Ophthalmic acceptable aqueous liquid compositions comprising muscarinic acetylcholine receptor antagonists

Abstract

The present invention provides ophthalmic acceptable formulations of atropine and other muscarinic acetylcholine receptor antagonists, which can be heat sterilized without significant degradation of the muscarinic acetylcholine receptor antagonists. The formulations are less acidic than previous muscarinic acetylcholine receptor antagonist ocular formulations, making them more comfortable when administered to the eye.

Description

Technical Field

[0001] This invention relates to heat-stable, ocularly acceptable liquid compositions comprising amine buffers and muscarinic acetylcholine receptor antagonists. The liquid compositions can be stored in heat-sterilized containers. Methods for manufacturing said containers are also described. Background Technology

[0002] Pharmaceutical agents containing hydrolyzable bonds can be unstable in aqueous liquid formulations (especially when exposed to heat), leading to decomposition into inert or toxic byproducts. Liquid formulations containing such unstable agents can have short shelf lives and therefore often need to be prepared from lyophilized powders at the point of care or at the time of prescription. Alternatively, the formulation may require filtration sterilization, which can cause handling problems.

[0003] Atropine is a safe and effective myopia control agent that slows the progression of myopia. Under heating conditions or during long-term storage, atropine degrades, producing byproducts. In aqueous solution, the main byproducts are the dehydrated product apoatropine, as well as hydrolysis products of tropinic acid and tropine. Among the degradation byproducts, apoatropine is approximately 20 times more toxic than atropine, which can increase drug safety risks or lead to a reduction in atropine dosage. There is a need to improve the aqueous stability of atropine to minimize toxicity, reduce dehydrated products, and increase the efficacy of atropine.

[0004] Atropine is most stable at approximately pH 4.0. Administration of eye drops at this acidic pH is uncomfortable for patients. There is a need for more patient-acceptable stable atropine compositions with a higher pH.

[0005] Pirenzepine is another antimuscarinic agent and is commonly used to treat duodenal ulcers. It is also effective in controlling myopia progression in children. Although more stable than atropine, pirenzepine still undergoes significant hydrolysis, especially upon exposure to heat.

[0006] Liquid pharmaceutical formulations typically contain phosphate-based buffers, such as phosphate-buffered saline. In this invention, amine buffers are used because these buffers have been found to reduce the hydrolysis of muscarinic acetylcholine receptor antagonists in aqueous formulations. Summary of the Invention

[0007] The present invention provides an ocularly acceptable liquid composition comprising a muscarinic acetylcholine receptor antagonist, wherein the composition is thermally stable.

[0008] The present invention also provides a heat-sterilized container for containing the heat-stable ocular-acceptable liquid composition of the present invention.

[0009] The present invention also provides a method for manufacturing the heat-sterilized container of the present invention, comprising: (a) placing an eye-acceptable packaging solution in the container, (b) sealing the container, and (c) heat-sterilizing the sealed container, wherein the packaging solution is the liquid eye-acceptable formulation of the present invention.

[0010] Additional features and advantages of the invention will be set forth in part in the description which follows, and will be apparent in part from this specification, or may be learned by practice of the invention. The objectives and other advantages of the invention will be realized and obtained by means of the elements and combinations particularly pointed out in this specification and the appended claims.

[0011] It should be understood that both the above general description and the following detailed description are exemplary and explanatory in nature, and are intended to provide further explanation of the claimed invention.

[0012] Unless otherwise stated, all percentages are by weight and are based on the total weight of the composition or solution.

[0013] The accompanying drawings are incorporated in and form a part of this application and illustrate some features of the invention. The drawings and descriptions serve to explain the principles of the invention. Attached Figure Description

[0015] Figure 1 This demonstrates a comparison of the degradation of atropine within a specific pH range in citrate, phosphate, and amine-based buffer solutions after autoclaving. Detailed Implementation

[0016] This invention provides ocularly acceptable liquid compositions comprising a muscarinic acetylcholine receptor antagonist that are relatively stable upon exposure to heat (e.g., by heat sterilization). The heat-stable ocularly acceptable liquid compositions comprise an amine buffer and a muscarinic acetylcholine receptor antagonist, wherein the muscarinic acetylcholine receptor antagonist comprises a hydrolyzable bond.

