Topical ophthalmic compositions

Abstract

To provide topical ophthalmic compositions of muscarinic receptor antagonists.SOLUTION: The topical ophthalmic composition comprises a muscarinic receptor antagonist as the active pharmaceutical ingredient and a medium chain triglyceride (MCT) or light liquid paraffin oil as the liquid vehicle. The muscarinic receptor antagonist is selected from the group consisting of atropine, pirenzepine, aclidinium bromide, benzatropine, cyclopentolate, diphenhydramine, doxylamine, dimenhydrinate, dicyclomine, darifenacin, flavoxate, hydroxyzine, ipratropium, mebeverine, oxybutynin, procyclidine, scopolamine, solifenacin, tropicamide, tiotropium, trihexyphenidyl and tolterodine.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 145,091, filed February 3, 2021, which is incorporated by reference for all purposes as if fully set forth herein.

[0002] (Technical field) The present invention relates to topical ophthalmic compositions of muscarinic receptor antagonists dissolved in medium chain triglycerides (MCT) or light liquid paraffin oil as a liquid vehicle, and formulations of atropine are used to treat myopia. [Background technology]

[0003] Atropine is an antimuscarinic compound, a competitive antagonist of muscarinic receptors, with antiparasympathetic activity and used for several indications, including anticholinergic intoxication and bradycardia. In the eye, atropine has traditionally been used to dilate the pupil. Recently, low-dose atropine has been shown to slow the progression of myopia in young adults (Li 2019). Atropine is currently approved for myopia treatment in only a few countries.

[0004] Myopia is a condition in which nearby objects appear clear but distant objects appear blurry. Myopia occurs when the eyeball is too long or the cornea (the clear front covering of the eyeball) is too curved to properly focus distant objects on the retina. Myopia is the most common eye disease in the world. Approximately 30 percent of the U.S. population is myopic. The etiology of myopia is unknown. Genetics is thought to play a role in myopia. The development of myopia can be influenced by how a person uses their eyes. Myopia develops in school-age children and can progress until around age 20. However, visual stress and health conditions such as diabetes can also lead to the development of myopia in adulthood. Myopia can increase the risk of other eye diseases (Wu 2019: Non-Patent Document 5).

[0005] Atropine solution (aqueous) formulations have been tested in multiple clinical trials and have proven to slow the progression of myopia (Cooper 2018: Non-Patent Document 2, Li 2019: Non-Patent Document 3, Yam 2020: Non-Patent Document 6). In aqueous formulations, atropine is easily degraded in neutral pH solutions when the container is open to air, so the shelf life of products at neutral pH is often less than one year. To increase the stability of atropine in solution, the pH of formulations has been lowered to 3–6 (Berton 2020: Non-Patent Document 1; Saito 2019: Non-Patent Document 4). However, low pH is also known to cause ocular irritation and discomfort. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Berton B, Chennell P, Yessaad M, BouattourY, Jouannet M, Wasiak M, Sautou V. Stability of Ophthalmic Atropine Solutions for Child Myopia Control.PharmaceutiCS.2020 Aug 17;12(8):E781. [Non-patent document 2] Cooper J,Tkatchenko AV.A Review of CurrentConcepts of the Etiology and Treatment of Myopia.Eye Contact Lens.2018 Jul;44(4):231-247. [Non-patent document 3] Li FF,Yam JC.Low-Concentration Atropine Eye Drops for Myopia Progression.Asia Pac J Ophthalmol(Phila).2019 Sep-Oct;8(5):360-365. [Non-patent document 4] Saito J, Imaizumi H, Yamatani A.Physical, chemical, and microbiological stability study of diluted atropine eye drops.J Pharm Health Care Sci.2019 Dec 5;5:25. [Non-Patent Document 5] Wu PC, Chuang MN, Choi J, Chen H, Wu G, Ohno-Matsui K, Jonas JB, Cheung CMG. Update in myopia and treatment strategy of atropine use in myopia control.Eye(Lond).2019 Jan;33(1):3-13. [Non-patent document 6] Yam JC,Li FF,Zhang Summary of the Invention [Problem to be solved by the invention]

[0007] In the present invention, an organic liquid carrier is used to create a more stable and gentler formulation of atropine for ophthalmic, particularly myopic, indications.

