Topical ophthalmic compositions

Abstract

A topical ophthalmic composition comprising a muscarinic receptor antagonist as an active pharmaceutical ingredient; and medium chain triglyceride (MCT) or light liquid paraffin oil as a liquid carrier. The topical ophthalmic composition treats ocular diseases.

Description

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

[0002] The present invention relates to topical ophthalmic compositions of muscarinic receptor antagonists dissolved in medium chain triglycerides (MCT) or light liquid paraffin as liquid vehicles, wherein the atropine formulation is used to treat myopia. Background Art

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

[0004] Myopia, or nearsightedness, is a condition in which a person can see close objects clearly, but objects that are far away appear blurry. Myopia occurs when the eyeball is too long or the cornea (the clear front cover of the eye) is too curved, so that distant objects cannot be focused correctly on the retina. Myopia is the most common eye condition worldwide. About 30% of the American population has myopia. The cause of myopia is unknown. Genetics are thought to play a role in myopia. Myopia development may be influenced by the way a person uses their eyes. It may appear in school-age children and progress until about 20 years of age. 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 (water-based) formulations have been tested in multiple clinical trials and have been shown to slow myopia progression (Cooper 2018, Li 2019, Yam 2020). In water-based formulations, atropine is easily degraded in neutral pH solutions once the container is exposed to air, and therefore, the shelf life of the product at neutral pH is generally less than 1 year. Low pH of 3-6 in the formulation is 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] The present invention uses an organic liquid carrier to form a more stable and less irritating atropine formulation for ocular use, particularly myopia indications.

[0007] Additionally, atropine solution is used to cause cycloplegic refraction in the eye of a subject, to cause pupil dilation in the eye of a subject, to treat amblyopia in a child, to relieve symptoms of vitreous floaters, to treat or prevent painful ciliary spasm, or to treat myopia progression in a pediatric subject. Summary of the invention

[0008] 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 carrier selected from the group consisting of medium chain triglycerides (MCT) and light liquid paraffin oil. The topical ophthalmic composition treats eye diseases.

[0009] In another embodiment, the muscarinic receptor antagonist is selected from the group consisting of atropine, pirenzepine, aclidinium bromide, benztropine, cyclopentolate, diphenhydramine, doxylamine, fentanyl, dicyclomine, darifenacin, flavoxate, hydroxyzine, ipratropium bromide, mebeverine, oxybutynin, procyclidine, scopolamine, solifenacin, tropicamide, tiotropium bromide, trihexyphenidyl and tolterodine.

[0010] In another embodiment, the muscarinic receptor antagonist is atropine.

[0011] In another embodiment, atropine is in free base form or in salt form.

[0012] In another embodiment, the concentration of atropine in free base form is from about 0.001% to about 0.1% (w / w).

[0013] In another embodiment, atropine free base is formulated in MCT or in light liquid paraffin.

[0014] In another embodiment, the MCT is a triglyceride of fatty acids, and the fatty acids are selected from the group consisting of caproic acid, caprylic acid, capric acid, and dodecanoic acid.

[0015] In another embodiment, the topical ophthalmic composition further comprises a semifluorinated alkane compound. The semifluorinated alkane compound has the formula RFRH or has the formula RFRHRF, RF is a perfluorinated hydrocarbon having 1 to 15 carbon atoms, and RH is a non-fluorinated hydrocarbon having 1 to 15 carbon atoms.

[0016] In another embodiment, the weight ratio of MCT or light liquid paraffin oil to semifluorinated alkane is 99 to 1.

[0017] In another embodiment, the semifluorinated alkane is selected from the group consisting of perfluorobutylheptane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8) and perfluorohexyldecane (F6H10); preferably, the semifluorinated alkane is F6H8 (perfluorohexyloctane).

[0018] In another embodiment, the topical ophthalmic composition further comprises an organic cosolvent. The organic cosolvent is selected from the group consisting of phenylethanol, ethanol, isopropyl alcohol, glycerol, propylene glycol and polyethylene glycol; preferably, the organic cosolvent is phenylethanol.

[0019] In another embodiment, the concentration of phenethyl alcohol is from about 0.01% to about 1% (w / w).