[0017] Typically, the liquid composition has a pH in the range of 5.0-7.5. Preferably, the composition has a pH of 6.2 to 7.4, more preferably 6.3 to 7.2, even more preferably 6.5 to 7.0, and even more preferably 6.8 to 7.0. The pH is determined using a calibrated benchtop pH meter (e.g., Hanna HI 9321 benchtop pH meter) or an equivalent device.

[0018] The liquid composition is an aqueous composition comprising an amine buffer having an effective pH in the range of 5.0-7.5. As used herein, "amine buffer" includes buffers containing amino groups. In one example, the amino-containing buffer is the only buffer contained in the composition. The amino group may be a primary, secondary, or tertiary amino group.

[0019] Suitable amine buffers or buffers containing amino groups include tris(hydroxymethyl)aminomethane (Tris), N-(2-acetamido)iminodiacetic acid (ADA), bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane (Bis-Tris), 2-morpholinoethanesulfonic acid (MES), histidine, ethanolamine, hydrazine, imidazole, pyridine, and piperazine. Preferably, the buffer containing amino groups is selected from Tris and Bis-Tris.

[0020] The buffer can be present in the composition at any concentration sufficient to maintain an eye-acceptable pH (e.g., 5.8 to 7.4). Typically, the buffer is present at a molar concentration of 0.001M to 0.5M. Preferably, the buffer is present at a molar concentration of 0.005M to 0.2M, more preferably 0.006M to 0.15M, and most preferably 0.008M to 0.12M.

[0021] Compared to buffer compositions lacking buffers containing amino groups (such as phosphate-buffered saline), the presence of amine buffers increases the thermal stability of muscarinic acetylcholine receptor antagonists, thereby reducing their degradation during heat sterilization. Additionally, amine buffers increase shelf life because the buffer prevents or reduces hydrolysis and / or degradation of the muscarinic acetylcholine receptor antagonist during storage. In some cases, the liquid composition remains stable when stored at room temperature (approximately 20°C), eliminating the need for refrigeration before or after first use. Liquid compositions at ambient temperature are generally more comfortable for patients when applied to the eye.

[0022] As used herein, a “heat-stable” composition is one in which less than 10% (by weight) of the muscarinic acetylcholine receptor antagonist degrades during autoclaving (hereinafter “autoclaving”) at 121°C (1 atm) and 17 psi for 30 minutes. Therefore, the heat-stable liquid compositions of the present invention can be packaged in containers and autoclaved to provide heat-sterilized containers, wherein the amount of the muscarinic acetylcholine receptor antagonist in the liquid composition after autoclaving is not less than 90% (by weight) of the initial amount of the muscarinic acetylcholine receptor antagonist present in the liquid composition prior to heat sterilization. In some instances, the amount of the muscarinic acetylcholine receptor antagonist in the liquid composition is not less than 95% of the initial amount of the muscarinic acetylcholine receptor antagonist present in the composition prior to heat sterilization. In some instances, the liquid compositions packaged in containers and autoclaved include less than 10% hydrolytic degradation products of muscarinic acetylcholine receptor antagonists and preferably less than 5% hydrolytic degradation products of muscarinic acetylcholine receptor antagonists.

[0023] Preferably, the autoclaved composition contains at least 50% less (by weight) less muscarinic acetylcholine receptor antagonist degradation products than the autoclaved control composition. As used herein, a “control composition” is a composition comprising phosphate-buffered saline (PBS) having the formulations provided in Table 1 below, in place of an amine buffer but otherwise identical. In other words, the control composition has the same pH and the same amounts of muscarinic acetylcholine receptor antagonist and excipients as the comparison composition containing the amine buffer. Thus, for example, if a liquid composition comprising an amine buffer and 1.00 wt.% atropine is autoclaved and 0.95 wt.% atropine remains in the composition after autoclaving, then the autoclaved composition contains 0.05 wt.% atropine degradation products. If the control composition (i.e., comprising 1.00 wt.% atropine in PBS buffer) contains 0.80 wt.% atropine after autoclaving, then the autoclaved composition comprising the amine buffer has less degradation products than 75% of the control composition. The heat-stable composition may contain at least 60%, 75%, or 80% less (by weight) of the muscarinic acetylcholine receptor antagonist degradation products after autoclaving than the control composition. The amount of muscarinic acetylcholine receptor antagonist degradation after autoclaving can be determined by conventional HPLC analysis (as described in the examples below).

