Topical ophthalmic compositions

Abstract

A topical ophthalmic composition comprising a therapeutically effective amount of a muscarinic receptor antagonist as an active pharmaceutical ingredient and a semi-fluorinated alkane as a liquid carrier. The topical ophthalmic composition is used to treat eye diseases.

Description

[0001] This application claims priority to U.S. Provisional Application No. 63 / 089,263, filed October 8, 2020, and U.S. Non-Provisional Application No. 17 / 317,551, filed May 11, 2021, both of which are incorporated herein by reference as if fully set forth herein for all purposes. Technical Field

[0002] This invention relates to a topical ophthalmic composition of a muscarinic receptor antagonist dissolved in a semi-fluorinated alkane as a liquid carrier, wherein the atropine formulation is used to treat myopia. Background Technology

[0003] Atropine is an antimuscarinic compound and a competitive antagonist of muscarinic receptors. It has anti-parasympathetic effects. It is used for several indications, such as anticholinergic and bradycardia. In the eye, it has traditionally been used to dilate the pupil. Recently, low doses of atropine have been shown to slow the progression of myopia in young adults (Li 2019). For the indication of myopia, atropine has so far been approved in only a few countries.

[0004] Myopia, or nearsightedness, is a condition where a person can see objects up close clearly, but distant objects appear blurry. Myopia occurs when the eyeball is too long or the cornea (the transparent cover of the eye) is too curved, preventing distant objects from being properly focused on the retina. Myopia is the most common eye condition worldwide. Approximately 30% of the U.S. population is nearsighted. The cause of myopia is unknown. Genetics is thought to play a role. The development of myopia can be influenced by how a person uses their eyes. It can appear in school-aged children and progress until around age 20. However, myopia can also develop in adults due to visual stress or health conditions such as diabetes. Myopia may increase the risk of other eye diseases (Wu 2019).

[0005] Atropine solution (aqueous-based) formulations have been tested in multiple clinical trials and have been shown to slow the progression of myopia (Cooper 2018, Li 2019, Yam 2020). In aqueous-based formulations, atropine is readily degraded at neutral pH once the container is exposed to air, therefore the shelf life of the product at neutral pH is typically less than one year. Lower pH values ​​of 3–6 in formulations are used to improve the stability of atropine in solution (Berton 2020, Saito 2019). However, low pH is also known to cause intraocular irritation and discomfort.

[0006] This invention uses an organic liquid carrier to form a more stable and less irritating atropine formulation for ocular indications, particularly myopia. Summary of the Invention

[0007] In one embodiment, the topical ophthalmic composition comprises: a therapeutically effective amount of a muscarinic receptor antagonist as the active pharmaceutical ingredient, and a semi-fluorinated alkane as a liquid carrier. The topical ophthalmic composition treats eye diseases.

[0008] In another embodiment, the muscarinic receptor antagonist is selected from the group consisting of: atropine, pirenzepine, adecyl bromide, benzalkonium chloride, cyclopentolate, diphenhydramine, doxylamine, dimenhydrinate, bicyclic amine, dapoxetine, flavonoids, hydroxyzine, ipratropium, mebendazole, oxybutynin, propranolol, scopolamine, sofinacin, tropicamide, tiotropium bromide, trihexyphenidyl, and tolterodine.

[0009] In another implementation, the muscarinic receptor antagonist is atropine.

[0010] In another embodiment, atropine is in the form of a free base or a salt.

[0011] In another embodiment, the concentration of atropine in the form of a free base is from about 0.0001% to about 1.0% (w / w), preferably from about 0.001% to about 0.1% (w / w), more preferably from about 0.01% to about 0.1% (w / w).

[0012] In another embodiment, the semi-fluorinated alkane is a compound having the formula RFRH or having the formula RFRHRF, wherein RF is a perfluorinated hydrocarbon having 15 or fewer carbon atoms, and wherein RH is a nonfluorinated hydrocarbon having 15 or fewer carbon atoms.

[0013] In another embodiment, the semifluorinated alkane is selected from F4H5, F4H6, F6H4, F6H6, F6H8 and F6H10.

[0014] In another embodiment, the semi-fluorinated alkane is F6H8 (perfluorohexyloctane).

[0015] In another embodiment, the topical ophthalmic composition further includes an organic cosolvent selected from the group consisting of phenylethanol, ethanol, isopropanol, glycerin, propylene glycol, and polyethylene glycol.

