Ophthalmic components

Abstract

To provide an ophthalmic composition containing a muscarinic antagonist that is stable over a long period.SOLUTION: An ophthalmic composition has a pH from about 3.8 to about 7.5 and comprises from about 0.001 wt.% to about 0.05 wt.% of atropine or a pharmaceutically acceptable salt thereof, 0.01% of benzalkonium chloride, glycerol, and water.SELECTED DRAWING: Figure 10

Description

[Technical Field]

[0001] <Cross reference> This application claims the interests of U.S. Provisional Application No. 62 / 016,502 filed on 24 June 2014, No. 62 / 096,433 filed on 23 December 2014, and No. 62 / 151,926 filed on 23 April 2015, and is a continuation-in-part application of U.S. Application No. 14 / 726,139 filed on 29 May 2015, which are incorporated herein by reference as a whole. [Background technology]

[0002] Pharmaceutical preparations have an expiration date based on the decomposition of their active ingredients. [Overview of the project]

[0003] Ophthalmic compositions are provided herein. In some embodiments, ophthalmic compositions with a pD of about 4.2 to about 7.9 are disclosed herein, comprising about 0.001 wt% to about 0.05 wt% of a muscarinic antagonist and deuterated water.

[0004] In some embodiments, the muscarinic antagonist includes atropine, atropine sulfate, noatropine, atropine-N-oxide, tropine, tropic acid, hyostine, scopolamine, tropicamide, cyclopentolate, pirenzapine, homatropin, or a combination thereof. In some embodiments, the muscarinic antagonist is atropine. In some embodiments, the muscarinic antagonist is atropine sulfate.

[0005] In some embodiments, the ophthalmic composition has one of the following pD values ​​after a long period of time under storage conditions: less than about 7.3, less than about 7.2, less than about 7.1, less than about 7, less than about 6.8, less than about 6.5, less than about 6.4, less than about 6.3, less than about 6.2, less than about 6.1, less than about 6, less than about 5.9, less than about 5.8, less than about 5.2, or less than about 4.8.

[0006] In some embodiments, the ophthalmic composition comprises one of the following: at least about 80%, at least about 85%, at least about 90%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% of a muscarinic antagonist, based on the initial concentration, after a long period of time under storage conditions. As described herein, the proportion of the ophthalmic agent in the composition after storage is based on the amount of the ophthalmic agent initially present in the composition (i.e., before storage).

[0007] In some embodiments, the ophthalmic composition further has one of the following efficacy: at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 97%, at least 98%, or at least 99% after a long period of time under storage conditions. As described herein, the efficacy of the ophthalmic agent in the composition after storage is based on the efficacy of the ophthalmic agent initially present in the composition (i.e., before storage).

[0008] In some embodiments, a long period of time is one of the following: about one week, about two weeks, about three weeks, about one month, about two months, about three months, about four months, about five months, about six months, about eight months, about ten months, about twelve months, about eighteen months, about twenty-four months, about thirty-six months, about four years, or about five years.

[0009] In some embodiments, the storage conditions have a storage temperature of 2°C to 10°C, or 16°C to 26°C. In some embodiments, the storage conditions have a storage temperature of approximately 25°C. In some embodiments, the storage conditions have a storage temperature of approximately 40°C. In some embodiments, the storage conditions have a storage temperature of approximately 60°C.

[0010] In some embodiments, the storage conditions have a relative humidity of approximately 60%. In some embodiments, the storage conditions have a relative humidity of approximately 75%.

[0011] In some embodiments, the muscarinic antagonist is present in the composition at one of the following concentrations: about 0.001 wt% to about 0.04 wt%, about 0.001 wt% to about 0.03 wt%, about 0.001 wt% to about 0.025 wt%, about 0.001 wt% to about 0.02 wt%, about 0.001 wt% to about 0.01 wt%, about 0.001 wt% to about 0.008 wt%, or about 0.001 wt% to about 0.005 wt%.

[0012] In some embodiments, the composition contains less than 20% of the main degradation products based on the concentration of the ophthalmic agent after a long period of time under storage conditions. In some embodiments, the composition contains less than 15% of the main degradation products based on the concentration of the ophthalmic agent after a long period of time under storage conditions.

[0013] In some embodiments, the composition contains less than 10% of the main degradation products based on the concentration of the ophthalmic agent after a long period of time under storage conditions. In some embodiments, the composition contains less than 5% of the main degradation products based on the concentration of the ophthalmic agent after a long period of time under storage conditions. In some embodiments, the composition contains less than 2.5% of the main degradation products based on the concentration of the ophthalmic agent after a long period of time under storage conditions. In some embodiments, the composition contains less than 2.0% of the main degradation products based on the concentration of the ophthalmic agent after a long period of time under storage conditions. In some embodiments, the composition contains less than 1.5% of the main degradation products based on the concentration of the ophthalmic agent after a long period of time under storage conditions. In some embodiments, the composition contains less than 1.0% of the main degradation products based on the concentration of the ophthalmic agent after a long period of time under storage conditions. In some embodiments, the composition contains less than 0.5% of the main degradation products based on the concentration of the ophthalmic agent after a long period of time under storage conditions. In some embodiments, the composition contains less than 0.4% of the main degradation products based on the concentration of the ophthalmic agent after a long period of time under storage conditions. In some embodiments, the composition contains less than 0.3% of the main degradation product based on the concentration of the ophthalmic agent after a long period of time under storage conditions. In some embodiments, the composition contains less than 0.2% of the main degradation product based on the concentration of the ophthalmic agent after a long period of time under storage conditions. In some embodiments, the composition contains less than 0.1% of the main degradation product based on the concentration of the ophthalmic agent after a long period of time under storage conditions. In some embodiments, the main degradation product is tropic acid. As described in this disclosure, the proportion of the main degradation product in the composition after storage is based on the amount of the ophthalmic agent originally present in the composition (i.e., before storage).

[0014] In some embodiments, the composition is in the form of an aqueous solution.

[0015] In some embodiments, the composition further comprises a molar osmotic pressure adjusting agent. In some embodiments, the molar osmotic pressure adjusting agent is sodium chloride.

[0016] In some embodiments, the ophthalmic composition further comprises a preservative. In some embodiments, the preservative is selected from benzalkonium chloride, cetrimonium, sodium perborate, stabilized oxychloro complex, SofZia, polyquaternium-1, chlorobutanol, disodium edetate, polyhexamethylene biguanide, or combinations thereof.

[0017] In some embodiments, the ophthalmic composition further comprises a buffering agent. In some embodiments, the buffering agent is selected from borate, borate-polyol complex, phosphate buffer, citrate buffer, acetate buffer, carbonate buffer, organic buffer, amino acid buffer, or combinations thereof.

[0018] In some embodiments, the ophthalmic composition further comprises an isotonic agent. In some embodiments, the isotonic agent is selected from sodium chloride, sodium nitrate, sodium sulfate, sodium bisulfate, potassium chloride, calcium chloride, magnesium chloride, zinc chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dextrose, mannitol, sorbitol, dextrose, sucrose, urea, propylene glycol, glycerin, or combinations thereof.

[0019] In some embodiments, the composition is stored in a plastic container. In some embodiments, the material of the plastic container comprises low density polyethylene (LDPE).

[0020] In some embodiments, the ophthalmic composition essentially does not contain procaine and benactyzine, or pharmaceutically acceptable salts thereof.

[0021] In some embodiments, the composition has a concentration change of less than 50% between doses. In some embodiments, the composition has a concentration change of less than 40% between doses. In some embodiments, the composition has a concentration change of less than 30% between doses. In some embodiments, the composition has a concentration change of less than 20% between doses. In some embodiments, the composition has a concentration change of less than 10% between doses. In some embodiments, the composition has a concentration change of less than 5% between doses. In some embodiments, the concentration change of the ophthalmic agent between doses is based on 10 consecutive doses. In some embodiments, the concentration change of the ophthalmic agent between doses is based on 8 consecutive doses. In some embodiments, the concentration change of the ophthalmic agent between doses is based on 5 consecutive doses. In some embodiments, the concentration change of the ophthalmic agent between doses is based on 3 consecutive doses. In some embodiments, the concentration change of the ophthalmic agent between doses is based on 2 consecutive doses.

[0022] In some embodiments, the composition further comprises a pD regulator. In some embodiments, the pD regulator comprises DCl, NaOD, CD3COOD, or C6D8O7.

[0023] In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the ophthalmally acceptable carrier further comprises at least one viscosity enhancer. In some embodiments, the viscosity enhancer is selected from cellulose-based polymers, polyoxyethylene-polyoxypropylene triblock copolymers, dextran-based polymers, polyvinyl alcohol, dextrin, polyvinylpyrrolidone, polyalkylene glycol, chitosan, collagen, gelatin, hyaluronic acid, or a combination thereof.

[0024] In some embodiments, the ophthalmic composition comprises one of the following: less than 60% H2O, less than 55% H2O, less than 50% H2O, less than 45% H2O, less than 40% H2O, less than 35% H2O, less than 30% H2O, less than 25% H2O, less than 20% H2O, less than 15% H2O, or less than 10% H2O.

[0025] In some embodiments, the ophthalmic composition comprises one of the following: less than 5% H2O, less than 4% H2O, less than 3% H2O, less than 2% H2O, less than 1% H2O, less than 0.5% H2O, less than 0.1% H2O, or 0% H2O.

[0026] In some embodiments, the ophthalmic composition is stored at or below room temperature before first use. In some embodiments, the ophthalmic composition is stored at approximately 2°C to approximately 10°C before first use. In some embodiments, the ophthalmic composition is stored at approximately 4°C to approximately 8°C before first use.

[0027] In some embodiments, the ophthalmic composition is stored at room temperature after initial use. In some embodiments, the ophthalmic composition is stored at approximately 16°C to approximately 26°C after initial use.

[0028] In some embodiments, the ophthalmic composition is not formulated as an injectable preparation.

[0029] In some embodiments, the ophthalmic composition is formulated as an ophthalmic solution for the treatment of an eye disease. In some embodiments, the eye disease or disorder is pre-myopia, myopia, or the progression of myopia. In some embodiments, the ophthalmic composition is formulated as an ophthalmic solution for the treatment of pre-myopia, myopia, or the progression of myopia.

[0030] In some embodiments, the ophthalmic composition is a solution.

[0031] In some embodiments, a method for suppressing the onset of myopia is disclosed herein, comprising the step of administering an effective amount of the ophthalmic composition described herein to the eye of an individual in need. Furthermore, a method for preventing the onset of myopia is disclosed herein, comprising the step of administering an effective amount of the ophthalmic composition described herein to the eye of an individual in need. In some embodiments, a method for suppressing or preventing the onset of myopia is disclosed herein, comprising the step of administering an effective amount of the ophthalmic composition having a pD of about 4.2 to about 7.9, comprising about 0.001 wt% to about 0.05 wt% of a muscarinic antagonist and deuterated water, to the eye of an individual in need. In some embodiments, the ophthalmic composition is administered at predetermined time intervals over a long period of time. In some embodiments, the ophthalmic composition is administered once daily. In some embodiments, the ophthalmic composition is administered every other day. In some embodiments, the ophthalmic composition is administered for 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, or 12-15 years. In some embodiments, the ophthalmic composition is stored below room temperature before first use. In some embodiments, the ophthalmic composition is stored at about 2°C to about 10°C before first use. In some embodiments, the ophthalmic composition is stored at about 4°C to about 8°C before first use. In some embodiments, the ophthalmic composition is stored at room temperature after first use. In some embodiments, the ophthalmic composition is stored at about 16°C to about 26°C after first use.

[0032] In some embodiments, ophthalmic solutions with pDs of about 4.2 to about 7.9 are disclosed herein, comprising about 0.001 wt% to about 0.05 wt% of a muscarinic antagonist and deuterated water. In some embodiments, the ophthalmic solutions have one of the following pDs after a long period of time under storage conditions: less than about 7.3, less than about 7.2, less than about 7.1, less than about 7, less than about 6.8, less than about 6.5, less than about 6.4, less than about 6.3, less than about 6.2, less than about 6.1, less than about 6, less than about 5.9, less than about 5.8, less than about 5.2, or less than about 4.8. In some embodiments, the muscarinic antagonist includes atropine, atropine sulfate, noatropine, atropine-N-oxide, tropine, tropic acid, hyostine, scopolamine, tropicamide, cyclopentolate, pirenzepine, homatropin, or a combination thereof. In some embodiments, the ophthalmic solution comprises one of the following: less than 5% H2O, less than 4% H2O, less than 3% H2O, less than 2% H2O, less than 1% H2O, less than 0.5% H2O, less than 0.1% H2O, or 0% H2O. In some embodiments, the ophthalmic composition comprises one of the following: at least about 80%, at least about 85%, at least about 90%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% of a muscarinic antagonist, based on the initial concentration, after a long period of time under storage conditions. In some embodiments, the ophthalmic composition further comprises one of the following efficacy: at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 97%, at least 98%, or at least 99%, after a long period of time under storage conditions. In some embodiments, a long period is one of the following: about one week, about two weeks, about three weeks, about one month, about two months, about three months, about four months, about five months, about six months, about eight months, about ten months, about twelve months, about eighteen months, about twenty-four months, about thirty-six months, about four years, or about five years.In some embodiments, the muscarinic antagonist is present in the composition at one of the following concentrations: about 0.001 wt% to about 0.04 wt%, about 0.001 wt% to about 0.03 wt%, about 0.001 wt% to about 0.025 wt%, about 0.001 wt% to about 0.02 wt%, about 0.001 wt% to about 0.01 wt%, about 0.001 wt% to about 0.008 wt%, or about 0.001 wt% to about 0.005 wt%. In some embodiments, the storage conditions have a storage temperature of 2°C to 10°C, or 16°C to 26°C. In some embodiments, the ophthalmic composition has a muscarinic antagonist concentration variation between the following doses: less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%. In some embodiments, the change in muscarinic antagonist concentration between doses is based on one of the following: 10 consecutive doses, 8 consecutive doses, 5 consecutive doses, 3 consecutive doses, or 2 consecutive doses.

[0033] In some embodiments, ophthalmic compositions comprising about 0.001 wt% to about 0.05 wt% of a muscarinic antagonist and water, with a pH of about 3.8 to about 7.5, are disclosed herein.

[0034] In some embodiments, the muscarinic antagonist includes atropine, atropine sulfate, noatropine, atropine-N-oxide, tropine, tropic acid, hyostine, scopolamine, tropicamide, cyclopentolate, pirenzepine, homatropin, or a combination thereof. In some embodiments, the muscarinic antagonist is atropine or atropine sulfate.

[0035] In some embodiments, the ophthalmic composition comprises one of the following: a muscarinic antagonist that, after a long period of time under storage conditions, is present in an amount of at least about 80%, at least about 85%, at least about 90%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, or at least about 99%, based on the initial concentration.

[0036] In some embodiments, the ophthalmic composition has one of the following pH values ​​after a long period of time under storage conditions: less than about 7.3, less than about 7.2, less than about 7.1, less than about 7, less than about 6.8, less than about 6.5, less than about 6.4, less than about 6.3, less than about 6.2, less than about 6.1, less than about 6, less than about 5.9, less than about 5.8, less than about 5.2, less than about 4.8, or less than 4.2.

[0037] In some embodiments, the ophthalmic composition has one further efficacy: at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 97%, at least 98%, or at least 99% after a long period of time under storage conditions.

[0038] In some embodiments, a long period is one of the following: about one week, about two weeks, about three weeks, about one month, about two months, about three months, about four months, about five months, about six months, about eight months, about ten months, about twelve months, about eighteen months, about twenty-four months, about thirty-six months, about four years, or about five years.

[0039] In some embodiments, the storage conditions have one of the following storage temperatures: about 25°C, about 40°C, or about 60°C. In some embodiments, the storage conditions have a storage temperature of about 2°C to about 10°C, or about 16°C to about 26°C.

[0040] In some embodiments, the storage conditions have a relative humidity of about 60% or about 75%.

[0041] In some embodiments, the muscarinic antagonist is present in the composition at one of the following concentrations: about 0.001 wt% to about 0.04 wt%, about 0.001 wt% to about 0.03 wt%, about 0.001 wt% to about 0.025 wt%, about 0.001 wt% to about 0.02 wt%, about 0.001 wt% to about 0.01 wt%, about 0.001 wt% to about 0.008 wt%, or about 0.001 wt% to about 0.005 wt%.

[0042] In some embodiments, the ophthalmic composition further includes a molar osmotic pressure modifier. In some embodiments, the molar osmotic pressure modifier is sodium chloride.

[0043] In some embodiments, the ophthalmic composition further comprises a preservative. In some embodiments, the preservative is selected from benzalkonium chloride, cetrimonium, sodium perborate, stabilized oxychloro complex, SofZia, polyquaternium-1, chlorobutanol, disodium edetate, polyhexamethylene biguanide, or a combination thereof.

[0044] In some embodiments, the ophthalmic composition further comprises a buffer. In some embodiments, the buffer is selected from borates, borate-polyol complexes, phosphate buffers, citrate buffers, acetate buffers, carbonate buffers, organic buffers, amino acid buffers, or combinations thereof.

[0045] In some embodiments, the ophthalmic composition further comprises an isotonic agent. In some embodiments, the isotonic agent is selected from sodium chloride, sodium nitrate, sodium sulfate, sodium bisulfate, potassium chloride, calcium chloride, magnesium chloride, zinc chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dextrose, mannitol, sorbitol, dextrose, sucrose, urea, propylene glycol, glycerin, or a combination thereof.

[0046] In some embodiments, the ophthalmic composition is stored in a plastic container. In some embodiments, the material of the plastic container includes low-density polyethylene (LDPE).

[0047] In some embodiments, the ophthalmic composition has the following muscarinic antagonist concentration changes between one of the following doses: less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%.

[0048] In some embodiments, the change in muscarinic antagonist concentration between doses is based on one of the following: 10 consecutive doses, 8 consecutive doses, 5 consecutive doses, 3 consecutive doses, or 2 consecutive doses.

[0049] In some embodiments, the ophthalmic composition has one of the following pH values: about 3.8 to about 7.5, about 4.2 to about 7.5, about 4.8 to about 7.3, about 5.2 to about 7.2, about 5.8 to about 7.1, about 6.0 to about 7.0, or about 6.2 to about 6.8.

[0050] In some embodiments, the ophthalmic composition further includes a pH adjuster. In some embodiments, the pH adjuster includes HCl, NaOH, CH3COOH, or C6H8O7.

[0051] In some embodiments, the ophthalmic composition comprises one of the following: less than 60% D2O, less than 55% D2O, less than 50% D2O, less than 45% D2O, less than 40% D2O, less than 35% D2O, less than 30% D2O, less than 25% D2O, less than 20% D2O, less than 15% D2O, or less than 10% D2O.

[0052] In some embodiments, the ophthalmic composition includes one of the following: less than 5% D2O, less than 4% D2O, less than 3% D2O, less than 2% D2O, less than 1% D2O, less than 0.5% D2O, less than 0.1% D2O, or 0% D2O. In some embodiments, the ophthalmic composition is essentially D2O-free.

[0053] In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0054] In some embodiments, the ophthalmic composition is formulated as an ophthalmic solution for the treatment of an eye disease. In some embodiments, the eye disease or disorder is pre-myopia, myopia, or progression of myopia.

[0055] In some embodiments, the ophthalmic composition is not formulated as an injectable preparation.

[0056] Other features and technical effects of the methods and compositions described herein will become apparent from the detailed description below. However, it should be understood that the detailed description and specific examples illustrate specific embodiments but are given for illustrative purposes only. [Brief explanation of the drawing]

[0057] Novel features of this disclosure are specifically described in the appended claims. A better understanding of the features and advantages of this disclosure can be obtained by referring to the following detailed description illustrating exemplary embodiments and accompanying drawings in which the principles of this disclosure are applied: [Figure 1] AC shows the predicted storage life of a 0.01% atropine sulfate solution with a major degradation product RRT of 0.87-0.89 and a range of less than 0.5%, based on data obtained from samples stored at 25°C and 40°C. The pH range of the atropine sulfate solution is 5.9-6.2. [Figure 2] AC shows the predicted storage life of a 0.01% atropine sulfate solution with a major degradation product RRT of 0.87-0.89% and a range of ≤0.5% based on data obtained from samples stored at 25°C and 60°C. The pH range of the atropine sulfate solution is 5.9-6.2. [Figure 3] The mass balance of the atropine sulfate formulation disclosed in Example 9 is illustrated at week 4 and under conditions of 60°C. [Figure 4] This study illustrates the stability of atropine sulfate (0.010%) formulations in acetic acid. Atropine sulfate formulations are prepared using either acetic acid and H2O (upper panel, formulation 3) or D2O (lower panel, formulation 7). Formulation 3 has a pH of 4.8, and formulation 7 has a pD of 5.2. Both formulations are stored at 60°C for 4 weeks prior to analysis. [Figure 5]This study illustrates the stability of atropine sulfate (0.01%) preparations in citrate. The atropine sulfate preparations are formulated using citrate and either H2O (upper panel, preparation 5) or D2O (lower panel, preparation 8). Preparation 5 has a pH of 5.8, and preparation 8 has a pD of 6.2. Both preparations are stored at 60°C for 4 weeks prior to analysis. [Figure 6] This example illustrates the comparison between the total RS and tropic acid of atropine sulfate (0.025%) preparation (Preparation 4) at pH 4.8 in H2O. [Figure 7] This illustrates a comparison of total RS and tropic acid in a 0.01% atropine sulfate preparation (Preparation 7) with a pD of 5.2 in D2O. [Figure 8] This example illustrates the comparison between the total RS and tropic acid of a 0.01% atropine sulfate preparation (Preparation 5) at pH 5.8 in H2O. [Figure 9] This example illustrates the comparison between the total RS and tropic acid of atropine sulfate (0.025%) preparation (preparation 6) at pH 5.8 in H2O. [Figure 10] Examples 11 and 12 illustrate the expected storage periods of the D2O and H2O formulations disclosed. [Modes for carrying out the invention]

[0058] This disclosure acknowledges the need for stable ophthalmic compositions with extended storage life. Furthermore, this disclosure acknowledges the need to stabilize ophthalmic compositions by inhibiting or reducing the hydrolysis of at least some of the active agents. This disclosure further acknowledges the need for ophthalmic compositions that conveniently and efficiently deliver muscarinic antagonists, such as atropine, into the patient's eye.

[0059] This disclosure acknowledges that muscarinic antagonists (e.g., atropine or a pharmaceutically acceptable salt thereof) prevent or inhibit the progression of myopia in humans, as evidenced, for example, by the reduced rate of myopia progression in young people. This disclosure further acknowledges the effects of muscarinic antagonists (e.g., atropine or a pharmaceutically acceptable salt thereof) on axial lengthening and myopia reduction in the eyes of visually impaired chicks, and on eye growth and muscarinic choline receptors in young rhesus monkeys.

[0060] In addition, this disclosure acknowledges that systemic absorption of muscarinic antagonists (e.g., atropine) often causes undesirable side effects, and that topical delivery of muscarinic antagonists (e.g., atropine or a pharmaceutically acceptable salt thereof) reduces or prevents the aforementioned systemic exposure.

[0061] Furthermore, this disclosure acknowledges that, for the stability of muscarinic antagonists (e.g., atropine or a pharmaceutically acceptable salt thereof), some liquid muscarinic antagonist (e.g., atropine) compositions are prescribed in a relatively low pH range (e.g., less than 4.5). For some individuals, the lower pH range in some cases may cause discomfort or other side effects such as eye pain or burning, which can be prevented or mitigated by prescribing the muscarinic antagonist (e.g., atropine) composition in a higher pH range. For some individuals, the lower pH in some cases may induce a tear response that reduces the absorption of the drug into the eye, and therefore reduces its efficacy.

[0062] Furthermore, this disclosure acknowledges that some liquid compositions of muscarinic antagonists (e.g., atropine) formulated at lower concentrations (e.g., 0.001% to 0.05%) exhibit stability problems not as pronounced at higher concentrations (e.g., 0.1-1%). Without being constrained by any particular theory, it is intended that some muscarinic antagonists (e.g., atropine) contribute to the stability of ophthalmic compositions, such as aqueous solutions. For example, the concentration of the muscarinic antagonist (e.g., atropine) in some embodiments affects the pH or pD of the ophthalmic composition, such as by using a muscarinic antagonist acting as a buffer. Furthermore, the concentration of the muscarinic antagonist (e.g., atropine) in some embodiments affects the interaction between the muscarinic antagonist and other components of the ophthalmic composition, which in turn affects the stability of the ophthalmic composition.

[0063] Finally, this disclosure acknowledges that deuterated water stabilizes ophthalmic compositions. In some cases, deuterated water is a weaker acid compared to H2O due to the presence of low concentrations of reactive species (e.g., -OD), and may cause base-catalyzed hydrolysis of active agents in ophthalmic compositions. Thus, in some cases, compositions containing deuterated water induce reductive base-catalyzed hydrolysis compared to compositions containing H2O. In some cases, deuterated water further reduces the buffering capacity of ophthalmic compositions and decreases tear reflex.

[0064] Myopia, which is an extension of the axial length of the eye, affects a large portion of the population. Myopia typically develops during elementary school and progresses until eye growth is complete. This disclosure recognizes the importance of compositions and treatments for preventing or slowing the progression of myopia, in particular, compositions and treatments that are easy to administer, have reduced potential side effects, boast adequate stability, and / or provide relatively consistent therapeutic effects.

[0065] Ophthalmic Muscarinic Antagonist Composition

[0066] Ophthalmic compositions comprising low concentrations of ophthalmic agents are provided herein. In some embodiments, the ophthalmic composition comprises about 0.001 wt% to about 0.05 wt% of the ophthalmic agent for the treatment of an eye disease or illness and an ophthalmally acceptable carrier, wherein the ophthalmic agent is substantially uniformly distributed throughout the ophthalmally acceptable carrier. In some examples, the ophthalmic agent is a muscarinic antagonist.

[0067] Ophthalmic compositions comprising low concentrations of muscarinic antagonists are provided herein. In some embodiments, the ophthalmic composition comprises about 0.001 wt% to about 0.05 wt% of a muscarinic antagonist and an ophthalmically acceptable carrier for the treatment of an eye disease or disorder, wherein the muscarinic antagonist is substantially uniformly distributed throughout the ophthalmally acceptable carrier.