[0008] Additionally, atropine solutions have been used to produce cycloplegic refraction in a subject's eye, to produce pupil dilation in a subject's eye, to treat amblyopia (or lazy eye) in children, to reduce the symptoms of floaters, to treat or prevent painful ciliary spasms, or to treat the progression of myopia in pediatric subjects. [Means for solving the problem]

[0009] (Summary of the Invention) In one embodiment, the present invention provides a topical ophthalmic composition comprising a muscarinic receptor antagonist as an active pharmaceutical ingredient (API) and a liquid vehicle selected from the group consisting of medium chain triglycerides (MCT) and light liquid paraffin oil, wherein the topical ophthalmic composition treats an ophthalmic disease.

[0010] In other embodiments, the muscarinic receptor antagonist is selected from the group consisting of atropine, pirenzepine, aclidinium bromide, benztropine, cyclopentolate, diphenhydramine, doxylamine, dimenhydrinate, dicyclomine, darifenacin, flavoxate, hydroxyzine, ipratropium, mebeverine, oxybutynin, procyclidine, scopolamine, solifenacin, tropicamide, tiotropium, trihexyphenidyl, and tolterodine.

[0011] In another embodiment, the muscarinic receptor antagonist is atropine.

[0012] In another embodiment, the atropine is in the free base form or a salt form.

[0013] In another embodiment, the concentration of the atropine in free base form is from about 0.001% to about 0.1% (w / w).

[0014] In another embodiment, the atropine free base is incorporated into the MCT or incorporated into the light liquid paraffin.

[0015] In other embodiments, The MCT is a triglyceride of fatty acids, The fatty acid is selected from the group consisting of hexanoic acid, octanoic acid, decanoic acid, and dodecanoic acid.

[0016] In another embodiment, the topical ophthalmic composition further comprises a partially fluorinated alkane compound having the formula RFRH or RFRHRF, where RF is a perfluorinated hydrocarbon having 1 to 15 carbon atoms and RH is a non-fluorinated hydrocarbon having 1 to 15 carbon atoms.

[0017] In another embodiment, the weight ratio of the MCT or the light liquid paraffin oil to the partially fluorinated alkane is 99-1.

[0018] In another embodiment, the partially fluorinated alkane is selected from the group consisting of perfluorobutylpentane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10), preferably F6H8 (perfluorohexyloctane).

[0019] In other embodiments, the topical ophthalmic composition further comprises an organic co-solvent selected from the group consisting of phenethyl alcohol, ethanol, isopropanol, glycerol, propylene glycol, and polyethylene glycol, preferably, the organic co-solvent is phenethyl alcohol.

[0020] In another embodiment, the concentration of the phenethyl alcohol is from about 0.01% to about 1% (w / w).

[0021] In other embodiments, the topical ophthalmic composition is a non-aqueous solution, suspension, or emulsion.

[0022] In other embodiments, the atropine is chemically stable for at least 0.5 years, at least 1 year, or at least 2 years.

[0023] In another embodiment, the topical ophthalmic composition is adapted to be administered topically to the patient's eye as eye drops.

[0024] In another embodiment, the topical ophthalmic composition causes minimal irritation to the eye.

[0025] In another embodiment, the eye condition is myopia.

[0026] In another embodiment, the topical ophthalmic composition comprises: Slows the progression of myopia, Treating amblyopia in children Reduce the symptoms of floaters, or Treats or prevents painful ciliary muscle spasms.

[0027] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.

