Atropine formulations

Abstract

A liquid ophthalmic composition comprising atropine or a pharmaceutically acceptable salt thereof, at least one buffering agent and at least one tonic agent, wherein Atropine or a pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.001% to 0.1% by weight. that at least one buffering agent is present in the composition at a concentration of 0.5 mM to 50 mM, that at least one tonic agent is present in the composition at a concentration of 100 mM to 500 mM, the composition has a pH value of 4.0 to 6.0.

Description

Technical field

[0001] The present invention relates to atropine formulations and the atropine formulations according to the invention for use in the treatment or prevention of the progression of myopia. background

[0002] Nearsightedness, or myopia, is a specific type of refractive error of the eye. In this condition, light is not focused directly onto the retina, but in front of it. This is usually the result of an elongated eyeball or a refractive power of the optical components that is too strong relative to its length. This creates an optical aberration that causes distant objects to appear blurrier than near ones. Affected individuals can therefore see better at close range (hence the term "nearsighted") than at a distance.

[0003] Both genetic and environmental factors play a role in the development of myopia. A significant risk factor is a lack of outdoor time during early childhood. This is related to the effects of daylight on the production and release of retinal dopamine.

[0004] Worldwide, approximately 1.5 billion people are affected by nearsightedness. The proportion of nearsighted individuals in the total population has increased significantly in recent years. Because nearsightedness is particularly widespread in industrialized nations, it is often considered a disease of civilization.

[0005] Atropine is the tropine ester of tropic acid and is generally available as the sulfate salt. Non-enzymatic spontaneous hydrolysis of atropine in aqueous solution yields tropine and tropic acid, which, while non-toxic, exhibit no biological activity when used ophthalmically.

[0006] For ophthalmic use, atropine is marketed under the name Atropine Care (Akorn) as a 1% solution for the treatment of, among other conditions, amblyopia, and also contains 0.01% w / w of the preservative benzalkonium chloride. In another indication, atropine has also been used in several pediatric studies to slow the progression of myopia. Specifically, the disease progressed more slowly in children who received topical atropine drops than in a control group in the same study. Advantageously, children who received eye drops with low atropine concentrations (e.g., in the range of 0.01–0.05% w / v (0.01% w / w)) experienced significantly less photophobia and other side effects.

[0007] In fact, the use of low-dose (e.g., 0.01%) atropine has become established as the preferred treatment for slowing the progression of myopia. Unfortunately, the toxic effects of benzalkonium chloride have been demonstrated in both laboratory and clinical settings. These include tear film instability, goblet cell loss, conjunctival squamous metaplasia and apoptosis, disruption of the corneal epithelial barrier, and damage to deeper ocular tissues.

[0008] Since normal tears have a pH of approximately 7.4, an ophthalmic solution should ideally have the same pH as tear fluid. However, this poses a challenge for ophthalmic solutions containing atropine sulfate, as atropine sulfate undergoes greater hydrolysis in solutions with a more neutral or alkaline pH. Therefore, atropine is more stable in ophthalmic solutions with a more acidic pH. For example, Atropine Care, with a 1% w / w concentration of atropine, remains stable at a pH of 5.5, but its shelf life is still limited to 15 months. Furthermore, the degradation of atropine to tropic acid in aqueous solutions is significantly accelerated at reduced atropine concentrations, further exacerbating stability issues, particularly with low-dose atropine formulations.

[0009] Therefore, there is a need for improved, storage-stable, ready-to-use aqueous compositions containing atropine in low concentrations, having a physiologically desirable pH value, and preferably containing no preservative. Summary of the invention

[0010] One aspect of the present invention relates to a liquid ophthalmic composition comprising atropine or a pharmaceutically acceptable salt thereof, at least one buffering agent and at least one tonic agent, wherein atropine or a pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.001 wt.% to 0.1 wt.%, the at least one buffering agent is present in the composition in a concentration of 0.5 mM to 50 mM, the at least one tonic agent is present in the composition in a concentration of 100 mM to 500 mM, wherein the composition has a pH of 4.0 to 6.0.

