. The individual dosage preferably contains the amount of effective drug administered in one dose (1-2 drops, 50 μL per drop), which usually corresponds to all, 1 / 2, 1 / 3 or 1 / 4 times the daily dosage. The effective dose of imatinib is concentration-dependent, but is preferably 0.005 to 5 wt%, more preferably 0.01 to 1 wt%, and can be administered 1 to 6 times daily.

[0051]

[0052] Another aspect of the present invention provides a method for treating dry eye or an ophthalmic disease associated with dry eye, comprising administering the composition to a patient with dry eye or an ophthalmic disease associated with dry eye.

[0053] Another aspect of the present invention provides a use of the composition for preparing a composition for preventing or treating dry eye or an ophthalmic disease associated with dry eye.

[0054]

[0055] Hereinafter, one or more specific examples will be described in more detail through examples. However, these examples are provided for illustrative purposes only and the scope of the present invention is not limited to these examples.

[0056]

[0057] Manufacturing Example 1: Manufacturing of the ophthalmic composition of the present invention

[0058] An ophthalmic composition of the present invention was prepared. Specifically, the main ingredient was added to sterile purified water (or water for injection) in an amount corresponding to 80% or more of the total manufacturing volume in the amount shown in Table 1, and then dissolved by stirring. When the main ingredient was completely dissolved, a 1N hydrochloric acid solution as a pH adjuster was added dropwise while stirring to adjust the pH to 5.5 to 6.5. Sterile purified water (or water for injection) was added to the above solution to adjust the total volume to the total manufacturing volume. The solution obtained above was filtered through a Polyethersulfone (PES) Membrane Filter having 0.2 μm pores to prepare an ophthalmic composition of the present invention.

[0059] Ingredient classification Composition amount (mg / mL) 0.3% 0.1% Imatinib mesylate Active ingredient 3.0 1.0 Sulfobutyl ether beta-cyclodextrin Solubilizer 15.0 15.0 Sterile purified water (or water for injection) Solvent 1 mL 1 mL

[0060]

[0061] Experimental Example 1: Evaluation of solubility and stability of the ophthalmic composition of the present invention

[0062] 1-1. Selection of solubilizer and upward adjustment of target pH (pH 5.5 -> 7.0)

[0063] Each of the three cyclodextrin solubilizers was dissolved by stirring as prescribed in Tables 2 and 3, and then adjusted to the target pH of 7.0 to prepare a formulation.

[0064] Original dosage (mg / mL) Formulation number 12-112-212-313-113-214-117-117-219 Imatinib mesylate 3.0 3.0 3.0 3.0 3.0 3.0 3.0 0.5 1.0 3.0 HP-β-CD 15.0 -------- HP-γ-CD-15.0 ------- SBE-β-CD-- 15.0 15.0 15.0 15.0 15.0 15.0 15.0 15.0 Target pH 7.0 7.0 7.0 5.0 6.0 6.0 6.0 6.0

[0065]

[0066] After one week of storage at 40℃ and 50℃, the results of observation of the properties showed that Formulations 12-1 and 12-2 produced a large amount of sediment under all conditions, and Formulation 12-3 produced a small amount of sediment only under the 50℃ condition. The changes in the properties of Formulation 12 are shown in Table 3 and Figure 1.

[0067] Preparation storage conditions Characteristics Initial 1 Main preparation 12-1 Accelerated (40℃) Colorless, transparent, produces a lot of sediment Harsh (50℃) Colorless, transparent, produces a lot of sediment Preparation 12-2 Accelerated (40℃) Colorless, transparent, produces a lot of sediment Harsh (50℃) Colorless, transparent, produces a lot of sediment Preparation 12-3 Accelerated (40℃) Colorless, transparent, colorless, transparent Harsh (50℃) Colorless, transparent, produces a little sediment

[0068]

[0069] As shown in Table 3 and Fig. 1, when SBE-β-CD was added as a solubilizer, the stability of the properties was the best, so SBE-β-CD was finally selected as a solubilizer, and it was confirmed through the results of Formulation 12-3 that the pH needed to be adjusted to a slightly lower value than pH 7.0.