[0028] The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and, together with the description, serve to explain the principles of the invention. [The present invention 1001] 1. A topical ophthalmic composition comprising: a muscarinic receptor antagonist as an active pharmaceutical ingredient (API); a liquid vehicle selected from the group consisting of medium chain triglycerides (MCT) and light liquid paraffin oil; A topical ophthalmic composition for treating eye diseases. [The present invention 1002] 1001. A topical ophthalmic composition according to the present invention, comprising: 1. A topical ophthalmic composition, wherein the muscarinic receptor antagonist is selected from the group consisting of atropine, pirenzepine, aclidinium bromide, benztropine, cyclopentolate, diphenhydramine, doxylamine, dimenhydrinate, dicyclomine, darifenacin, flavoxate, hydroxyzine, ipratropium, mebeverine, oxybutynin, procyclidine, scopolamine, solifenacin, tropicamide, tiotropium, trihexyphenidyl, and tolterodine. [The present invention 1003] 1002. The topical ophthalmic composition of claim 1002, wherein said muscarinic receptor antagonist is atropine. [The present invention 1004] The topical ophthalmic composition of claim 1003, wherein said atropine is in free base form or salt form. [The present invention 1005] 1005. The topical ophthalmic composition of any of claims 1001 to 1004, wherein the concentration of atropine in free base form is from about 0.001% to about 0.1% (w / w). [The present invention 1006] The topical ophthalmic composition of the present invention 1004, wherein the atropine free base is incorporated into the MCT or the light liquid paraffin. [The present invention 1007] The MCT is a triglyceride of fatty acids, 1001. The topical ophthalmic composition of claim 1001, wherein said fatty acid is selected from the group consisting of hexanoic acid, octanoic acid, decanoic acid, and dodecanoic acid. [The present invention 1008] further comprising a partially fluorinated alkane compound; 1006 or 1007, the topical ophthalmic composition of invention 1006 or 1007, wherein said partially fluorinated alkane compound has the formula RFRH or RFRHRF, where RF is a perfluorinated hydrocarbon having 1 to 15 carbon atoms and RH is a non-fluorinated hydrocarbon having 1 to 15 carbon atoms. [The present invention 1009] 1008. The topical ophthalmic composition of the present invention, wherein the weight ratio of said MCT or said light liquid paraffin oil to said partially fluorinated alkane is 99 to 1. [The present invention 1010] 1008. A topical ophthalmic composition of the present invention, wherein said partially fluorinated alkane is selected from the group consisting of perfluorobutylpentane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10), preferably, said partially fluorinated alkane is F6H8 (perfluorohexyloctane). [The present invention 1011] further comprising an organic co-solvent; 1001. The topical ophthalmic composition of this invention, wherein the organic co-solvent is selected from the group consisting of phenethyl alcohol, ethanol, isopropanol, glycerol, propylene glycol, and polyethylene glycol, preferably, the organic co-solvent is phenethyl alcohol. [The present invention 1012] 1011. A topical ophthalmic composition according to claim 10, wherein the concentration of said phenethyl alcohol is from about 0.01% to about 1% (w / w). [The present invention 1013] The topical ophthalmic composition of any of claims 1001 to 1012, which is a non-aqueous solution, suspension, or emulsion. [The present invention 1014] 1014. The topical ophthalmic composition of any of claims 1001 to 1013, 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. [The present invention 1015] The topical ophthalmic composition of any of claims 1001 to 1014, adapted to be administered topically as eye drops to the eye of a patient. [The present invention 1016] 1016. The topical ophthalmic composition of any of claims 1001 to 1015, which causes only minor eye irritation. [The present invention 1017] 1016. The topical ophthalmic composition of any of claims 1001 to 1016, wherein said eye disease is myopia. [The present invention 1018] Slows the progression of myopia, Treating amblyopia in children Reduce the symptoms of floaters, or The topical ophthalmic composition of any of claims 1001 to 1016, for treating or preventing painful ciliary muscle spasms. [Brief explanation of the drawings]

[0029] [Figure 1] The chromatogram of atropine (tR: 12.947) standard solution is shown. [Figure 2] 1 shows the measured pupil size on day 7 after administration in Example 5. [Figure 3] 1 shows the measured pupil size on day 22 after administration in Example 5. DETAILED DESCRIPTION OF THE INVENTION

[0030] Reference will now be made in detail to the embodiments of the present invention, examples of which are illustrated in the accompanying drawings.

[0031] Muscarinic receptor antagonist is an anticholinergic agent that inhibits the activity of muscarinic acetylcholine receptor.The muscarinic receptor antagonist is atropine, pirenzepine, aclidinium bromide, benztropine, cyclopentolate, diphenhydramine, doxylamine, dimenhydrinate, dicyclomine, darifenacin, flavoxate, hydroxyzine, ipratropium, mebeverine, oxybutynin, procyclidine, scopolamine, solifenacin, tropicamide, tiotropium, trihexyphenidyl, or tolterodine.Preferably, the muscarinic receptor antagonist is atropine or pirenzepine.More preferably, the muscarinic receptor antagonist is atropine.