[0016] In another embodiment, the organic co-solvent is ethanol or phenylethanol.

[0017] In another embodiment, the concentration of ethanol is about 1% (w / w) or less, for example, from 0.001% to 1% (w / w); or the concentration of phenylethanol is about 1% (w / w) or less, for example, from 0.001% to 1% (w / w).

[0018] In another embodiment, the topical ophthalmic composition is a non-aqueous solution, suspension, or emulsion.

[0019] In another embodiment, the atropine in the topical ophthalmic composition is chemically stable for at least 0.5 years, at least 1 year, or at least 2 years.

[0020] In another embodiment, the topical ophthalmic composition is suitable for topical application as an eye drop to a patient's eye.

[0021] In another embodiment, the topical ophthalmic composition causes minimal intraocular irritation.

[0022] In another implementation scheme, the eye disease is myopia.

[0023] In another embodiment, the topical ophthalmic composition slows the progression of myopia.

[0024] It is to be understood that the foregoing overview and the following detailed description are exemplary and explanatory, and are intended to provide further explanation of the invention as claimed.

[0025] Brief description of the attached figures

[0026] The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and form part of this specification, illustrate embodiments of the invention and, together with the description, serve to explain the principles of the invention.

[0027] In the attached diagram:

[0028] Figure 1 The chromatogram of atropine (tR: 12.947) standard solution is shown.

[0029] Figure 2 The pupillary dilation effect in rabbits was shown: CBT-009 = atropine F6H8 preparation, comparison substance = atropine aqueous preparation. Detailed Implementation

[0030] The embodiments of the present invention will now be described in detail, examples of which are shown in the accompanying drawings.

[0031] Muscarinic receptor antagonists are anticholinergic drugs that block the activity of muscarinic acetylcholine receptors. Muscarinic receptor antagonists may be atropine, pirenzepine, adecanoate, benzalkonium bromide, cyclopentolate, diphenhydramine, doxylamine, dimenhydrinate, bicyclicamine, dapoxetine, flavonoids, hydroxyzine, ipratropium, mebivelin, oxybutynin, propranolol, scopolamine, sofinaine, tropicamide, tiotropium bromide, trihexyphenidyl, or tolterodine. Preferably, the muscarinic receptor antagonist is atropine or pirenzepine. More preferably, the muscarinic receptor antagonist is atropine.

[0032] The topical ophthalmic composition of the present invention comprises a therapeutically effective amount of a muscarinic receptor antagonist, such as atropine. A therapeutically effective amount means an amount that effectively prevents the development of existing symptoms in the treated subject or alleviates existing symptoms. The determination of an effective amount is within the competence of those skilled in the art, particularly in accordance with the detailed disclosure provided herein.

[0033] Atropine solution (aqueous) formulations have previously been shown to be effective in treating myopia, particularly in reducing myopia progression (Li 2019, Wu 2019). Aqueous atropine sulfate monohydrate has been clinically tested at concentrations ranging from 0.01% to 1%, and all these doses have demonstrated efficacy in myopia treatment. Solution formulations have two drawbacks. First, atropine in the solution at a neutral pH is easily degraded once the container is exposed to air, therefore the shelf life of the product at neutral pH is typically less than one year. Furthermore, this instability of atropine in solution necessitates that the formulation be used within approximately one month. The second drawback is that low pH levels, such as those in the range of 3.5 to 6.0, used to reduce atropine degradation and increase product shelf life, can cause eye irritation or discomfort, as reported in patient adverse events.

[0034] This invention provides a solution that uses a semi-fluorinated alkane, specifically F6H8 (perfluorohexyloctane), as a liquid carrier to dissolve atropine in a composition, thereby eliminating two drawbacks of solution formulations. F6H8 is an amphiphilic liquid having two covalently bonded, immiscible portions (the hydrocarbon segment RH and the perfluorinated segment RF). Other relevant analogues used in the compositions of this invention may be F4H5 (perfluorobutylpentane), F4H6 (perfluorobutylhexane), F6H4 (perfluorohexylbutane), F6H6 (perfluorohexylhexane), and F6H10 (perfluorohexyldecane).

[0035] The structure of F6H8 is shown below.