[0070]

[0071] 1-2. pH adjustment (pH 7.0 -> 5.0 to 6.5)

[0072] To confirm the stability of the properties according to pH, formulations 13-1, 13-2, and 14-1 were manufactured by mixing as shown in Table 2 and adjusting to the target pH of 5.0, 6.0, or 6.5.

[0073] The changes in the properties of the manufactured preparations according to storage conditions are shown in Table 4.

[0074] Preparation storage conditions Characteristics Initial 1 week 2 weeks Preparation 13-1 Accelerated (40℃) Colorless transparent Colorless transparent Colorless transparent Colorless transparent Colorless transparent Colorless transparent Preparation 13-2 Accelerated (40℃) Colorless transparent Colorless transparent Colorless transparent Colorless transparent Colorless transparent Colorless transparent Colorless transparent Preparation 14-1 Accelerated (40℃) Colorless transparent Colorless transparent Colorless transparent Colorless transparent Colorless transparent Colorless transparent Colorless transparent Colorless transparent Colorless transparent Colorless transparent Colorless transparent

[0075]

[0076] As a result, the properties of the preparations remained stable without any precipitation at pH 5.0 to 6.5 for up to two weeks of storage at temperatures of 40°C and 50°C.

[0077]

[0078] 1-3. Application test according to change in main ingredient activity

[0079] In order to test the application of the formulation according to the change in the potency of the main ingredient of the composition of the present invention by 0.05% and 0.1%, respectively, Formulations 17-1 and 17-2 were prepared as shown in Table 2.

[0080] The content, pH, and osmotic pressure results of Formulation 17 immediately after manufacturing are shown in Table 5.

[0081] Formulation content (%) pH osmolality (mOsm / kg) Formulation 17-1 (0.05%) 101.06.01313 Formulation 17-2 (0.1%) 101.66.02314

[0082]

[0083] Quality testing results showed no significant changes in appearance, content, pH, or osmotic pressure. Therefore, the developed formulation was confirmed to be stable regardless of changes in the concentration of the main ingredient.

[0084]

[0085] Experimental Example 2: Stability Test of the Composition of the Present Invention

[0086] Formulation 19 was prepared in three batches as shown in Table 2 with the final selected formulation and target pH 6.0, and a 6-month long-term and accelerated stability test was conducted.

[0087] The results of long-term and accelerated stability tests of Formulation 19 are shown in Table 9.

[0088] All three batches were confirmed to be stable under long-term and accelerated stability testing conditions for six months, with no significant changes in appearance, pH, osmotic pressure, content, or flexible substances compared to the initial test results. Based on these results, the developed composition demonstrated excellent stability in maintaining the physicochemical properties of imatinib, the main ingredient, in ophthalmic formulations.

[0089] Formulation 19 Initial long-term stability (25±2 ℃ / 40±5%RH) Accelerated stability (40±2 ℃ / 25%RH or less) Test item Batch number 1 month 3 months 6 months 1 month 3 months 6 months Characteristics 1 Colorless to slightly yellow transparent liquid in a transparent plastic container Eye dropsNo changeNo changeNo changeNo changeNo change23pH16.146.156.176.146.156.156.0426.106.126.136.076.096.086.0136.086.116.086.036.076.055.96OsmolaritymOsm / kg13223203213223213243262321323322325322325328332132232 3323322325328 Content Test 1100.0% 101.3% 99.0% 101.3% 101.7% 99.5% 101.9% 2100.0% 101.6% 99.2% 101.5% 101.6% 98.9% 102.7% 399.6% 101.2% 99.1% 100.9% 101.6% 98.5% 101.8% Flexible Substance 1 Below Standard Below Standard Below Standard Below Standard Below Standard Below Standard Below Standard Below Standard Below Standard Below Standard Below Standard 23

[0090]

[0091] In addition, a pharmaceutical product for clinical trials was manufactured using the composition of the present invention, and a long-term stability evaluation was performed on the same, and the main test results are shown in Table 7.

[0092] Long-term stability evaluation of the manufactured drug confirmed that its properties, pH, and osmotic pressure remained stable for the 36-month shelf life. Furthermore, as shown in Table 7 and Figure 3, which displays a representative chromatogram from the content test using HPLC analysis, the results of the content of the main ingredient, imatinib, and related substances demonstrated that this formulation was excellent for maintaining the stability of the main ingredient.