[0011] Another aspect of the present invention relates to a liquid ophthalmic composition comprising atropine or a pharmaceutically acceptable salt thereof, at least one buffering agent, at least one tonic agent, and water, wherein atropine or a pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.001 wt.% to 0.1 wt.%, the at least one buffering agent is present in the composition in a concentration of 0.5 mM to 50 mM, the at least one tonic agent is present in the composition in a concentration of 100 mM to 500 mM, and wherein the composition has a pH of 4.0 to 6.0.

[0012] Another aspect of the present invention relates to a composition according to the invention for use in the treatment or prevention of the progression of myopia. Detailed description

[0013] The invention is explained in more detail below. Definitions

[0014] To make the present invention easy to understand, several definitions of the terms used in the invention are set out below.

[0015] The terms “formulation(s)” and “composition(s)” are used synonymously in the context of this disclosure.

[0016] The term "ophthalmic composition" as used here refers to liquid compositions suitable for topical administration to the eye or as eye drops, including solutions, suspensions, and emulsions. In one particular embodiment, the term "ophthalmic composition" refers to an ophthalmic solution. In another specific embodiment, the term "ophthalmic composition" refers to an aqueous ophthalmic solution.

[0017] Within the scope of the present invention, "preservative-free" or "free from preservatives" means that the ophthalmic solution of the present invention does not contain a preservative, such as quaternary ammonium salts, e.g., benzalkonium chloride (BAK). Other pharmaceutically acceptable preservatives for ophthalmic solutions include, for example, boric acid polyol zinc chloride or chlorine oxide compounds, chlorhexidine gluconate, benzethonium chloride, sorbic acid, potassium sorbate, ethyl p-hydroxybenzoate, and butyl p-hydroxybenzoate.

[0018] Within the scope of the present invention, “treat” or “treatment” means the application of therapeutic methods and active substances to alleviate, control or cure a disease in a patient.

[0019] Within the scope of the present invention, “prevention” means reducing the risk, delaying the occurrence or preventing the development of a disease in a subject.

[0020] As used herein, the term “comprehensive” is to be interpreted as encompassing both “including” and “consisting of”, both meanings being specifically intended for embodiments according to the present invention and therefore being disclosed separately.

[0021] Unless otherwise stated, all percentages are weight percentages (wt%) or weight per volume (wt / vol). Furthermore, it should be noted that the weight percentages of atropine sulfate given here are based on atropine sulfate monohydrate.

[0022] As used here, the term "approximately" refers to changes in the quantity of a substance, ingredient, component, or parameter used, specifically variations in the numerical quantity that may occur, for example, through typical measurement and handling procedures, such as liquid handling procedures used to produce concentrates or solutions. Furthermore, variations may occur due to unintentional errors in measurement procedures, differences in the preparation, source, or purity of the ingredients used to carry out the methods, and the like. In one embodiment, the term "approximately" means within 10% of the stated numerical value. In a more specific embodiment, the term "approximately" means within 5% of the stated numerical value.

[0023] As explained above, one aspect of the invention relates to a liquid ophthalmic composition comprising atropine or a pharmaceutically acceptable salt thereof, at least one buffering agent and at least one tonic agent, wherein atropine or a pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.001 wt.% to 0.1 wt.%, the at least one buffering agent is present in the composition in a concentration of 0.5 mM to 50 mM, the at least one tonic agent is present in the composition in a concentration of 100 mM to 500 mM, wherein the composition has a pH of 4.0 to 6.0.

[0024] In one embodiment, the pharmaceutically acceptable salt of atropine is atropine sulfate.

[0025] In one embodiment, atropine or a pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.005 wt.% to 0.07 wt.%. Preferably, atropine or a pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.01 wt.% to 0.05 wt.%. For example, atropine or a pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.01 wt.%, 0.02 wt.%, 0.025 wt.%, or 0.05 wt.%.

[0026] In one embodiment, the at least one buffering agent is selected from the group consisting of carboxylic acids, phosphates, amino acids and combinations thereof.