[0024] Although the compositions described herein are heat-stable, they can be sterilized using any known sterilization method, including filtration methods commonly used for ophthalmic preparations. In one example, the composition was filtered through a 0.22 µm filter. The heat-stable compositions sterilized by filtration can be stored and administered at room temperature, which is more comfortable for patients than administering ophthalmic preparations that require refrigeration.

[0025] Muscarinic acetylcholine receptor antagonists can be thermosensitive. As used herein, “thermosensitive muscarinic acetylcholine receptor antagonist” refers to a pharmaceutically active muscarinic acetylcholine receptor antagonist that is readily degraded upon autoclaving. Specifically, when prepared as a 0.1% solution in PBS, less than 95% (by weight) of the initial amount of thermosensitive muscarinic acetylcholine receptor antagonist is present after autoclaving at pH 7.0. In some instances, less than 90% (by weight), less than 80% (by weight), or less than 70% (by weight) of the initial amount of thermosensitive muscarinic acetylcholine receptor antagonist is present after autoclaving.

[0026] Muscarinic acetylcholine receptor antagonists include hydrolyzable bonds. A hydrolyzable bond is one that breaks through a hydrolysis process. As used herein, a muscarinic acetylcholine receptor antagonist is considered to contain a hydrolyzable bond if an aqueous solution of the muscarinic acetylcholine receptor antagonist contains at least 5% (by weight) of decomposition products after autoclaving. The hydrolyzable bond can be an ester bond or an amide bond. In some instances, the hydrolyzable bond is a covalent bond to an ester or amide bond containing an N-containing heterocyclic group. Examples of N-containing heterocyclic groups include substituted or unsubstituted aziridine, aziridine propene, aziridine butane, aziridine butadiene, pyrrolidone, pyrrole, pyrimidine, imidazoline, pyrazolidine, imidazolium, pyrazole, pyridine, piperidine, tetrazolium, pentazolium, diazine, diazineane, triazineane, triazine, tetrazine, and tropane groups.

[0027] The composition comprises a muscarinic acetylcholine receptor antagonist. Suitable muscarinic acetylcholine receptor antagonists include atropine, pirenzepine, scopolamine, trospium chloride, dicycloverine, oxybutynin, ipratropium bromide, and telenzepine. Preferably, the muscarinic acetylcholine receptor antagonist is atropine or pirenzepine, or a derivative or analogue thereof, or a pharmaceutically acceptable salt thereof. As used herein, "atropine" comprises D-atropine, L-atropine (hyoscyamine), or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof. Suitable salts include hydrochloride, sulfate, acetate, phosphate, bisphosphate, chloride, maleate, citrate, methanesulfonate, nitrate, tartrate, maleate, bicarbonate, fumarate, toluenesulfonate, succinate, stearate, and gluconate. Preferably, the muscarinic acetylcholine receptor antagonist is atropine sulfate.

[0028] In some instances, the composition comprises a muscarinic acetylcholine receptor antagonist of formula (I) or (II):

[0029] Formula (I)

[0030] Equation (II)

[0031] Where A is O or NH;

[0032] R1 is a C1-C group consisting of H, D (deuterium), hydroxyl, alkoxy, nitrile, halogen atom, or optionally substituted with one or more halogen atoms. 10 Straight-chain, branched, or cyclic alkyl groups; or phenyl or benzyl groups, optionally derived from one or more C1-C6 groups. 10The ring is substituted with a straight-chain, branched or cyclic alkyl, haloalkyl, hydroxyl, alkoxy, nitrile, nitro, amino, amide, ester, sulfone, sulfoxide, sulfonamide, or halogen atom; or a heterocyclic saturated, unsaturated, or aromatic 5- or 6-membered ring containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, each optionally via one or more C1-C2 atoms. 10 Substitution of straight-chain, branched or cyclic alkyl, haloalkyl, hydroxyl, alkoxy, nitrile, nitro, amino, amide, ester, sulfone, sulfoxide, sulfonamide and halogen atoms;

[0033] X is -OH, O, or -ONO2.

[0034] Me is CH3; and

[0035] W can be N or CH.

[0036] Preferably, A is O.

[0037] Preferably, R1 is an H, D, or halogen atom. Preferably, the halogen atom is F.