[0068] In some examples, muscarinic antagonists include atropine, atropine sulfate, noatropine, atropine-N-oxide, tropine, tropic acid, methylatropine nitrate, diphenhydramine, dimenhydrinate, dicyclomine, flavoxate, oxybutynin, tiotropium, hyostine, scopolamine (L-hyostine), hydroxyzine, ipratropium, tropicamide, cyclopentolate, pirenzepine, homatropin, solifenacin, dalifenacin, benzatropin, mebeberine, procyclidine, acridinium bromide, trihexyphenidyl / benzhexol, tolterodine, or combinations thereof. In some examples, the muscarinic antagonist includes atropine, atropine sulfate, noatropine, atropine-N-oxide, tropine, tropic acid, hyostine, scopolamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or combinations thereof. In some embodiments, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the muscarinic antagonist is atropine sulfate.

[0069] In some embodiments, the ophthalmic composition comprises a muscarinic antagonist selected from atropine, atropine sulfate, noatropine, atropine-N-oxide, tropine, tropic acid, methylatropine nitrate, diphenhydramine, dimenhydrinate, dicyclomine, flavoxate, oxybutynin, tiotropium, hyostine, scopolamine (L-hyostine), hydroxyzine, ipratropium, tropicamide, cyclopentolate, pirenzepine, homatropine, solifenacin, dalifenacin, benzatropine, mebeberine, procyclidine, acridinium bromide, trihexyphenidyl / benzhexol, tolterodine, or a combination thereof. In some cases, muscarinic antagonists include atropine, atropine sulfate, noatropine, atropine-N-oxide, tropine, tropic acid, hyostine, scopolamine, tropicamide, cyclopentolate, pirenzepine, or homatropin.

[0070] In some embodiments, the ophthalmic composition comprises two or more muscarinic antagonists, the two or more muscarinic antagonists include atropine, atropine sulfate, noatropine, atropine-N-oxide, tropine, tropic acid, methylatropine nitrate, diphenhydramine, dimenhydrinate, dicyclomine, flavoxate, oxybutynin, tiotropium, hyostine, scopolamine (L-hyostine), hydroxyzine, ipratropium, tropicamide, cyclopentolate, pirenzepine, homatropin, solifenacin, dalifenacin, benzatropin, mebeberine, procyclidine, acridinium bromide, trihexyphenidyl / benzhexol, tolterodine, or a combination thereof. In some examples, muscarinic antagonists include atropine, atropine sulfate, noatropine, atropine-N-oxide, tropine, tropic acid, hyostine, scopolamine, tropicamide, cyclopentolate, pirenzepine, homatropin, or any combination thereof.

[0071] In some embodiments, the ophthalmic composition comprises one or more muscarinic antagonists combined with one or more sympathetic agonists. In some embodiments, the sympathetic agonists are selected from phenylephrine or hydroxyamphetamine. In some embodiments, the ophthalmic composition comprises one or more muscarinic antagonists: in combination with one or more sympathetic agonists, atropine, atropine sulfate, noatropine, atropine-N-oxide, tropine, tropic acid, methylatropine nitrate, diphenhydramine, dimenhydrinate, dicyclomine, flavoxate, oxybutynin, tiotropium, hyostine, scopolamine (L-hyostine), hydroxyzine, ipratropium, tropicamide, cyclopentolate, pirenzepine, homatropin, solifenacin, dalifenacin, benzatropin, mebeberine, procyclidine, acridinium bromide, trihexyphenidyl / benzhexol, or tolterodine; phenylephrine or hydroxyamphetamine.

[0072] Ophthalmic compositions comprising low concentrations of atropine or a pharmaceutically acceptable salt thereof are provided herein. In some embodiments, the ophthalmic composition comprises about 0.001 wt% to about 0.05 wt% of atropine or a pharmaceutically acceptable salt thereof for the treatment of an eye disease or disorder, and an ophthalmally acceptable carrier, wherein the ophthalmic agent is substantially uniformly distributed throughout the ophthalmally acceptable carrier.

[0073] Ophthalmic compositions containing low concentrations of atropine sulfate are provided herein. In some embodiments, the ophthalmic composition comprises about 0.001 wt% to about 0.05 wt% of atropine sulfate for the treatment of an eye disease or disorder, and an ophthalmally acceptable carrier, wherein the ophthalmic agent is substantially uniformly distributed throughout the ophthalmally acceptable carrier.

[0074] In some embodiments, the eye disease or disorder is pre-myopia, myopia, or progression of myopia.

[0075] This disclosure further acknowledges that the clinical use of atropine as a treatment is limited by ocular side effects, including pupillary dilation due to loss of accommodation and glare from blurred vision. Without being constrained by any particular theory, the limitation of atropine's use for the development of myopia is due to the concentrations of atropine used in existing ophthalmic formulations (e.g., ≥1 wt%).

[0076] This disclosure further acknowledges problems in the formulation of compositions containing ophthalmic agents such as muscarinic antagonists (e.g., atropine or a pharmaceutically acceptable salt thereof) at low concentrations, particularly very low concentrations (e.g., about 0.001 wt% to about 0.5 wt%). In particular, pharmaceutical compositions containing such low concentrations of ophthalmic agents are difficult to maintain in terms of dose-to-dose uniformity in terms of the contents and / or distribution of the ophthalmic agent.

[0077] In some embodiments, formulations or solutions of muscarinic antagonists (e.g., atropine) formulated in deuterated water are described herein. In some embodiments, formulations or solutions of muscarinic antagonists (e.g., atropine) formulated in deuterated water are more stable than ophthalmic formulations at a range of temperatures, relative humidity, acidic pD, and at least 80% efficacy. In further embodiments, formulations or solutions of muscarinic antagonists (e.g., atropine) formulated in deuterated water have low buffering capacity. In such examples, when a formulation or solution with low buffering capacity is administered to the eye, the ophthalmic formulation or solution reaches physiological pH more quickly than an equivalent ophthalmic formulation or solution formulated in H2O.

[0078] In some embodiments, formulations of low-concentration muscarinic antagonists (e.g., atropine) that exhibit no variation between doses are described herein. In some embodiments, formulations of low-concentration muscarinic antagonists (e.g., atropine) that are more stable than ophthalmic agents at various temperatures, various relative humidities, acidic pDs, and at at least 80% efficacy are described herein.

[0079] In other embodiments, the description herein includes formulating ophthalmic compositions as ophthalmic gels or ophthalmic ointments. For example, the ophthalmic gels or ophthalmic ointments described herein enable desirable uniformity between doses, reduction or limitation of systemic exposure, or a combination thereof.

[0080] Ophthalmic solution muscarinic antagonist composition

[0081] In some embodiments, ophthalmic compositions formulated as aqueous solutions are disclosed herein. In some embodiments, the ophthalmic composition comprises about 0.001 wt% to about 0.05 wt% of a muscarinic antagonist and deuterated water. As used herein, deuterated water refers to D2O, DHO, heavy water, and / or deuterium oxide.

[0082] In some embodiments, the composition contains at least about 80% of an ophthalmic agent (e.g., a muscarinic antagonist) over a long period of time under storage conditions. In some embodiments, the composition contains at least about 81% of an ophthalmic agent (e.g., a muscarinic antagonist) over a long period of time under storage conditions. In some embodiments, the composition contains at least about 82% of an ophthalmic agent (e.g., a muscarinic antagonist) over a long period of time under storage conditions. In some embodiments, the composition contains at least about 83% of an ophthalmic agent (e.g., a muscarinic antagonist) over a long period of time under storage conditions. In some embodiments, the composition contains at least about 84% of an ophthalmic agent (e.g., a muscarinic antagonist) over a long period of time under storage conditions. In some embodiments, the composition contains at least about 85% of an ophthalmic agent (e.g., a muscarinic antagonist) over a long period of time under storage conditions. In some embodiments, the composition contains at least about 86% of an ophthalmic agent (e.g., a muscarinic antagonist) over a long period of time under storage conditions. In some embodiments, the composition contains at least about 87% of an ophthalmic agent (e.g., a muscarinic antagonist) over a long period of time under storage conditions. In some embodiments, the composition contains at least about 88% of an ophthalmic agent (e.g., a muscarinic antagonist) over a long period of time under storage conditions. In some embodiments, the composition contains at least about 89% of an ophthalmic agent (e.g., a muscarinic antagonist) over a long period of time under storage conditions. In some embodiments, the composition contains at least about 90% of an ophthalmic agent (e.g., a muscarinic antagonist) over a long period of time under storage conditions. In some embodiments, the composition contains at least about 91% of an ophthalmic agent (e.g., a muscarinic antagonist) over a long period of time under storage conditions. In some embodiments, the composition contains at least about 92% of an ophthalmic agent (e.g., a muscarinic antagonist) over a long period of time under storage conditions. In some embodiments, the composition contains at least about 93% of an ophthalmic agent (e.g., a muscarinic antagonist) over a long period of time under storage conditions. In some embodiments, the composition contains at least about 94% of an ophthalmic agent (e.g., a muscarinic antagonist) over a long period of time under storage conditions.In some embodiments, the composition contains at least about 95% of an ophthalmic agent (e.g., a muscarinic antagonist) over a long period of time under storage conditions. In some embodiments, the composition contains at least about 96% of an ophthalmic agent (e.g., a muscarinic antagonist) over a long period of time under storage conditions. In some embodiments, the composition contains at least about 97% of an ophthalmic agent (e.g., a muscarinic antagonist) over a long period of time under storage conditions. In some embodiments, the composition contains at least about 98% of an ophthalmic agent (e.g., a muscarinic antagonist) over a long period of time under storage conditions. In some embodiments, the composition contains at least about 99% of an ophthalmic agent (e.g., a muscarinic antagonist) over a long period of time under storage conditions.

[0083] In some embodiments, the composition retains at least about 80% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition retains at least about 81% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition retains at least about 82% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition retains at least about 83% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition retains at least about 84% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition retains at least about 85% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition retains at least about 86% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition retains at least about 87% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition retains at least about 88% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition retains at least about 89% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition retains at least 90% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition retains at least 91% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition retains at least 92% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition retains at least 93% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition retains at least 94% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition retains at least 95% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition retains at least 96% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition retains at least 97% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition retains at least 98% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition retains at least 99% of its efficacy after a long period of time under storage conditions.

[0084] In some embodiments, the duration is at least one week. In some embodiments, the duration is at least two weeks. In some embodiments, the duration is at least three weeks. In some embodiments, the duration is at least one month. In some embodiments, the duration is at least two months. In some embodiments, the duration is at least three months. In some embodiments, the duration is at least four months. In some embodiments, the duration is at least five months. In some embodiments, the duration is at least six months. In some embodiments, the duration is at least seven months. In some embodiments, the duration is at least eight months. In some embodiments, the duration is at least nine months. In some embodiments, the duration is at least ten months. In some embodiments, the duration is at least eleven months. In some embodiments, the duration is at least twelve months (i.e., one year). In some embodiments, the duration is at least eighteen months (i.e., 1.5 years). In some embodiments, the duration is at least twenty-four months (i.e., two years). In some embodiments, the duration is at least thirty-six months (i.e., three years). In some embodiments, the duration is at least three years. In some embodiments, the duration is at least five years or more.

[0085] In some embodiments, the storage temperature is approximately 20°C to approximately 70°C. In some embodiments, the storage temperature is approximately 25°C to approximately 65°C, approximately 30°C to approximately 60°C, approximately 35°C to approximately 55°C, or approximately 40°C to approximately 50°C. In some embodiments, the storage temperature is approximately 25°C. In some embodiments, the storage temperature is approximately 40°C. In some embodiments, the storage temperature is approximately 60°C.

[0086] In some embodiments, the relative humidity under storage conditions is approximately 50%–80%, or approximately 60%–75%. In some embodiments, the relative humidity under storage conditions is approximately 60%. In some embodiments, the relative humidity under storage conditions is approximately 75%.

[0087] In some embodiments, the composition contains less than 60% H2O. In some embodiments, the composition contains less than 55% H2O. In some embodiments, the composition contains less than 50% H2O. In some embodiments, the composition contains less than 45% H2O. In some embodiments, the composition contains less than 40% H2O. In some embodiments, the composition contains less than 35% H2O. In some embodiments, the composition contains less than 30% H2O. In some embodiments, the composition contains less than 25% H2O. In some embodiments, the composition contains less than 20% H2O. In some embodiments, the composition contains less than 15% H2O. In some embodiments, the composition contains less than 10% H2O.

[0088] In some embodiments, the composition contains less than 5% H2O to 0% H2O. In some embodiments, the composition contains less than 5% H2O. In some embodiments, the composition contains less than 4.5% H2O. In some embodiments, the composition contains less than 4% H2O. In some embodiments, the composition contains less than 3.5% H2O. In some embodiments, the composition contains less than 3% H2O. In some embodiments, the composition contains less than 2.5% H2O. In some embodiments, the composition contains less than 2% H2O. In some embodiments, the composition contains less than 1.5% H2O. In some embodiments, the composition contains less than 1% H2O. In some embodiments, the composition contains less than 0.5% H2O. In some embodiments, the composition contains less than 0.4% H2O. In some embodiments, the composition contains less than 0.3% H2O. In some embodiments, the composition contains less than 0.2% H2O. In some embodiments, the composition contains less than 0.1% H2O. In some embodiments, the composition contains 0% H2O.

[0089] In some embodiments, the composition has a pD of about 4–about 8, about 4.5–about 7.8, 5–about 7.5, or about 5.5–about 7. In some embodiments, the composition has a pD of less than about 7.5. In some embodiments, the composition has a pD of less than about 7.4. In some embodiments, the composition has a pD of less than about 7.3. In some embodiments, the composition has a pD of less than about 7.2. In some embodiments, the composition has a pD of less than about 7.1. In some embodiments, the composition has a pD of less than about 7. In some embodiments, the composition has a pD of less than about 6.9. In some embodiments, the composition has a pD of less than about 6.8. In some embodiments, the composition has a pD of less than about 6.7. In some embodiments, the composition has a pD of less than about 6.6. In some embodiments, the composition has a pD of less than about 6.5. In some embodiments, the composition has a pD of less than about 6.4. In some embodiments, the composition has a pD of less than about 6.3. In some embodiments, the composition has a pD of less than about 6.2. In some embodiments, the composition has a pD of less than about 6.1. In some embodiments, the composition has a pD of less than 6. In some embodiments, the composition has a pD of less than about 5.9. In some embodiments, the composition has a pD of less than about 5.8. In some embodiments, the composition has a pD of less than about 5.7. In some embodiments, the composition has a pD of less than about 5.6. In some embodiments, the composition has a pD of less than about 5.5. In some embodiments, the composition has a pD of less than about 5.4. In some embodiments, the composition has a pD of less than about 5.3. In some embodiments, the composition has a pD of less than about 5.2. In some embodiments, the composition has a pD of less than about 5.1. In some embodiments, the composition has a pD of less than about 5. In some embodiments, the composition has a pD of less than about 5.9. In some embodiments, the composition has a pD of less than about 4.8. In some embodiments, the composition has a pD of less than about 4.7. In some embodiments, the composition has a pD of less than about 4.6. In some embodiments, the composition has a pD of less than about 4.5.In some embodiments, the composition has a pD of less than about 4.4. In some embodiments, the composition has a pD of less than about 4.3. In some embodiments, the composition has a pD of less than about 4.2. In some embodiments, the composition has a pD of less than about 4.1. In some embodiments, the composition has a pD of less than about 4.

[0090] In some embodiments, compositions containing deuterated water have a lower buffering capacity than equivalent compositions containing H2O. As described separately herein, in some embodiments, the reduced buffering capacity causes compositions containing deuterated water to normalize to a physiological pH more quickly than compositions containing H2O. In some embodiments, the reduced buffering capacity causes compositions to induce less tear reflection than equivalent compositions containing H2O.

[0091] In some cases, compositions containing deuterated water stabilize muscarinic antagonists (e.g., atropine). In some embodiments, this is because the concentration of the reactant (e.g., -OD) in the D2O aqueous solution is lower compared to the concentration of the reactant (e.g., -OH) in the equivalent H2O aqueous solution. In some cases, tropine degradation products are obtained from atropine by base-catalyzed hydrolysis. In some cases, the atropine solution is more stable in a D2O aqueous system than in an equivalent H2O aqueous system because the concentration of the reactant that causes the formation of tropine degradation products is low. In some embodiments, ophthalmic compositions can be more stabilized when formulated with deuterated water than when formulated with H2O.

[0092] In some embodiments, the composition contains less than 20% of the major degradation products, based on the concentration of the ophthalmic agent, after a long period of time under storage conditions. In some embodiments, the composition contains less than 15% of the major degradation products, based on the concentration of the ophthalmic agent, after a long period of time under storage conditions.

[0093] In some embodiments, the composition contains less than 10% of the major degradation products based on the concentration of the ophthalmic agent after a long period of storage under certain conditions. In some embodiments, the composition contains less than 5% of the major degradation products based on the concentration of the ophthalmic agent after a long period of storage under certain conditions. In some embodiments, the composition contains less than 2.0% of the major degradation products based on the concentration of the ophthalmic agent after a long period of storage under certain conditions. In some embodiments, the composition contains less than 1.5% of the major degradation products based on the concentration of the ophthalmic agent after a long period of storage under certain conditions. In some embodiments, the composition contains less than 1.0% of the major degradation products based on the concentration of the ophthalmic agent after a long period of storage under certain conditions. In some embodiments, the composition contains less than 0.5% of the major degradation products based on the concentration of the ophthalmic agent after a long period of storage under certain conditions. In some embodiments, the composition contains less than 0.4% of the major degradation products based on the concentration of the ophthalmic agent after a long period of storage under certain conditions. In some embodiments, the composition contains less than 0.3% of the major degradation products based on the concentration of the ophthalmic agent after a long period of storage under certain conditions. In some embodiments, the composition contains less than 0.2% of the main degradation product, based on the concentration of the ophthalmic agent, after a long period of storage under certain conditions. In some embodiments, the composition contains less than 0.1% of the main degradation product, based on the concentration of the ophthalmic agent, after a long period of storage under certain conditions. In some embodiments, the main degradation product is tropic acid.

[0094] In some embodiments, the main degradation product is a related substance that elutes early at RRT 0.87-0.89 according to the UPLC method described herein (Table 10). In some examples, the early-elute related substance is referred to as RRT 0.87-0.89. In some embodiments, the main degradation product is RRT-0.87-0.89.

[0095] <Concentrations of ophthalmic muscarinic antagonists> In some embodiments, the compositions described herein have concentrations of the ophthalmic agent, or a pharmaceutically acceptable prodrug or salt thereof, between about 0.001% and about 0.050% by weight, between about 0.005% and about 0.050% by weight, between about 0.010% and about 0.050% by weight, between about 0.015% and about 0.050% by weight, between about 0.020% and about 0.050% by weight, between about 0.025% and about 0.050% by weight, between about 0.030% and about 0.050% by weight, between about 0.035% and about 0.050% by weight, between about 0.040% and about 0.050% by weight, or between about 0.045% and about 0.050% by weight. In some embodiments, the prodrug of an ophthalmic agent (e.g., a muscarinic antagonist) is chemically converted to the ophthalmic agent (e.g., a muscarinic antagonist) after administration of the ophthalmic composition. In some embodiments, the prodrug of a muscarinic antagonist has a chemical bond that can be cleaved by one or more enzymes in tears. In some embodiments, the ophthalmic agent is a muscarinic antagonist. In some embodiments, the muscarinic antagonist includes atropine, atropine sulfate, noatropine, atropine-N-oxide, tropine, tropic acid, hyostine, scopolamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof. In some embodiments, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt thereof. In some embodiments, the muscarinic antagonist is atropine sulfate. As described herein, ophthalmic preparations include optically pure stereoisomers, optically rich stereoisomers, and racemic mixtures of stereoisomers. For example, some ophthalmic crudes disclosed herein contain atropine, or atropine sulfate, which is a racemic mixture of the D and L isomers of atropine; and some ophthalmic crudes disclosed herein contain atropine, or atropine sulfate, which is optically rich in the more optically active L isomer.

[0096] In some embodiments, the compositions described herein have concentrations of an ophthalmic agent, or a pharmaceutically acceptable prodrug or salt thereof, between about 0.001% and about 0.045% by weight, between about 0.005% and about 0.045% by weight, between about 0.010% and about 0.045% by weight, between about 0.015% and about 0.045% by weight, between about 0.020% and about 0.045% by weight, between about 0.025% and about 0.045% by weight, between about 0.030% and about 0.045% by weight, between about 0.035% and about 0.045% by weight, or between about 0.040% and about 0.045% by weight. In some embodiments, the ophthalmic agent is a muscarinic antagonist. In some embodiments, the muscarinic antagonist includes atropine, atropine sulfate, noatropine, atropine-N-oxide, tropine, tropic acid, hyostine, scopolamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof. In some embodiments, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt thereof. In some embodiments, the muscarinic antagonist is atropine sulfate.

[0097] In some embodiments, the compositions described herein have concentrations of an ophthalmic agent, i.e., an active ingredient, or a pharmaceutically acceptable prodrug or salt thereof, between about 0.001% and about 0.040% by weight, between about 0.005% and about 0.040% by weight, between about 0.010% and about 0.040% by weight, between about 0.015% and about 0.040% by weight, between about 0.020% and 0.040% by weight, between about 0.025% and 0.040% by weight, between about 0.030% and about 0.040% by weight, and between about 0.035% and about 40% by weight. In some embodiments, the ophthalmic agent is a muscarinic antagonist. In some embodiments, the muscarinic antagonist includes atropine, atropine sulfate, noatropine, atropine-N-oxide, tropine, tropic acid, hyostine, scopolamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof. In some embodiments, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt thereof. In some embodiments, the muscarinic antagonist is atropine sulfate.

[0098] In some embodiments, the compositions described herein have concentrations of an ophthalmic agent, or a pharmaceutically acceptable prodrug or salt thereof, between about 0.001% and about 0.035% by weight, between about 0.005% and about 0.035% by weight, between about 0.010% and about 0.035% by weight, between about 0.015% and about 0.035% by weight, between about 0.020% and about 0.035% by weight, between about 0.025% and about 0.035% by weight, or between about 0.030% and about 0.035% by weight. In some embodiments, the ophthalmic agent is a muscarinic antagonist. In some embodiments, the muscarinic antagonist includes atropine, atropine sulfate, noatropine, atropine-N-oxide, tropine, tropic acid, hyostine, scopolamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof. In some embodiments, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt thereof. In some embodiments, the muscarinic antagonist is atropine sulfate.

[0099] In some embodiments, the compositions described herein have concentrations of an ophthalmic agent, i.e., an active ingredient, or a pharmaceutically acceptable prodrug or salt thereof, between about 0.001% and about 0.030% by weight, between about 0.005% and about 0.030% by weight, between about 0.010% and about 0.030% by weight, between about 0.015% and about 0.030% by weight, between about 0.020% and about 0.030% by weight, or between about 0.025% and about 0.030% by weight. In some embodiments, the ophthalmic agent is a muscarinic antagonist. In some embodiments, the muscarinic antagonist includes atropine, atropine sulfate, noatropine, atropine-N-oxide, tropine, tropic acid, hyostine, scopolamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof. In some embodiments, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt thereof. In some embodiments, the muscarinic antagonist is atropine sulfate.

[0100] In some embodiments, the compositions described herein have concentrations of an ophthalmic agent, or a pharmaceutically acceptable prodrug or salt thereof, between about 0.001% and about 0.025% by weight, between about 0.005% and about 0.025% by weight, between about 0.010% and about 0.025% by weight, between about 0.015% and about 0.025% by weight, or between about 0.020% and about 0.025% by weight. In some embodiments, the ophthalmic agent is a muscarinic antagonist. In some embodiments, the muscarinic antagonist includes atropine, atropine sulfate, noatropine, atropine-N-oxide, tropine, tropic acid, hyostine, scopolamine, tropicamide, cyclopentolate, pirenzepine, homatropin, or combinations thereof. In some embodiments, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt thereof. In some embodiments, the muscarinic antagonist is atropine sulfate.

[0101] In some embodiments, the compositions described herein have concentrations of an ophthalmic agent, i.e., an active ingredient, or a pharmaceutically acceptable prodrug or salt thereof, between about 0.001% and about 0.020% by weight, between about 0.005% and about 0.020% by weight, between about 0.010% and about 0.020% by weight, or between about 0.015% and about 0.020% by weight. In some embodiments, the ophthalmic agent is a muscarinic antagonist. In some embodiments, the muscarinic antagonist includes atropine, atropine sulfate, noatropine, atropine-N-oxide, tropine, tropic acid, hyostine, scopolamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or combinations thereof. In some embodiments, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt thereof. In some embodiments, the muscarinic antagonist is atropine sulfate.

[0102] In some embodiments, the compositions described herein have a concentration of an ophthalmic agent, or a pharmaceutically acceptable prodrug or salt thereof, between about 0.001% and about 0.015% by weight, between about 0.005% and about 0.015% by weight, or between about 0.010% and about 0.015% by weight of the composition. In some embodiments, the ophthalmic agent is a muscarinic antagonist. In some embodiments, the muscarinic antagonist includes atropine, atropine sulfate, noatropine, atropine-N-oxide, tropine, tropic acid, hyostine, scopolamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof. In some embodiments, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt thereof. In some embodiments, the muscarinic antagonist is atropine sulfate.

[0103] In some embodiments, the compositions described herein have a concentration of an ophthalmic agent, or a pharmaceutically acceptable prodrug or salt thereof, between about 0.001% and about 0.010% by weight, between about 0.005% and about 0.010% by weight, or between about 0.008% and about 0.010% by weight. In some embodiments, the ophthalmic agent is a muscarinic antagonist. In some embodiments, the muscarinic antagonist includes atropine, atropine sulfate, noatropine, atropine-N-oxide, tropine, tropic acid, hyostine, scopolamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof. In some embodiments, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt thereof. In some embodiments, the muscarinic antagonist is atropine sulfate.

[0104] In some embodiments, the compositions described herein have concentrations of an ophthalmic agent, a pharmaceutically acceptable prodrug, or a salt thereof in an amount of about 0.001% by weight, 0.005% by weight, 0.010% by weight, 0.015% by weight, 0.020% by weight, 0.025% by weight, 0.030% by weight, 0.035% by weight, 0.040% by weight, 0.045% by weight, or 0.050% by weight of the composition. In some embodiments, the ophthalmic agent is a muscarinic antagonist. In some embodiments, the muscarinic antagonist includes atropine, atropine sulfate, noatropine, atropine-N-oxide, tropine, tropic acid, hyostine, scopolamine, tropicamide, cyclopentolate, pirenzepine, homatropine, or a combination thereof. In some embodiments, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt thereof. In some embodiments, the muscarinic antagonist is atropine sulfate.