[0036]

[0037] In some embodiments, the invention is based on studies described in the examples, which show that atropine can dissolve in F6H8 at sufficient concentrations to have biological efficacy. Formulations of atropine in F6H8 are stable for extended periods at room temperature and can be formulated into products with sufficient shelf life to achieve regulatory approval. In animal model studies, this formulation was non-irritating to the eyes when administered at concentrations higher than required for some indications.

[0038] Examples 1 and 2 demonstrate that a stable atropine formulation of approximately 0.0001% to 0.15% can be achieved in F6H8 with the addition of three cosolvents. Example 7 shows that, in a rabbit model, an equivalent dose of the organic formulation of atropine free base F6H8 achieves similar efficacy to the aqueous formulation of atropine sulfate monohydrate. Combined with the known efficacy of the aqueous formulation of 0.01-1%, this study indicates that an achievable concentration range of approximately 0.0001% to approximately 1.0% or 0.0001% to 1.0% (free base, w / w) in the F6H8 formulation, preferably approximately 0.001% to approximately 0.1% or 0.001% to 0.1%, and more preferably approximately 0.01% to approximately 0.1% or 0.01% to 0.1%, will also be effective.

[0039] Example

[0040] Example 1: Dissolution of atropine in F6H8

[0041] Methods: The preparation of free atropine base was studied according to the following procedure:

[0042] 1. Dissolve atropine

[0043] Add more than 4 mg of atropine powder to 4 mL of F6H8 or F6H8 containing 0.1% ethanol to produce approximately 1 mg / mL. Stir the preparation for 2 days.

[0044] 2. Preparation of HPLC samples

[0045] The above formulations were centrifuged and the supernatant was filtered through a 0.45-micron filter without further dilution. One sample was prepared for each solvent for HPLC analysis.

[0046] 3. Analyze HPLC samples

[0047] Samples were analyzed using RP-HPLC with an Agilent EclipsePlus C18 HPLC column (150 mm × 2.1 mm inner diameter) connected to a guard column (12.5 mm × 2.1 mm inner diameter) via gradient elution from 100% water to 100% acetonitrile at a flow rate of 0.2 mL / min. Chromatograms were monitored at UV 220 nm. The atropine peak was observed at a retention time of 12.947. Figure 1 As shown in the chromatogram.

[0048] result

[0049] The solubility of atropine in F6H8 alone was determined to be 129 μg / ml (0.0129% w / w). With the addition of 0.1% ethanol, the solubility was 171.5 μg / ml (0.0173% w / w). In this specific study, the free base form of atropine was used, whereas the monosulfate form was previously used in solution formulations approved for myopia treatment. The MW of the free base (83%) is equivalent to that of the monosulfate form of atropine solution. A 0.01% atropine monosulfate solution has previously shown clinical efficacy for myopia treatment and has been approved in several countries. This 0.01% atropine salt concentration is equivalent to a 0.0083% free base concentration. Because the maximum free base of atropine observed in F6H8 was 0.0129%, it is inferred that the F6H8 formulation delivers a sufficient amount of atropine to treat myopia. The observed concentration of 0.0129% was approximately 55% higher than the 0.0083% required for efficacy. Furthermore, it was observed that the concentration of atropine could be further increased by adding ethanol to the formulation. Adding only 0.1% ethanol increased solubility by 33%. Higher concentrations of ethanol could potentially further improve the solubility of atropine in F6H8. The concentrations of atropine in the F6H8 formulation are shown in Table 1.

[0050] Table 1: Concentration of atropine in F6H8 formulation

[0051] Sample Description Atropine in F6H8 Atropine in F6H8 containing 0.1% (v / v) ethanol Solubility (concentration) 129.0 μg / mL 171.5 μg / mL

[0052] Using a slightly different preparation method, excess atropine free base was added to 100% F6H8. The mixture was heated to 40°C and stirred for 15 minutes. After centrifugation and standing for 16 hours, the sample (sample ID 1379308) was aliquoted, and the concentration was measured to be 214.55 μg / mL. Further atropine free base was added, and stirring was continued for 66 hours. The sample (sample ID 140933) was then centrifuged, aliquoted, and the concentration was measured to be 219.47 μg / mL. Therefore, the saturated solubility of atropine free base in 100% F6H8 was determined to be 217.01 μg / mL by averaging the values ​​of 214.55 μg / mL and 219.47 μg / mL.