[0020] In another embodiment, the topical ophthalmic composition is a non-aqueous solution, suspension, or emulsion.

[0021] 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.

[0022] In another embodiment, the topical ophthalmic composition is suitable for topical administration to the patient's eye as eye drops.

[0023] In another embodiment, the topical ophthalmic composition causes minimal irritation in the eye.

[0024] In another embodiment, the ocular disease is myopia.

[0025] In another embodiment, the topical ophthalmic composition slows myopia progression, the topical ophthalmic composition treats amblyopia in children, the topical ophthalmic composition relieves symptoms of vitreous floaters, or the topical ophthalmic composition treats or prevents painful ciliary spasm.

[0026] 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.

[0027] BRIEF DESCRIPTION OF THE DRAWINGS

[0028] The accompanying drawings are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification. The drawings illustrate embodiments of the invention and together with the description serve to explain the principles of the invention.

[0029] In the attached picture:

[0030] Figure 1 A chromatogram of atropine (tR: 12.947) standard solution is shown.

[0031] Figure 2 Pupil size measurements at day 7 following dosing of Example 5 are shown.

[0032] Figure 3 Pupil size measurements at day 22 following dosing of Example 5 are shown. DETAILED DESCRIPTION

[0033] Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings.

[0034] Muscarinic receptor antagonists are anticholinergics that block the activity of muscarinic acetylcholine receptors. Muscarinic receptor antagonists can be atropine, pirenzepine, aclidinium bromide, benztropine, cyclopentolate, diphenhydramine, doxylamine, fentanyl, dicyclomine, darifenacin, flavoxate, hydroxyzine, ipratropium bromide, mebeverine, oxybutynin, procyclidine, scopolamine, solifenacin, tropicamide, tiotropium bromide, trihexyphenidyl or tolterodine. Preferably, the muscarinic receptor antagonist is atropine or pirenzepine. More preferably, the muscarinic receptor antagonist is atropine.

[0035] Medium chain triglycerides (MCT) are triglycerides of fatty acids. The fatty acids have aliphatic chains of 6-12 carbon atoms and can be, for example, caproic acid, caprylic acid, capric acid, and dodecanoic acid. MCT can be a single triglyceride or a mixture of triglycerides. A representative chemical structure of MCT is shown below.

[0036]

[0037] Light liquid paraffin oil (petrolatum) is a refined mineral oil used in cosmetics and medicines. It contains a mixture of liquid saturated hydrocarbons.

[0038] Semifluorinated alkanes are amphiphilic liquids with two covalently bonded immiscible parts (a hydrocarbon segment and a perfluorinated segment). Examples of semifluorinated alkanes include perfluorobutylpentane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8) and perfluorohexyldecane (F6H10); preferably, perfluorobutylpentane (F4H5), perfluorohexylhexane (F6H6) and perfluorohexyloctane (F6H8).

[0039] The structure of F6H8 is shown below.

[0040]

[0041] Atropine solution (water) preparation has previously been shown to be effective in treating myopia, particularly in alleviating myopia progression. Solution preparations have two drawbacks. The first is that atropine at a neutral pH in the solution is susceptible to degradation once the container is exposed to air, so the shelf life of the product is generally shorter than 1 year at a neutral pH. In addition, this instability of atropine in the solution requires the preparation to be used within about one month. The second disadvantage is that low pH such as in a pH range of 3.5 to 6.0, which is used to reduce atropine degradation to increase the shelf life of the product, may cause irritation or discomfort to the human eye, as reported by adverse events in patients. The term "about" means in the range of +20% to -20% of a value, +10% to -10% of a value, or +5% to -5% of a value.

[0042] The present invention provides a composition using MCT or light liquid paraffin oil as a liquid carrier to dissolve atropine to eliminate the two disadvantages of solution formulations. The present invention shown in the examples demonstrates that these carriers can dissolve atropine in a sufficient concentration range to be effective in myopia treatment.

[0043] In some embodiments, the present invention is based on studies described in the Examples showing that atropine can be dissolved in MCT or light liquid paraffin oil in sufficient concentrations to be biologically effective.