[0105] Without being combined with any particular theory, this specification considers that low concentrations of ophthalmic agents (e.g., muscarinic antagonists such as atropine or atropine sulfate) in the disclosed ophthalmic compositions provide sufficient and consistent therapeutic effects to individuals in need, while reducing or avoiding ocular side effects, including pupillary dilation and glare from blurred vision, associated with ophthalmic formulations containing higher concentrations of ophthalmic agents (e.g., muscarinic antagonists such as atropine or atropine sulfate), due to loss of accommodative effects.

[0106] <Stability of aqueous solutions> In some embodiments, the compositions described herein include a buffer. In some embodiments, the buffer is selected from borates, borate-polyol complexes, phosphate buffers, citrate buffers, acetate buffers, carbonate buffers, organic buffers, amino acid buffers, or combinations thereof. In some embodiments, the compositions described herein include a buffer containing deuterated water. In some embodiments, the deuterated buffer is selected from borates, borate-polyol complexes, phosphate buffers, citrate buffers, acetate buffers, carbonate buffers, organic buffers, amino acid buffers, or combinations thereof, and is formulated in deuterated water.

[0107] In some cases, borates include boric acid, salts of boric acid, other pharmaceutically acceptable borates, and combinations thereof. In some cases, borates include boric acid, sodium borate, potassium borate, calcium borate, magnesium borate, manganese borate, and other such borates.

[0108] As used herein, the term “polyol” includes any compound having at least one hydroxyl group on each of two adjacent carbon atoms that are not in a trans structure relative to each other. In some embodiments, polyols are linear or cyclic, substituted or unsubstituted, or mixtures thereof, insofar as the resulting complex is water-soluble and pharmaceutically acceptable. In some examples, examples of polyols include sugars, sugar alcohols, sugar acids, and uronic acids. In some cases, polyols include, but are not limited to, mannitol, glycerin, xylitol, and sorbitol.

[0109] In some embodiments, the phosphate buffer includes phosphoric acid; alkali metal phosphates such as disodium hydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, potassium phosphate, potassium dihydrogen phosphate, and tripotassium phosphate; alkaline earth metal phosphates such as calcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, monomagnesium phosphate, dimamagnesium phosphate (magnesium hydrogen phosphate), and trimagnesium phosphate; ammonium phosphate such as diammonium hydrogen phosphate and ammonium dihydrogen phosphate; or combinations thereof. In some examples, the phosphate buffer is an anhydrous. In some examples, the phosphate buffer is a hydrate.

[0110] In some embodiments, the borate-polyol complex includes those described in U.S. Patent No. 6,503,497. In some examples, the borate-polyol complex comprises a borate in an amount of about 0.01 to about 2.0% w / v and one or more polyols in an amount of about 0.01% to about 5.0% w / v.

[0111] In some cases, citrate buffers contain citric acid and sodium citrate.

[0112] In some cases, acetate buffers include acetic acid, potassium acetate, and sodium acetate.

[0113] In some cases, carbonate buffers include sodium bicarbonate and sodium carbonate.

[0114] In some cases, organic buffers are used, such as Good Buffers, for example, 2-(N-morpholino)ethanesulfonic acid (MES), N-(2-acetamide)iminodiacetic acid, N-(carbamoylmethyl)iminodiacetic acid (ADA), piperazine-N,N'-bis(2-ethanesulfonic acid) (PIPES), N-(2-acetamide)-2-aminoethanesulfonic acid (ACES), and β-hydroxy-4-morpholinepropanesulfonic acid. 3-Morpholino-2-hydroxypropanesulfonic acid (MOPSO), coramine chloride, 3-(N-Morpholino)propanesulfonic acid (MOPS), N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 2-[(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)amino]ethanesulfonic acid (TES), 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid This includes glycine (HEPES), 3-(N,N-bis[2-hydroxyethyl]amino)-2-hydroxypropanesulfonic acid (DIPSO), acetamide glycine, 3-{[1,3-dihydroxy-2-(hydroxymethyl)-2-propanyl]amino}-2-hydroxy-1-propanesulfonic acid (TAPSO), piperazine-1,4,-bis(2-hydroxypropanesulfonic acid (POPSO), 4-(2-hydroxyethyl)piperazine-1-(2-hydroxypropanesulfonic acid) hydrate (HEPPSO), 3-[4-(2-hydroxyethyl)-1-piperazinyl]propanesulfonic acid (HEPPS), tricine, glycinamide, bicine, or sodium N-tris(hydroxymethyl)methyl-3-aminopropanesulfonate (TAPS); glycine; and diethanolamine (DEA), etc.

[0115] In some cases, amino acid buffers include taurine, aspartic acid and its salts (e.g., potassium salts), and E-aminocaproic acid.

[0116] In some cases, the compositions described herein further comprise isotonic agents. Isotonic agents are agents introduced into preparations such as ophthalmic compositions to reduce local irritation by preventing osmotic stimulation at the site of application. In some cases, buffer solutions and / or pD modifiers that broadly maintain pD with ophthalmic solutions at specific ion concentrations are considered isotonic agents. In some cases, isotonic agents comprise various salts, such as halogen salts of monovalent cations. In some cases, isotonic agents comprise mannitol, sorbitol, dextrose, sucrose, urea, and glycerin. In some examples, suitable isotonic modifiers include sodium chloride, sodium nitrate, sodium sulfate, sodium bisulfate, potassium chloride, calcium chloride, magnesium chloride, zinc chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dextrose, mannitol, sorbitol, dextrose, sucrose, urea, propylene glycol, glycerin, or combinations thereof.

[0117] In some cases, the concentration of the isotonic agent in the compositions described herein is between about 0.5% and about 2.0%. In some cases, the concentration of the isotonic agent in the compositions described herein is between about 0.7% and about 1.8%, between about 0.8% and about 1.5%, or between about 1% and about 1.3%. In some cases, the concentration of the isotonic agent is about 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, or 1.9%. In some cases, the percentage is by weight.

[0118] In some cases, the compositions described herein further comprise pD modifiers. In some embodiments, the pD modifier used is an acid or a base. In some embodiments, the base is an oxide, hydroxide, carbonate, bicarbonate, etc. In some examples, the oxide is a metal oxide such as calcium oxide or magnesium oxide; the hydroxide is an alkali metal or alkaline earth metal such as sodium hydroxide, potassium hydroxide, or calcium hydroxide, or their deuterated hydrogenated equivalents; and the carbonate is an alkali metal or alkaline earth metal such as sodium carbonate, sodium bicarbonate, or potassium bicarbonate, etc. In some examples, the acid is a mineral or organic acid such as hydrochloric acid, nitric acid, phosphoric acid, acetic acid, citric acid, fumaric acid, malic acid, or tartaric acid, or their deuterated hydrogenated equivalents. In some examples, the pD modifier includes, but is not limited to, acetates, bicarbonates, ammonium chloride, citrates, phosphates, pharmaceutically acceptable salts thereof, and combinations or mixtures thereof. In some embodiments, the pD modifier includes DCl and NaOD.

[0119] In some embodiments, the composition has a pD between about 4 and about 8, between about 4.5 and about 7.8, between about 5 and about 7.5, or between about 5.5 and about 7. In some embodiments, the composition has a pD of less than about 7.5. In some embodiments, the composition has a pD of less than about 7.4. In some embodiments, the composition has a pD of less than about 7.3. In some embodiments, the composition has a pD of less than about 7.2. In some embodiments, the composition has a pD of less than about 7.1. In some embodiments, the composition has a pD of less than about 7. In some embodiments, the composition has a pD of less than about 6.9. In some embodiments, the composition has a pD of less than about 6.8. In some embodiments, the composition has a pD of less than about 6.7. In some embodiments, the composition has a pD of less than about 6.6. In some embodiments, the composition has a pD of less than about 6.5. In some embodiments, the composition has a pD of less than about 6.4. In some embodiments, the composition has a pD of less than about 6.3. In some embodiments, the composition has a pD of less than about 6.2. In some embodiments, the composition has a pD of less than about 6.1. In some embodiments, the composition has a pD of less than about 6. In some embodiments, the composition has a pD of less than about 5.9. In some embodiments, the composition has a pD of less than about 5.8. In some embodiments, the composition has a pD of less than about 5.7. In some embodiments, the composition has a pD of less than about 5.6. In some embodiments, the composition has a pD of less than about 5.5. In some embodiments, the composition has a pD of less than about 5.4. In some embodiments, the composition has a pD of less than about 5.3. In some embodiments, the composition has a pD of less than about 5.2. In some embodiments, the composition has a pD of less than about 5.1. In some embodiments, the composition has a pD of less than about 5. In some embodiments, the composition has a pD of less than about 5. In some embodiments, the composition has a pD of less than about 4.9. In some embodiments, the composition has a pD of less than about 4.8. In some embodiments, the composition has a pD of less than about 4.7.In some embodiments, the composition has a pD of less than about 4.6. In some embodiments, the composition has a pD of less than about 4.5. In some embodiments, the composition has a pD of less than about 4.4. In some embodiments, the composition has a pD of less than about 4.3. In some embodiments, the composition has a pD of less than about 4.2. In some embodiments, the composition has a pD of less than about 4.1. In some embodiments, the composition has a pD of less than about 4. In some embodiments, pD is the pD of the composition after a long period of time under storage conditions.

[0120] In some embodiments, the composition has an initial pD between about 4 and about 8, between about 4.5 and about 7.8, between about 5 and about 7.5, or between about 5.5 and about 7. In some embodiments, the composition has an initial pD of about 7.5. In some embodiments, the composition has an initial pD of about 7.4. In some embodiments, the composition has an initial pD of about 7.3. In some embodiments, the composition has an initial pD of about 7.2. In some embodiments, the composition has an initial pD of about 7.1. In some embodiments, the composition has an initial pD of about 7. In some embodiments, the composition has an initial pD of about 6.9. In some embodiments, the composition has an initial pD of about 6.8. In some embodiments, the composition has an initial pD of about 6.7. In some embodiments, the composition has an initial pD of about 6.6. In some embodiments, the composition has an initial pD of about 6.5. In some embodiments, the composition has an initial pD of about 6.4. In some embodiments, the composition has an initial pD of about 6.3. In some embodiments, the composition has an initial pD of about 6.2. In some embodiments, the composition has an initial pD of about 6.1. In some embodiments, the composition has an initial pD of about 6. In some embodiments, the composition has an initial pD of about 5.9. In some embodiments, the composition has an initial pD of about 5.8. In some embodiments, the composition has an initial pD of about 5.7. In some embodiments, the composition has an initial pD of about 5.6. In some embodiments, the composition has an initial pD of about 5.5. In some embodiments, the composition has an initial pD of about 5.4. In some embodiments, the composition has an initial pD of about 5.3. In some embodiments, the composition has an initial pD of about 5.2. In some embodiments, the composition has an initial pD of about 5.1. In some embodiments, the composition has an initial pD of about 5. In some embodiments, the composition has an initial pD of about 5.9. In some embodiments, the composition has an initial pD of about 4.8.In some embodiments, the composition has an initial pD of about 4.7. In some embodiments, the composition has an initial pD of about 4.6. In some embodiments, the composition has an initial pD of about 4.5. In some embodiments, the composition has an initial pD of about 4.4. In some embodiments, the composition has an initial pD of about 4.3. In some embodiments, the composition has an initial pD of about 4.2. In some embodiments, the composition has an initial pD of about 4.1. In some embodiments, the composition has an initial pD of about 4.

[0121] In some embodiments, the pD of the compositions described herein relates to the stability of the composition. In some embodiments, stable compositions include pDs between about 4 and about 8, between about 4.5 and about 7.8, between about 5 and about 7.5, or between about 5.5 and about 7. In some embodiments, stable compositions include pDs less than about 7.5. In some embodiments, stable compositions include pDs less than about 7.4. In some embodiments, stable compositions include pDs less than about 7.3. In some embodiments, stable compositions include pDs less than about 7.2. In some embodiments, stable compositions include pDs less than about 7.1. In some embodiments, stable compositions include pDs less than about 7. In some embodiments, stable compositions include pDs less than about 6.9. In some embodiments, stable compositions include pDs less than about 6.8. In some embodiments, stable compositions include pDs less than about 6.7. In some embodiments, stable compositions include pDs less than about 6.6. In some embodiments, stable compositions include pDs less than about 6.5. In some embodiments, the stable composition contains a pD of less than about 6.4. In some embodiments, the stable composition contains a pD of less than about 6.3. In some embodiments, the stable composition contains a pD of less than about 6.2. In some embodiments, the stable composition contains a pD of less than about 6.1. In some embodiments, the stable composition contains a pD of less than about 6. In some embodiments, the stable composition contains a pD of less than about 5.9. In some embodiments, the stable composition contains a pD of less than about 5.8. In some embodiments, the stable composition contains a pD of less than about 5.7. In some embodiments, the stable composition contains a pD of less than about 5.6. In some embodiments, the stable composition contains a pD of less than about 5.5. In some embodiments, the stable composition contains a pD of less than about 5.4. In some embodiments, the stable composition contains a pD of less than about 5.3. In some embodiments, the stable composition contains a pD of less than about 5.2. In some embodiments, the stable composition contains a pD of less than about 5.1.In some embodiments, the stable composition contains a pD of less than about 5. In some embodiments, the stable composition contains a pD of less than about 4.9. In some embodiments, the stable composition contains a pD of less than about 4.8. In some embodiments, the stable composition contains a pD of less than about 4.7. In some embodiments, the stable composition contains a pD of less than about 4.6. In some embodiments, the stable composition contains a pD of less than about 4.5. In some embodiments, the stable composition contains a pD of less than about 4.4. In some embodiments, the stable composition contains a pD of less than about 4.3. In some embodiments, the stable composition contains a pD of less than about 4.2. In some embodiments, the stable composition contains a pD of less than about 4.1. In some embodiments, the stable composition contains a pD of less than about 4.

[0122] As described throughout this specification, in several examples, a D2O aqueous solution system stabilizes a muscarinic antagonist (e.g., atropine). In some embodiments, this is because the concentration of the reactant (e.g., -OD) in the D2O aqueous solution system is lower than the concentration of the reactant (e.g., -OH) in an equivalent H2O aqueous solution system. In some examples, the concentration of the reactant (e.g., -OD) in the D2O aqueous solution system is less than about one-third of the concentration of the reactant (e.g., -OH) in an equivalent H2O aqueous solution system. In some cases, this is due to the fact that the dissociation constant of D2O is lower or smaller than that of H2O. For example, K a (H2O) is 1 x 10 -14 On the other hand, K a (D2O) is 1 x 10 -15 Therefore, D2O is a weaker acid than H2O. In some cases, atropine is converted to tropine degradation products by base-catalyzed hydrolysis. In some cases, the atropine solution is more stable in an aqueous D2O system than in an equivalent aqueous H2O system because the reactant species are at a low concentration that causes the formation of tropine degradation products. In some embodiments, ophthalmic compositions can be more stabilized when formulated with deuterated water than when formulated with H2O.

[0123] In some embodiments, the presence of deuterated water alters the pKa of the buffer. In some embodiments, the presence of deuterated water allows the ophthalmic composition to simulate stability at lower pH systems. In some examples, the buffering capacity of the ophthalmic composition is reduced, thereby enabling faster pH changes. In some examples, the reduced buffering capacity of the ophthalmic composition upon administration to the eye allows the ophthalmic composition to reach physiological pH at a faster rate than an ophthalmic composition formulated in H2O. In some examples, an ophthalmic composition formulated in deuterated water allows for lower tear production or less tear reflex in the eye compared to an ophthalmic composition formulated in H2O.

[0124] In some cases, the compositions described herein further include a bactericide. In some cases, the bactericide includes polymeric biguanides, polymeric quaternary ammonium compounds, chlorites, bisbiguanides, chlorite compounds (e.g., potassium chlorite, sodium chlorite, calcium chloride, magnesium chlorite, or mixtures thereof), and combinations thereof.

[0125] In some cases, the compositions described herein further include preservatives. In some cases, preservatives are added to the compositions described herein at certain concentrations to prevent the growth of microorganisms introduced into the composition or to destroy such microorganisms. In some cases, microorganisms refer to bacteria (e.g., Proteus mirabilis, Serratia marcesens), viruses (e.g., Herpes simplex virus, Herpes zoster virus), fungi (e.g., fungi from the genus Fusarium), yeasts (e.g., Candida albicans), parasites (e.g., Plasmodium spp., Gnathostoma spp.), protozoa (e.g., Giardia lamblia), nematodes (e.g., Onchocercus volvulus), worms (e.g., Dirofilaria immitis), and / or amoebas (e.g., Acanthameoba).

[0126] In several examples, the preservative concentrations were between approximately 0.0001% and 1%, between approximately 0.001% and 0.8%, between approximately 0.004% and 0.5%, between approximately 0.008% and 0.1%, and between approximately 0.01% and 0.08%. In some cases, the concentration of preservatives is approximately 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.008%, 0.009%, 0.009%, 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1.0%.

[0127] In some embodiments, the preservative is selected from benzalkonium chloride, cetrimonium, sodium perborate, stable oxychloro complex, SofZia(Alcon), polyquaternium-1, chlorobutanol, disodium edetate, and polyhexamethylene biguanide.

[0128] In some embodiments, the compositions described herein are stored in plastic containers. In some embodiments, the material of the plastic container includes high-density polyethylene (HDPE), low-density polyethylene (LDPE), polyethylene terephthalate (PET), polyvinyl chloride (PVC), polypropylene (PP), polystyrene (PS), fluorinated HDPE, post-consumer resin (PCR), K-resin (SBC), or bioblast. In some embodiments, the material of the plastic container includes LDPE.

[0129] In some embodiments, the compositions described herein are stored in plastic containers. In some embodiments, the compositions stored in plastic containers have a pD between about 4 and about 8, between about 4.5 and about 7.9, or between about 4.9 and about 7.5. In some embodiments, the compositions stored in plastic containers have a pD of less than about 7.4. In some embodiments, the compositions stored in plastic containers have a pD of less than about 7.3. In some embodiments, the compositions stored in plastic containers have a pD of less than about 7.2. In some embodiments, the compositions stored in plastic containers have a pD of less than about 7.1. In some embodiments, the compositions stored in plastic containers have a pD of less than about 7. In some embodiments, the compositions stored in plastic containers have a pD of less than about 6.9. In some embodiments, the compositions stored in plastic containers have a pD of less than about 6.8. In some embodiments, the compositions stored in plastic containers have a pD of less than about 6.7. In some embodiments, the compositions stored in plastic containers have a pD of less than about 6.6. In some embodiments, the compositions stored in plastic containers have a pD of less than about 6.5. In some embodiments, the composition stored in the plastic container has a pD of less than about 6.4. In some embodiments, the composition stored in the plastic container has a pD of less than about 6.3. In some embodiments, the composition stored in the plastic container has a pD of less than about 6.2. In some embodiments, the composition stored in the plastic container has a pD of less than about 6.1. In some embodiments, the composition stored in the plastic container has a pD of less than about 6. In some embodiments, the composition stored in the plastic container has a pD of less than about 5.9. In some embodiments, the composition stored in the plastic container has a pD of less than about 5.8. In some embodiments, the composition stored in the plastic container has a pD of less than about 5.7. In some embodiments, the composition stored in the plastic container has a pD of less than about 5.6.In some embodiments, the composition stored in the plastic container has a pD of less than about 5.5. In some embodiments, the composition stored in the plastic container has a pD of less than about 5.4. In some embodiments, the composition stored in the plastic container has a pD of less than about 5.3. In some embodiments, the composition stored in the plastic container has a pD of less than about 5.2. In some embodiments, the composition stored in the plastic container has a pD of less than about 5.1. In some embodiments, the composition stored in the plastic container has a pD of less than about 5. In some embodiments, the composition stored in the plastic container has a pD of less than about 4.9. In some embodiments, the composition stored in the plastic container has a pD of less than about 4.8. In some embodiments, the composition stored in the plastic container has a pD of less than about 4.7. In some embodiments, the composition stored in the plastic container has a pD of less than about 4.6. In some embodiments, the composition stored in the plastic container has a pD of less than about 4.5. In some embodiments, the composition stored in the plastic container has a pD of less than about 4.4. In some embodiments, the composition stored in the plastic container has a pD of less than about 4.3. In some embodiments, the composition stored in the plastic container has a pD of less than about 4.2. In some embodiments, the composition stored in the plastic container has a pD of less than about 4.1. In some embodiments, the composition stored in the plastic container has a pD of less than about 4.

[0130] In some embodiments, the composition stored in a plastic container retains at least 80% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition stored in a plastic container retains at least 85% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition stored in a plastic container retains at least 90% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition stored in a plastic container retains at least 93% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition stored in a plastic container retains at least 95% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition stored in a plastic container retains at least 97% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition stored in a plastic container retains at least 98% of its efficacy after a long period of time under storage conditions. In some embodiments, the composition stored in a plastic container retains at least 99% of its efficacy after a long period of time under storage conditions. In some examples, the storage conditions include temperatures of about 25°C, about 40°C, or about 60°C. In some cases, a longer period is at least one week, at least two weeks, at least three weeks, at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least eight months, at least ten months, at least twelve months, at least eighteen months, or at least twenty-four months.

[0131] In some embodiments, the composition stored in the plastic container has at least 80% efficacy at temperatures of about 25°C, about 40°C, or about 60°C. In some embodiments, the composition stored in the plastic container has at least 85% efficacy at temperatures of about 25°C, about 40°C, or about 60°C. In some embodiments, the composition stored in the plastic container has at least 90% efficacy at temperatures of about 25°C, about 40°C, or about 60°C. In some embodiments, the composition stored in the plastic container has at least 93% efficacy at temperatures of about 25°C, about 40°C, or about 60°C. In some embodiments, the composition stored in the plastic container has at least 95% efficacy at temperatures of about 25°C, about 40°C, or about 60°C. In some embodiments, the composition stored in the plastic container has at least 97% efficacy at temperatures of about 25°C, about 40°C, or about 60°C. In some embodiments, the composition stored in the plastic container has at least 98% efficacy at temperatures of about 25°C, about 40°C, or about 60°C. In some embodiments, the composition stored in the plastic container has at least 99% efficacy at temperatures of about 25°C, about 40°C, or about 60°C.

[0132] In some embodiments, a composition stored in a plastic container has at least 80% efficacy for a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, a composition stored in a plastic container has at least 85% efficacy for a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, a composition stored in a plastic container has at least 90% efficacy for a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the composition stored in the plastic container has at least 93% efficacy for a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the composition stored in the plastic container has at least 95% efficacy for a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months.In some embodiments, the composition stored in the plastic container has at least 97% efficacy for a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the composition stored in the plastic container has at least 98% efficacy for a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the composition stored in the plastic container has at least 99% efficacy for a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months.

[0133] In some embodiments, the composition stored in the plastic container contains less than 20% of the major degradation products, based on the concentration of the ophthalmic agent, after a long period of time under storage conditions. In some embodiments, the composition stored in the plastic container contains less than 15% of the major degradation products, based on the concentration of the ophthalmic agent, after a long period of time under storage conditions. In some embodiments, the composition stored in the plastic container contains less than 10% of the major degradation products, based on the concentration of the ophthalmic agent, after a long period of time under storage conditions. In some embodiments, the composition stored in the plastic container contains less than 5% of the major degradation products, based on the concentration of the ophthalmic agent, after a long period of time under storage conditions.

[0134] In some embodiments, the composition stored in the plastic container contains less than 2.5% to less than 0.1% of the major degradation products, based on the concentration of the ophthalmic agent, after a long period of time under storage conditions. In some embodiments, the composition stored in the plastic container contains less than 2.5% of the major degradation products, based on the concentration of the ophthalmic agent, after a long period of time under storage conditions. In some embodiments, the composition stored in the plastic container contains less than 2.0% of the major degradation products, based on the concentration of the ophthalmic agent, after a long period of time under storage conditions. In some embodiments, the composition stored in the plastic container contains less than 1.5% of the major degradation products, based on the concentration of the ophthalmic agent, after a long period of time under storage conditions. In some embodiments, the composition stored in the plastic container contains less than 1.0% of the major degradation products, based on the concentration of the ophthalmic agent, after a long period of time under storage conditions. In some embodiments, the composition stored in the plastic container contains less than 0.5% of the major degradation products, based on the concentration of the ophthalmic agent, after a long period of time under storage conditions. In some embodiments, the composition stored in the plastic container contains less than 0.4% of the major degradation products, based on the concentration of the ophthalmic agent, after a long period of time under storage conditions. In some embodiments, the composition stored in the plastic container contains less than 0.3% of the major degradation products, based on the concentration of the ophthalmic agent, after a long period of time under storage conditions. In some embodiments, the composition stored in the plastic container contains less than 0.2% of the major degradation products, based on the concentration of the ophthalmic agent, after a long period of time under storage conditions. In some embodiments, the composition stored in the plastic container contains less than 0.1% of the major degradation products, based on the concentration of the ophthalmic agent, after a long period of time under storage conditions. In some examples, the storage conditions include temperatures of about 25°C, about 40°C, or about 60°C. In some examples, the long period is at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months.

[0135] In some embodiments, the composition stored in the plastic container contains less than 20% of the major degradation products at a temperature of about 25°C, about 40°C, or about 60°C, based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container contains less than 15% of the major degradation products at a temperature of about 25°C, about 40°C, or about 60°C, based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container contains less than 10% of the major degradation products at a temperature of about 25°C, about 40°C, or about 60°C, based on the concentration of the ophthalmic agent. In some embodiments, the composition stored in the plastic container contains less than 5% of the major degradation products at a temperature of about 25°C, about 40°C, or about 60°C, based on the concentration of the ophthalmic agent.