[0038] Preferably, A is O and R1 is H, D, or a halogen atom. Preferably, the halogen atom is F.

[0039] Preferably, A is O and R1 is H.

[0040] Preferably, X is 0.

[0041] Preferably, W is N.

[0042] Preferably, X is 0 and W is N.

[0043] The composition may include 0.001 wt.% to 5.0 wt.% of a muscarinic acetylcholine receptor antagonist. In some examples, the composition includes 0.005 wt.% to 3.0 wt.% or 0.01 wt.% to 2.0 wt.% of a muscarinic acetylcholine receptor antagonist.

[0044] An ocularly acceptable composition means that it can come into direct contact with the ocular environment without causing any physiological or pharmacologically harmful effects. Initial stinging or mild discomfort is common in topical ocular formulations and is not considered harmful. The compositions disclosed herein have the advantage of reducing or eliminating stinging or discomfort associated with previous ocular formulations of muscarinic acetylcholine receptor antagonists.

[0045] Compared to filtration sterilization, heat sterilization eliminates the need for preservatives. Preferably, the composition is preservative-free. In some examples, the composition includes less than 0.001 wt% of a preservative. Examples of preservatives used in ophthalmic solutions include benzyl ammonium chloride, cetrimonium, sodium perborate, sodium hypochlorite, stable oxychloride complexes, SofZia, polyquaternium-1, chlorobutanol, disodium edetate, polyhexamethylene biguanide, or combinations thereof.

[0046] The presence of trace heavy metals in a buffer solution can accelerate the hydrolysis of muscarinic acetylcholine receptor antagonists containing hydrolyzable bonds. The composition may optionally further comprise a heavy metal chelating agent, such as ethylenediaminetetraacetic acid (EDTA). The amount of the chelating agent (e.g., EDTA) present in the composition may be from about 10 ppm to 5000 ppm, preferably from about 100 ppm to about 1000 ppm, and more preferably from about 100 ppm to about 500 ppm. In one example, the composition comprises 200 ppm or 150 ppm EDTA.

[0047] The composition may optionally further include agents capable of increasing intermolecular hydrogen bonding. These agents can help further stabilize the muscarinic acetylcholine receptor antagonist after autoclaving, thereby reducing muscarinic acetylcholine receptor antagonist degradation products. Preferably, the presence of agents capable of increasing intermolecular hydrogen bonding results in at least 5% (by weight) less degradation products of the muscarinic acetylcholine receptor antagonist after autoclaving than in the original identical control composition without agents capable of increasing intermolecular hydrogen bonding. Examples of agents capable of increasing intermolecular hydrogen bonding include trehalose, ethylene glycol, and mannitol. Preferably, the agent capable of increasing intermolecular hydrogen bonding is trehalose.

[0048] The agent capable of increasing intermolecular hydrogen bonding may be present in the composition in an amount from about 0.1 wt% to about 10.0 wt%. Preferably, the composition comprises about 0.5 wt% to about 5.0 wt%, more preferably about 1.0 wt% to about 4.0 wt%, and even more preferably about 2.0 wt% to about 3.0 wt% of the agent capable of increasing intermolecular hydrogen bonding. In some examples, the composition may include 2.0 wt.% trehalose.

[0049] Intermolecular hydrogen bonding can also be increased by using deuterated water (D2O) instead of ordinary water to formulate the composition. Thus, in some instances, heat-stable ocularly acceptable aqueous liquid compositions include amine buffers and muscarinic acetylcholine receptor antagonists that include hydrolyzable bonds, wherein the aqueous component of the composition consists of or includes deuterated water.

[0050] The liquid composition has an ocularly acceptable osmotic pressure. The ocularly acceptable osmotic pressure is in the range of about 200 mOsm / kg to about 400 mOsm / kg and typically from about 270 mOsm / kg to about 330 mOsm / kg.

[0051] The liquid composition optionally includes an elastomer in an amount (e.g., from about 0.1 wt.% to 5.0 wt.% or from about 0.5 wt.% to about 3.0 wt.%) that maintains an acceptable osmotic pressure in the eye. Suitable elastomers 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.