[0044] In some embodiments, a co-solvent and / or a semifluorinated alkane is added to the formulation. The co-solvent may be, for example, phenylethyl alcohol, ethanol, isopropyl alcohol, glycerol, propylene glycol, or polyethylene glycol. Co-solvents and semifluorinated alkanes increase the solubility of atropine and the stability of the formulation over a long period of time.

[0045] Example

[0046] Example 1: Atropine dissolved in MCT or light liquid paraffin oil

[0047] Methods: The preparation of atropine free base was studied according to the following procedure:

[0048] 1. Dissolve atropine

[0049] More than 4 mg of atropine powder was added to 4 mL of study solvent, and the formulation was stirred for 2 days.

[0050] 2. Preparation of HPLC Samples

[0051] The preparations were centrifuged and the supernatant was filtered through a 0.45 micron filter without further dilution. One sample was prepared from each solvent for HPLC analysis.

[0052] 3. Analysis of HPLC Samples

[0053] The samples were analyzed using the RP-HPLC method using an Agilent EclipsePlus C18 HPLC column (150 mm x 2.1 mm id) connected to a guard column (12.5 mm x 2.1 mm id) and a gradient elution from 100% water to 100% acetonitrile at a flow rate of 0.2 ml / min. The chromatogram was monitored at UV 220 nm. The atropine peak was at retention time 12.947, as Figure 1 Shown in the chromatogram.

[0054] result

[0055] The solubility of atropine free base in MCT or light liquid paraffin oil is shown in Table 1.

[0056] Table 1: Concentration of atropine in MCT or light liquid paraffin oil preparations

[0057] Formulation system and preparation procedure Measured concentration (μg / mL) Saturated Atropine Free Base in Light Paraffin Oil 75 Saturated atropine free base in paraffin oil with 0.1% ethanol 82 Atropine free base in paraffin oil with 0.25% phenylethanol >100 Saturated Atropine Free Base in MCT 3100

[0058] Atropine free base was determined to be soluble in light liquid paraffin oil at 75 μg / ml (0.0075% w / w). The addition of 0.1% ethanol to light liquid paraffin oil increased the solubility to 82 mg / ml, and the addition of 0.25% phenylethanol 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). In this specific study, the free base form of atropine was used, whereas the monosulfate salt was previously used in solution formulations approved for myopic use. The MW 83% of the free base is equivalent to atropine monosulfate salt form solution formulation. A 0.01% atropine monosulfate solution has previously been shown to be clinically effective for the treatment of myopia and has been approved in several countries. This 0.01% atropine salt concentration is equivalent to a free base concentration of 0.0083%. The solubility observed in MCT is much higher than that required for efficacy, and the concentration in light liquid paraffin is also within the efficacy range. In the present application, the concentration of atropine in the free base form can be about 0.001% to about 0.5% (w / w), or about 0.001% to about 0.1% (w / w), for example, 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.

[0059] Example 2: Miscibility of Semifluorinated Alkanes with MCT or Light Liquid Paraffin Oil

[0060] The miscibility of semifluorinated alkane F6H8 with MCT was tested at a ratio of F6H8 to MCT of 1:99 to 99:1. The results showed that F6H8 was miscible with MCT at all ratios. The miscibility of semifluorinated alkane F6H8 with light liquid paraffin oil was tested at a ratio of F6H8 to light liquid paraffin oil of 1:99 to 99:1. The results showed that F6H8 was miscible with light liquid paraffin oil at all ratios.

[0061] Example 3: Solubility of atropine in formulations of MCT and F6H8 with or without cosolvents

[0062] Using similar formulation preparation and sample analysis methods as described in Example 1, the solubility of atropine in formulations of MCT and F6H8 with or without the co-solvent phenylethanol was determined, and the results are summarized in Table 2.

[0063] Table 2: Solubility of atropine in formulations containing MCT, F6H8 and phenylethanol

[0064] preparation Measured concentration (μg / mL) 10% MCT, 90% F6H8 600 15% MCT, 85% F6H8 600 20% MCT, 80% F6H8 600 50% MCT, 50% F6H8 1500 70% MCT, 30% F6H8 3000 0.25% Phenylethanol, 10% MCT, 89.75% F6H8 1200 0.5% phenylethanol, 10% MCT, 89.5% F6H8 2500 100% F6H8 133

[0065] The data show that atropine is well soluble in a mixture of MCT and F6H8 at various ratios of MCT:F6H8 from 10% MCT and 90% F6H8 to 70% MCT and 30% F6H8. Addition of the cosolvent phenylethanol further increases the solubility of atropine in a mixture of MCT and F6H8. The solubility of atropine is greatly increased when MCT or MCT and the cosolvent phenylethanol are added compared to the solubility of atropine in 100% F6H8.