[0136] In some embodiments, the composition stored in the plastic container contains less than 2.5% to less than 0.1% of the major hydrolysates, based on the concentration of the ophthalmic agent, at temperatures of about 25°C, about 40°C, or about 60°C. In some embodiments, the composition stored in the plastic container contains less than 2.5% of the major hydrolysates, based on the concentration of the ophthalmic agent, at temperatures of about 25°C, about 40°C, or about 60°C. In some embodiments, the composition stored in the plastic container contains less than 2.0% of the major hydrolysates, based on the concentration of the ophthalmic agent, at temperatures of about 25°C, about 40°C, or about 60°C. In some embodiments, the composition stored in the plastic container contains less than 1.5% of the major hydrolysates, based on the concentration of the ophthalmic agent, at temperatures of about 25°C, about 40°C, or about 60°C. In some embodiments, the composition stored in the plastic container contains less than 1.0% of the major hydrolysates, based on the concentration of the ophthalmic agent, at temperatures of about 25°C, about 40°C, or about 60°C. In some embodiments, the composition stored in the plastic container contains less than 0.5% of the major hydrolysates, based on the concentration of the ophthalmic agent, at temperatures of about 25°C, about 40°C, or about 60°C. In some embodiments, the composition stored in the plastic container contains less than 0.4% of the major hydrolysates, based on the concentration of the ophthalmic agent, at temperatures of about 25°C, about 40°C, or about 60°C. In some embodiments, the composition stored in the plastic container contains less than 0.3% of the major hydrolysates, based on the concentration of the ophthalmic agent, at temperatures of about 25°C, about 40°C, or about 60°C. In some embodiments, the composition stored in the plastic container contains less than 0.2% of the major hydrolysates, based on the concentration of the ophthalmic agent, at temperatures of about 25°C, about 40°C, or about 60°C. In some embodiments, the composition stored in the plastic container contains less than 0.1% of the major hydrolysates, based on the concentration of the ophthalmic agent, at temperatures of about 25°C, about 40°C, or about 60°C.

[0137] In some embodiments, the composition stored in the plastic container contains less than 20% of the major degradation products, based on the concentration of the ophthalmic agent, for a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the composition stored in the plastic container contains less than 15% of the major degradation products, based on the concentration of the ophthalmic agent, for a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the composition stored in the plastic container contains less than 10% of the major degradation products, based on the concentration of the ophthalmic agent, for a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the composition stored in the plastic container contains less than 5% of the major degradation products, based on the concentration of the ophthalmic agent, for a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months.

[0138] In some embodiments, the composition stored in the plastic container contains less than 2.5% to less than 0.1% of major degradation products, based on the concentration of the ophthalmic agent, for a period of at least one week, at least two weeks, at least three weeks, at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least eight months, at least ten months, at least twelve months, at least eighteen months, or at least twenty-four months. In some embodiments, the composition stored in the plastic container contains less than 2.0% of major degradation products, based on the concentration of the ophthalmic agent, for a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the composition stored in the plastic container contains less than 1.5% of major degradation products, based on the concentration of the ophthalmic agent, for a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months.In some embodiments, the composition stored in the plastic container contains less than 1.0% of major degradation products, based on the concentration of the ophthalmic agent, for a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the composition stored in the plastic container contains less than 0.5% of major degradation products, based on the concentration of the ophthalmic agent, for a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the composition stored in the plastic container contains less than 0.4% of major degradation products, based on the concentration of the ophthalmic agent, for a period of at least one week, at least two weeks, at least three weeks, at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least eight months, at least ten months, at least twelve months, at least eighteen months, or at least twenty-four months. In some embodiments, the composition stored in the plastic container contains less than 0.3% of major degradation products, based on the concentration of the ophthalmic agent, for a period of at least one week, at least two weeks, at least three weeks, at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least eight months, at least ten months, at least twelve months, at least eighteen months, or at least twenty-four months. In some embodiments, the composition stored in the plastic container contains less than 0.2% of the main breakdown products, based on the concentration of the ophthalmic agent, for a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months.In some embodiments, the composition stored in the plastic container contains less than 0.1% of the main breakdown products, based on the concentration of the ophthalmic agent, for a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months.

[0139] In some embodiments, the compositions described herein are stored in glass containers. In some embodiments, the glass container is a glass vial, such as a Type I, Type II, or Type III glass vial. In some embodiments, the glass container is a Type I glass vial. In some embodiments, the Type I glass vial is a borosilicate glass vial.

[0140] In some embodiments, the composition stored in the glass container has a pD higher than about 7. In some embodiments, the composition stored in the glass container has a pD higher than about 7.5. In some embodiments, the composition stored in the glass container has a pD higher than about 8. In some embodiments, the composition stored in the glass container has a pD higher than about 8.5. In some embodiments, the composition stored in the glass container has a pD higher than about 9.

[0141] In some embodiments, the composition stored in the glass container has less than 60% efficacy at temperatures of about 25°C, about 40°C, or about 60°C. In some embodiments, the composition stored in the glass container has less than 60% efficacy for a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, or at least 24 months.

[0142] In some embodiments, compositions stored in glass containers are less stable than compositions stored in plastic containers.

[0143] In some embodiments, the composition is stored in the dark. In some examples, the composition is stored in the presence of light. In some examples, the light is indoor light, ambient light, or sunlight. In some examples, the composition remains stable while stored in the presence of light.

[0144] In some embodiments, the compositions described herein are formulated as aqueous solutions. In some embodiments, the aqueous solutions are stable aqueous solutions. In some examples, the aqueous solutions are stored in plastic containers as described above. In some examples, the aqueous solutions are not stored in glass containers. In some examples, the aqueous solutions are stored in the dark. In some examples, the aqueous solutions are stored in the presence of light. In some examples, the aqueous solutions are stable in the presence of light.

[0145] In specific embodiments, ophthalmally acceptable formulations may contain cyclodextrins as an alternative. Cyclodextrins are cyclic oligosaccharides containing 6, 7, or 8 glucopyranose units, respectively, and are called α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin. Cyclodextrins have a hydrophilic exterior that enhances water solubility and a hydrophobic interior that forms a cavity. In an aqueous environment, the hydrophobic portions of other molecules often enter the hydrophobic cavity of the cyclodextrin, forming inclusion compounds. Furthermore, cyclodextrins are also capable of other types of non-bonding interactions with molecules not located inside the hydrophobic cavity. Cyclodextrins have three free hydroxyl groups per glucopyranose unit, or 18 hydroxyl groups on α-cyclodextrin, 21 hydroxyl groups on β-cyclodextrin, and 24 hydroxyl groups on γ-cyclodextrin. In some embodiments, one or more of these hydroxyl groups are reacted with one of many reagents to form a wide variety of cyclodextrin derivatives, including hydroxypropyl ethers, sulfonates, and sulfoalkyl ethers. The structures of β-cyclodextrin and hydroxypropyl-β-cyclodextrin (HPβCD) are shown below.

[0146] [ka]

[0147] In some embodiments, the use of cyclodextrins in the pharmaceutical compositions described herein enhances the solubility of the drug. While inclusion compounds are associated with many cases of enhanced solubility, other interactions between cyclodextrins and insoluble compounds also enhance solubility. Hydroxypropyl-β-cyclodextrin (HPβCD) is commercially available as a pyrogen-free product. It is a non-hygroscopic white powder that readily dissolves in water. HPβCD is thermally stable and does not decompose at a neutral pH. Therefore, cyclodextrins enhance the solubility of therapeutic agents in compositions or formulations. Thus, in some embodiments, cyclodextrins are included to increase the solubility of ophthalmological preparations that are acceptable to the eye in the formulations described herein. In other embodiments, cyclodextrins further act as controlled-release excipients in the formulations described herein.

[0148] To name just a few examples, cyclodextrin derivatives for use include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxy-ethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfated β-cyclodextrin, sulfated α-cyclodextrin, and sulfobutyl ether β-cyclodextrin.

[0149] The concentrations of cyclodextrin used in the compositions and methods disclosed herein vary depending on the physiological and chemical properties, pharmacokinetic properties, side effects or adverse events, formulation considerations, or other factors relating to the properties of the therapeutic ophthalmic agent, its salt or prodrug, or other excipients in the composition. Therefore, in a given environment, the concentration or amount of cyclodextrin used according to the compositions and methods disclosed herein may vary as needed. The amount of cyclodextrin used in any of the formulations described herein that is required to increase the solubility of the ophthalmic agent and / or to function as a controlled-release excipient should be selected using the principles, examples, and teachings described herein.

[0150] Other stabilizers useful for ophthalmally acceptable formulations disclosed herein include, for example, fatty acids, fatty alcohols, alcohols, long-chain fatty acid esters, long-chain ethers, hydrophilic derivatives of fatty acids, polyvinylpyrrolidone, polyvinyl ethers, polyvinyl alcohols, hydrocarbons, hydrophobic polymers, hygroscopic polymers, and combinations thereof. In some embodiments, amide analogs of stabilizers are also used. In further embodiments, the selected stabilizer alters the hydrophobicity of the formulation, improves the mixing of various components in the formulation, controls the water level in the formulation, or controls the mobility of the phases.

[0151] In other embodiments, the stabilizer is present in an amount sufficient to inhibit the degradation of the ophthalmic agent. Examples of such stabilizers include, but are not limited to, glycerol, methionine, monothioglycerol, EDTA, ascorbic acid, polysorbate 80, polysorbate 20, arginine, heparin, dextran sulfate, cyclodextrin, pentosan polysulfate and other heparinoids, divalent cations such as magnesium and zinc, or combinations thereof.

[0152] Additional useful stabilizers for ophthalmally acceptable formulations include one or more anti-agglutination additives that enhance the stability of the ophthalmic formulation by reducing the protein aggregation rate. The choice of anti-agglutination additive depends on the nature of the condition to which the ophthalmic formulation, e.g., a muscarinic antagonist (e.g., atropine or a pharmaceutically acceptable salt thereof), is subjected. For example, formulations subjected to agitation and thermal stress require different anti-agglutination additives than those subjected to lyophilization and reconstitution. Useful anti-agglutination additives include, but are not limited to, urea, guanidinium chloride, simple amino acids such as glycine or arginine, sugars, polyalcohols, polysorbates, polymers such as polyethylene glycol and dextran, alkyl saccharides such as alkyl glycosides, and surfactants.

[0153] Other useful formulations optionally include one or more eye-tolerant antioxidants to enhance chemical stability as needed. Suitable antioxidants include, but are not limited to, ascorbic acid, methionine, sodium thiosulfate, and sodium metabisulfite. In one embodiment, the antioxidant is selected from metal chelating agents, thiol-containing compounds, and other common stabilizers.

[0154] Other useful compositions may include one or more eye-acceptable surfactants for enhancing physical stability or for other purposes. Suitable nonionic surfactants include, but are not limited to, polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.

[0155] In some embodiments, the ophthalmally acceptable pharmaceutical formulations described herein are stable against compound degradation for any of the following periods under storage conditions (e.g., room temperature): at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months (e.g., less than 30% degradation, less than 25% degradation, less than 20% degradation, less than 15% degradation, less than 10% degradation, less than 8% degradation, less than 5% degradation, less than 3% degradation, less than 2% degradation, or less than 5% degradation). In other embodiments, the formulations described herein are stable against compound degradation for a period of at least about 1 week. The specification also describes formulations that are stable with respect to compound degradation for a period of at least about 1 month.

[0156] In other embodiments, additional surfactants (auxiliary surfactants) and / or buffers are combined with one or more pharmaceutically acceptable vehicles previously described herein, so that the surfactants and / or buffers maintain the product at an optimal pD for stability. Suitable auxiliary surfactants include, but are not limited to, the following: a) natural and synthetic lipophilic agents, e.g., phospholipids, cholesterol, cholesterol fatty acid esters, and their derivatives; b) e.g., polyoxyethylene fatty alcohol esters, sorbitan fatty acid esters (Spans), polyoxyethylene sorbitan fatty acid esters (e.g., polyoxyethylene (20) sorbitan monooleate (Tween 80), polyoxyethylene (20) sorbitan monostearate (Tween 60), polyoxyethylene (20) sorbitan monolaurate (Tween 20), and other Tween), sorbitan esters, glycerol esters, e.g., Myrj and glycerol triacetate (triacetin), polyethylene glycol, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, polysorbate 80, poloxamer, poloxamine, polyoxyethylene, castor oil derivatives (e.g., Cremophor® RH40, Cremphor A25, Cremphor Nonionic surfactants including A20, Cremophor® EL) and other Cremophors, sulfosuccinates, alkyl sulfates (SLS); PEG glyceryl fatty acid esters such as PEG-8 glyceryl caprylate / caprate (Labrasol), PEG-4 glyceryl caprylate / caprate (Labrafac Hydro WL 1219), PEG-32 glyceryl laurate (Gelucire 444 / 14), PEG-6 glyceryl monooleate (Labrafil M 1944 CS), and PEG-6 glyceryl linoleate (Labrafil M 2125 CS); propylene glycol mono-fatty acid esters and propylene glycol di-fatty acid esters such as propylene glycol laurate, propylene glycol caprylate / caprate;c) Anionic surfactants, but not limited to, calcium carboxymethylcellulose, sodium carboxymethylcellulose, sodium sulfosuccinate, dioctyl, sodium alginate, alkyl polyoxyethylene sulfate, sodium lauryl sulfate, triethanolamine stearate, potassium laurate, bile salts, and any combination or mixture thereof; and d) Cationic surfactants such as cetyltrimethylammonium bromide and lauryldimethylbenzyl ammonium chloride.

[0157] In further embodiments, one or more auxiliary surfactants, when used in the ophthalmally acceptable formulations of the present disclosure, are combined with, for example, a pharmaceutically acceptable vehicle and present in the final formulation in amounts ranging from about 0.1% to about 20% and about 0.5% to about 10%.

[0158] In one embodiment, the surfactant has an HLB value of 0 to 20. In an additional embodiment, the surfactant has an HLB value of 0 to 3, 4 to 6, 7 to 9, 8 to 18, 13 to 15, or 10 to 18.

[0159] <pd> In some embodiments, the pD of the compositions described herein is adjusted (for example, by the use of buffers and / or pD modifiers) to an ophthalmally suitable pD range of about 4 to about 8, about 4.5 to about 7.5, or about 5 to about 7. In some embodiments, the ophthalmic composition has a pD of about 5.0 to about 7.0. In some embodiments, the ophthalmic composition has a pD of about 5.5 to about 7.0. In some embodiments, the ophthalmic composition has a pD of about 6.0 to about 7.0.

[0160] In some embodiments, the useful formulation comprises one or more pD modifiers or buffers. Suitable pD modifiers or buffers include, but are not limited to, acetates, bicarbonates, ammonium chloride, citrates, phosphates, deuterated forms of acetates, bicarbonates, ammonium chloride, citrates, phosphates, or pharmaceutically acceptable salts thereof and combinations and mixtures thereof. In some embodiments, the pD modifier or buffer includes deuterated hydrochloric acid (DCl), deuterated sodium hydroxide (NaOD), deuterated acetic acid (CD3COOD), or deuterated citrate (C6D8O7).

[0161] In one embodiment, one or more buffers, when used in the formulation of the Disclosure, are combined with, for example, a pharmaceutically acceptable vehicle and are present in the final formulation in amounts ranging from, for example, about 0.1% to about 20% or about 0.5% to about 10%. In certain embodiments of the Disclosure, the amount of buffer included in the gel formulation is such that the pD of the gel formulation does not interfere with the body's natural buffering system.

[0162] In one embodiment, a diluent is also used to stabilize the compound because the diluent provides a more stable environment. In some examples, a salt dissolved in a buffer (which also provides control or maintenance of pD) is used as a diluent in the art, including, but not limited to, phosphate-buffered saline solution.

[0163] In some embodiments, pD is calculated according to the formula disclosed in Glasoe et al., “Use of glass electrodes to measure acidities in deuterium oxide,” J. Physical Chem. 64(1): 188-190 (1960). In some embodiments, pD is calculated as pD = pH * It is calculated as +0.4, and in the formula, pH * This is the measured or observed pH of an ophthalmic composition formulated in a solution containing deuterated water (e.g., D2O).

[0164] In some embodiments, the ophthalmic, aqueous, gel or ointment compositions described herein have a pD between about 4 and about 8, between about 4.5 and about 8, between about 4.9 and about 7.9, between about 5.4 and about 7.9, between about 5.9 and about 7.9, between about 6.4 and about 7.9, or between about 7.4 and about 7.9. In some embodiments, the ophthalmic, aqueous, gel or ointment compositions described herein have a pD between about 4.5 and about 7.5, between about 5.0 and about 7.5, between about 5.5 and about 7.5, between about 6.0 and about 7.5, or between about 7.0 and about 7.5. In some embodiments, the ophthalmic, aqueous, gel or ointment compositions described herein have a pD between about 4.5 and about 7.0, between about 5.0 and about 7.0, between about 5.5 and about 7.0, between about 6.0 and about 7.0, or between about 6.5 and about 7.0. In some embodiments, the ophthalmic, aqueous, gel or ointment compositions described herein have a pD between about 4.9 and about 7.4, between about 5.4 and about 7.4, between about 5.9 and about 7.4, between about 6.4 and about 7.4, or between about 6.9 and about 7.4. In some embodiments, the ophthalmic, aqueous, gel or ointment compositions described herein have a pD between about 4.5 and about 6.5, between about 5.0 and about 6.5, between about 5.5 and about 6.5, or between about 6.0 and about 6.5. In some embodiments, the ophthalmic, aqueous, gel or ointment compositions described herein have a pD between about 4.9 and 6.9, between about 5.4 and 6.9, between about 5.9 and 6.9, or between about 6.4 and 6.9. In some embodiments, the ophthalmic, aqueous, gel or ointment compositions described herein have a pD between about 4.5 and 6.0, between about 5.0 and 6.0, or between about 5.5 and 6.0. In some embodiments, the ophthalmic, aqueous, gel or ointment compositions described herein have a pD between about 4.9 and 6.4, between about 5.4 and 6.4, or between about 5.9 and 6.4. In some embodiments, the ophthalmic, aqueous, gel or ointment compositions described herein have a pD between about 4.5 and 5.5, or between about 5.0 and 5.5.In some embodiments, the ophthalmic, aqueous, gel, or ointment compositions described herein have a pD between about 4.9 and 5.9, or between about 5.4 and 5.9. In some embodiments, the ophthalmic, aqueous, gel, or ointment compositions described herein have a pD between about 4.5 and 5.0. In some embodiments, the ophthalmic, aqueous, gel, or ointment compositions described herein have a pD between about 4.9 and 5.4.

[0165] In some embodiments, the ophthalmic composition is an aqueous ophthalmic composition. In some examples, the aqueous ophthalmic composition has a pD between about 4 and about 8, about 4.5 and about 7.8, about 5 and about 7.5, or about 5.5 and about 7. In some embodiments, the aqueous ophthalmic composition has a pD of about 7.5. In some embodiments, the aqueous ophthalmic composition has a pD of about 7.4. In some embodiments, the aqueous ophthalmic composition has a pD of about 7.3. In some embodiments, the aqueous ophthalmic composition has a pD of about 7.2. In some embodiments, the aqueous ophthalmic composition has a pD of about 7.1. In some embodiments, the aqueous ophthalmic composition has a pD of about 7. In some embodiments, the aqueous ophthalmic composition has a pD of about 6.9. In some embodiments, the aqueous ophthalmic composition has a pD of about 6.8. In some embodiments, the aqueous ophthalmic composition has a pD of about 6.7. In some embodiments, the aqueous ophthalmic composition has a pD of about 6.6. In some embodiments, the aqueous ophthalmic composition has a pD of about 6.5. In some embodiments, the ophthalmic aqueous composition has a pD of about 6.4. In some embodiments, the ophthalmic aqueous composition has a pD of about 6.3. In some embodiments, the ophthalmic aqueous composition has a pD of about 6.2. In some embodiments, the ophthalmic aqueous composition has a pD of about 6.1. In some embodiments, the ophthalmic aqueous composition has a pD of about 6. In some embodiments, the ophthalmic aqueous composition has a pD of about 5.9. In some embodiments, the ophthalmic aqueous composition has a pD of about 5.8. In some embodiments, the ophthalmic aqueous composition has a pD of about 5.7. In some embodiments, the ophthalmic aqueous composition has a pD of about 5.6. In some embodiments, the ophthalmic aqueous composition has a pD of about 5.5. In some embodiments, the ophthalmic aqueous composition has a pD of about 5.4. In some embodiments, the ophthalmic aqueous composition has a pD of about 5.3. In some embodiments, the ophthalmic aqueous composition has a pD of about 5.2. In some embodiments, the ophthalmic aqueous composition has a pD of about 5.1. In some embodiments, the ophthalmic aqueous composition has a pD of about 5. In some embodiments, the ophthalmic aqueous composition has a pD of about 4.9.In some embodiments, the ophthalmic aqueous composition has a pD of about 4.8. In some embodiments, the ophthalmic aqueous composition has a pD of about 4.7. In some embodiments, the ophthalmic aqueous composition has a pD of about 4.6. In some embodiments, the ophthalmic aqueous composition has a pD of about 4.5. In some embodiments, the ophthalmic aqueous composition has a pD of about 4.4. In some embodiments, the ophthalmic aqueous composition has a pD of about 4.3. In some embodiments, the ophthalmic aqueous composition has a pD of about 4.2. In some embodiments, the ophthalmic aqueous composition has a pD of about 4.1. In some embodiments, the ophthalmic aqueous composition has a pD of about 4. In some embodiments, pD is the initial pD of the ophthalmic aqueous composition. In some embodiments, pD is the pD of the ophthalmic aqueous composition after a long period of time under storage conditions.

[0166] In some examples, the ophthalmic aqueous composition has an initial pD between about 4 and about 8, about 4.5 and about 7.8, about 5 and about 7.5, or about 5.5 and about 7. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 7.5. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 7.4. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 7.3. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 7.2. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 7.1. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 7. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 6.9. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 6.8. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 6.7. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 6.6. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 6.5. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 6.4. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 6.3. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 6.2. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 6.1. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 6. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 5.9. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 5.8. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 5.7. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 5.6. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 5.5. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 5.4. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 5.3. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 5.2. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 5.1. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 5.In some embodiments, the ophthalmic aqueous composition has an initial pD of about 4.9. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 4.8. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 4.7. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 4.6. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 4.5. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 4.4. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 4.3. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 4.2. In some embodiments, the ophthalmic aqueous composition has an initial pD of about 4.

[0167] In some examples, the ophthalmic aqueous composition has a pD between about 4 and about 8, about 4.5 and about 7.8, about 5 and about 7.5, or about 5.5 and about 7. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 7.5. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 7.4. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 7.3. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 7.2. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 7.1. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 7. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 6.9. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 6.8. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 6.7. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 6.6. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 6.5. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 6.4. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 6.3. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 6.2. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 6.1. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 6. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 5.9. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 5.8. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 5.7. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 5.6. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 5.5. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 5.4. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 5.3. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 5.2. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 5.1. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 5.In some embodiments, the ophthalmic aqueous composition has a pD of less than about 4.9. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 4.8. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 4.7. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 4.6. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 4.5. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 4.4. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 4.3. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 4.2. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 4.1. In some embodiments, the ophthalmic aqueous composition has a pD of less than about 4. In some embodiments, pD is the pD of the ophthalmic aqueous composition after a long period of time under storage conditions.

[0168] In some embodiments, the pD of the ophthalmic aqueous compositions described herein relates to the stability of the ophthalmic aqueous compositions. In some embodiments, stable compositions include pDs between about 4 and about 8, about 4.5 and about 7.8, about 5 and about 7.5, or about 5.5 and about 7. In some embodiments, stable compositions include pDs less than about 7.5. In some embodiments, stable compositions include pDs less than about 7.4. In some embodiments, stable compositions include pDs less than about 7.3. In some embodiments, stable compositions include pDs less than about 7.2. In some embodiments, stable compositions include pDs less than about 7.1. In some embodiments, stable compositions include pDs less than about 7.9. In some embodiments, stable compositions include pDs less than about 6.8. In some embodiments, stable compositions include pDs less than about 6.7. In some embodiments, stable compositions include pDs less than about 6.6. In some embodiments, stable compositions include pDs less than about 6.5. In some embodiments, stable compositions include pDs less than about 6.4. In some embodiments, the stable composition contains less than about 6.3 pD. In some embodiments, the stable composition contains less than about 6.2 pD. In some embodiments, the stable composition contains less than about 6.1 pD. In some embodiments, the stable composition contains less than about 6 pD. In some embodiments, the stable composition contains less than about 5.9 pD. In some embodiments, the stable composition contains less than about 5.8 pD. In some embodiments, the stable composition contains less than about 5.7 pD. In some embodiments, the stable composition contains less than about 5.6 pD. In some embodiments, the stable composition contains less than about 5.5 pD. In some embodiments, the stable composition contains less than about 5.4 pD. In some embodiments, the stable composition contains less than about 5.3 pD. In some embodiments, the stable composition contains less than about 5.2 pD. In some embodiments, the stable composition contains less than about 5.1 pD. In some embodiments, the stable composition contains less than about 5 pD.In some embodiments, the stable composition comprises a pD of less than about 4.9. In some embodiments, the stable composition comprises a pD of less than about 4.8. In some embodiments, the stable composition comprises a pD of less than about 4.7. In some embodiments, the stable composition comprises a pD of less than about 4.6. In some embodiments, the stable composition comprises a pD of less than about 4.5. In some embodiments, the stable composition comprises a pD of less than about 4.4. In some embodiments, the stable composition comprises a pD of less than about 4.3. In some embodiments, the stable composition comprises a pD of less than about 4.2. In some embodiments, the stable composition comprises a pD of less than about 4.1. In some embodiments, the stable composition comprises a pD of less than about 4.

[0169] In some embodiments, the aqueous system of D2O stabilizes a muscarinic antagonist (e.g., atropine). In some embodiments, this is because the concentration of reactive species (e.g., -OD) in the aqueous system of D2O is lower compared to the concentration of reactive species (e.g., -OH) in an equivalent aqueous system of H2O. In some examples, the concentration of reactive species (e.g., -OD) in the aqueous system of D2O is less than about one-third of the concentration of reactive species (e.g., -OH) in an equivalent aqueous system of H2O. In some cases, this is because the dissociation constant of D2O is lower or less than that of H2O. For example, Ka(H2O) is 1×10 -14 whereas K a (D2O) is 1×10 -15 . Therefore, D2O is less acidic than H2O. In some cases, tropine degradation products are brought about from atropine by base-catalyzed hydrolysis. In some cases, the atropine solution is more stable in the aqueous system of D2O compared to an equivalent aqueous system of H2O due to the low concentration of reactive species that cause the formation of tropine degradation products. In some embodiments, an ophthalmic composition can be more stabilized when formulated with deuterated water than when formulated with H2O.

[0170] In some embodiments, the presence of deuterated water alters the pKa of the buffer. In some embodiments, the presence of deuterated water allows the ophthalmic composition to simulate stability at lower pH systems. In some examples, the buffering capacity of the ophthalmic composition is reduced, thereby allowing for faster pH changes. In some examples, the reduced buffering capacity of the ophthalmic composition upon administration to the eye allows the ophthalmic composition to reach physiological pH at a faster rate than an ophthalmic composition formulated in H2O. In some examples, an ophthalmic composition formulated in deuterated water allows for lower tear production or less tear reflection in the eye compared to an ophthalmic composition formulated in H2O.