[0032] Medium-chain triglycerides (MCTs) are triglycerides of fatty acids. The fatty acids have fatty chains of 6 to 12 carbon atoms, such as hexanoic acid, octanoic acid, decanoic acid, and dodecanoic acid. MCTs can be a single triglyceride or a mixture of multiple triglycerides. A representative chemical structure of MCTs is shown below. [ka]

[0033] Light liquid paraffin oil (Paraffinum liquidum) is a refined mineral oil used in cosmetics and pharmaceuticals. It contains a mixture of liquid saturated hydrocarbons.

[0034] Partially fluorinated alkanes are amphiphilic liquids consisting of two immiscible moieties (a hydrocarbon segment and a perfluorinated segment) covalently bonded together. Examples of partially fluorinated alkanes include perfluorobutylpentane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10), with perfluorobutylpentane (F4H5), perfluorohexylhexane (F6H6), and perfluorohexyloctane (F6H8) being preferred.

[0035] The structure of F6H8 is shown below. [ka]

[0036] Atropine solution (aqueous) formulations have proven effective in treating myopia, particularly in slowing myopia progression. These solution formulations have two drawbacks. First, atropine at neutral pH in solution is prone to degradation when the container is open to air, often resulting in a shelf life of less than one year. Furthermore, this instability of atropine in solution necessitates use of the formulation within approximately one month. Second, low pH values, such as pH 3.5 to 6.0, used to limit atropine degradation for product shelf life, can cause irritation or discomfort to the human eye, as reported by patients. The term "about" refers to a range of +20% to -20%, +10% to -10%, or +5% to -5% of a value.

[0037] To overcome the two drawbacks of solution formulations, the present disclosure provides a composition that uses MCT or light liquid paraffin oil as a liquid vehicle to dissolve atropine. As shown in the examples, the present disclosure demonstrates that these vehicles can dissolve atropine in a concentration range sufficient to be effective in treating myopia.

[0038] In some embodiments, the present disclosure is based on studies described in the Examples showing that atropine can be dissolved in MCT or light liquid paraffin oil at concentrations sufficient to have biological effectiveness.

[0039] In some embodiments, a cosolvent and / or a partially fluorinated alkane is added to the formulation. The cosolvent may be, for example, phenethyl alcohol, ethanol, isopropanol, glycerol, propylene glycol, or polyethylene glycol. The cosolvent and the partially fluorinated alkane improve the solubility of atropine and the stability of the formulation over time. [Example]

[0040] Example 1: Dissolution of atropine in MCT or light liquid paraffin oil

[0041] Methods: The formulation of atropine free base was investigated using the following procedure.

[0042] 1. Dissolving atropine 4 mg of atropine powder is added to 4 mL of study solvent and the formulation is stirred for 2 days.

[0043] 2. HPLC Sample Preparation The above formulations were centrifuged and the supernatants were filtered through a 0.45 micron filter without further dilution. One sample was prepared from each solvent for HPLC analysis.

[0044] 3. HPLC Sample Analysis Samples were analyzed by RP-HPLC using an Agilent Eclipse Plus C18 HPLC column (150 mm x 2.1 mm ID) connected to a guard column (12.5 mm x 2.1 mm ID) with a gradient elution from 100% water to 100% acetonitrile at a flow rate of 0.2 ml / min. Chromatograms were monitored with UV at 220 nm. The atropine peak is at a retention time of 12:947, as shown in the chromatogram in Figure 1.

[0045] result The solubility of atropine free base in MCT or light liquid paraffin oil is shown in Table 1.

[0046] [Table 1]

[0047] Atropine free base was determined to be soluble in light liquid paraffin oil at 75 μg / ml (0.0075% w / w). Adding 0.1% ethanol to light liquid paraffin oil increased the solubility to 82 μg / ml, and adding 0.25% phenethyl alcohol to light liquid paraffin oil increased the solubility to over 100 μg / ml. Atropine free base was determined to be soluble in MCT at 3100 μg / ml (0.31% w / w). This particular study used the free base form of atropine; however, the monosulfate salt is already used in solution formulations approved for myopia. The molecular weight (MW) of the free base corresponds to 83% of that of the monosulfate form of atropine solution formulations. A 0.01% atropine monosulfate solution has already been shown to be effective in the clinic for the treatment of myopia and is approved in several countries. This 0.01% atropine salt concentration corresponded to a free base concentration of 0.0083%. Our observed solubility in MCT well exceeds that required for efficacy, and concentrations in light liquid paraffin are also within the effective range. In the present application, the concentration of atropine in its free base form may be about 0.001% to about 0.5% (w / w), or about 0.001% to about 0.1% (w / w), e.g., about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, or any range thereof.