[0066] Example 4: Stability of atropine in formulations of MCT and F6H8 with or without cosolvents

[0067] Using similar formulation preparation and sample analysis methods as described in Example 1, the stability of atropine in formulations of MCT and F6H8 with or without the co-solvent phenylethanol was monitored at baseline, 1 month, 2 months, and 3 months at room temperature, and the results are summarized in Tables 3-7.

[0068] Table 3: Stability of atropine (expressed as a percentage relative to target dose) in a 10% MCT, 90% F6H8 formulation

[0069]

[0070]

[0071] Table 4: Stability of atropine (expressed as a percentage relative to target dose) in a 15% MCT, 85% F6H8 formulation

[0072] Percentage of target dose Baseline 1 month 2 months 3 months 0.01％ 99.26％ 103.88％ 102.29％ 98.61％ 0.025％ 100.86％ 101.14％ 100.68％ 98.79％ 0.05％ 98.98％ 99.90％ 101.04％ 97.58％

[0073] Table 5: Stability of atropine (expressed as a percentage relative to target dose) in a 20% MCT, 80% F6H8 formulation

[0074] Percentage of target dose Baseline 1 month 2 months 3 months 0.01％ 98.76％ 99.54％ 99.58％ 99.24％ 0.025％ 96.92％ 96.52％ 97.45％ 96.98％ 0.05％ 100.25％ 97.45％ 97.16％ 97.23％

[0075] Table 6: Stability of atropine (expressed as a percentage relative to target dose) in a formulation of 0.25% phenylethanol, 10% MCT, 89.75% F6H8

[0076] Percentage of target dose Baseline 1 month 2 months 3 months 0.01％ 98.80％ 99.12％ 98.92％ 92.60％ 0.025％ 102.49％ 99.72％ 97.74％ 95.27％ 0.05％ 106.24％ 99.09％ 97.84％ 93.35％

[0077] Table 7: Stability of atropine (expressed as a percentage relative to target dose) in a formulation of 0.5% phenylethanol, 10% MCT, 89.5% F6H8

[0078] Percentage of target dose Baseline 1 month 2 months 3 months 0.01％ 100％ 101.00％ 99.08％ 94.70％ 0.025％ 98.95％ 102.25％ 97.84％ 95.68％ 0.05％ 98.95％ 100.30％ 98.83％ 95.28％

[0079] The data show that atropine at doses of 0.01%, 0.025%, and 0.05% in formulations containing MCT, F6H8, and / or phenylethanol is stable at room temperature for at least 3 months.

[0080] Example 5: In vivo pharmacology and ocular toxicity studies in a rabbit model

[0081] The purpose of this study is to determine the pharmacological efficacy and potential ocular toxicity of atropine formulations in 0.25% phenylethanol, 10% MCT and 89.75% F6H8. The test article was administered by topical ocular instillation twice daily in New Zealand white rabbits for 28 days. The pharmacological efficacy was measured as pupil dilation in normal untested rabbits. Three concentrations of atropine in the above formulations (0.01%, 0.025%, 0.05%) were compared with a 0.03% aqueous formulation of atropine sulfate, which is known to have a good pupil dilation effect. The formulation without atropine served as a vehicle control in the study.

[0082] Study Design:

[0083] The study design is shown in Table 8. Forty-eight rabbits (24 of each sex) were randomly assigned to five groups to determine the toxicity of atropine when applied twice daily for 28 days by topical instillation. The control group was administered with vehicle. Animals were randomly assigned to each group based on body weight. The control and high-dose groups were 6 / sex / group, and the low, medium and comparative groups were 4 / sex / group. The last surviving animals in the control and high-dose groups were assigned to recovery.