[0171] In some embodiments, the ophthalmic gel or ointment compositions described herein have a pD of about 4, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, or about 7.9.

[0172] In some embodiments, the pD of the ophthalmic, aqueous, gel, or ointment compositions described herein is suitable for sterilization of the ophthalmic formulations described herein (e.g., by filtration or sterile mixing or by heat treatment and / or autoclaving (e.g., final sterilization)). As used in this disclosure, the term “aqueous composition” includes compositions based on D2O.

[0173] In some embodiments, the pharmaceutical formulations described herein are stable to pD for a period of at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 3 years, at least about 4 years, at least about 5 years, at least about 6 years, at least about 7 years, at least about 8 years, at least about 9 years, at least about 10 years, or any of these periods. In other embodiments, the formulations described herein are stable to pD for a period of at least about 1 week. In other embodiments, the formulations described herein are stable against pD for a period of at least about two weeks. In other embodiments, the formulations described herein are stable against pD for a period of at least about three weeks. In other embodiments, the formulations described herein are stable against pD for a period of at least about one month. The specification also describes formulations that are stable against pD for a period of at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about twelve months, at least about eighteen months, at least about two years, or longer.

[0174] <Uniformity of aqueous solution dosages> Typical ophthalmic aqueous solutions are packaged in eye drop bottles and administered as drops. For example, a single dose (i.e., single dose) of an ophthalmic aqueous solution may consist of one, two, three, or more drops administered to the patient's eye. In some embodiments, a single dose of an ophthalmic aqueous solution described herein is one drop of the aqueous composition from an eye drop bottle.

[0175] In some cases, the ophthalmic aqueous solutions described herein include ophthalmic aqueous compositions that provide uniform concentrations between doses. In some examples, uniform concentrations between doses do not show a significant change in drug content from one dose to another. In some examples, uniform concentrations between doses provide a consistent drug content from one dose to another.

[0176] In some embodiments, the composition has a concentration change of less than 50% between doses. In some embodiments, the composition has a concentration change of less than 40% between doses. In some embodiments, the composition has a concentration change of less than 30% between doses. In some embodiments, the composition has a concentration change of less than 20% between doses. In some embodiments, the composition has a concentration change of less than 10% between doses. In some embodiments, the composition has a concentration change of less than 5% between doses.

[0177] In some embodiments, the change in concentration of the ophthalmic agent between doses is based on 10 consecutive doses. In some embodiments, the change in concentration of the ophthalmic agent between doses is based on 8 consecutive doses. In some embodiments, the change in concentration of the ophthalmic agent between doses is based on 5 consecutive doses. In some embodiments, the change in concentration of the ophthalmic agent between doses is based on 3 consecutive doses. In some embodiments, the change in concentration of the ophthalmic agent between doses is based on 2 consecutive doses.

[0178] Nonsettling formulations should not require shaking to uniformly disperse the drug. “No-shake” formulations have potential advantages over those requiring shaking for the simple reason that patient shaking behavior is the primary source of variability in the amount of drug administered. It has been reported that patients often fail to shake or forget to shake ophthalmic compositions that require shaking before administration, even when instructions to do so are clearly indicated on the label. On the other hand, even for these patients who do shake the product, it is usually not possible to determine whether the shaking is sufficient in terms of intensity and / or duration to homogenize the product. In some embodiments, the ophthalmic gel and ophthalmic ointment compositions described herein are “no-shake” formulations that maintain the uniformity between the doses described herein.

[0179] To evaluate uniformity between doses, dropper bottles or tubes containing ophthalmic aqueous compositions, ophthalmic gel compositions, or ophthalmic ointment compositions are stored upright for a minimum of 12 hours before the start of the test. To simulate the recommended dosage of these products, predetermined amounts of drops or strips are dispensed from each commercial bottle or tube at predetermined intervals over a long period or until no product remains in the bottle or tube. All drops or strips are dispensed into tared glass vials and stored at room temperature until analysis. The concentrations of muscarinic antagonists, such as atropine, in the expressed drops were determined using reversed-phase HPLC.

[0180] <Aqueous solution viscosity> In some embodiments, the composition is approximately 20°C and 1 second -1 At a shear rate of , it has a Brookfield RVDV viscosity of about 10 to about 50,000 cps. In some embodiments, the composition is about 20°C and 1 s -1 At a shear rate of approximately 100 to 40,000 cps, the composition has a Brookfield RVDV viscosity. In some embodiments, the composition is approximately 20°C and 1 s -1 At a shear rate of approximately 500 to 30,000 cps, the composition has a Brookfield RVDV viscosity. In some embodiments, the composition is approximately 20°C and 1 s -1 At a shear rate of , it has a Brookfield RVDV viscosity of about 1,000 to about 20,000 cps. In some embodiments, the composition is about 20°C and 1 s -1 At a shear rate, it has a Brookfield RVDV viscosity of about 2,000 to about 10,000 cps. In some embodiments, the composition is about 20°C and 1 s -1 At a shear rate, it has a Brookfield RVDV viscosity of approximately 4000 to 8000 cps.

[0181] In some embodiments, the ophthalmic aqueous formulation contains a viscosity enhancer sufficient to provide a viscosity between approximately 500 and 50,000 centipoise, between approximately 750 and 50,000 centipoise; between approximately 1,000 and 50,000 centipoise; between approximately 1,000 and 40,000 centipoise; between approximately 2,000 and 30,000 centipoise; between approximately 3,000 and 20,000 centipoise; between approximately 4,000 and 10,000 centipoise; or between approximately 5,000 and 8,000 centipoise.

[0182] In some embodiments, the compositions described herein are low viscosity compositions at body temperature. In some embodiments, the low viscosity compositions contain about 1% to about 10% of a viscosity enhancer (e.g., a gelling component such as polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the low viscosity compositions contain about 2% to about 10% of a viscosity enhancer (e.g., a gelling component such as polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the low viscosity compositions contain about 5% to about 10% of a viscosity enhancer (e.g., a gelling component such as polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the low viscosity compositions contain substantially no viscosity enhancer (e.g., a gelling component such as polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the low viscosity ophthalmic formulation compositions described herein provide an apparent viscosity from about 100 cP to about 10,000 cP. In some embodiments, the ophthalmic formulation compositions described herein provide an apparent viscosity from about 500 cP to about 10,000 cP. In some embodiments, the ophthalmic composition described herein provides an apparent viscosity ranging from about 1,000 cP to about 10,000 cP.

[0183] <Molar osmotic pressure> In some embodiments, the compositions disclosed herein are formulated so as not to disrupt the ion balance of the eye. In some embodiments, the compositions disclosed herein have the same or substantially the same ion balance as the eye. In some embodiments, the compositions disclosed herein do not disrupt the ion balance of the eye.

[0184] As used herein, “practical osmolarity / osmolality” or “deliverable osmolarity / osmolality” means the molar osmolality of a composition, which is determined by measuring the molar osmolality of all excipients except ophthalmic agents and gelling agents and / or thickeners (e.g., polyoxyethylene-polyoxypropylene copolymer, carboxymethylcellulose, etc.). The practical molar osmolality of the compositions disclosed herein is measured by a suitable method, e.g., the freezing point depression method as described in Viegas et. al., Int. J. Pharm., 1998, 160, 157-162. In some cases, the practical molar osmolality of the compositions disclosed herein is measured by the vapor pressure osmotic method (e.g., vapor pressure depression method), which allows for the determination of the molar osmolality of the composition at higher temperatures. In some cases, vapor pressure lowering allows for the determination of the molar osmotic concentration of compositions containing a gelling agent (e.g., a thermoreversible polymer) at higher temperatures, where the gelling agent is in the form of a gel.

[0185] In some embodiments, the molar osmotic concentration at the target site of action (e.g., the eye) is approximately the same as the delivered molar osmotic concentration of the composition described herein. In some embodiments, the composition described herein has deliverable molar osmotic concentrations ranging from about 150 mOsm / L to about 500 mOsm / L, about 250 mOsm / L to about 500 mOsm / L, about 250 mOsm / L to about 350 mOsm / L, about 280 mOsm / L to about 370 mOsm / L, or about 250 mOsm / L to about 320 mOsm / L.

[0186] The practical molar osmotic concentrations of the ophthalmic compositions disclosed herein range from approximately 100 mOsm / kg to approximately 1000 mOsm / kg, approximately 200 mOsm / kg to approximately 800 mOsm / kg, approximately 250 mOsm / kg to approximately 500 mOsm / kg, approximately 250 mOsm / kg to approximately 320 mOsm / kg, approximately 250 mOsm / kg to approximately 350 mOsm / kg, or approximately 280 mOsm / kg to approximately 320 mOsm / kg. In some embodiments, the compositions described herein have practical molar osmotic concentrations ranging from about 100 mOsm / L to about 1000 mOsm / L, about 200 mOsm / L to about 800 mOsm / L, about 250 mOsm / L to about 500 mOsm / L, about 250 mOsm / L to about 350 mOsm / L, about 250 mOsm / L to about 320 mOsm / L, or about 280 mOsm / L to about 320 mOsm / L.

[0187] In some embodiments, suitable isotonic agents include, but are not limited to, any pharmaceutically acceptable sugars, salts, or any combination or mixture thereof, such as dextrose, glycerin, mannitol, sorbitol, sodium chloride, and other electrolytes. In some examples, the isotonic agent is selected from sodium chloride, sodium nitrate, sodium sulfate, disodium bisulfate, potassium chloride, calcium chloride, magnesium chloride, zinc chloride, potassium acetate, sodium acetate, disodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dextrose, mannitol, sorbitol, dextrose, sucrose, urea, propylene glycol, glycerin, or combinations thereof.

[0188] In some embodiments, the ophthalmic compositions described herein contain one or more salts in amounts required to bring the molar osmotic concentration of the composition into an acceptable range. Such salts include those having a sodium cation, a potassium cation, or an ammonium cation, and a chloride anion, a citrate anion, an ascorbate anion, a borate anion, a phosphate anion, a bicarbonate anion, a sulfate anion, a thiosulfate anion, or a bisulfite anion; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0189] <Sterilization> In some embodiments, the compositions are sterilized. Embodiments disclosed herein include means and processes for sterilizing the pharmaceutical compositions disclosed herein for human use. The objective is to provide safe pharmaceutical products that are relatively free of infection-causing microorganisms. The U.S. Food and Drug Administration provides regulatory guidance in its publication, “Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing,” available at http: / / www.fda.gov / cder / guidance / 5882fnl.htm, which is incorporated herein by reference in its entirety.

[0190] As used herein, sterilization means a process used to destroy or remove microorganisms present in a product or packaging. Any suitable method available for sterilizing the subject and composition is used. Methods available for inactivating microorganisms include, but are not limited to, the application of extreme heat, lethal agents, or gamma rays. In some embodiments, the process for preparing ophthalmic formulations includes exposing the formulation to a sterilization method selected from thermal sterilization, chemical sterilization, radiation sterilization, or filtration sterilization. The method used depends largely on the nature of the device or composition being sterilized. A detailed description of many methods of sterilization is given in Chapter 40 of Remington: The Science and Practice of Pharmacy, published by Lippincott, Williams & Wilkins, and is incorporated by citations relating to this subject.

[0191] <filtration> Filtration sterilization is a method used to remove microorganisms from a solution without destroying them. Membrane filters are used to filter thermosensitive solutions. Such membrane filters are thin, strong, homogeneous polymers of mixed cellulose esters (MCE), polyvinylidene fluoride (PVF; also known as PVDF), or polytetrafluoroethylene (PTFE), with pore sizes ranging from 0.1 to 0.22 μm. Solutions with various properties are filtered using different membrane filters as needed. For example, PVF and PTFE membranes are well-suited to the organic solvent being filtered, while aqueous solutions are filtered through PVF or MCE membranes. Filtration equipment is available for a wide range of uses, from single-point-of-use disposable filters attached to syringes to industrial-scale filters for use in manufacturing plants. Membrane filters are sterilized by autoclaving or chemical sterilization. The membrane filtration system was validated according to a standardized protocol (Microbiological Evaluation of Filters for Sterilizing Liquids, Vol 4, No. 3. Washington, DC: Health Industry Manufacturers Association, 1981), and known quantities (approximately 10) of Brevundimonas diminuta (ATCC 19146) were tested. 7 / cm 2 This includes challenging the membrane filter using unusually small microorganisms.

[0192] The pharmaceutical composition is sterilized by passing through a membrane filter, as desired. Formulations containing nanoparticles (U.S. Patent No. 6,139,870) or multilayer vesicles (Richard et al., International Journal of Pharmaceutics (2006), 312(1-2):144-50) are suitable for sterilization by filtration through a 0.22 μm filter without destroying their organized structure.

[0193] In some embodiments, the methods disclosed herein include a step of sterilizing the formulation (or its components) by filtration. In ophthalmic gel compositions comprising a thermosetting polymer, filtration is performed at a temperature below the gelation temperature (Tgel) of the formulation described herein (e.g., about 5°C) and at a viscosity (e.g., below a theoretical value of 100 cP) that allows filtration within a reasonable time using a peristaltic pump.

[0194] Accordingly, methods for sterilizing ophthalmic formulations are provided herein that prevent the degradation of polymer components (e.g., thermosetting agents and / or other viscosity enhancers) and / or ophthalmic formulations during the sterilization process. In some embodiments, degradation of ophthalmic formulations (e.g., muscarinic antagonists such as atropine or atropine sulfate) is reduced or eliminated through the use of buffer components and specific pD ranges for viscosity enhancers in the formulations at specific ratios. In some embodiments, the selection of appropriate viscosity enhancers or thermosetting polymers allows sterilization of the formulations described herein by filtration. In some embodiments, the use of appropriate thermosetting polymers or other viscosity enhancers in combination with specific pD ranges for the formulations allows high-temperature sterilization of the formulations described herein with substantially no degradation of the therapeutic agents or polymer excipients. The advantage of the sterilization methods provided herein is that, in certain cases, the formulations are subjected to final sterilization by autoclaving with no loss of ophthalmic agents and / or excipients and / or viscosity enhancers during the sterilization process, and microorganisms and / or pyrogens are substantially eliminated.

[0195] Radiation sterilization One advantage of radiation sterilization is its ability to sterilize many types of products without causing thermal decomposition or other damage. The radiation commonly used is beta radiation, or alternatively, 60 The gamma rays are derived from a Co source. The penetrating ability of gamma rays allows for their use in the sterilization of many types of products, including solutions, compositions, and heterogeneous mixtures. The bactericidal effect of irradiation arises from the interaction between gamma rays and biopolymers. This interaction generates charged species and free radicals. Subsequent chemical reactions, such as rearrangement and crosslinking processes, result in the loss of normal function of these biopolymers. The formulations described herein may also be sterilized using beta irradiation as optional.

[0196] Heat sterilization Many methods are available for sterilization by the application of high heat. One method involves the use of a saturated steam autoclave. In this sterilization method, saturated steam at a temperature of at least 121°C is brought into contact with the object to be sterilized. Heat transfer occurs either directly to the microorganisms in the case of the object to be sterilized, or indirectly to the microorganisms by heating a large amount of aqueous solution to be sterilized. This method is widely implemented because it allows for flexibility, safety, and cost-effectiveness in the sterilization process.

[0197] microorganisms In some embodiments, the composition is substantially free of microorganisms. Acceptable levels of biocontamination or sterility are, but are not limited to, those specified in the United States Pharmacopeia Chapters. <1111> Based on applicable criteria that define therapeutically acceptable compositions, including the following: For example, acceptable sterile (e.g., biocontamination level) levels include about 10 colony-forming units (cfu) per gram of formulation, about 50 cfu per gram of formulation, about 100 cfu per gram of formulation, about 500 cfu per gram of formulation, or about 1000 cfu per gram of formulation. In some embodiments, acceptable biocontamination level or sterile for a formulation includes microbial agents less than 10 cfu / mL, less than 50 cfu / mL, less than 500 cfu / mL, or less than 1000 cfu / mL. Furthermore, acceptable biocontamination level or sterile includes the elimination of identified undesirable microbiological agents. As an example, identified undesirable microbiological agents include, but are not limited to, Escherichia coli (E. coli), Salmonella sp., Pseudomonas aeruginosa (P. aeruginosa), and / or other specific microbial agents.

[0198] A critical component of the sterility assurance quality control, quality assurance, and verification process is the method of sterility testing. Sterility testing is performed in two ways, for example. The first is direct inoculation, in which a sample of the composition to be tested is added to a growth medium and incubated for up to 21 days. The turbidity of the growth medium indicates contamination. Disadvantages of this method include the small sample size of the bulk material, which weakens sensitivity, and the detection of microbial growth based on visual observation. An alternative method is sterility testing by membrane filtration. In this method, a large amount of product is passed through a small membrane filter paper. The filter paper is then placed in the medium to promote microbial growth. This method has the advantage of higher sensitivity because the entire bulk material is sampled. For determination in sterility testing by membrane filtration, commercially available Millipore Steritest sterility testing systems are optionally used. For filtration testing with creams or ointments, the Steritest filter system No. TLHVSL210 is used. For filtration testing of emulsions or viscous products, the Steritest filter system No. TLAREM210 or TDAREM210 is used. For filtration testing of pre-filled syringes, the Steritest filter system No. TTHASY210 is used. For filtration testing of substances prepared as aerosols or foams, the Steritest filter system No. TTHVA210 is used. For filtration testing of soluble powders in ampoules or vials, the Steritest filter system No. TTHADA210 or TTHADV210 is used.

[0199] Testing for E. coli and Salmonella involves the use of lactose broth incubated at 30-35°C for 24-72 hours, incubation in MacConkey and / or EMB agar for 18-24 hours, and / or the use of Rappaport medium. Testing for the detection of P. aeruginosa involves the use of NAC agar. United States Pharmacopeia Chapter <62> This further lists test procedures for specific undesirable microorganisms.

[0200] In certain embodiments, the ophthalmic formulations described herein contain a microbial agent with fewer than 60 colony-forming units (CFUs), fewer than 50 colony-forming units, fewer than 40 colony-forming units, or fewer than 30 colony-forming units per gram of formulation. In certain embodiments, the ophthalmic formulations described herein are formulated to be isotonic with the eye.

[0201] endotoxins An additional aspect of the sterilization process is the removal of by-products from the sterilization of microorganisms (hereinafter referred to as "Product"). The pyrogen removal process removes pyrogenic substances from the sample. Pyrogenic substances are endotoxins or exotoxins that trigger an immune response. An example of an endotoxin is lipopolysaccharide (LPS) molecules found in the cell walls of Gram-negative bacteria. Sterilization treatments, such as autoclaving or treatments using ethylene oxide, kill bacteria, but LPS residues can trigger pro-inflammatory immune responses, such as septic shock. Because the molecular size of endotoxins varies widely, the presence of endotoxins is indicated in "endotoxin units" (EU). 1 EU is equivalent to 100 picograms of E. coli LPS. In some cases, humans react to as little as 5 EU / kg of body weight. The degree of biocontamination (e.g., microbial limits) and / or sterility (e.g., endotoxin levels) are expressed in units recognized by the technology. In certain embodiments, the ophthalmic compositions described herein contain lower endotoxin levels (e.g., less than 4 EU / kg of body weight) compared to conventionally acceptable endotoxin levels (e.g., 5 EU / kg of body weight). In some embodiments, the ophthalmic formulation has less than about 5 EU / kg of body weight. In other embodiments, the ophthalmic formulation has less than about 4 EU / kg of body weight. In additional embodiments, the ophthalmic formulation has less than about 3 EU / kg of body weight. In additional embodiments, the ophthalmic formulation has less than about 2 EU / kg of body weight.

[0202] In some embodiments, the ophthalmic formulation has a formulation of less than approximately 5 EU / kg. In other embodiments, the ophthalmic formulation has a formulation of less than approximately 4 EU / kg. In additional embodiments, the ophthalmic formulation has a formulation of less than approximately 3 EU / kg. In some embodiments, the ophthalmic formulation has a product of less than approximately 5 EU / kg. In other embodiments, the ophthalmic formulation has a product of less than approximately 1 EU / kg. In additional embodiments, the ophthalmic formulation has a product of less than approximately 0.2 EU / kg. In some embodiments, the ophthalmic formulation has units or products of less than approximately 5 EU / g. In other embodiments, the ophthalmic formulation has units or products of less than approximately 4 EU / g. In additional embodiments, the ophthalmic formulation has units or products of less than approximately 3 EU / g. In some embodiments, the ophthalmic formulation has units or products of less than approximately 5 EU / mg. In other embodiments, the ophthalmic formulation has units or products of less than approximately 4 EU / mg. In additional embodiments, the ophthalmic formulation has units or products of less than approximately 3 EU / mg. In certain embodiments, the ophthalmic formulations described herein contain formulations in concentrations of about 1 to about 5 EU / mL. In certain embodiments, the ophthalmic formulations described herein contain formulations in concentrations of about 2 to about 5 EU / mL, formulations in concentrations of about 3 to about 5 EU / mL, or formulations in concentrations of about 4 to about 5 EU / mL.

[0203] In certain embodiments, the ophthalmic compositions described herein contain lower endotoxin levels (e.g., formulations with less than 0.5 EU / mL) compared to conventionally acceptable endotoxin levels (e.g., formulations with 0.5 EU / mL). In some embodiments, the ophthalmic formulation has a formulation with less than about 0.5 EU / mL. In other embodiments, the ophthalmic formulation has a formulation with less than about 0.4 EU / mL. In additional embodiments, the ophthalmic formulation has a formulation with less than about 0.2 EU / mL.

[0204] The detection of pyrogens is performed in several ways, for example. A suitable test for sterilization is the United States Pharmacopoeia (USP) standard. <71> This includes tests described in Sterility Tests (23rd edition, 1995). The rabbit pyrogenic substance test and the horseshoe crab hematopoietic cell extract test are included in the United States Pharmacopeia Chapters. <85> and <151> Both are specified in (USP23 / NF 18, Biological Tests, The United States Pharmacopeial Convention, Rockville, MD, 1995). Based on the monocyte-activated cytokine assay, alternative pyrogen assays have been developed. Specific cell lines suitable for quality control applications have been developed and have demonstrated the ability to detect pyrogenity from samples that have passed the rabbit pyrogen test and the horseshoe crab hematopoietic extract test (Taktak et al, J. Pharm. Pharmacol. (1990), 43:578-82). In additional embodiments, ophthalmic formulations are subjected to pyrogen removal. In further embodiments, the manufacturing process of ophthalmic formulations includes testing the formulations for pyrogenity. In certain embodiments, the formulations described herein are substantially pyrogen-free.

[0205] Composition of ophthalmic muscarinic antagonists - mucus-penetrating particles (MPPs)

[0206] Mucous-permeable particles (MPPs) are particles that rapidly traverse mucus (e.g., human mucus). In some cases, MPPs consist of nanoparticles having a particle size between approximately 200 nm and 500 nm. In some examples, the nanoparticles are further coated with a mucous-permeable agent. In some examples, the compositions described herein are formulated with MPPs for mucous-permeability. In some examples, the ophthalmic agent compositions described herein are formulated with MPPs for mucous-permeability. In some examples, the ophthalmic agent is a muscarinic antagonist. In some examples, the muscarinic antagonist compositions described herein are formulated with MPPs for mucous-permeability. In some instances, muscarinic antagonists include atropine, atropine sulfate, noratropine, atropine N-oxide, tropine, tropic acid, methylatropine nitrate, diphenhydramine, dimenhydrinate, dicyclomine, flavoxate, oxybutynin, tiotropium, hyostine, scopolamine (L-hyostine), hydroxyzine, ipratropium, tropicamide, cyclopentolate, pirenzepine, homatropine, solifenacin, dalifenacin, benzatropine, mebeberine, procyclidine, acridinium bromide, trihexyphenidyl / benzhexol, or tolterodine. In some instances, the muscarinic antagonist is atropine or a pharmaceutically acceptable salt thereof. In some instances, the muscarinic antagonist is a salt of atropine sulfate. In some examples, the atropine compositions described herein are formulated with MPP for mucous passage. In some examples, the atropine sulfate compositions described herein are formulated with MPP for mucous passage. In non-limiting examples, the MMP used in the disclosed compositions is obtained from Kala Pharmaceuticals Inc. (100 Beaver Street #201, Waltham, MA 02453).

[0207] In some embodiments, the nanoparticles include any suitable material, such as organic substances, inorganic substances, polymers, or combinations thereof. In some examples, the nanoparticles include inorganic substances such as metals (e.g., Ag, Au, Pt, Fe, Cr, Co, Ni, Cu, Zn, and other transition metals), semiconductors (e.g., silicon, silicon compounds and alloys, cadmium selenide, cadmium sulfide, indium arsenide, and indium phosphide), or insulators (e.g., ceramics such as silicon oxide). In some examples, the nanoparticles include organic substances such as synthetic polymers and / or natural polymers. Examples of synthetic polymers include non-degradable polymers such as polymethacrylates, and degradable polymers such as polylactic acid and polyglycolic acid, and copolymers thereof. Examples of natural polymers include hyaluronic acid, chitosan, and collagen.

[0208] In some embodiments, nanoparticles are coated with a mucous permeable agent. In some examples, the mucous permeable agent includes any suitable substance, such as a hydrophobic substance, a hydrophilic substance, and / or an amphiphilic substance. In some examples, the mucous permeable agent is a polymer. In some examples, the polymer is a synthetic polymer (i.e., a polymer not produced naturally). In other embodiments, the polymer is a natural polymer (e.g., a protein, polysaccharide, rubber). In certain embodiments, the polymer is a surfactant polymer. In certain embodiments, the polymer is a nonionic polymer. In certain embodiments, the polymer is a nonionic block copolymer. In some embodiments, the polymer is a diblock copolymer, a triblock copolymer, for example, one block being a hydrophobic polymer and another block being a hydrophilic polymer. In some embodiments, the polymer is charged or uncharged.