[0093]

[0094]

[0095] Experimental Example 3: Pharmacokinetic Analysis in Ocular Tissue

[0096] In order to confirm the effect of increasing the biological half-life of the ophthalmic composition of the present invention, pharmacokinetic analysis in ocular tissues using rabbits was conducted.

[0097] Specifically, after a single 50 mL drop administration of the test substance to each eye of a male New Zealand White Rabbit, the blood concentration and the concentration in the ocular tissues, the conjunctiva and cornea, were measured over time. In the case of Comparative Example 1, imatinib mesylate was administered by drop administration at a concentration of 0.5% (w / v) in 100 mM Tris buffer (pH 5.5), and in Example 1, 0.3% imatinib mesylate ophthalmic solution of the ophthalmic composition formulation No. 19 of the present invention was used for administration. Then, blood was collected through the jugular vein at set times from time 0 (before test substance administration) to 24 hours, and the animals were euthanized, and the eyes were enucleated to secure ocular tissues. In all of the above tests, 5 rabbits were used per timepoint.

[0098] The main pharmacokinetic parameters for ocular tissue in the above test results are shown in Table 8.

[0099] Parameter (Units)CorneaConjunctivaComparative Example 1Example 1Comparative Example 1Example 1Imatinib mesylate Dosage (mg / eye)0.250.150.250.15C max (ng / mg)24.87315.781.025.85t 1 / 2 (h)(L) 6.56(R) 6.8714.4(L) 9.55(R) 5.418.7AUC last (ng·h / mg)(L) 266.93(R) 282.36152.31(L) 7.95(R) 8.5718.96

[0100]

[0101] The above results confirmed that the composition of Example 1 of the present invention showed a significant increase in biological half-life in the cornea, which is the main etiological site of dry eye, compared to the composition of Comparative Example 1. In addition, as shown in Table 8, it was confirmed that the AUC and Cmax in the conjunctiva, which is the main site of dry eye, significantly increased, even though Example 1 had a relatively lower content of imatinib mesylate than Comparative Example 1. These results indicate that the bioavailability of imatinib mesylate in the target ocular tissues (cornea and conjunctiva) of dry eye was improved by the imatinib mesylate ophthalmic solution formulation of the present invention.

[0102]

[0103] Experimental Example 4: Measurement of local irritation and burning sensation in the eyes after eye drops

[0104] Using the ophthalmic composition of the present invention, local irritation and ocular burning sensation were measured in 16 normal subjects.

[0105] A total of 16 subjects were randomly assigned to Comparative Example 1 (placebo composition, 4 subjects), Example 1 (imatinib mesylate 0.1% of Preparation Example 1, 6 subjects), and Example 2 (imatinib mesylate 0.3% of Preparation Example 1, 6 subjects). From the day after assignment (Day 1), one drop was administered to each eye twice a day for a total of 7 days. (The recommended times for administering the eye drop composition were 9:00 AM (±1 hour) and 9:00 PM (±1 hour). However, on Day 7, it was administered only in the morning. Local irritation and ocular burning sensation were measured from Day 1 to Day 8.

[0106] 1) Local irritation evaluation

[0107] The frequency and proportion (%) of ocular symptoms (foreign body sensation, dry eye, stinging or pain, photophobia or photophobia, blurred vision, and unintentional tearing) in both eyes in response to local irritation were investigated at each time point and administration group. Subjective assessment of each local irritation symptom was evaluated using the Ocular Surface Disease Index (OSDI) according to the criteria in Table 9.

[0108] Score: Local irritation (foreign body sensation, dry eye, stinging or pain, photophobia or photophobia, blurred vision, unintentional tearing) 0: None of the time 1: Symptoms some of the time 2: Symptoms half of the time 3: Symptoms most of the time 4: Symptoms all of the time

[0109]

[0110] Day 1 (Pre-dose) Day 1 Day 2 Day 3 Day 5 Day 7 Day 8 Comparative Example 10000000 Example 10000000 Example 20000000

[0111] Local irritation rating % (foreign body sensation, dry eye, stinging or pain, photophobia or photophobia, unintentional tearing)

[0112]

[0113] As shown in Table 10, no symptoms such as foreign body sensation, dry eye, stinging or pain, photophobia or photophobia, and unintentional tearing were observed in any of the subjects.