[0053] Atropine solubility can be improved by adding a solubilizing agent:

[0054] Further studies were conducted to determine the stable concentration of atropine when a solubilizer was added. As shown in Table 2, the addition of 0.25%, 0.50%, or 0.75% phenylethanol increased the solubility of atropine to 0.043%, 0.055%, or 0.085%, respectively; the addition of 0.25%, 0.5%, or 0.75% ethanol increased the solubility to 0.031%, 0.089%, or 0.108%, respectively; and the addition of 0.25%, 0.5%, 0.75%, or 2% isopropanol increased the solubility to 0.046%, 0.055%, 0.082%, or 0.153%, respectively. After each sample was serially diluted 10× in F6H8 with 0.75% solubilizer, the atropine formulation remained stable at concentrations as low as approximately 0.00008%.

[0055] Table 2 shows the concentrations of atropine in F6H8 with different types of cosolvents at various concentrations. Compositions using phenethyl alcohol as a cosolvent...

[0056]

[0057] Compositions using ethanol as a cosolvent

[0058]

[0059] Compositions using isopropanol as a cosolvent

[0060]

[0061]

[0062] Example 2: Atropine F6H8 formulation stabilizes over time

[0063] method

[0064] Atropine was dissolved in F6H8 as described in Example 1. The atropine content was measured by HPLC at 25°C for 1, 3, 6, 9, and 12 months. If the content remained at 90%–110% of the original content, the atropine in the formulation was defined as stable.

[0065] result

[0066] During the study period, atropine was stable as shown in Table 3 below.

[0067] Table 3: Stability of atropine in F6H8 formulation

[0068] Point in time (month) 1 3 6 9 12 Retain 90%-110% of the initial value (Yes / No) yes yes yes yes yes

[0069] Example 3: Atropine F6H8 formulation is a tolerable method in rabbit studies.

[0070] The ocular tolerability of atropine F6H8 formulation was evaluated in rabbits. The study design and evaluation are shown in Tables 4 and 5.

[0071] Table 4: Experimental Design

[0072] Group Animals and sex numbers right eye Left eye Dosage frequency 3 3F Carrier 0.01% atropine Four times a day, 4 hours apart

[0073] Table 5: Research Evaluation

[0074]

[0075] Results and Conclusions

[0076] Atropine formulations were well tolerated in rabbits, with no obvious irritation or discomfort.

[0077] Example 4: Stability of atropine in F6H8

[0078] 0.0125% atropine was prepared by dissolving an appropriate amount of free atropine base in 100% F6H8. The stability of the atropine formulation over time was evaluated at 25°C. Atropine was extracted twice with acetonitrile at 1, 2, and 3 months and quantified by HPLC as described in Example 1. Table 6 below shows that the atropine content remained stable for at least 3 months, with minimal variation from the target concentration. This first-disclosed example demonstrates the stability of the atropine formulation of the present invention at room temperature.

[0079] Table 6: Stability of 0.0125% atropine free base in 100% F6H8

[0080]

[0081] In another experiment, 0.01% atropine was dissolved in F6H8 and 0.25% phenylethanol. The stability of the atropine formulation over time was evaluated at 25°C and 40°C. At selected time points, atropine was extracted twice with acetonitrile and quantified by HPLC as described in Example 1. Table 7 below shows that the atropine content remained stable at days 32 and 84, with no significant change from the baseline of day 0. Similar results were obtained at room temperature and accelerated temperature. The stability at accelerated temperature indicates that the formulation can potentially be stored at room temperature for months or years without significant loss of atropine. This first disclosed example confirms the stability of the atropine formulation of the present invention for long-term storage at room temperature.

[0082] Table 7 shows the stability of atropine in F6H8 and 0.25% phenylethanol.

[0083]

[0084] Example 5: In vivo ocular tolerance in rabbits

[0085] Research Design:

[0086] Three female Dutch rabbits were administered 40 μL of the control (0.01% atropine sulfate monohydrate in physiological saline) to their right eye and 40 μL of 0.012% atropine free base in 0.25% phenylethanol (PEA) in F6H8 to their left eye, one drop per eye, twice daily, 12 hours apart, for 14 consecutive days. Ocular discomfort and irritation were observed in all animals before administration (once on different days) and daily after the last day of administration. Corneal examinations were performed on all animals once before administration (once) and once on day 1 and day 14 after the last day of administration. The day of the first administration was designated Day 1.

[0087] The eye stimulation scores on day 14 are shown in Table 8 below. Similar or better results were observed at other time points.