[0048] Example 2: Miscibility of partially fluorinated alkanes in MCT or light liquid paraffin oil

[0049] The miscibility of F6H8, a partially fluorinated alkane, with MCT was tested at F6H8:MCT ratios of 1:99 to 99:1. The results showed that F6H8 was miscible with MCT at all ratios. The miscibility of F6H8, a partially fluorinated alkane, with light liquid paraffin oil was tested at F6H8:light liquid paraffin oil ratios of 1:99 to 99:1. The results showed that F6H8 was miscible with light liquid paraffin oil at all ratios.

[0050] Example 3: Atropine solubility in MCT and F6H8 formulations with and without co-solvents

[0051] The solubility of atropine in formulations of MCT and F6H8 with and without the co-solvent phenethyl alcohol was determined using formulation preparation and sample analysis methods similar to those described in Example 1. The results are summarized in Table 2.

[0052] [Table 2]

[0053] The data showed that atropine was well soluble in mixtures of MCT and F6H8 at various ratios, ranging from 10% MCT:90% F6H8 to 70% MCT:30% F6H8. The addition of the cosolvent phenethyl alcohol further improved the solubility of atropine in mixtures of MCT and F6H8. Compared to the solubility of atropine in 100% F6H8, the addition of MCT or the addition of MCT and the cosolvent phenethyl alcohol significantly improved the solubility of atropine.

[0054] Example 4: Stability of Atropine in Formulations of MCT and F6H8 with and without Co-solvents

[0055] Using formulation preparation and sample analysis methods similar to those described in Example 1, the stability of atropine at room temperature in formulations of MCT and F6H8 with and without the cosolvent phenethyl alcohol was monitored at baseline, 1 month, 2 months, and 3 months. The results are summarized in Tables 3-7.

[0056] [Table 3]

[0057] [Table 4] [Table 5]

[0058] [Table 6]

[0059] [Table 7]

[0060] Data showed that atropine at doses of 0.01%, 0.025%, and 0.05% was stable at room temperature for at least 3 months in formulations containing MCT, F6H8, and / or phenethyl alcohol.

[0061] Example 5: In vivo pharmacological and ocular toxicity studies in a rabbit model

[0062] The purpose of this study was to determine the pharmacological efficacy and potential ocular toxicity of an atropine formulation in 0.25% phenylethyl alcohol, 10% MCT, and 89.75% F6H8. Test substances were administered by topical eye drop to New Zealand White rabbits twice daily for 28 days. Pharmacological effects were measured as pupil dilation in normal, naive rabbits. Three concentrations of atropine in the formulation (0.01%, 0.025%, and 0.05%) were compared with that of an aqueous formulation containing 0.03% atropine sulfate, a salt known to have good pupil dilation effects. An atropine-free formulation served as the vehicle control for the study.

[0063] Test Design

[0064] The study design is shown in Table 8. Forty-eight rabbits (24 per sex) were randomly assigned to five groups to determine the toxicity of atropine when administered twice daily via topical eye drops for 28 days. The control group received vehicle. Animals were randomly assigned to groups based on body weight. The control and high-dose groups had six animals per sex per group, while the low-, mid-, and comparison groups had four animals per sex per group. The last surviving animals from the control and high-dose groups were assigned for evaluation of recovery.

[0065] [Table 8]

[0066] Atropine in vehicle or control or comparative substance alone was administered to the left eye of the animals by topical instillation twice daily, approximately 12 hours apart, for 28 days. The right eye was left untreated as a control. The left eye of the animals was administered 40 μL / eye by topical instillation.

[0067] The study included various in-life measurements, including survival rate, clinical findings, body weight, food consumption, ophthalmologic examination, intraocular pressure, electroretinography, as well as pharmacological evaluation of pupil size measurements. Additionally, necropsy macroscopic examination, gross observations, organ weight measurements, and histopathology were performed at the end of the study. The study followed Good Laboratory Practice (GLP).