[0084] Table 8: Study design

[0085]

[0086] NOTE: In this protocol, “dose level” and “dose” are used interchangeably, and “concentration” and “intensity” are used interchangeably.

[0087] a The dose represents the active ingredient, the left eye will be treated and the right eye will remain untreated.

[0088] b Replacement animals, if any, will be numbered per the testing facility SOP and included in the study report.

[0089] c An estimated daily dosage level was calculated from the dosing concentration, volume and frequency.

[0090] d The comparator was 0.03% atropine sulfate monohydrate in saline containing 100 ppm benzalkonium chloride (BAK).

[0091] Conc. = concentration, M = male, F = female

[0092] The animals were dosed with atropine in vehicle or control or comparator alone by topical instillation twice daily, approximately 12 hours apart, to the left eye for 28 days. The right eye remained as an untreated control eye. Animals were dosed via topical ocular instillation in the left eye at a volume of 40 μL / eye.

[0093] Various life measurements were performed during the study, including activity, clinical observations, body weight, food intake, ophthalmological examinations, intraocular pressure, electroretinography, and pharmacological evaluations with pupil size measurement. In addition, post-mortem macroscopic examinations, gross observations, organ weight measurements, and histopathology were performed at the end of the study. The study followed good laboratory practices (GLP).

[0094] result:

[0095] Pharmacological evaluation: Pupil size was measured in both eyes of all animals on 3 different days during the adaptation period before the start of dosing to establish a baseline and to acclimate the animals to the procedure. The results are shown in Figure 2 (Pupil size measurement at 7 days post-dosing) and Figure 3(Pupil size measurements at 22 days after dosing). Pupil size was measured in both eyes of all animals at baseline (30 minutes before dosing), 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours and 12 hours after the first dosing on days 7 and 22. CBT-009 represents atropine. The data showed that pupil size dilation was observed in all three dose groups of CBT-009 (atropine) at 0.01%, 0.025% and 0.05%, as well as in the comparison group of 0.03% atropine sulfate in the aqueous formulation, while no pupil size change was observed in the vehicle-treated group. In addition, a dose response of pupil size dilation from 0.01% to 0.05% for atropine was observed on both days 7 and 22, and the degree of pupil size change between atropine in the F6H8-based formulation and atropine sulfate in the aqueous solution was similar at similar doses.

[0096] Ocular toxicity: 0.01%, 0.025% and 0.05% atropine in a F6H8-based formulation, 0.03% atropine sulfate comparator in a control vehicle or aqueous solution were applied to the left eye of male and female New Zealand white rabbits by topical instillation twice daily, and the right eye was not treated. After the end of the dosing period, the terminal interphase animals were euthanized, and the recovery interphase animals were maintained for a 14-day recovery period and then euthanized. All animals were maintained for a 14-day recovery period and then euthanized. All animals in the terminal and recovery intervals survived until their scheduled euthanasia. No atropine-related macroscopic (macro-autopsy) observations or microscopic findings were noted in any interphase ocular and non-ocular tissues. Very few microscopic findings in each ocular and non-ocular tissues of male and female in the two interphase control, atropine-treated and / or comparison groups were considered to be incidental and unrelated to atropine. Treatment was tolerated in all study groups, and no deaths were observed in the study.

[0097] Example 6: In vivo ocular tolerance study in a rabbit model

[0098] Study Design:

[0099] Three female Dutch rabbits were administered 40 μL of 0.012% atropine free base in 100% MCT in the right eye and 40 μL of 0.012% atropine free base in 100% light liquid paraffin (LLP) in the left eye, 1 drop / eye, twice a day, 12 hours apart, for 14 consecutive days. Before administration (twice, on different days) and after administration on the last day during the administration, all animals were observed for ocular discomfort and ocular irritation. Before administration (once) and after administration on the 1st day and the 14th day on the last day, all animals were examined for cornea. The first administration day was named D1, and the last administration day was named D14.

[0100] The eye irritation results are shown in Tables 9 and 10.

[0101] Table 9

[0102]

[0103] Table 10

[0104]

[0105] The atropine formulations were well tolerated in all rabbits. No significant ocular irritation or ophthalmitis findings were observed in any animal. There were no test article related effects on body weight and food intake during the study. No other test article related ophthalmological findings were observed in any animal during scheduled examinations. No or slight (+1) conjunctival swelling or conjunctival hyperemia were observed during the study. This example demonstrates the safety of the claimed novel atropine formulations for ocular use.