[0088] Table 8

[0089]

[0090] McDonald-Shadduck ratings (categories of positive scores) are shown in Table 9 below.

[0091] Table 9

[0092]

[0093] Conclusion: The atropine formulation was well tolerated in all animals. No significant eye irritation or conjunctivitis was observed in any animal. No test-product-related effects on body weight or food intake were observed in either species during the study period. No other test-product-related conjunctivitis was observed in any of the animals during the scheduled examinations. This example confirms the safety of the proposed novel atropine formulation for ocular use.

[0094] Example 6: In vivo ocular tolerance in dogs

[0095] Research Design

[0096] Three male beagle dogs were administered 40 μL of control (0.01% atropine sulfate monohydrate in physiological saline) to the right eye and 40 μL of 0.012% atropine free base in 0.25% phenylethanol (PEA) in LF6H8 to the left eye, one drop per eye, twice daily, 12 hours apart, for 14 consecutive days. Ocular discomfort and irritation were observed in all animals before administration (once on different days) and daily after the last day of administration. Corneal examinations were performed on all animals once before administration (once) and once on day 1 and day 14 after the last day of administration. The day of the first administration was designated Day 1.

[0097] The eye irritation scores on day 14 are shown in Table 10 below. Similar or better results were observed at other time points.

[0098] Table 10

[0099]

[0100] McDonald-Shadduck ratings (categories of positive scores) are shown in Table 11 below.

[0101] Table 11

[0102]

[0103] Conclusion: The atropine formulation was well tolerated in all animals. No significant eye irritation or conjunctivitis was observed in any animal. No test-product-related effects on body weight or food intake were observed in either species during the study period. No other test-product-related conjunctivitis was observed in any of the animals during the scheduled examinations. This example confirms the safety of the proposed novel atropine formulation for ocular use.

[0104] Example 7: In vivo pharmacological efficacy in a rabbit model

[0105] The pharmacological potency of atropine formulations in F6H8 and 0.25% phenylethanol was tested in a rabbit model. Potency was measured as pupillary dilation in normal, untested rabbits. Three concentrations (0.012%, 0.01%, and 0.08%) of the F6H8 formulation of atropine were compared with an aqueous formulation of 0.01% atropine, which is known to have a good pupillary dilating effect. One drop of each formulation was administered to the eye, and eye and pupil size were measured over the following 8 hours.

[0106] Research Design

[0107] Fifteen female Netherland Dwarf rabbits were divided into five groups of three animals each. The three female rabbits were randomly assigned to each group based on body weight using Provantis or Excel. Dosing was administered in two phases, Phase 1 and Phase 2.

[0108] In Phase 1, 40 μL of the test sample was administered to both eyes of each animal (see Table 12 below). The first day of administration was designated Day 1. Pupil size was measured in both eyes of all animals at baseline (30 minutes before administration) and at 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, and 8 h after administration on Day 1. The efficacy of the pupil size measurements was analyzed to determine which dose of atropine free base in the carrier was equivalent to the dose of 0.01% atropine sulfate monohydrate in physiological saline in the control group. Animals were allowed a 2-day interval.

[0109] In Phase 2, each animal was administered 40 μL of the test sample to both eyes for 14 days (see Table 13 below). The first day of administration in Phase 2 was designated as Day 4. Pupil size was measured in both eyes of all animals at baseline (30 minutes before administration), and at 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, and 8 h after administration on Day 4 and Day 17.

[0110] Table 12: Research Design for Phase 1

[0111]

[0112] Note: a Replacement animals (if any) will be included in the study report according to the testing facility SOP number. Loading agent: 0.25% phenylethanol in 1-(perfluorohexyl)octane.

[0113] Table 13: Research Design for Phase 2

[0114]

[0115] Note: a Replacement animals (if any) will be included in the study report in accordance with the testing facility SOP number.

[0116] b The equivalent dose was determined from the efficacy data of Phase 1. The optimized concentration of free atropine base in the carrier with equivalent efficacy to 0.01% atropine sulfate monohydrate in physiological saline is given.

[0117] Loading agent: 0.25% phenylethanol in 1-(perfluorohexyl)octane

[0118] result

[0119] like Figure 2 As shown, the F6H8 formulation of atropine increases pupil size with similar potency to its aqueous formulation. The 0.01% F6H8 formulation is slightly more effective than the aqueous formulation. This observation suggests that the novel atropine F6H8 is as effective as proven atropine formulations and could be used to treat diseases treated with aqueous formulations. Figure 2 The pupillary dilation effect was shown in rabbits. CBT-009 = atropine F6H8 preparation, and the comparative substance = atropine aqueous preparation.