[0209] Examples of suitable polymer additions include, but are not limited to, polyamines, polyethers, polyamides, polyesters, polycarbamates, polyureas, polycarbonates, polystyrenes, polyimides, polysulfones, polyurethanes, polyacetylenes, polyethylenes, polyethyleneimines, polyisocyanates, polyacrylates, poly(meth)acrylates, polyacrylonitriles, and polyarylates. Non-limiting examples of specific polymers include poly(caprolactone) (PCL), ethylene vinyl acetate polymer (EVA), poly(lactic acid) (PLA), poly(L-lactic acid) (PLLA), poly(glycolic acid) (PGA), poly(lactic acid-co-glycolic acid) (PLGA), poly(L-lactic acid-co-glycolic acid) (PLLGA), poly(D,L-lactide) (PDLA), poly(L-lactide) (PLLA), poly(D,L-lactide-co-caprolactone), poly(D,L-lactide-co-PEO-co-D,L-lactide), poly(D,L-lactide-co-PPO-co-D,Polyalkylenes such as L-lactide, polyalkylcyanoacrylate, polyurethane, poly-L-lysine (PLL), hydroxypropyl methacrylate (HPMA), poly(ethylene glycol), poly-L-glutamic acid, poly(hydroxy acid), polyanhydride, polyoltoester, poly(esteramide), polyamide, poly(ester ether), polycarbonate, polyethylene and polypropylene, polyalkylene glycols such as poly(ethylene glycol) (PEG), polyalkylene oxide (PEO), polyalkylene terephthalates such as poly(ethylene terephthalate), polyvinyl alcohol (PVA), polyvinyl ether, polyvinyl esters such as poly(vinyl acetate), polyvinyl halides such as poly(vinyl chloride) (PVC), polyvinylpyrrolidone, polysiloxane, polystyrene (PS), polyurethane, derived cellulose such as alkylcellulose, hydroxyalkylcellulose, cellulose ether, cellulose ester, nitrite This includes polymers of acrylic acids such as polycellulose, hydroxypropylcellulose, carboxymethylcellulose, poly(methyl(meth)acrylate) (PMMA), poly(ethyl(meth)acrylate), poly(butyl(meth)acrylate), poly(isobutyl(meth)acrylate), poly(hexyl(meth)acrylate), poly(isodecyl(meth)acrylate), poly(lauryl(meth)acrylate), poly(phenyl(meth)acrylate), poly(methylacrylate), poly(isopropylacrylate), poly(isobutylacrylate), poly(octadecylacrylate), and polymers and mixtures thereof, polydioxanone and its copolymers, polyhydroxyalkanoates, polypropylene fumarates, polyoxymethylene, poloxamers, poly(ortho)esters, poly(butyric acid), poly(valeric acid), poly(lactide-co-caprolactone), and trimethylene carbonates, and polyvinylpyrrolidone.

[0210] In some cases, the ophthalmic agent (e.g., a muscarinic antagonist such as atropine or atropine sulfate) is present in amounts between approximately 0.001 wt% and approximately 0.05 wt%, between approximately 0.005 wt% and approximately 0.050 wt%, between approximately 0.010 wt% and approximately 0.050 wt%, between approximately 0.015 wt% and approximately 0.050 wt%, and between approximately 0.020 wt% and approximately 0.050 wt% by weight of the composition. It is present in MPP formulations at concentrations between t%, between approximately 0.025 wt% and 0.050 wt%, between approximately 0.030 wt% and 0.050 wt%, between approximately 0.035 wt% and 0.050 wt%, between approximately 0.040 wt% and 0.050 wt%, or between approximately 0.045 wt% and 0.050 wt%, or as a pharmaceutically acceptable prodrug or salt thereof. In some practice, additional agents such as buffers, pD modifiers, and / or preservatives are prescribed in MPP formulations.

[0211] In some examples, ophthalmic preparations-MPP compositions are formulated in any suitable manner. In some embodiments, grinding processes are used to reduce the size of solids to form particles ranging from micrometers to nanometers in size. In some cases, dry and wet grinding processes such as jet grinding, freeze grinding, ball mill grinding, solvent grinding, and homogenization are known and used in the methods described herein. Generally, in a wet grinding process, a suspension of the substance to be used as nanoparticles is mixed with a grinding medium, or without an excipient, to reduce the particle size. Dry grinding is a process in which the substance to be used as nanoparticles is mixed with a grinding medium, or without an excipient, to reduce the particle size. In the freeze-milling process, the suspension of the material to be used as nanoparticles is mixed with the milling medium, with or without the excipient, at a cooled temperature.

[0212] In some embodiments, any suitable abrasive medium is used for grinding. In some embodiments, ceramics and / or polymeric materials and / or metals are used. Examples of suitable materials include zirconium oxide, silicon carbide, silicon oxide, silicon nitride, zirconium silicate, yttrium oxide, glass, alumina, alpha-alumina, aluminum oxide, polystyrene, poly(methyl methacrylate), titanium, and steel. In some cases, the abrasive medium has any suitable size. For example, the abrasive medium has an average diameter of at least about 0.1 mm, at least about 0.2 mm, at least about 0.5 mm, at least about 0.8 mm, at least about 1 mm, at least about 2 mm, or at least about 5 mm. In some cases, the abrasive medium has an average diameter of about 5 mm or less, about 2 mm or less, about 1 mm or less, about 0.8 mm or less, about 0.5 mm or less, or about 0.2 mm or less. Combinations of the aforementioned ranges are also possible (e.g., at least about 0.5 mm and an average diameter of about 1 mm or less). Other ranges are also possible.

[0213] In some embodiments, any suitable solvent is used for grinding. In some cases, the choice of solvent depends, among other factors, on the solid material being ground (e.g., a muscarinic antagonist such as atropine), the specific type of stabilizer / mucus penetrant used (e.g., one that allows particles to pass through the mucus), and the abrasive material being used. In some cases, a suitable solvent is one that does not substantially dissolve the solid or abrasive material but dissolves the stabilizer / mucus penetrant to a suitable degree. Non-limiting examples of solvents include, but are not limited to, water, buffers, other aqueous solutions, alcohols (e.g., ethanol, methanol, butanol), and mixtures thereof, optionally containing other components such as pharmaceutical excipients, polymers, drugs, salts, preservatives, viscosity-modifying genes, isotonic agents, flavoring agents, antioxidants, pD-modifying genes, and other pharmaceutical excipients. In other embodiments, organic solvents are used. In some cases, the drug (e.g., a muscarinic antagonist such as atropine) has any suitable solubility in these solvents or other solvents, such as solubility in one or more of the ranges described above, relative to, for example, water solubility or coating solution solubility.

[0214] In some instances, the MPP is an MPP as described in WO2013 / 166385. In some instances, the MPP is an MPP as described in Lai et al., "Rapid transport of large polymeric nanoparticles in fresh undiluted human mucus", PNAS 104(5):1482-1487(2007). In some instances, the ophthalmic agent-MPP composition is formulated using a method as described in WO2013 / 166385. In some instances, the ophthalmic agent-MPP composition is formulated using a method as described in Lai et al., "Rapid transport of large polymeric nanoparticles in fresh undiluted human mucus", PNAS 104(5):1482-1487(2007). In some embodiments, the ophthalmic agent is a muscarinic antagonist such as atropine or atropine sulfate.

[0215] Composition of germscarine antagonists for ophthalmic use

[0216] Gel agents are defined in various ways. For example, the United States Pharmacopoeia defines a gel agent as a semi-solid system consisting of a suspension of either small inorganic particles or large organic molecules impregnated by a liquid. Gel agents include single-phase or two-phase systems. Single-phase gel agents consist of an organic polymer uniformly distributed throughout a liquid in such a way that there is no obvious boundary between the dispersed polymer and the liquid. Some single-phase gel agents are prepared from synthetic polymers (e.g., carbomer) or natural rubber (e.g., tragacanth rubber). In some embodiments, single-phase gel agents are generally aqueous, but they can also be produced using alcohols and oils. Two-phase gel agents consist of a network of small discrete particles.

[0217] In some embodiments, gelling agents are also classified as hydrophobic or hydrophilic. In certain embodiments, bases of non-limiting examples of hydrophobic gels include liquid paraffin having polyethylene or fatty oil, gelled with colloidal silica or aluminum or zinc soap. In contrast, bases of non-limiting examples of hydrophilic gels include water, glycerol, or propylene glycol gelled with a suitable gelling agent (e.g., tragacanth, starch, cellulose derivatives, carboxyvinyl polymers, and aluminum magnesium silicate). In certain embodiments, the rheology of the compositions disclosed herein is pseudoplastic, plastic, thixotropic, or dilatant.

[0218] In some embodiments, the ophthalmic composition is an ophthalmic gel, in which the ophthalmically acceptable carrier comprises water and at least one viscosity enhancer. In some embodiments, the viscosity enhancer is selected from the group consisting of cellulose-based polymers, polyoxyethylene polyoxypropylene triblock copolymers, dextran-based polymers, polyvinyl alcohol, dextrin, polyvinylpyrrolidone, polyalkylene glycol, chitosan, collagen, gelatin, hyaluronic acid, or combinations thereof.

[0219] In some embodiments, the ophthalmic gel compositions described herein are semi-solid or solid in a gelled state before topical administration (e.g., at room temperature). Suitable viscosity enhancers for such gels include, for example, gelling agents and suspending agents. In one embodiment, the thickening formulation does not contain a buffer. In other embodiments, the thickening formulation contains a pharmaceutically acceptable buffer. If necessary, sodium chloride or other isotonic agents are optionally used to adjust the tonicity.

[0220] One example of an ocularly acceptable viscosity formulation is hydroxypropyl methylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, polyvinyl alcohol, sodium chondroitin sulfate, and sodium hyaluronate. Other viscosity enhancers suitable for the targeted ocular site include, but are not limited to, acacia (gum arabic), agar, magnesium aluminum silicate, sodium alginate, sodium stearate, fucus vesiculosus, bentonite, carbomer, carrageenan, carbopole, xanthan gum, cellulose, microcrystalline cellulose (MCC), ceratonia, chitin, carboxymethylated chitosan, coriander, dextrose, fercerelan, gelatin, and ghattigum. gum, guar gum, hectorite, lactose, sucrose, maltodextrin, mannitol, sorbitol, honey, corn starch, wheat starch, rice starch, potato starch, gelatin, araya gum, xanthan gum, tragacanth gum, ethylcellulose, ethyl hydroxyethylcellulose, ethyl methylcellulose, methylcellulose, hydroxyethylcellulose, hydroxyethyl methylcellulose, hydroxypropylcellulose, poly(hydroxyethyl) methacrylate, oxypolygelatin, pectin, This includes ligerin, povidone, propylene carbonate, methyl vinyl ether / maleic anhydride copolymer (PVM / MA), poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate), hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (CMC), silicon dioxide, polyvinylpyrrolidone (PVP:povidone), Splenda® (dextrose, maltodextrin, and sucralose), or combinations thereof. In specific embodiments, the viscosity-enhancing excipient is a combination of MCC and CMC. In other embodiments, the viscosity enhancer is carboxymethylated chitosan, or a combination of chitin and alginate. The combination of chitin and alginate with the ophthalmic formulations disclosed herein acts as a controlled-release formulation that limits the diffusion of the ophthalmic formulation from the formulation.Furthermore, the combination of carboxymethylated chitosan and alginate is optionally used to help increase the penetration of ophthalmic formulations within the eye.

[0221] In some embodiments, the viscous formulation is sufficient to provide a viscous formulation comprising ophthalmic preparations, pharmaceutically acceptable viscous preparations, and distilled water for injection at concentrations of about 0.1 mM and about 100 mM, wherein the concentration of the viscous preparation in water is about 100 to about 100,000 cP, resulting in a final viscosity of about 100 to about 100,000 cP. In certain embodiments, the viscosity of the gel formulation is in the range of about 100 to about 50,000 cP, about 100 cP to about 1,000 cP, about 500 cP to about 1,500 cP, about 1,000 cP to about 3,000 cP, about 2,000 cP to about 8,000 cP, about 4,000 cP to about 50,000 cP, about 10,000 cP to about 500,000 cP, and about 15,000 cP to about 1,000,000 cP. In other embodiments, if a more viscous medium is desired, the biocompatible gelling agent may also be present in amounts of at least about 35%, at least about 45%, at least about 55%, at least about 65%, at least about 70%, at least about 75%, or even at least about 80% by weight of the ophthalmic preparation. In highly concentrated samples, the biocompatible thickening formulation may be present in amounts of at least about 25%, at least about 35%, at least about 45%, at least about 55%, at least about 65%, at least about 75%, at least about 85%, at least about 90%, or at least about 95% or more by weight of the ophthalmic preparation.

[0222] In one embodiment, a pharmaceutically acceptable, ophthalmally acceptable formulation comprises at least one ophthalmic formulation and at least one gelling agent. Suitable gelling agents used in the preparation of gel formulations include, but are not limited to, cellulose, cellulose derivatives, cellulose ethers (e.g., carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose), guar gum, xanthan gum, locust bean gum, alginates (e.g., alginic acid), silicates, starch, tragacanth, carboxyvinyl polymers, carrageenan, paraffin, petrolatum, and any combination or mixture thereof. In some other embodiments, hydroxypropylmethylcellulose (Methocel®) is used as a gelling agent. In certain embodiments, viscosity enhancers described herein are used as gelling agents for gel formulations shown herein.

[0223] In some embodiments, the ophthalmic gel compositions described herein are in situ gel formulations. In some examples, the in situ gel formulations are based on increasing the pre-corneal residence time of the ophthalmic composition, improving ocular biocompatibility, corneal mucosal adhesion, lysosome interaction, and ion gelation, improved corneal absorption, thermal gelation, or a combination thereof. In some examples, the in situ gel formulations are activated by pH, temperature, ions, UV, or solution exchange.

[0224] In some examples, ophthalmic gel compositions include a muscarinic antagonist and one or more gelling agents. In some examples, the gelling agents include, but are not limited to, poloxamer (e.g., Poloxamer 407), tetronix, ethyl (hydroxyethyl)cellulose, cellulose phthalate acetate (CAP), Carbopol (e.g., Carbopol 1342P NF, Carbopol 980 NF)), alginates (e.g., low acetylgellan gum (Gelrite®)), guerlain, hyaluronic acid, pluronic acid (e.g., Pluronic F-127), chitosan, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), dextran, hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose (HEC), methylcellulose (MC), thiolated xyloglucan, polymethacrylic acid (PMMA), polyethylene glycol (PEG), pseudolatex, xyloglucan, or combinations thereof. In some cases, the in situ gel formulation further includes a permeation enhancer. In some examples, the permeation enhancer includes surfactants (e.g., nonionic surfactants), benzalkonium chloride, EDTA, surface-active heteroglycosides, calcium chelating agents, hydroxyl-propyl beta-cyclodextrin (HP beta-CD), bile salts, etc.

[0225] In some embodiments, other gel formulations are useful depending on the specific ophthalmic formulation, other drugs or excipients / additives used, and are therefore considered to be within the scope of this disclosure. For example, other commercially available glycerin-based gel formulations, glycerin-derived compounds, conjugated or crosslinked gels, matrices, hydrogels, and polymers, as well as gelatin and its derivatives, alginates, and alginate-based gel formulations, and various natural and synthetic hydrogels, and further compounds derived from hydrogels, are all presumed to be useful in the ophthalmic formulations described herein. In some embodiments, ophthalmally acceptable gel formulations include, but are not limited to, alginate hydrogel SAF®-Gel (ConvaTec, Princeton (NJ)), Duoderm® HydroactiveGel (ConvaTec), Nu-gel® (Johnson & Johnson Medical, Arlington, Tex.); Carrasyn®(V)AcemannanHydrogel (Carrington Laboratories, Inc., Irving, Tex.); glycerin gel Elta® Hydrogel (Swiss-American Products, Inc., Dallas, Tex.) and KY® Sterile (Johnson & Johnson). In further embodiments, biodegradable and biocompatible gel formulations represent compounds present in ophthalmally acceptable formulations, similarly disclosed and described herein.

[0226] In some embodiments, the viscosity enhancer is a cellulose-based polymer selected from cellulose gum, alkylcellulose, hydroxyl-alkylcellulose, hydroxyl-alkylalkylcellulose, carboxy-alkylcellulose, or a combination thereof. In some embodiments, the viscosity enhancer is hydroxyl-alkylalkylcellulose. In some embodiments, the viscosity enhancer is hydroxypropylmethylcellulose.

[0227] In certain embodiments, the thickening formulations are characterized by a phase transition between room temperature and body temperature (including individuals with severe fever up to approximately 42°C). In some embodiments, the phase transition occurs at 1°C, 2°C, 3°C, 4°C, 6°C, 8°C, or 10°C below body temperature. In some embodiments, the phase transition occurs at 15°C, 20°C, or 25°C below body temperature. In specific embodiments, the gelation temperature (Tgel) of the formulations described herein is around 20°C, 25°C, or 30°C. In certain embodiments, the gelation temperature (Tgel) of the formulations described herein is around 35°C or 40°C. Within the definition of body temperature, there is the body temperature of a healthy individual or an unhealthy individual, including individuals with fever (up to 42°C). In some embodiments, the drug compositions described herein are liquid at room temperature and are administered at room temperature or below room temperature.

[0228] Copolymers of polyoxypropylene and polyoxyethylene (e.g., polyoxyethylene-polyoxypropylene triblock copolymer) form thermosetting gels when incorporated into aqueous solutions. These polymers have the ability to change from a liquid state to a gel state at temperatures close to body temperature, thus enabling the application of useful formulations to targeted eye areas. The phase transition from liquid to gel state depends on the concentration and composition of the polymer in the solution.

[0229] In some embodiments, the amount of thermosetting polymer in any formulation described herein is about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer in any formulation described herein is about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., Poloxamer 407) in any formulation described herein is about 7.5% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., Poloxamer 407) in any formulation described herein is about 10% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., Poloxamer 407) in any formulation described herein is about 11% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., Poloxamer 407) in any formulation described herein is about 12% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., Poloxamer 407) in any formulation described herein is about 13% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., Poloxamer 407) in any formulation described herein is about 14% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., Poloxamer 407) in any formulation described herein is about 15% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., Poloxamer 407) in any formulation described herein is about 16% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., Poloxamer 407) in any formulation described herein is about 17% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., Poloxamer 407) in any formulation described herein is about 18% of the total weight of the formulation.In some embodiments, the amount of thermosetting polymer (e.g., Poloxamer 407) in any formulation described herein is about 19% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., Poloxamer 407) in any formulation described herein is about 20% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., Poloxamer 407) in any formulation described herein is about 21% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., Poloxamer 407) in any formulation described herein is about 23% of the total weight of the formulation. In some embodiments, the amount of thermosetting polymer (e.g., Poloxamer 407) in any formulation described herein is about 25% of the total weight of the formulation. In some embodiments, the amount of thickener (e.g., gelling agent) in any formulation described herein is about 1%, about 5%, about 10%, or about 15% of the total weight of the formulation. In some embodiments, the amount of a thickening agent (e.g., a gelling agent) in any formulation described herein is about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5% of the total weight of the formulation.

[0230] In alternative embodiments, the thermogel is a PEG-PLGA-PEG triblock copolymer (Jeong et al, Nature (1997), 388:860-2; Jeong et al, J. Control. Release (2000), 63:155-63; Jeong et al, Adv. Drug Delivery Rev. (2002), 54:37-51). The polymer exhibits sol-gel behavior over concentrations ranging from approximately 5% w / w to approximately 40% w / w. Depending on the desired properties, the molar ratio of lactide / glycolide in the PLGA copolymer ranges from approximately 1:1 to approximately 20:1. The resulting copolymer is water-soluble and forms a freely flowing liquid at room temperature, but forms a hydrogel at body temperature. A commercially available PEG-PLGA-PEG triblock copolymer is RESOMER RGP t50106 manufactured by Boehringer Ingelheim. This substance is composed of a 50:50 poly(DL-lactide-co-glycolide) PLGA copolymer, is 10% w / w of PEG, and has a molecular weight of approximately 6000.

[0231] Additional biodegradable thermoplastic polyesters include those disclosed in, for example, U.S. Patent Nos. 5,324,519; 4,938,763; 5,702,716; 5,744,153; and 5,990,194, where a suitable biodegradable thermoplastic polyester is disclosed as a thermoplastic polymer. Examples of suitable biodegradable thermoplastic polyesters include polylactides, polyglycolides, polycaprolactones, their copolymers, their terpolymers, and any combination thereof. In some such embodiments, a suitable biodegradable thermoplastic polyester is a polylactide, polyglycolides, their copolymers, their terpolymers, and any combination thereof. In one embodiment, the biodegradable thermoplastic polyester is a 50 / 50 poly(DL-lactide-co-glycolide) having carboxyl-terminated groups; It is present in about 30% to about 40% by weight of the composition; and has an average molecular weight of about 23,000 to about 45,000. Alternatively, in another embodiment, the biodegradable thermoplastic polyester is 75 / 25 poly(DL-lactide-co-glycolide) without carboxyl-terminated groups; it is present in about 40% to about 50% by weight of the composition; and has an average molecular weight of about 15,000 to about 24,000. In further or alternative embodiments, the terminal groups of poly(DL-lactide-co-glycolide) are either hydroxyl, carboxyl, or ester, depending on the method of polymerization. Polycondensation of lactic acid or glycolic acid provides polymers having terminal hydroxyl and carboxyl groups. Ring-opening polymerization of cyclic lactide or glycolide monomers having water, lactic acid, or glycolic acid provides polymers having the same terminal groups. However, ring-opening polymerization of cyclic monomers having monofunctional alcohols such as methanol, ethanol, or 1-dodecanol provides polymers having one hydroxyl group and one ester-terminated group. Ring-opening polymerization of cyclic monomers having diols such as 1,6-hexanediol or polyethylene glycol provides polymers having only hydroxyl-terminated groups.

[0232] Since the polymer systems of thermosetting gels dissolve more completely at the reducing temperature, the solubilization method involves adding the required amount of polymer to the amount of water used at the reducing temperature. Generally, after wetting the polymer by shaking, the mixture is capped and placed in a cold chamber or thermostat container at about 0-10°C to dissolve the polymer. The mixture is stirred or shaken to cause a more rapid dissolution of the thermosetting gel polymer. Ophthalmic formulations and various additives such as buffers, salts, and preservatives are then added and dissolved. In some examples, if the formulation is pharmaceutically insoluble in water, it is suspended. The pD is adjusted by adding appropriate buffers.

[0233] Composition of muscarine antagonist ophthalmic ointment

[0234] Ointments are homogeneous, viscous, semi-solid preparations intended for external application to the skin or mucous membranes, most commonly being highly viscous, grease-like, concentrated oils (e.g., 80% oil - 20% water). Ointments have a water number that defines the maximum water content they may contain. They are used as emollients or for the application of active ingredients to the skin, for protective, therapeutic, or preventative purposes, and where some degree of occlusion is desired. Ointments are used topically on various parts of the body surface, including the skin, and the mucous membranes of the eyes (ophthalmic ointments), genitals, anus, and nose.

[0235] The vehicle for ointments is known as the ointment base. The choice of base depends on the clinical indication of the ointment. Different types of ointment bases include: hydrocarbon bases, e.g., solid paraffin, soft paraffin, microcrystalline wax, and ceresin; and water-absorbing bases, e.g., lanolin fat and beeswax. Water-soluble bases, such as macrogol 200, 300, and 400; emulsifying bases, such as emulsifying wax and cetrimide; and vegetable oils, such as olive oil, coconut oil, sesame oil, tonsil oil, and peanut oil.

[0236] Ointments are formulated using hydrophobic, hydrophilic, or water-emulsifying bases to provide a preparation that is immiscible, miscible, or emulsifiable with respect to skin secretions. In some embodiments, they also derive from hydrocarbon (fatty), absorbent, water-removable, or water-soluble bases. The activators are dispersed within the base, and then they are dispersed after the drug has penetrated the target site (e.g., a membrane, skin, etc.).

[0237] This disclosure recognizes that incorporating low concentrations of a drug into an ointment with sufficient uniformity between doses to effectively treat a disorder or disease is sometimes difficult. In some embodiments, poly(ethylene glycol), polyoxyethylene castor oil (Cremophor® EL), alcohols having 12 to 20 carbon atoms, or mixtures of two or more of the said components have been effective excipients for dispersing and / or dissolving effective amounts of ophthalmic drugs, particularly ascomycin and staurosporine derivatives, in ointment bases, especially those containing oily and hydrocarbon components, and the resulting ointments have shown excellent tolerance in skin and eye tissues.

[0238] This disclosure further recognizes that ophthalmic drugs, such as muscarinic antagonists (e.g., atropine or a pharmaceutically acceptable salt thereof), incorporated into the ointment compositions described herein, target the choroid and / or retina of the patient when the composition is administered topically to the surface of the eye, particularly to the patient's sclera. In some embodiments, the composition of an ophthalmic ointment comprises an ophthalmic drug, an ointment base, and a drug for dispersing and / or dissolving the drug in the ointment base, selected from poly(ethylene glycol, polyoxyethylene castor oil, alcohols having 12 to 20 carbon atoms, and mixtures of two or more of the components).

[0239] In some embodiments, the ointment base comprises ophthalmally acceptable oily and greasey-based bases, such as natural waxes, e.g., white and yellow beeswax, carnauba wax, wool wax (wool fat), refined lanolin, dehydrated lanolin; petroleum waxes, e.g., solid paraffin, microwax; hydrocarbons, e.g., liquid paraffin, white and yellow soft paraffin, white petrolatum, yellow petrolatum); or combinations thereof.

[0240] The aforementioned oil and fat bases are described in more detail, for example, in British Pharmacopoeia, Edition 2001, or European Pharmacopoeia, 3rd Edition.

[0241] In some embodiments, the ointment base is present in an amount of about 50% to about 95% by weight, preferably 70% to 90% by weight, based on the total weight of the composition.

[0242] A preferred ointment base comprises one or more combinations of one or more natural waxes, preferably wool wax (wool fat), as shown above, and one or more hydrocarbons, preferably soft paraffin or petrolatum, as shown above, combined with liquid paraffin, and more preferably a combination with liquid paraffin.

[0243] A special embodiment of the aforementioned ointment base comprises, for example, 5 to 17 parts by weight of lanolin and 50 to 65 parts by weight of white petrolatum, as well as 20 to 30 parts by weight of liquid paraffin.

[0244] In some embodiments, the agent for dispersing and / or dissolving the ophthalmic drug in the ointment base is selected from poly(ethylene glycol), polyoxyethylene castor oil, alcohols having 12 to 20 carbon atoms, and mixtures of two or more of the above components. The agent is preferably used in an amount of 1 to 20 weight percent, more preferably 1 to 10 weight percent, of the entire semi-solid ophthalmic composition.