[0052] The liquid composition optionally includes excipients that prolong the time during which the composition dose remains in contact with the cornea. For example, the excipients may be viscosity enhancers and / or mucosal adhesives. Suitable viscosity enhancers include cellulose-based polymers (e.g., hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and hydroxyethyl cellulose), polyoxyethylene-polyoxypropylene triblock copolymers (e.g., poloxamer 407), dextran-based polymers, polyvinyl alcohol, dextrin, polyvinylpyrrolidone, polyalkylene glycols, chitosan, collagen, gelatin, glucon, xanthan gum, guar gum, tamarind seed polysaccharide, hyaluronic acid, or combinations thereof.

[0053] In one instance, the composition is formulated as a sustained-release liquid. For example, the composition may be in the form of an ocular suspension comprising mucosal adhesion microspheres that sustainably release a muscarinic acetylcholine receptor antagonist. Methods for preparing mucosal adhesion microspheres for ocular suspensions are described in the literature (see, for example, Dandagi et al., SciPharm (2013) 81(1):259-280).

[0054] The liquid composition may optionally contain other ingredients, such as comfort agents, hydrophilic polymers, wetting agents, surfactants, or other additives.

[0055] This invention also provides containers for containing heat-stable ocularly acceptable liquid compositions as described herein. In some instances, the containers are heat-sterilized. In other instances, the containers are not heat-sterilized, and the ocularly acceptable liquid compositions are filtered and sterilized. The container may be an eye drop dispenser, such as an eye drop dispensing bottle or vial. The dispenser may be for single or multiple use. Some eye drop dispensers have a nozzle connected to a reservoir containing the liquid composition. The reservoir may have deformable walls, allowing the user to squeeze the reservoir to push the liquid composition into the nozzle. The nozzle may drop the composition to be administered into the lower conjunctival sac and thereby reach the surface of the eye. Alternatively, a multi-dose dispenser may include a bottle containing the liquid composition of the invention, a tip or dropper, and a cap. The bottle may be rigid, for example made from glass or rigid plastic. The bottle may have a movable pipette with a deformable bulb to control the movement of the liquid within the dropper.

[0056] Reservoirs typically hold a volume from 0.01 mL to 20 mL. Single-use dispensers typically hold enough fluid to provide the patient with the required dose for a single administration. This can be one drop for a single eye or multiple drops (e.g., 2 or 3 drops) for one or both eyes. Single-use dispensers typically hold a volume from 0.01 mL to 0.1 mL. Reusable dispensers hold multiple doses for multiple administrations and typically hold a volume from 1.0 mL to 20 mL. Preferably, reusable dispensers are compatible with any device designed to facilitate the administration of eye drops.

[0057] The container may also contain contact lenses. The container may include a base member comprising: a bowl defining a blister cavity sized to receive the contact lens and a liquid composition; and a flange projecting from the blister cavity. The base member may be formed from any suitable material, such as glass or thermoplastic. A liquid-tight seal may be provided by a cap attached to the flange area, such as by adhesive or heat-sealing a removable foil to the flange area. Such contact lens containers (i.e., packages), commonly referred to as “blister packs,” are well known in the industry (see, for example, U.S. Patent No. 7,426,993). Typically, the container is configured to receive a single contact lens and an amount (typically about 0.5–1.5 mL) of liquid composition sufficient to completely cover the contact lens. The contact lens may be a so-called “myopia control” contact lens with a lens design designed to slow the progression of myopia. Myopia control lenses are well known in the industry (see, for example, U.S. Patent Nos. 7,832,859, 8,899,749, and 11,934,043).

[0058] The container can also be a "foil-foil package," comprising two foil members joined together, which may be flat, or one or both foil members may be formed into a suitable geometry to accommodate contact lenses and a liquid composition. In another example, the container is in the form of a plastic base member including multiple threads, and the lid includes a plastic cap member containing a set of compatible threads that engage with the threads of the base member, thereby providing a resealable cap. It will be understood that other types of containers may be used.

[0059] Sealed packaging can be sterilized by radiation (including heat or steam) of a sterilizing amount, for example by autoclaving. Preferably, the packaged contact lenses are sterilized by autoclaving. Autoclaving of contact lens packaging typically involves subjecting the sealed contact lens package to a temperature of at least 121°C at 17 psi (117 kPa) for at least 30 minutes.