[0120] Those skilled in the art will understand that various modifications and variations can be made to this invention without departing from the spirit or scope thereof. Therefore, this invention is intended to cover modifications and variations thereof, provided they fall within the scope of the appended claims and their equivalents.

[0121] References

[0122] Berton B,Chennell P,Yessaad M,Bouattour Y,Jouannet M,Wasiak M,SautouV.Stability of Ophthalmic Atropine Solutions for Child MyopiaControl.Pharmaceutics.2020Aug 17;12(8):E781.

[0123] Cooper J,Tkatchenko AV.A Review of Current Concepts of the Etiologyand Treatment ofMyopia.Eye Contact Lens.2018 Jul;44(4):231-247.

[0124] Li FF,Yam JC.Low-Concentration Atropine Eye Drops for MyopiaProgression.Asia Pac J Ophthalmol(Phila).2019 Sep-Oct;8(5):360-365.

[0125] Saito J,Imaizumi H,Yamatani A.Physical,chemical,and microbiologicalstability study of diluted atropine eye drops.J Pharm Health Care Sci.2019Dec 5;5:25.

[0126] Wu PC,Chuang MN,Choi J,Chen H,Wu G,Ohno-Matsui K,Jonas JB,CheungCMG.Update in myopia and treatment strategy of atropine use in myopiacontrol.Eye(Lond).2019 Jan;33(1):3-13.

[0127] Yam JC,Li FF,Zhang X,Tang SM,Yip BHK,Kam KW,Ko ST,Young AL,Tham CC,Chen LJ,Pang CP.Two-Year Clinical Trial of the Low-Concentration Atropine forMyopia Progression(LAMP)Study:Phase 2 Report.Ophthalmology.2020 Jul;127(7):910-919.

Claims

1. A topical ophthalmic composition comprising: A therapeutically effective amount of atropine as the active pharmaceutical ingredient; and Perfluorohexyl octane, i.e., F6H8, is used as a liquid carrier; The topical ophthalmic composition described herein is used to treat eye diseases.

2. The topical ophthalmic composition of claim 1, wherein the atropine is in free alkali form or salt form.

3. The topical ophthalmic composition of claim 2, wherein the concentration of atropine in the form of a free base is from 0.0001% to 1.0% w / w.

4. The topical ophthalmic composition of claim 3, wherein the concentration of atropine in the form of a free base is 0.001% to 0.1% w / w.

5. The topical ophthalmic composition of claim 3, wherein the concentration of atropine in the form of a free base is 0.01% to 0.1% w / w.

6. The topical ophthalmic composition according to any one of claims 1-5, further comprising an organic cosolvent selected from the group consisting of phenylethanol, ethanol, isopropanol, glycerol, propylene glycol and polyethylene glycol.

7. The topical ophthalmic composition of claim 6, wherein the organic co-solvent is ethanol or phenylethanol.

8. The topical ophthalmic composition of claim 7, wherein the concentration of ethanol is 1% w / w or less; or the concentration of phenylethanol is 1% w / w or less.

9. The topical ophthalmic composition according to any one of claims 1-5, wherein the topical ophthalmic composition is a non-aqueous solution, a suspension, or an emulsion.

10. The topical ophthalmic composition of claim 9, wherein the atropine in the topical ophthalmic composition is chemically stable for at least 0.5 years, at least 1 year, or at least 2 years.

11. The topical ophthalmic composition of any one of claims 1-5, wherein the topical ophthalmic composition is suitable for topical application as an eye drop to a patient's eye.

12. The topical ophthalmic composition of claim 11, wherein the topical ophthalmic composition causes minimal intraocular irritation.

13. The topical ophthalmic composition according to any one of claims 1-5, wherein the eye disease is myopia.

14. The topical ophthalmic composition of claim 13, wherein the topical ophthalmic composition slows the progression of myopia.

15. Use of the topical ophthalmic composition according to any one of claims 1-14 in the preparation of a medicament for treating eye diseases.

16. The use as described in claim 15, wherein the drug is in the form of eye drops.

17. The use as described in claim 15 or claim 16, wherein the eye disease is myopia.

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