[0245] Alcohols having 12 to 20 carbon atoms include, in particular, stearyl alcohol (C18H37OH), cetyl alcohol (C16H33OH), and mixtures thereof. Preferred compositions include so-called cetostearyl alcohol, a mixture of solid alcohols consisting substantially of stearyl and cetyl alcohol, and preferably containing 40% by weight or more of stearyl alcohol, and a total of stearyl alcohol and cetyl alcohol amounting to at least 90% by weight, and cetylstearyl alcohol and, particularly preferably, at least 7% by weight or more of an emulsifier, sodium cetostearyl sulfate and / or sodium lauryl sulfate in amounts of at least 80% by weight.

[0246] Polyethoxylated castor oil is a reaction product of natural or hydrogenated castor oil and ethylene glycol. In some examples, such products are obtained by known methods, for example, by the reaction of natural or hydrogenated castor oil, or a small portion thereof, with ethylene oxide, in a molar ratio of about 1:30 to about 1:60, with optional removal of the freed polyethylene glycol component from the product according to the methods disclosed in German Auslegeschriften 1,182,388 and 1,518,819. Particularly suitable and preferred are products commercially available under the trademark Cremophor® EL, having a molecular weight (by vapor osmotic pressure measurement) = ca. 1630, saponification, No. = ca. 65-70, acid, No. = ca. 2, iodine, No. = ca. 28-32, and nD 25 = ca. 1.471. Similarly, suitable for use in this category include, for example, Nikkol® HCO-60, hydrogenated castor oil, ethylene oxide, and reaction products exhibiting the following properties: acid no. = 0.3; saponification, no. = 47.4; hydroxy value = 42.5; pH (5%) = 4.6; color APHA = 40; mp = 36.0°C; freezing point = 32.4°C; H2O content (%), KF = 0.03.

[0247] Poly(ethylene-glycol) is used in several embodiments in accordance with this disclosure as a formulation for dispersing and / or dissolving ophthalmic drugs in ointment bases. A suitable poly(ethylene-glycol) is typically a mixture of polymer compounds of the common formula H-(OCH2-CH2)nOH, where the exponent n typically varies from 4 to 230, and the average molecular weight is about 200 to about 10000. Preferably, n is a number from about 6 to about 22, and the average molecular weight is between about 300 and about 1000; more preferably, n varies from about 6 to about 13, and the average molecular weight is about 300 to about 600; most preferably, n has a value of about 8.5 to 9, and the relative molecular weight is about 400. Suitable poly(ethylene glycols), such as those with average molecular weights of approximately 200, 300, 400, 600, 1000, 1500, 2000, 3000, 4000, 6000, 8000, and 10000, are readily available commercially.

[0248] Poly(ethylene glycol), particularly the preferred type described in the preceding paragraph, is used in an amount of preferably 1 to 10, more preferably 1 to 5 weight percent of the total semi-solid ophthalmic composition.

[0249] Particularly preferred embodiments of compositions according to the disclosure of the present invention include agents for dispersing and / or dissolving drugs in an ointment base selected from poly(ethylene glycol), polyoxyethylene-castor oil, and preferably a mixture of the aforementioned components.

[0250] Gel / Ointment viscosity

[0251] In some embodiments, the composition is 20°C and 1s -1 At a shear rate of , the BrookfieldRVDV viscosity is approximately 10,000 to approximately 300,000 cps. In some embodiments, the composition is 20°C and 1s -1 At a shear rate of , the BrookfieldRVDV viscosity is approximately 15,000 to approximately 200,000 cps. In some embodiments, the composition is 20°C and 1s -1 At a shear rate, the BrookfieldRVDV viscosity is approximately 50,000 to approximately 150,000 cps. In some embodiments, the composition is 20°C and 1 s -1 At a shear rate, the BrookfieldRVDV viscosity is approximately 70,000 to approximately 130,000 cps. In some embodiments, the composition is 20°C and 1 s -1 At a shear rate, it has a BrookfieldRVDV viscosity of approximately 90,000 to 110,000 cps.

[0252] In some embodiments, the ophthalmic gel formulation includes a viscosity enhancer sufficient to provide a viscosity between approximately 500 and 1,000,000 centipoise; between approximately 750 and 1,000,000 centipoise; between approximately 1,000 and 1,000,000 centipoise; between approximately 1,000 and 400,000 centipoise; between approximately 2,000 and 100,000 centipoise; between approximately 3,000 and 50,000 centipoise; between approximately 4,000 and 25,000 centipoise; between approximately 5,000 and 20,000 centipoise; or between approximately 6,000 and 15,000 centipoise. In some embodiments, the ophthalmic gel formulation includes a viscosity enhancer sufficient to provide a viscosity between approximately 50,000 and 1,000,000 centipoise.

[0253] In some embodiments, the compositions described herein are compositions with low viscosity at body temperature. In some embodiments, the low viscosity compositions contain about 1% to about 10% viscosity enhancers (e.g., gelling components such as polyoxyethylene-polyoxypropylene copolymers). In some embodiments, the low viscosity compositions contain about 2% to about 10% viscosity enhancers (e.g., gelling components such as polyoxyethylene-polyoxypropylene copolymers). In some embodiments, the low viscosity compositions contain about 5% to about 10% viscosity enhancers (e.g., gelling components such as polyoxyethylene-polyoxypropylene copolymers). In some embodiments, the low viscosity compositions are substantially free of viscosity enhancers (e.g., gelling components such as polyoxyethylene-polyoxypropylene copolymers). In some embodiments, the low viscosity ophthalmic compositions described herein provide apparent viscosities from about 100 cP to about 10,000 cP. In some embodiments, the low viscosity ophthalmic compositions described herein provide apparent viscosities from about 500 cP to about 10,000 cP. In some embodiments, the low-viscosity ophthalmic formulations described herein provide apparent viscosities ranging from about 1,000 cP to about 10,000 cP.

[0254] In some embodiments, the compositions described herein are viscous compositions at body temperature. In some embodiments, the viscous compositions contain about 10% to about 25% viscosity enhancers (e.g., gelling components such as polyoxyethylene-polyoxypropylene copolymers). In some embodiments, the viscous compositions contain about 14% to about 22% viscosity enhancers (e.g., gelling components such as polyoxyethylene-polyoxypropylene copolymers). In some embodiments, the viscous compositions contain about 15% to about 21% viscosity enhancers (e.g., gelling components such as polyoxyethylene-polyoxypropylene copolymers). In some embodiments, the viscous ophthalmic compositions described herein provide an apparent viscosity of about 100,000 cP to about 1,000,000 cP. In some embodiments, the viscous ophthalmic compositions described herein provide an apparent viscosity of about 150,000 cP to about 500,000 cP. In some embodiments, the viscous ophthalmic compositions described herein provide an apparent viscosity of about 250,000 cP to about 500,000 cP. In some of such embodiments, the viscous ophthalmic compositions are liquid at room temperature and gel-like between room temperature and body temperature (including solids with significant heat up to, for example, about 42°C). In some embodiments, the viscous ophthalmic compositions are administered as monotherapy for the treatment of eye diseases or illnesses described herein.

[0255] In some embodiments, the viscosity of the gel formulations described herein is measured by any of the means described herein. For example, in some embodiments, an LVDV-II+CPCone Plate Viscometer and a Cone Sprindle CPE-40 are used to calculate the viscosity of the gel formulations described herein. In other embodiments, a Brookfield (spindle and cup) viscometer is used to calculate the viscosity of the gel formulations described herein. In some embodiments, the viscosity ranges referred to herein are measured at room temperature. In other embodiments, the viscosity ranges referred to herein are measured at the body temperature referred to herein (e.g., the average body temperature of a healthy person).

[0256] Uniformity of gel / ointment dosages

[0257] Typical ophthalmic gels are packaged in eyedropper bottles and administered as drops. For example, a single dose (i.e., a single application) of an ophthalmic gel may consist of one, two, three, or more drops administered into the patient's eye. Furthermore, typical ophthalmic ointments are packaged in tubes or other dispensable containers equipped with a dispensing nozzle that delivers small pieces of ointment. For example, a single dose (i.e., a single application) of an ophthalmic ointment may consist of one or more pieces delivered into the patient's eye. In some embodiments, a single dose of an ophthalmic gel described herein is one drop of the gel composition from an eyedropper bottle. In some embodiments, a single dose of an ophthalmic ointment is one small piece of the ointment composition dispensed through the nozzle of a dispensing tube.

[0258] In some cases, the compositions described herein include ophthalmic gel compositions that provide a constant concentration between doses. In some examples, a constant concentration between doses does not result in significant variation in drug content from one dose to another. In some examples, a specific concentration between doses provides a consistent drug content from one dose to another.

[0259] In some cases, the compositions described herein include ophthalmic ointment compositions that provide a specific concentration between doses. In some examples, the specific concentration between doses does not result in significant variation in drug content from one dose to another. In some examples, the specific concentration between doses provides a consistent drug content from one dose to another.

[0260] In some embodiments, the composition exhibits a variation in ophthalmic formulation concentration of less than 50% between doses. In some embodiments, the composition exhibits a variation of less than 40% in the concentration of the ophthalmic agent between doses. In some embodiments, the composition exhibits a variation of less than 30% in the concentration of the ophthalmic agent between doses. In some embodiments, the composition exhibits a variation of less than 20% in the concentration of the ophthalmic agent between doses. In some embodiments, the composition exhibits a variation of less than 10% in the concentration of the ophthalmic agent between doses. In some embodiments, the composition exhibits a variation of less than 5% in the concentration of the ophthalmic agent between doses.

[0261] In some embodiments, the concentration variation of the ophthalmic agent between doses is based on 10 consecutive doses. In some embodiments, the concentration variation of the ophthalmic formulation between doses is based on 8 consecutive doses. In some embodiments, the concentration variation of the ophthalmic formulation between doses is based on 5 consecutive doses. In some embodiments, the concentration variation of the ophthalmic formulation between doses is based on 3 consecutive doses. In some embodiments, the concentration variation of the ophthalmic formulation between doses is based on 2 consecutive doses.

[0262] Non-precipitating formulations should not require shaking to uniformly disperse the drug. “Non-shaking” formulations are potentially advantageous over those requiring shaking for the simple reason that patient shaking is a major cause of drug dose instability. Patients have often reported not shaking or forgetting to shake ophthalmic compositions that require shaking before administering a dose, despite clear instructions to shake on the label. Even for patients who shake the product, it is usually impossible to determine whether the shaking intensity and / or duration is appropriate to give uniformity to the product. In some embodiments, the ophthalmic gel compositions and ophthalmic ointment compositions described herein are “non-shaking” formulations that maintain uniformity between doses as described herein.

[0263] To evaluate uniformity between doses, dropper bottles or tubes containing ophthalmic aqueous compositions, ophthalmic gel compositions, or ophthalmic ointment compositions are stored upright for a minimum of 12 hours prior to the start of the test. To simulate the recommended dosage of these products, a set number of drops or fragments are dispensed from individual commercial bottles or tubes at predetermined intervals for an extended period or until no product remains to be dispensed from the bottle or tube. All drops and fragments are dispensed into tare-weighted glass vials, capped, and stored at room temperature until analysis. The concentration of muscarinic antagonists, such as atropine, in the dispensed drops is determined using a reverse-phase HPLC method.

[0264] treatment method

[0265] A method for preventing the progression of myopia is disclosed herein by administering an effective amount of the ophthalmic composition described above to the eye of an individual in need. Similarly, a method for preventing the development of myopia is disclosed herein by administering an effective amount of the ophthalmic composition described above to the eye of an individual in need.

[0266] In some embodiments, the ophthalmic water-soluble formulations described herein are packaged in dropper bottles and administered as a dropper. For example, a single dose (i.e., a single application) of the ophthalmic aqueous formulation comprises one, two, three, or more drops into the patient's eye. In some embodiments, the ophthalmic gel formulations described herein are packaged in eyedropper bottles and administered as drops. For example, a single dose (i.e., a single application) of the ophthalmic gel formulation comprises one, two, three, or more drops into the patient's eye. In some embodiments, the ophthalmic ointment formulations described herein are packaged in tubes or other extrudeable containers equipped with a dispensing nozzle for delivering small pieces of ointment. For example, a single dose (i.e., a single application) of the ophthalmic ointment comprises one or more small pieces into the patient's eye. In some embodiments, a single dose of the ophthalmic aqueous formulation described herein is one drop of the aqueous composition from an eyedropper bottle. In some embodiments, a single dose of the ophthalmic gel described herein is one drop of the gel composition from an eye drop bottle. In some embodiments, a single dose of the ophthalmic ointment is one small piece of the ointment composition dispensed through the nozzle of a dispersion tube.

[0267] In some embodiments of the disclosed method, the ophthalmic composition is stored below room temperature before first use. In some embodiments of the disclosed method, the ophthalmic composition is stored between about 2°C and about 10°C before first use. In some embodiments of the disclosed method, the ophthalmic composition is stored at about 2°C, about 3°C, about 4°C, about 5°C, about 6°C, about 7°C, about 8°C, about 9°C, or about 10°C before first use. In some embodiments of the disclosed method, the ophthalmic composition is stored between about 4°C and about 8°C before first use.

[0268] In some embodiments of the disclosed method, the ophthalmic composition is stored at room temperature after the first use. In some embodiments of the disclosed method, the ophthalmic composition is stored between about 16°C and about 26°C after the first use. In some embodiments of the disclosed method, the ophthalmic composition is stored at about 16°C, about 17°C, about 18°C, about 19°C, about 20°C, about 21°C, about 22°C, about 23°C, about 24°C, about 25°C, or about 26°C after the first use.

[0269] In some embodiments, an ophthalmic aqueous formulation is dosed as follows: the lower eyelid of the eye to be dosed is pulled down, and a predetermined amount of the aqueous formulation (e.g., 1 - 3 drops) is applied inside the eyelid. The tip of the ophthalmic dispensing mechanism does not touch the surface to avoid contamination and / or trauma.

[0270] In some embodiments, an ophthalmic gel formulation is dosed as follows: the lower eyelid of the eye to be dosed is pulled down, and a predetermined amount of the gel (e.g., 1 - 3 drops) is applied inside the eyelid. The tip of the ophthalmic dispensing mechanism does not touch the surface to avoid contamination and / or trauma.

[0271] In some embodiments, an eye ointment formulation is dosed as follows: the lower eyelid of the eye to be treated is pulled down, and a small amount of ointment (approximately ⅛ inch) is applied inside the eyelid. The tip of the ophthalmic dispensing mechanism does not touch the surface to avoid contamination and / or trauma.

[0272] In some embodiments, the ophthalmic composition is dosed at predetermined intervals over a long period of time. In some embodiments, the ophthalmic composition is dosed once daily. In some embodiments, the ophthalmic composition is dosed every other day. In some embodiments, the ophthalmic composition is dosed over a period of 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, or 12 - 15 years.

[0273] In some embodiments, the ophthalmic composition is dosed in an administration with a concentration variation of the ophthalmic formulation between dosages of less than 50%, less than 40%, less than 30%, less than 20%, less than 10% or less than 5%.

[0274] The number of times the composition is administered to an individual in need thereof depends on the judgment of a medical professional, the disorder, the severity of the disorder, and the individual's response to the formulation. In some embodiments, the compositions disclosed herein are administered once to an individual in need thereof having a mild acute disease. In some embodiments, the compositions disclosed herein are administered more than once to an individual in need thereof having a moderate or severe acute disease. If the patient's disease does not improve, at the discretion of the physician, the administration of the ophthalmic agent is carried out chronically, i.e., over a long period including the entire period of the patient's life, in order to restore the symptoms of the patient's disease or condition, or otherwise control or suppress them.

[0275] If the patient's disease does not improve, at the discretion of the physician, the administration of the ophthalmic agent is carried out chronically, i.e., over a long period including the entire period of the patient's life, in order to restore the symptoms of the patient's disease or condition, or otherwise control or suppress them.

[0276] If the patient's disease improves, at the discretion of the physician, the administration of the ophthalmic formulation is given continuously; alternatively, the administration of the drug being administered is temporarily reduced or temporarily stopped for a specific period (i.e., "drug holiday"). The length of the drug holiday varies between 2 days and 1 year, including, but not limited to, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, and 365 days. The reduction in the dosage during the drug holiday is between 10% - 100%, including, but not limited to, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0277] Once improvement in the patient's eye condition occurs, maintenance doses of ophthalmic agents are administered if necessary. Thereafter, the amount and / or frequency of administration may be optionally reduced to a level that maintains the improved disease, impairment, or condition, as a symptom-suppressing ophthalmological treatment. In certain embodiments, the patient may require intermittent treatment over a long period with any recurrence of symptoms.

[0278] The amount of ophthalmic preparation equivalent to such a quantity varies depending on factors such as the specific compound, disease state and severity, and the specific circumstances surrounding the case, including the particular ophthalmic preparation being administered, the route of administration, the situation being treated, the scope of the target being treated, and the subject or host being treated. The desired dose is provided as a single dose, or as divided doses administered simultaneously (or over a short period) or at appropriate intervals.

[0279] In some embodiments, the initial administration is a specific ophthalmic agent, followed by the administration of different types of formulations or ophthalmic agents.

[0280] Kit / Product

[0281] The disclosure of the present invention also provides a kit for preventing or halting the progression of myopia. Such a kit would generally include one or more of the ophthalmic compositions disclosed herein and instructions for using the kit. The disclosure of the present invention also considers the use of one or more ophthalmic compositions in the manufacture of drugs to treat, alleviate, reduce or improve symptoms of diseases, dysfunctions, or disorders in mammals such as humans that are at risk or suspected of causing myopia progression.

[0282] In some embodiments, the kit includes a carrier, packaging, or container partitioned to accommodate one or more containers, such as glass bottles or tubes, each containing one of the separated elements used in the manner described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In other embodiments, the containers are formed from a variety of materials, such as glass or plastic.

[0283] Products provided herein include packaging materials. Packaging materials used in the packaging of pharmaceuticals are also shown herein. See, for example, U.S. Patents 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, dropper bottles, tubes, pumps, bags, vials, containers, syringes, bottles, and any packaging materials suitable for selected formulations and the intended mode of administration and treatment. Many ophthalmic compositions provided herein are considered as there are various treatments for any disease, abnormality, or condition for which the benefits of controlled-release administration of ophthalmic formulations to the eye can be obtained.

[0284] In some embodiments, the kit includes one or more additional containers, each containing one or more materials (such as rinses, wipes, and / or devices) that are commercially and user-desirable for the use of the formulations described herein. Such materials also include a label listing the contents and / or instructions for use, and a package insert containing instructions for use. A set of instructions is optionally included. In further embodiments, the label is on or accompanying the container. In yet another embodiment, the label is on the container if the letters, numbers, or other features forming the label are affixed, molded, or engraved onto the container itself; similarly, the label is accompanying the container if it exists, for example, as a package insert, within the container or carrier that holds the container. In other embodiments, the label is used to indicate that the contents are to be used for a particular therapeutic application. In yet another embodiment, the label also indicates instructions for the use of the contents, such as in the manner described herein.

[0285] In certain embodiments, the ophthalmic composition is provided in a dispenser device containing one or more units of dosage form comprising the compounds provided herein. In further embodiments, the dispenser device is accompanied by instructions for administration. In yet another embodiment, the dispenser is also accompanied by a notice attached to the container in a format prescribed by government agencies that regulate the manufacture, use, and sale of the drug, such notice reflecting that the form of the drug for human or veterinary administration is approved by the government agency. In yet another embodiment, such notice is, for example, a label approved by the U.S. Food and Drug Administration for prescription dispensing drugs, or an approved product insert. In yet another embodiment, the composition comprising the compounds provided herein, formulated in a compatible pharmaceutical carrier, is also prepared for the treatment of an indicated disease, placed in a suitable container, and labeled. [Examples]

[0286] Example 1 - Ophthalmic preparation Typical compositions for the preparation of ophthalmic preparations are described in Tables 1-8.

[0287]

Table 1

[0288]

Table 2

[0289]

Table 3

[0290]

Table 4

[0291]

Table 5

[0292] <00s00983>

Table 6

[0293]

Table 7

[0294]

Table 8

[0295] Example 2 - Preparation of an aqueous solution preparation containing 0.01% atropine in D2O Stock 1% solution To 100 mL of solution, add 1 gram of atropine and 0.77 g of NaCl (and preferably other dry components / ingredients) in a sufficient amount equal to 100 mL of sterile deuterated water for injection. Mix the solution in a appropriately sized beaker using a stirring rod on a hot plate until all the solid powder is dissolved and the solution is clear with no visible particles. Then remove the stirring rod and pour the solution into a filter bottle and vacuum filter it through a 0.22 micron polyethersulfone membrane filter into a sterile bottle. Remove the top of the filter from the sterile stock bottle and cap the stock bottle for storage using a sterile bottle cap.

[0296] <Diluted 0.01% solution> 0.3 mL of the 1% solution was combined with enough sterile 0.9% sodium chloride for injection USP to reach a total of 30 mL. The solutions were thoroughly mixed. The pH of the solution was recorded. A 0.22 micron filter was placed on the tip of the syringe, and the solutions were divided equally into separate sterile containers.

[0297] Example 3 - Preparation of an aqueous solution containing 0.01% atropine sulfate Stock 1% solution To 100 mL of solution, 1 gram of atropine sulfate and 0.77 g of NaCl (and preferably other components / components in a dry state) were added in a sufficient amount equal to 100 mL of sterile water for injection. The solution was mixed in a appropriately sized beaker using a stirring rod on a hot plate until all the solid powder was dissolved and the solution was clear with no visible particles. The stirring rod was then removed, and the solution was poured into a filter bottle and vacuum filtered through a 0.22 micron polyethersulfone membrane filter into a sterile bottle. The top of the filter was removed from the sterile stock bottle, and the stock bottle was capped for storage using a sterile bottle cap.

[0298] <Diluted 0.01% solution> 0.3 mL of the 1% solution was combined with enough sterile 0.9% sodium chloride for injection USP to reach a total of 30 mL. The solutions were thoroughly mixed. The pH of the solution was recorded. A 0.22 micron filter was placed on the tip of the syringe, and the solutions were divided equally into separate sterile containers.

[0299] Example 4 - Stability Analysis Five 0.01% atropine sulfate solutions were prepared from a 1% atropine sulfate preservative solution (as described in Example 2). The pH of the five solutions was 5.87, 5.97, 5.90, 6.24, and 6.16 for solutions 1-5, respectively. Each solution was thoroughly mixed. A 0.22 micron filter was placed on the tip of a syringe, and the solutions were divided equally into separate sterile containers according to Table 9.

[0300] [Table 9]

[0301] Subsequently, the samples were stored under different conditions for stability analysis. The samples were analyzed at different time points up to two months. Storage conditions included: 40°C at 75% relative humidity (RH) (samples were moved from 2–8°C after 3 days), 25°C at 60% RH, and 60°C. The time points were 1 week, 2 weeks, 1 month, and 2 months. At each time point, one plastic eye dropper (LDPE plastic) and one glass vial were removed from each storage condition and equilibrated to ambient conditions. Once equilibrated, both the plastic eye dropper and glass vial were inverted three times. The solution in the eye dropper was transferred to the HPLC vial by dropper drop. The solution in the glass vial was divided equally into the HPLC vial using a glass Pasteur pipette. The samples were then tested for purity and efficacy using the UPLC methods listed in Table 10.

[0302] [Table 10]

[0303] Table 11 lists the stability data for a 0.01% atropine sulfate solution.

[0304] [Table 11]

[0305] The pH change of a 0.01% atropine sulfate solution was observed over the duration of the stability study. Plastic (LDPE) eyedroppers maintained a pH of approximately 6.2 when stored at 25°C for two months. However, at the same time point, the pH of 0.01% atropine increased to 7.2 when stored in a glass vial. Furthermore, when stored at high temperatures (e.g., 40°C and 60°C), the pH in plastic (LDPE) eyedroppers decreased to approximately 4-5, while the pH in glass vials remained at approximately 7.2.

[0306] Furthermore, there was a significant difference in the rate of degradation of atropine sulfate (0.01%) when stored in plastic (LDPE) eyedroppers versus Type I glass vials. However, in both containers, there was an increase in early elution-related substances at relative retention times (RRT) = 0.87–0.89. In some cases, these early elution-related substances are referred to as the major degradation products. In some examples, the major degradation products are referred to as RRT 0.87–0.89. These early elution-related substances tend to be the first parameter of failure specification, regardless of the container. The amount of these early elution-related substances was tracked at each time point and is listed in Table 12.

[0307] [Table 12]

[0308] Arrhenius-based storage life predictions were calculated using data for relevant substances from Table 12. These predictions are based on the assumption that degradation is first-order (linear). These predictions are illustrated in Figures 1 and 2. Figure 1 shows the predicted storage life of a 0.01% atropine sulfate solution in the range of major degradation product RRT 0.87–0.89 and up to 0.5%, based on data obtained from samples stored at 25°C and 40°C. The pH range of the atropine sulfate solution is 5.9–6.2. Figure 2 shows the predicted storage life of a 0.01% atropine sulfate solution in the range of major degradation product RRT 0.87–0.89 and up to 0.5%, based on data obtained from samples stored at 25°C and 60°C. The pH range of the atropine sulfate solution is 5.9–6.2.

[0309] Example 5 - Sample analysis of 1% atropine sulfate (Bausch + Lomb) A sample of 1% atropine sulfate was obtained from Bausch + Lomb (Lot 198421). For comparison, the pH of the 1% atropine sulfate preparation was determined in both the undiluted (neat) solution and in the sample diluted to the current nominal concentration (0.01% atropine sulfate) using a vehicle. Furthermore, the sample was diluted to the nominal concentration using the method diluent. Both nominal-concentration diluted samples were analyzed using the RP-UPLC method (Table 10). The results are listed in Table 13.

[0310] [Table 13]

[0311] Example 6 - Uniformity of administration (10 doses) To evaluate the uniformity of the dosage, dropper bottles containing the ophthalmic aqueous composition are stored upright for a predetermined period (e.g., 12 hours) before the start of the test. To simulate the recommended dosage of the product, 10 drops of the aqueous composition are dispensed from each bottle at predetermined time intervals (e.g., continuously, every minute, every 10 minutes, every hour, or every 24 hours). All drops or fragments are dispensed into tare glass vials, capped, and stored at room temperature until analysis. The concentration of atropine in the expressed drops is determined using reversed-phase HPLC.

[0312] Example 7 - Uniformity of administration (5 doses) To evaluate the uniformity of the dosage, dropper bottles containing the ophthalmic aqueous composition are stored upright for a predetermined period (e.g., 12 hours) before the start of the test. To simulate the recommended dosage of the product, five drops of the aqueous composition are dispensed from each bottle at predetermined time intervals (e.g., continuously, every minute, every 10 minutes, every hour, or every 24 hours). All drops or fragments are dispensed into tare glass vials, capped, and stored at room temperature until analysis. The concentration of atropine in the expressed drops is determined using reversed-phase HPLC.