[0068] result

[0069] Pharmacological Evaluation: During acclimation prior to the start of dosing, pupil size was measured in both eyes of all animals on three separate days to establish a baseline and confirm the animals' acclimation to the procedure. Results are shown in Figure 2 (pupillary size measurements on day 7 post-dose) and Figure 3 (pupillary size measurements on day 22 post-dose). Pupil size was measured in both eyes of all animals at baseline (30 minutes before dosing) and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the first dose on days 7 and 22. CBT-009 stands for atropine. Data showed pupil dilation in all three groups treated with 0.01%, 0.025%, and 0.05% CBT-009 (atropine), as well as in a comparison group treated with an aqueous formulation of 0.03% atropine sulfate, but no change in pupil size was observed in the vehicle-treated group. In addition, a dose-response of pupil dilation was observed for atropine from 0.01% to 0.05% on both days 7 and 22. The magnitude of change in pupil size was comparable between F6H8-based atropine formulations and aqueous atropine sulfate at comparable doses.

[0070] Ocular Toxicity: Male and female New Zealand White rabbits were administered twice-daily topical instillations of F6H8f-based formulations containing 0.01%, 0.025%, and 0.05% atropine, control vehicle, or a 0.03% aqueous atropine sulfate comparator solution to the left eye. The right eye was untreated. Following the end of the treatment period, terminal animals were euthanized, and recovery animals were maintained for a 14-day recovery period before being euthanized. All animals were maintained for a 14-day recovery period before being euthanized. All terminal and recovery animals survived until scheduled euthanasia. No atropine-related macroscopic (gross necropsy) or microscopic findings were noted in ocular or nonocular tissues at any time. A small number of microscopic findings in various ocular and non-ocular tissues in males and females in the control, atropine-treated, and / or comparison groups during both periods were considered incidental and unrelated to atropine. Treatment was well tolerated in all study groups, and no animal deaths were observed during the study.

[0071] Example 6: In vivo ocular tolerability testing in a rabbit model

[0072] Test Design

[0073] Three female Dutch-Belted rabbits received 40 μL of 100% MCT containing 0.012% atropine free base in the right eye and 40 μL of 100% light liquid paraffin (LLP) containing 0.012% atropine free base in the left eye, one drop per eye, twice daily, 12 hours apart, for 14 consecutive days. Observations for ocular discomfort and irritation were performed on all animals before administration (twice on different days) and daily during the administration phase after the final daily dose. Corneal examinations were performed on all animals once before administration and once after the final daily dose on days 1 and 14. The first administration day was designated D1, and the last administration day was designated D14.

[0074] The results for eye irritation are shown in Tables 9 and 10.

[0075] [Table 9]

[0076] [Table 10]

[0077] The atropine formulation was well tolerated in all rabbits. No significant eye irritation or ophthalmic findings were observed in any animal. There were no test substance-related effects on body weight and food consumption during the study. No other test substance-related ophthalmic findings were noted at scheduled examinations of all animals. No or only mild (+1) conjunctival swelling or hyperemia was observed during the study. This example demonstrates the safety of the claimed novel formulation of ophthalmic atropine.

[0078] Example 7: In vivo ocular tolerability testing in a dog model

[0079] Test Design

[0080] Three male beagle dogs received 40 μL of 100% MCT containing 0.012% atropine free base in the right eye and 40 μL of 100% LLP containing 0.012% atropine free base in the left eye, one drop per eye, twice daily, 12 hours apart, for 14 consecutive days. Observations for ocular discomfort and irritation were performed on all animals before administration (twice on different days) and daily during the administration phase after the final daily dose. Corneal examinations were performed on all animals once before administration and once after the final daily dose on days 1 and 14. The first administration day was designated D1, and the last administration day was designated D14.

[0081] The results of eye irritation are shown in Tables 11 and 12.

[0082] [Table 11]

[0083] [Table 12]

[0084] The atropine formulation was well tolerated in all dogs. No significant eye irritation or ophthalmic findings were observed in any animal. There were no test substance-related effects on body weight and food consumption during the study. No other test substance-related ophthalmic findings were noted at scheduled examinations of all animals. No or only mild (+1) conjunctival swelling or hyperemia was observed during the study. This example demonstrates the safety of the claimed novel formulation of ophthalmic atropine.