[0106] Example 7: In vivo ocular tolerance study in dog model

[0107] Study Design

[0108] Three male beagles were administered 40 μL of 0.012% atropine free base in 100% MCT in the right eye and 40 μL of 0.012% atropine free base in 100% LLP in the left eye, 1 drop / eye, twice a day, 12 hours apart, for 14 consecutive days. Before administration (twice, on different days) and every day after administration on the last day during the administration, all animals were observed for ocular discomfort and ocular irritation. Before administration (once) and once on the 1st day and 14th day after administration on the last day, all animals were examined for cornea. The first administration day was named D1, and the last administration day was named D14.

[0109] The eye irritation results are shown in Tables 11 and 12.

[0110] Table 11

[0111]

[0112] Table 12

[0113]

[0114] The atropine formulation was well tolerated in all dogs. No significant ocular irritation or ophthalmitis findings were observed in any animal. There were no test article related effects on body weight and food intake during the study. No other test article related ophthalmological findings were observed in any animal during scheduled examinations. No or slight (+1) conjunctival swelling or conjunctival hyperemia were observed during the study. This example demonstrates the safety of the claimed novel atropine formulation for ocular use.

[0115] References

[0116] 1.Berton B,Chennell P,Yessaad M,Bouattour Y,Jouannet M,Wasiak M,Sautou V.Stability of Ophthalmic Atropine Solutions for Child MyopiaControl.Pharmaceutics.2020Aug 17;12(8):E781.

[0117] 2.Cooper J,Tkatchenko AV.A Review of Current Concepts of the Etiologyand Treatment ofMyopia.Eye Contact Lens.2018Jul;44(4):231-247.

[0118] 3.Li FF,Yam JC.Low-Concentration Atropine Eye Drops for MyopiaProgression.Asia Pac J Ophthalmol(Phila).2019Sep-Oct;8(5):360-365.

[0119] 4.Saito J,Imaizumi H,Yamatani A.Physical,chemical,and microbiologicalstability study ofdiluted atropine eye drops.J Pharm Health Care Sci.2019Dec5;5:25.

[0120] 5.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.

[0121] 6.Yam JC,Li FF,Zhang X,Tang SM,Yip BHK,Kam KW,Ko ST,Young AL,ThamCC,Chen LJ,Pang CP.Two-Year Clinical Trial of the Low-Concentration AtropineforMyopia Progression(LAMP)Study:Phase 2 Report.Ophthalmology.2020 Jul;127(7):910-919.

Claims

1. A topical ophthalmic composition comprising: Muscarinic receptor antagonists as active pharmaceutical ingredients (API); and A liquid carrier selected from medium chain triglycerides (MCT) and light liquid paraffin oil, wherein the topical ophthalmic composition treats an ocular disease.

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

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

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

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

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

7. The topical ophthalmic composition of claim 1, wherein the MCT is a triglyceride of a fatty acid, and the fatty acid is selected from the group consisting of caproic acid, caprylic acid, capric acid, and dodecanoic acid.

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

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

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

11. The topical ophthalmic composition of claim 1 further comprising an organic cosolvent, The organic latent solvent is selected from the group consisting of phenylethanol, ethanol, isopropanol, glycerol, propylene glycol and polyethylene glycol; preferably, the organic latent solvent is phenylethanol.

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

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

14. The topical ophthalmic composition of any one of claims 1-13, 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. The topical ophthalmic composition of any one of claims 1-14, wherein the topical ophthalmic composition is suitable for topical administration to the eye of a patient as eye drops.

16. The topical ophthalmic composition of any one of claims 1-15, wherein the topical ophthalmic composition causes minimal irritation in the eye.

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

18. The topical ophthalmic composition of claims 1-16, wherein the topical ophthalmic composition slows myopia progression, the topical ophthalmic composition treats amblyopia in children, the topical ophthalmic composition relieves vitreous floaters symptoms, or the topical ophthalmic composition treats or prevents painful ciliary spasm.

Images