[0060] The liquid compositions of the present invention can be used to treat eye conditions. Preferably, the eye conditions or symptom are pre-myopia, myopia, or myopia progression. The present invention also provides heat-stable, ocularly acceptable liquid compositions for medical use. Specifically, heat-stable, ocularly acceptable liquid compositions can be used to treat eye conditions, such as myopia.

[0061] A heat-stable, ocularly acceptable liquid composition is prepared for application to the surface of the eye. It is not prepared for administration by injection.

[0062] The following examples illustrate certain aspects and advantages of the present invention and should not be construed as limiting the invention.

[0063] Example 1: The effect of buffer solution on the high-pressure stability of atropine

[0064] Studies were conducted to evaluate the stability of atropine in various buffer solutions at pH 6–7 after autoclaving. Buffer formulations are provided in Tables 1–5. The structures of the amine components of the amine-containing buffers are provided.

[0065] Table 1: Phosphate-Buffered Saline (PBS)

[0066]

[0067] Table 2: EBS solutions

[0068]

[0069] Table 3: Bis-Tris solutions

[0070]

[0071] Table 4: Bis-Tris solution containing 2% trehalose (T)

[0072]

[0073] Table 5: ADA solution

[0074]

[0075] Dissolve atropine (dl-atropine, Sigma) in each buffer solution to obtain a 0.1% solution and adjust the sspH to the value shown in Table 7 using HCl or NH4OH. Add 4 mL of each solution to a 6 mL glass vial and seal with the cap. Autoclave the vials at 121°C and 17 psi (117 kPa) for 30 minutes (n = 3).

[0076] The presence of racemic atropine was detected using reversed-phase HPLC under the conditions shown in Table 6.

[0077] Table 6:

[0078]

[0079] The percentage of atropine that degraded from the autoclaved sample compared to the composition before autoclaving is shown in Table 7.

[0080] Table 7:

[0081]

[0082] Example 2: The effect of buffer solution on the high-pressure stability of pirenzepine

[0083] A 0.1% pirenzepine hydrochloride solution was prepared by dissolving pirenzepine in each buffer solution and adjusting the pH to the values ​​shown in Table 8 using HCl or NH4OH (Cayman Chemical).

[0084] The solution was placed in vials and autoclaved as described above for atropine. Analysis was performed by reversed-phase HPLC using a UV detector at 281 nm. The percentage of pirenzepine degraded from the autoclaved sample is shown in Table 8.

[0085] Table 8:

[0086]

[0087] The results showed that pirenzepine was more thermally stable in EBS and Bis-Tris solutions than in PBS solutions. Amine-type nonphosphate buffers were beneficial in improving the stability of atropine and pirenzepine.

[0088] Example 3: The effect of citrate buffer on the high-pressure stability of atropine

[0089] Studies were conducted to compare the high-pressure stability of atropine in citrate, PBS, and Tris-bis buffers at pH 6 to 7. Formulations for PBS and Bis-Tris buffers are provided in Tables 1 and 3 above, respectively. The formulation for citrate buffer is shown in Table 9.

[0090] Table 9: Citrate Buffer

[0091]

[0092] A 0.05% atropine solution was prepared in each buffer solution, and the pH was adjusted to the values ​​shown in Table 10. Each vial of atropine solution was autoclaved and analyzed by reversed-phase HPLC using the method of Example 1. The results are shown in Table 10 and... Figure 1 middle.

[0093] Table 10:

[0094]

[0095] The results showed that atropine degradation was more rapid in citrate-based buffers than in PBS. Atropine compositions including amine buffers were the most stable at a wide range of pH values.

[0096] The disclosure herein refers to certain illustrated examples, which should be understood to be presented by way of example only and not as limiting. Although exemplary examples are discussed, the detailed description above is intended to cover all modifications, alternatives, and equivalents that may fall within the spirit and scope of the invention as defined by the additional disclosure.

[0097] The applicant has intentionally incorporated the entire contents of all cited references into this disclosure. Furthermore, when quantities, concentrations, or other values ​​or parameters are given as ranges, preferred ranges, or lists of preferred upper and lower limits, this should be understood as all ranges formed by any pair of any upper or lower limit limits or preferred values, whether or not such ranges are disclosed individually. When numerical ranges are listed herein, unless otherwise stated, the range is intended to include its endpoints and all integers and fractions within the range. This document is not intended to limit the scope of the invention to the specific values ​​listed when defining the range.