[0114]

[0115] Day 1 (Pre-dose) Day 1 Day 2 Day 3 Day 5 Day 7 Day 8 Comparative Example 10000000 Example 1000001 (16.17)0 Example 20000000

[0116] Local irritation - blurred vision [n, (%)]

[0117] In the case of blurred vision during local stimulation, as shown in Table 14, one patient in Example 1 showed 'blurred vision' symptoms of 1 point (occasionally) in both eyes on Day 7. The reported 'blurred vision' symptom was not judged to be a clinically significant symptom because it was infrequent and was not accompanied by other symptoms related to dry eye.

[0118]

[0119] 2) Evaluation of eye burning sensation intensity

[0120] Subjective symptoms were evaluated using a visual analogue scale (VAS), which asks participants to indicate the intensity of the burning sensation in both eyes on a scale of 0 to 10 for each time point and administration group, and the results are shown in Table 12.

[0121] Day 1 (Pre-dose) Day 1 Day 2 Day 3 Day 5 Day 7 Day 8 Comparative Example 10.25 (0.50) 0.00 (0.00) 0.23 (0.45) 0.25 (0.50) 0.00 (0.00) 0.00 (0.00) 0.00 (0.00) Example 10.17 (0.41) 0.00 (0.00) 0.00 (0.00) 0.17 (0.41) 0.00 (0.00) 0.00 (0.00) 0.00 (0.00) Example 20.17(0.41)0.17(0.41)0.00(0.00)0.00(0.00)0.00(0.00)0.00(0.00)0.00(0.00)

[0122] Burning eye sensation[(Mean (SD)]

[0123] The intensity of ocular burning sensation evaluated by VAS was observed in 2 subjects in Comparative Example 1, 2 subjects in Example 1, and 1 subject in Example 2 on Day 1 (pre-dose), Day 1, Day 2, and Day 3, respectively. However, most of them were less than 1 point and did not last for more than a day. This was confirmed to be a very low level when referring to the results of clinical studies of other eye drops targeting healthy adults. Therefore, it was confirmed that the ophthalmic compositions of 0.1% and 0.3% imatinib mesylate had excellent ophthalmic comfort based on results such as ocular local irritation and burning sensation.

[0124]

[0125] The present invention has been described above, focusing on preferred embodiments thereof. Those skilled in the art will appreciate that the present invention can be implemented in modified forms without departing from its essential characteristics. Therefore, the disclosed embodiments should be considered illustrative rather than limiting. The scope of the present invention is set forth in the claims, not the foregoing description, and all differences within the scope equivalent thereto should be construed as being encompassed by the present invention.

Claims

1. An ophthalmic composition comprising an imatinib derivative and sulfobutylether beta cyclodextrin (SBE-β-CD).

2. In paragraph 1, An ophthalmic composition comprising at least one of the imatinib derivatives selected from the group consisting of imatinib, imatinib mesylate, N-desmethyl imatinib, imatinib hydrochloride, imatinib acid, imatinib caffeic acid, imatinib ferulic acid, imatinib p-coumaric acid, imatinib 4-benzoic acid, imatinib acetate, imatinib dichloroacetate, imatinib regioisomer, and imatinib carbaldehyde.

3. In paragraph 1, An ophthalmic composition comprising 0.3 to 4.0 mg / mL of the imatinib derivative and 5 to 20 mg / mL of sulfobutyl ether beta cyclodextrin.

4. In paragraph 1, The above ophthalmic composition is an ophthalmic composition having a pH of 5.5 to 7.

0.

5. In paragraph 1, The above ophthalmic composition is an ophthalmic composition for the prevention or treatment of dry eye or ophthalmic diseases related to dry eye.

6. A method for treating dry eye or an ophthalmic disease associated with dry eye, comprising administering the composition of paragraph 1 to a patient suffering from dry eye or an ophthalmic disease associated with dry eye.

7. Use of the composition of paragraph 1 for preparing a composition for preventing or treating dry eye or ophthalmic diseases related to dry eye.

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