[0085] References 1.Berton B, Chennell P, Yessaad M, BouattourY, Jouannet M, Wasiak M, Sautou V. Stability of Ophthalmic Atropine Solutions for Child Myopia Control.PharmaceutiCS.2020 Aug 17;12(8):E781. 2.Cooper J,Tkatchenko AV.A Review of CurrentConcepts of the Etiology and Treatment of Myopia.Eye Contact Lens.2018 Jul;44(4):231-247. 3.Li FF,Yam JC.Low-Concentration Atropine Eye Drops for Myopia Progression.Asia Pac J Ophthalmol(Phila).2019 Sep-Oct;8(5):360-365. 4.Saito J, Imaizumi H, Yamatani A.Physical, chemical, and microbiological stability study of diluted atropine eye drops.J Pharm Health Care Sci.2019 Dec 5;5:25. 5.Wu PC,Chuang MN,Choi J,Chen H,Wu G,Ohno-Matsui K,Jonas JB, Cheung CMG. Update in myopia and treatment strategy of atropine use in myopia control.Eye(Lond).2019 Jan;33(1):3-13. 6.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 for Myopia Progression(LAMP)Study:Phase 2 Report.Ophthalmology.2020 Jul;127(7):910-919.

Claims

1. 1. A topical ophthalmic composition comprising: a muscarinic receptor antagonist as an active pharmaceutical ingredient (API); a liquid vehicle selected from the group consisting of medium chain triglycerides (MCT) and light liquid paraffin oil; A topical ophthalmic composition for treating eye diseases.

2. 10. The topical ophthalmic composition of claim 1, 1. A topical ophthalmic composition, wherein the muscarinic receptor antagonist is selected from the group consisting of atropine, pirenzepine, aclidinium bromide, benztropine, cyclopentolate, diphenhydramine, doxylamine, dimenhydrinate, dicyclomine, darifenacin, flavoxate, hydroxyzine, ipratropium, mebeverine, oxybutynin, procyclidine, scopolamine, solifenacin, tropicamide, tiotropium, trihexyphenidyl, and tolterodine.

3. 3. The topical ophthalmic composition of claim 2, wherein the muscarinic receptor antagonist is atropine.

4. 4. The topical ophthalmic composition of claim 3, wherein the atropine is in free base form or salt form.

5. 5. The topical ophthalmic composition of any one of claims 1 to 4, wherein the concentration of atropine in free base form is from about 0.001% to about 0.1% (w / w).

6. 5. The topical ophthalmic composition of claim 4, wherein the atropine free base is incorporated into the MCT or the light liquid paraffin.

7. The MCT is a triglyceride of fatty acids, 10. The topical ophthalmic composition of claim 1, wherein the fatty acid is selected from the group consisting of hexanoic acid, octanoic acid, decanoic acid, and dodecanoic acid.

8. further comprising a partially fluorinated alkane compound; 8. The topical ophthalmic composition of claim 6 or 7, wherein the partially fluorinated alkane compound has the formula RFRH or RFRHRF, where RF is a perfluorinated hydrocarbon having 1 to 15 carbon atoms and RH is a non-fluorinated hydrocarbon having 1 to 15 carbon atoms.

9. 9. The topical ophthalmic composition of claim 8, wherein the weight ratio of the MCT or the light liquid paraffin oil to the partially fluorinated alkane is 99 to 1.

10. 9. The topical ophthalmic composition of claim 8, wherein the partially fluorinated alkane is selected from the group consisting of perfluorobutylpentane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10), preferably, the partially fluorinated alkane is F6H8 (perfluorohexyloctane).

11. further comprising an organic co-solvent; 2. The topical ophthalmic composition of claim 1, wherein the organic co-solvent is selected from the group consisting of phenethyl alcohol, ethanol, isopropanol, glycerol, propylene glycol, and polyethylene glycol, preferably, the organic co-solvent is phenethyl alcohol.

12. 12. The topical ophthalmic composition of claim 11, wherein the concentration of the phenethyl alcohol is from about 0.01% to about 1% (w / w).

13. 13. The topical ophthalmic composition of any one of claims 1 to 12, which is a non-aqueous solution, suspension, or emulsion.

14. 14. The topical ophthalmic composition of any one of claims 1 to 13, 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.

15. 15. The topical ophthalmic composition of any one of claims 1 to 14, adapted to be administered topically as eye drops to the eye of a patient.

16. 16. The topical ophthalmic composition of any one of claims 1 to 15, which causes minimal eye irritation.

17. 17. The topical ophthalmic composition of any one of claims 1 to 16, wherein the eye disease is myopia.

18. Slows the progression of myopia, Treating amblyopia in children Reduce the symptoms of floaters, or 17. The topical ophthalmic composition of any one of claims 1 to 16, for treating or preventing painful ciliary muscle spasms.

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