[0098] This invention may include any combination of the various described features or embodiments set forth in sentences and / or paragraphs in the claims above and / or below. Any combination of features disclosed herein is considered part of this invention and no limitation is intended with respect to composable features.

[0099] Other embodiments of the invention will become apparent to those skilled in the art upon consideration of this specification and practice of the invention disclosed herein. This specification and examples are intended to be illustrative only, and the true scope and spirit of the invention are indicated by the following claims and their equivalents.

Claims

1. A heat-stable, ophthalmically acceptable aqueous liquid composition comprising an amine buffer and a muscarinic acetylcholine receptor antagonist comprising a hydrolysable bond.

2. The heat-stable, ophthalmically acceptable liquid composition of claim 1 having a pH in the range of 5.0 to 7.

5.

3. The heat-stable, ophthalmically acceptable aqueous liquid composition of claim 1 having a pH of 5.8 to 7.

4.

4. The heat-stable, ophthalmically acceptable aqueous liquid composition of any one of the preceding claims, wherein the hydrolysable bond is an ester bond or an amide bond attached to a nitrogen-containing heterocyclic group.

5. The heat-stable, ophthalmically acceptable aqueous liquid composition of any one of the preceding claims, wherein the muscarinic acetylcholine receptor antagonist is atropine or pirenzepine.

6. The heat-stable, ophthalmically acceptable aqueous liquid composition of any one of the preceding claims, wherein the composition is preservative-free.

7. The heat-stable, ophthalmically acceptable aqueous liquid composition of any one of the preceding claims, wherein the composition further comprises EDTA.

8. The heat-stable, ophthalmically acceptable aqueous liquid composition of any one of the preceding claims, wherein the amine buffer is selected from tris(hydroxymethyl)aminomethane (Tris), N-(2-acetylamino)iminodiacetic acid (ADA), bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane (Bis-Tris), 2-morpholinoethanesulfonic acid (MES), histidine, ethanolamine, hydrazine, imidazole, pyridine, and piperazine.

9. The heat-stable, ophthalmically acceptable aqueous liquid composition of any one of the preceding claims, wherein the amine buffer is selected from Tris and Bis-Tris.

10. The heat-stable, ophthalmically acceptable aqueous liquid composition of any one of the preceding claims, wherein the composition further comprises an agent capable of increasing intermolecular hydrogen bonding.

11. The heat-stable, ophthalmically acceptable aqueous liquid composition of any one of the preceding claims, comprising an aqueous component consisting of or comprising deuterated water.

12. The heat-stable, ophthalmically acceptable aqueous liquid composition of any one of the preceding claims, wherein the composition further comprises trehalose.

13. A heat-sterilized container containing the heat-stable, ophthalmically acceptable aqueous liquid composition of any one of the preceding claims.

14. The heat-sterilized container of claim 13, wherein the liquid composition comprises less than 10% of a hydrolytic degradation product of the muscarinic acetylcholine receptor antagonist.

15. The heat-sterilized container of claim 13 or 14, wherein the container is a multi-use or single-use eye drop dispensing bottle or vial.

16. The heat-sterilized container of any one of claims 13-15, wherein the container further contains a contact lens.

17. The heat sterilized container of any one of claims 13-16, wherein the amount of muscarinic acetylcholine receptor antagonist in the composition is not less than 90% of an initial amount of the muscarinic acetylcholine receptor antagonist present in the composition prior to heat sterilization.

18. The heat sterilized container of any one of claims 13-17, wherein the composition comprises less than at least 90% (by weight) of a hydrolytic degradation product of the muscarinic acetylcholine receptor antagonist than a control composition comprising PBS in place of the amine buffer.

19. The heat sterilized container of any one of claims 13-18, wherein the heat sterilized container is sterilized by autoclaving.

20. A method of manufacturing the heat sterilized container of any one of claims 13-19, comprising: (a) placing an ophthalmically acceptable packaging solution in a container, (b) sealing the container, and (c) heat sterilizing the sealed container, wherein the packaging solution is a liquid ophthalmically acceptable composition.

21. A container containing the ophthalmically acceptable aqueous liquid composition of any one of claims 1-12, wherein the liquid composition has been sterilized by filtration.

22. The container of claim 21, wherein the container is a multi-use or single-use eye drop dispensing bottle or vial.

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