[0313] Example 8 - Uniformity of administration (two doses) To evaluate the uniformity of the dosage, dropper bottles containing the ophthalmic aqueous composition are stored upright for a predetermined period (e.g., 12 hours) before the start of the test. To simulate the recommended dosage of the product, two drops of the aqueous composition are dispensed from each bottle at predetermined time intervals (e.g., continuously, every minute, every 10 minutes, every hour, or every 24 hours). All drops or fragments are dispensed into tare glass vials, capped, and stored at room temperature until analysis. The concentration of atropine in the expressed drops is determined using reversed-phase HPLC.

[0314] Example 9 - Comparison of Formulation Stability Atropine sulfate monohydrate (MP Bio; Lot Number 7825K) and tropic acid (Sigma Aldrich; Lot Number STBD6457V) were used in this experiment. Eight formulations illustrated in Table 14A were analyzed at t=0, 2 weeks, and 4 weeks. RP-HPLC was used for the analysis.

[0315] [Table 14A]

[0316] The values ​​are in %w / v. The formulations were prepared in 100 mL scales in measuring glassware. The pD values ​​for formulations 7 and 8 are 5.2 and 6.2, respectively. In some examples, pD is expressed as pD = 0.4 + pH * Calculated as follows, in the formula, pH * This is the measured or observed pH of a solution formulated in a solution containing deuterated water.

[0317] Table 14B illustrates the analysis time points for the formulations listed in Table 14A.

[0318] [Table 14B]

[0319] Table 15 illustrates the atropine sulfate purity data related to each of the eight formulations. Purity is expressed as a percentage of the area under the curve.

[0320] [Table 15] In some cases, it was proposed that it be associated with a system.

[0321] After four weeks of storage at 60°C, in some cases, the atropine sulfate concentration affected the stability of formulations containing acetic acid at pH 4.2. For example, the atropine sulfate concentration at 0.025% w / v (Formulation 2) showed a 2.8% increase in % purity at pH 4.2 compared to the atropine sulfate concentration at 0.010% w / v (Formulation 1). This trend was not observed for the acetic acid formulations (Formulations 3 and 4) at pH 4.8; rather, a 0.6% decrease in % purity was observed for higher doses.

[0322] The dose-dependent stability trend observed at pH=4.2 was also seen in the citrate-containing formulations (formulations 5 and 6) at pH 5.8. After 4 weeks of storage at 60°C, approximately 14% less degradation was observed at higher doses than at lower doses.

[0323] At both high and low doses, greater degradation is observed in formulations that begin at higher pH levels. This degradation is primarily due to the growth of tropacin. In some cases, buffer species play a role in the degradation observed between different pH values.

[0324] The percentage of tropic acid observed for each formulation at t=4 weeks and 60°C is as follows: Formulation 1 - The observed tropic acid content was 0.54%. Formulation 2 - The observed tropic acid content was 0.93%. Formulation 3 - The observed tropic acid content was 1.58%. Formulation 4 - The observed tropic acid content was 3.03%. Formulation 5 - The observed tropic acid content was 29.13%. Formulation 6 - The observed tropic acid content was 16.84%. Formulation 7 - The observed tropic acid content was 1.07%. Formulation 8 - The observed tropic acid content was 4.03%.

[0325] In some embodiments, switching from a water source to deuterated water (D2O) affects the stabilization of the tropic acid peak growth in a formulation containing acetic acid at pD 5.2 (Formulation 7) (see Figure 4). Furthermore, in a formulation containing citric acid at pD 6.2 (Formulation 8), deuterated water also stabilizes atropine sulfate (see Figure 5).

[0326] Table 16 illustrates tropic acid as the area under the curve for each of the eight formulations. Tropacic acid is a degradation product of atropine sulfate. In some cases, the LOQ has previously been found to be 0.05% for RP-HPLC.

[0327] [Table 16]

[0328] Table 17 illustrates the percentage of efficacy of atropine in eight formulations.

[0329] [Table 17]

[0330] After four weeks of storage, observed efficacy values ​​increased from t=0 and the 2-week time point, with the exception of formulations 5 and 6 at 60°C, where efficacy decreased due to degradation. In some cases, these efficacy values ​​tended to increase, although they were within the margin of error of the HPLC method. Mass balances were calculated for the 60°C data, and the results were consistent across formulation and degradation levels, but skewed downward because they were higher than the expected efficacy values ​​at 4 weeks (see Figure 3).

[0331] Table 18 illustrates the pH or pD stability of the eight formulations.

[0332] [Table 18]

[0333] The values ​​in italics are the pD values ​​for the deuterated sample. In some embodiments, the pD of the deuterated sample is pD = pH reading +0.4 (Glasoe, et al. "Use of glass electrodes to measure acidities in deuterium oxide" J. Physical Chem. 64(1): 188-190 (1960)).

[0334] At two lower temperatures, the pH value at t=4 weeks was slightly higher than the time point at t=2 weeks. These data were generated using a new glass pH probe. In some cases, the observed differences are due to probe differences or additional variables, such as the age of the standard buffer or temperature gradients within the laboratory environment. The decreasing pH trend for each formulation using rising temperatures at t=4 weeks is consistent with the previous data and corresponds to an increase in the amount of tropic acid present in the stable sample.

[0335] Example 10 - Determination of storage period and activation energy The activation energy was calculated for the eight formulations disclosed in Example 9, and a comparison with a reference standard was performed using formulations 4-7.

[0336] Table 19 illustrates the calculation of activation energy (Ea). The minimum value of Ea is 17.8 kcal / mol, the maximum value of Ea is 21.3 kcal / mol, and the average value of Ea is 19.5 kcal / mol. The average is ±3. * This is stdev. Figures 6 and 7 illustrate the poor correlation between RS and tropic acid using formulations 4 and 7, respectively. Figures 8 and 9 illustrate the improved correlation between RS and tropic acid using formulations 5 and 6, respectively. Poor correlation was observed at lower pH levels (e.g., pH 4.8 or lower) (formulations 4 and 7). This was due to delayed hydrolysis and an increase in alternative degradation pathways. Improved or better correlation was observed at higher pH levels (e.g., pH 5.8 or higher) (formulations 5 and 6). This was due to the hydrolysis of atropine as the main degradation product. It should be noted that the activation energy is for the degradation of the special acid catalyst to tropic acid-main degradation product and the degradation mechanism, which operates at pH 5.8 or higher.

[0337] [Table 19]

[0338] Table 20 illustrates the rate of RS or tropic acid formation per week at 40°C.

[0339] [Table 20]

[0340] Table 21 illustrates the activation energy at 30°C and the predicted storage period calculated based on Table 20. The calculation assumes that the tropic acid and total RS are 5% (storage period).

[0341] [Table 21A]

[0342] [Table 21B]

[0343] At pD6.2, the deuterated formulation (formulation 8) has a predicted storage life of nearly two years at 30°C.

[0344] Table 22 illustrates the predicted storage periods for total RS and tropic acid at temperatures of 40°C, 30°C, 25°C, and 2-8°C for formulations 4-8, respectively.

[0345] [Table 22]

[0346] Example 11 - Comparison of additional formulation stability Atropine sulfate monohydrate (MP Bio; Lot Number 7825K) and tropic acid (Sigma Aldrich; Lot Number STBD6457V) were used in this experiment. Thirteen formulations illustrated in Table 23A were analyzed. Formulations 1-8 were analyzed at t=0, 2 weeks, 4 weeks, and 8 weeks. Formulations 9-13 were analyzed at t=0, 2 weeks, and 4 weeks. The pH values ​​reported herein are measured pH values ​​obtained using a Thermo Scientific, Orion Dual Star pH / IS benchtop pH meter and an Orion Double Junction Micro pH probe S / N S01-18520 calibrated to H2O-based standards.

[0347] [Table 23A]

[0348] The value is %w / v. The formulation was prepared in a 100 mL scale in a measuring glass and filled into an LDPE eye drop bottle. In some examples, pD was set to pD = 0.4 + pH * Calculated as follows, in the formula, pH * This is the measured or observed pH of a solution formulated in a solution containing deuterated water.

[0349] Table 23B illustrates the analysis time points for the formulations listed in Table 23A.

[0350] [Table 23B]

[0351] Tables 24A and 24B illustrate atropine sulfate purity data related to atropine sulfate preparations. Purity is shown as a percentage of the area under the curve. ↑ and ↓ indicate high and low concentrations (0.01% and 0.025%) of atropine sulfate monohydrate. A and C represent acetic acid and citrate, respectively, which are the buffer species used.

[0352] [Table 24A]

[0353] [Table 24B]

[0354] Tables 25A and 25B illustrate the formation of tropic acid related to atropine sulfate preparations. Tropacic acid is a degradation product of atropine sulfate and is shown as a percentage of the area under the curve. LOQ was found to be 0.05% for RP-HPLC. ↑ and ↓ indicate high and low concentrations (0.01% and 0.025%) of atropine sulfate monohydrate. A and C represent acetic acid and citrate, respectively, which are buffer species used.

[0355] [Table 25A]

[0356] [Table 25B]

[0357] Tables 26A and 26B illustrate the percentage of atropine efficacy in the formulations. ↑ and ↓ indicate high and low concentrations (0.01% and 0.025%) of atropine sulfate monohydrate. A and C represent the buffer species used, acetic acid and citrate, respectively.

[0358] [Table 26A]

[0359] [Table 26B]

[0360] Tables 27A and 27B illustrate the pH or pD stability of atropine sulfate preparations. ↑ and ↓ indicate high and low concentrations (0.01% and 0.025%) of atropine sulfate monohydrate. A and C indicate the buffer species used, acetic acid and citrate, respectively.

[0361] [Table 27A]

[0362] [Table 27B]

[0363] <Example 12: Determination of storage period and activation energy for the atropine sulfate preparation of Example 11> The activation energy was calculated for the atropine sulfate formulation disclosed in Example 11. Specifically, the activation energy was calculated from the total percentage of the related substance (RS) at 40°C and 60°C (two-point calculation), and from the tropic acid formation at 40°C and 60°C (two-point calculation). These values ​​were then averaged. Table 28 shows the activation energy calculations. Table 29 shows the storage period estimated from the %RS and the rate of tropic acid formation at 40°C. Figure 10 shows the estimated storage period for the D2O and H2O formulations.

[0364] [Table 28]

[0365] [Table 29-1]

[0366] [Table 29-2]

[0367] Table 30 shows the predicted storage periods for formulations 2-8 with total RS and tropic acid at temperatures of 40°C, 30°C, 25°C, and 2-8°C, respectively.

[0368] [Table 30-1]

[0369] [Table 30-2]

[0370] <Example 13 - Effect of pH on eye tolerance in guinea pigs> A cohort of guinea pigs is administered 50 μL of ophthalmic formulations having different pH values ​​as described herein. For example, ophthalmic formulations containing H2O or deuterated water (e.g., D2O) are administered to the animals. The animals' behavior is recorded at predetermined time intervals to evaluate the acceptance of the ophthalmic formulations.

[0371] <Example 14 - In vivo eye irritation test in rabbits> Typical compositions disclosed herein are subjected to rabbit eye irritation tests to evaluate their safety profiles. The test compositions are tested for eye irritation in New Zealand rabbits (see, for example, Abraham MH, et al., Draize rabbit eye test compatibility with eye irritation thresholds in humans: a quantitative structure-activity relationship analysis. Toxicol Sci. 2003 December; 76(2):384-91. Epub 2003 Sep. 26; also, Gettings SD et al., A comparison of low volume, Draize and in vitro eye irritation test data. III. Surfactant-based formulations. Food Chem Toxicol. 1998 March; 36(3):209-31). The study includes single-eye administration to the right eye of each of three rabbits, and administration of the same volume of placebo to the left eye. If present, examine the rabbits immediately after injection of the composition and at 4, 24, 48, and 72 hours after injection to monitor for any signs / symptoms of eye irritation. The test composition does not show any signs of irritation in the cornea, iris, and conjunctiva of the rabbit's eye.

[0372] <Example 15 - In vivo testing of ophthalmic aqueous formulations in guinea pigs> Focal defocus myopia (FDM) was achieved by covering one eye with a latex shield. Due to myopia induced by blurred focus, a latex face mask was held in place around the animal's head with elastic bands, leaving both eyes, nose, mouth, and ears freely exposed. An A-4.00D lens was bonded onto a plastic lens frame. After aligning the optical center of the lens with the center of the pupil, the lens frame was attached to the face mask around one eye with a cloth hook-and-loop fastener. At least once a day, the lens was removed, both sides were cleaned with water-soaked gauze, and then it was reattached to the face mask. All animals were maintained in a 12-hour light (500 Lux) and 12-hour dark cycle throughout the experimental period.

[0373] A cohort of 3-week-old guinea pigs was randomly assigned to either a FDM (face mask worn over one eye), a focus-deafness-induced myopia (-4.00D lens worn over one eye), or a control group. The FDM group was treated with an aqueous ophthalmic formulation, an ophthalmic carrier (without ophthalmic agent), or FDM alone. The focus-deafness-induced myopia group was treated with an aqueous ophthalmic formulation, an ophthalmic carrier (without ophthalmic agent), or focus deafness alone. The control group was treated with an aqueous ophthalmic formulation, an ophthalmic carrier (without ophthalmic agent), or no treatment. Biometric parameters of both eyes in each animal were measured before and at 11 days prior to treatment.

[0374] Biometric parameters (e.g., eye refraction, corneal curvature, and axial component) are measured by an optometrist, orthoptist, or ophthalmologist during a daytime light cycle after the removal of the face mask or lenses, with the cooperation of the animal caregiver. The optometrist, orthoptist, or ophthalmologist is kept confidential regarding the treatment conditions of each animal.

[0375] After the pupil is fully dilated by topical administration of 1% cyclopentate hydrochloride, refraction is measured by retinal retinal examination. The results of the retinal retinal examination are recorded as the average value of horizontal and vertical meridians.

[0376] Corneal curvature is measured using a keratometer modified by attaching a +8D lens to the anterior surface of the keratometer. A group of stainless steel balls with diameters ranging from 5.5 to 11.0 mm are measured with the modified keratometer. Three readings are recorded for each measurement, and the average result is obtained. The radius of corneal curvature is then estimated from the readings on balls of known radius.

[0377] The axial components of the eye (lens thickness, glass length, and axial length) were measured using a scanning ultrasound device. The execution speed was 1,723.3 m / s for measuring lens thickness and 1,540 m / s for measuring glass length, as mentioned above. Each axial component was calculated as the average of 10 repeated measurements.

[0378] <Example 16 - Study on the safety and efficacy of an aqueous ophthalmic formulation> Clinical trials will be conducted to investigate the efficacy and safety of the aqueous ophthalmic formulations described herein in patients (patents) with myopia. In some cases, the studies will be open-label, single-blind, or double-blind. Patient selection criteria will include a refractive error of at least 1.0 D in both eyes, as well as additional factors such as astigmatism, documented myopia progression, age, sex, and / or health status.

[0379] Patients were randomized and administered a 0.05%, 0.01%, or 0.001% aqueous atropine formulation, prescribed in either H2O or deuterated water (e.g., D2O), once nightly in both eyes. Allocation ratios in several cases were determined based on the patient population.

[0380] Patients will be evaluated at day 0 (baseline), day 14, day 30, and thereafter at months 2, 3, 4, 5, 6, 8, 10, 12, 18, 20, 24, and 36. At each visit, best-corrected distance logMar visual acuity (BCVA) will be assessed by an optometrist, orthoptist, or ophthalmologist using the chart from the Early Treatment Study of Diabetic Retinopathy. Near visual acuity will be assessed using best-corrected distance spectable correction with a reduced logMar reading chart placed at 40 cm under bright conditions. The near point of accommodation (NPA) will be measured using the RAF rule with best-corrected distance spectable correction. Patients will be instructed to move the target inward until the N5 print is slightly blurred, and then outward until the N5 print is just clear. The range of accommodation will be calculated as the inverse of the NPA. The pupil size in twilight vision is measured using a Procyon3000 pupillary meter. The pupil size in photopic vision is measured using a Neurooptics pupillary meter.

[0381] After administering three drops of 1% cyclopentolate at 5-minute intervals, ciliary muscle paralysis-induced automatic refraction is assessed 30 minutes later using a Canon RK-F1 automatic refractometer. The axial length of the eye is measured using a Zeiss IOL Master, i.e., non-contact partial coherence interference.

[0382] The primary outcome is myopia progression over the study period. Safety will be assessed by adverse events, including allergic reactions, irritation, or progression of blurred vision in one or both eyes.

[0383] <Example 17 - Preparation of an ointment containing atropine sulfate> Atropine sulfate is mixed with a dispersant (e.g., polyethylene glycol) under heating and sonication, and this mixture is further thoroughly mixed with a molten ointment base (e.g., a mixture of wool wax, white petrolatum, and liquid paraffin). The mixture is placed in a pressure vessel and sterilized at 125°C for 30-45 minutes, then cooled to room temperature. In another embodiment, autoclave sterilization is performed under nitrogen. The resulting ophthalmic ointment is aseptically filled into pre-sterilized containers (e.g., tubes).

[0384] <Example 18 - Composition of atropine mucus-penetrating particles> A composition of 0.01% atropine mucus-penetrating particles was prepared using a milling procedure. The aqueous dispersion containing the atropine particles and the MPP-enabling mucus-penetrating agent were milled in a milling medium until the particle size was reduced to approximately 200 nm and the polydispersity index was less than 0.15, as measured by dynamic light scattering. Additional agents, such as preservatives, were also added during the milling procedure. The atropine-MPP composition was then stored at a temperature between approximately 15°C and approximately 25°C.

[0385] <Example 19 - Composition of atropine sulfate mucus-penetrating particles> A composition of 0.01% atropine sulfate mucus-penetrating particles was prepared using a milling procedure. The aqueous dispersion containing the atropine particles and the MPP-enabling mucus-penetrating agent were milled in a milling medium until the particle size was reduced to approximately 200 nm, with a polydispersity index of less than 0.15, as measured by dynamic light scattering. Additional agents, such as preservatives, were also added during the milling procedure. The atropine-MPP composition was then stored at a temperature between approximately 15°C and approximately 25°C.

[0386] In accordance with another aspect of the disclosure, this specification describes ophthalmic compositions comprising about 0.001 wt% to about 0.05 wt% of a muscarinic antagonist and water at a pH of about 3.8 to about 7.5.

[0387] In some cases, muscarinic antagonists include atropine, atropine sulfate, noatropine, atropine-N-oxide, tropine, tropic acid, hyostine, scopolamine, tropicamide, cyclopentolate, pirenzepine, homatropin, or combinations thereof. In some cases, the muscarinic antagonist is atropine. In some cases, the muscarinic antagonist is atropine sulfate.

[0388] In some cases, the ophthalmic composition, after a long period of time under storage conditions, contains, based on the initial concentration, at least about 80%, at least about 85%, at least about 90%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% of one of the muscarinic antagonists.

[0389] In some cases, the ophthalmic composition, after a long period of time under storage conditions, has a pH of less than approximately 7.3, less than approximately 7.2, less than approximately 7.1, less than approximately 7, less than approximately 6.8, less than approximately 6.5, less than approximately 6.4, less than approximately 6.3, less than approximately 6.2, less than approximately 6.1, less than approximately 6, less than approximately 5.9, less than approximately 5.8, less than approximately 5.2, less than approximately 4.8, or less than approximately 4.2.

[0390] In some cases, the ophthalmic composition, after a long period of time under storage conditions, has at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 97%, at least 98%, or at least 99% of one efficacy.

[0391] In some cases, a long period is one of the following: approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 1 month, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, approximately 6 months, approximately 8 months, approximately 10 months, approximately 12 months, approximately 18 months, approximately 24 months, approximately 36 months, approximately 4 years, or approximately 5 years.

[0392] In some cases, storage conditions involve a single storage temperature of approximately 25°C, 40°C, or 60°C. In other cases, storage conditions involve a storage temperature of approximately 2°C to 10°C, or approximately 16°C to 26°C. In other cases, storage conditions involve a relative humidity of approximately 60% or 75%.

[0393] In some cases, the ophthalmic composition is in the form of an aqueous solution. In some cases, the muscarinic antagonist is present in the composition at one of the following concentrations: about 0.001 wt% to about 0.04 wt%, about 0.001 wt% to about 0.03 wt%, about 0.001 wt% to about 0.025 wt%, about 0.001 wt% to about 0.02 wt%, about 0.001 wt% to about 0.01 wt%, about 0.001 wt% to about 0.008 wt%, or about 0.001 wt% to about 0.005 wt%.

[0394] In some cases, the ophthalmic composition further includes a molar osmotic pressure modifier. In some cases, the molar osmotic pressure modifier is sodium chloride.

[0395] In some cases, the ophthalmic composition further comprises a preservative. In some cases, the preservative is selected from benzalkonium chloride, cetrimonium, sodium perborate, stable oxychloro complex, SofZia, polyquaternium-1, chlorobutanol, disodium edetate, polyhexamethylene biguanide, or a combination thereof.

[0396] In some cases, ophthalmic compositions further include buffers. In some cases, the buffer is selected from borates, borate-polyol complexes, phosphate buffers, citrate buffers, acetate buffers, carbonate buffers, organic buffers, amino acid buffers, or combinations thereof.

[0397] In some cases, the ophthalmic composition further comprises an isotonic agent. In some cases, the isotonic agent is selected from sodium chloride, sodium nitrate, sodium sulfate, sodium bisulfate, potassium chloride, calcium chloride, magnesium chloride, zinc chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dextrose, mannitol, sorbitol, dextrose, sucrose, urea, propylene glycol, glycerin, or a combination thereof.

[0398] In some cases, ophthalmic compositions are stored in plastic containers. In some instances, the material of the plastic container includes low-density polyethylene (LDPE).

[0399] In some cases, ophthalmic compositions have a dose-to-dose variation in the concentration of the muscarinic antagonist, such as less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%. In some cases, the dose-to-dose variation in the concentration of the muscarinic antagonist is based on one of 10 consecutive doses, 8 consecutive doses, 5 consecutive doses, 3 consecutive doses, or 2 consecutive doses.

[0400] In some examples, the ophthalmic composition has one pH range of about 3.8 to about 7.5, about 4.2 to about 7.5, about 4.8 to about 7.3, about 5.2 to about 7.2, about 5.8 to about 7.1, about 6.0 to about 7.0, or about 6.2 to about 6.8.

[0401] In some cases, the ophthalmic composition further includes a pH adjuster. In some cases, the pH adjuster includes HCl, NaOH, CH3COOH, or C6H8O7.

[0402] In some cases, an ophthalmic composition contains one of the following: less than 5% D2O, less than 4% D2O, less than 3% D2O, less than 2% D2O, less than 1% D2O, less than 0.5% D2O, less than 0.1% D2O, or 0% D2O. In some cases, an ophthalmic composition is substantially D2O-free.

[0403] In some cases, the ophthalmic composition further comprises a pharmaceutically acceptable carrier.

[0404] In some cases, ophthalmic compositions are prescribed as ophthalmic solutions for the treatment of ophthalmic disorders. In some cases, the ophthalmic disorder or disease is pre-myopia, myopia, or progression of myopia.

[0405] In some cases, ophthalmic compositions are not prescribed as injectable formulations.

[0406] While preferred embodiments of the Disclosure have been shown and described herein, such embodiments are provided only as examples. Various alternative forms of the embodiments described herein may be adopted at will when carrying out the Disclosure. The following claims define the scope of the Disclosure, and the methods and configurations within the scope of these claims and their equivalents are intended to be encompassed thereby.< / pd>

Claims

1. An ophthalmic composition having a pH of approximately 4.2 to approximately 6.4, comprising approximately 0.001 wt% to approximately 0.05 wt% of atropine or a pharmaceutically acceptable salt thereof, 0.01% of benzalkonium chloride, glycerin, and water, wherein, after two weeks under storage conditions at 40°C and 75% relative humidity, the ophthalmic composition contains, based on the initial concentration, at least approximately 80%, at least approximately 85%, at least approximately 90%, at least approximately 93%, at least approximately 95%, at least approximately 97%, at least approximately 98%, or at least approximately 99% of the atropine or a pharmaceutically acceptable salt thereof.

2. The ophthalmic composition according to claim 1, further comprising a phosphate buffer, a citrate buffer, or an acetate buffer.

3. An ophthalmic composition comprising approximately 0.001 wt% to approximately 0.05 wt% of atropine or a pharmaceutically acceptable salt thereof, a phosphate buffer, and water, wherein the ophthalmic composition contains at least 90% of the atropine based on the initial concentration after two weeks under storage conditions at 40°C and 75% relative humidity at a pH of approximately 4.2 to approximately 6.

4.

4. The ophthalmic composition according to claim 1 or 3, wherein the ophthalmic composition comprises about 0.01% atropine or a pharmaceutically acceptable salt thereof.

5. The ophthalmic composition according to claim 1 or 3, wherein the ophthalmic composition comprises about 0.035% atropine or a pharmaceutically acceptable salt thereof.

6. The ophthalmic composition according to claim 2 or 3, wherein the phosphate buffer comprises phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, tripotassium phosphate, calcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, monomagnesium phosphate, dimamagnesium phosphate (magnesium hydrogen phosphate), trimagnesium phosphate, diammonium hydrogen phosphate, ammonium dihydrogen phosphate, or a combination thereof.

7. The ophthalmic composition according to claim 1 or 3, wherein after two weeks under storage conditions at 40°C and 75% relative humidity, the pH of the ophthalmic composition is one of the following: less than 7.3, less than 7.2, less than 7.1, less than 7, less than 6.8, less than 6.5, less than 6.4, less than 6.3, less than 6.2, less than 6.1, less than 6, less than 5.9, less than 5.8, less than 5.2, less than 4.8, or less than 4.

2.

8. The ophthalmic composition according to claim 1 or 3, wherein the ophthalmic composition has a change in atropine concentration between doses of less than 20%.

9. The ophthalmic composition according to claim 3, wherein, after two weeks under storage conditions of 40°C and 75% relative humidity, the ophthalmic composition contains, based on the initial concentration, at least about 80%, at least about 85%, at least about 90%, at least about 93%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% of the atropine or a pharmaceutically acceptable salt thereof.

10. The ophthalmic composition according to claim 1 or 3, wherein the ophthalmic composition further has at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 97%, at least 98%, or at least 99% efficacy after two weeks under storage conditions at 40°C and 75% relative humidity.

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