[0027] In one embodiment, at least one buffering agent is citric acid.

[0028] In one embodiment, the at least one buffer agent is present in a concentration of 1 mM to 10 mM. Preferably, the at least one buffer agent is present in a concentration of 1 mM to 5 mM.

[0029] The amount of tonic used can be adjusted to achieve an osmolality of the formulations in the range of 260 to 340 mOsm / kg. An osmometer can be used to check and adjust the amount of tonic added to achieve the desired osmolality.

[0030] In one embodiment, the at least one tonic agent is present in a concentration of 100 mM to 200 mM. Preferably, the at least one tonic agent is present in a concentration of 125 mM to 175 mM.

[0031] In one embodiment, the at least one tonic agent is a pharmaceutically acceptable salt. In another embodiment, the at least one tonic agent is sodium chloride.

[0032] In one embodiment, the composition has a pH value of 4.5 to 5.0. Preferably, the composition has a pH value of 4.7 to 4.9.

[0033] The composition according to the invention may optionally also contain a pH regulator.

[0034] The term "pH regulator" refers to a chemical compound used to adjust the pH of an aqueous solution to a desired range, for example, a pH of 4.0 to 6.0. If the pH needs to be lowered, an acid, such as hydrochloric acid, is used as the pH regulator. If the pH needs to be raised, the pH regulator is a base, such as sodium hydroxide or potassium hydroxide. The preferred acid for pH adjustment is hydrochloric acid. The preferred base for pH adjustment is sodium hydroxide. The acid and the base, as defined above, can optionally be used in combination as pH regulators to adjust the pH of the solution to the desired value. In one embodiment, the pH regulator is hydrochloric acid. In another embodiment, the pH regulator is sodium hydroxide.The amount of pH regulator required to adjust the pH of the composition to the desired range, for example pH 4.0 to 6.0, is usually very small.

[0035] In one embodiment, the composition comprises atropine sulfate in an amount of 0.01 wt.% to 0.05 wt.%, citric acid in a concentration of 1 mM to 10 mM, and sodium chloride in a concentration of 100 mM to 200 mM, and has a pH of 4.5 to 5.0.

[0036] In one embodiment, the composition comprises atropine sulfate in an amount of 0.01 wt.% to 0.05 wt.%, citric acid in a concentration of 1 mM to 5 mM, and sodium chloride in a concentration of 125 mM to 175 mM, and has a pH of 4.5 to 5.0, preferably a pH of 4.7 to 4.9.

[0037] In one embodiment, the liquid ophthalmic composition is an aqueous composition. Preferably, the solvent of the aqueous composition is water, preferably sterile water.

[0038] In one embodiment, the composition is free of preservatives, viscosity modifiers and chelators.

[0039] Chelators include monomeric polyacids such as ethylenediaminetetraacetic acid (EDTA), cyclohexanediaminetetraacetic acid (CDTA), hydroxyethylethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), dimercaptopropanesulfonic acid (DMPS), dimercaptosuccinic acid (DMSA), aminotrimethylenephosphonic acid (ATPA), as well as ophthalmologically acceptable salts thereof and combinations of any of the aforementioned.

[0040] In one embodiment, the composition is free of ethylenediaminetetraacetic acid (EDTA) and / or salts thereof.

[0041] The inventors have discovered that low-dose ophthalmic atropine compositions can be produced with atropine in a ready-to-use concentration (e.g., for the treatment of myopia) that have a near-physiological pH and preferably contain no preservatives in the formulation. Surprisingly, the storage stability of the ophthalmic compositions presented here is remarkably high.

[0042] Therefore, the intended atropine formulations of the inventive subject matter can advantageously be provided in a ready-to-use format, thus avoiding the inconveniences associated with diluting concentrated atropine formulations in diluents before administration. This also eliminates the risks of microbial contamination and / or calculation errors associated with dilution. Typically, the intended formulations will be available in a concentration range commonly required by physicians for the treatment of myopia, particularly myopia in children.

[0043] Regarding the sterilization of the intended formulations, it should be noted that the intended formulations can be sterilized using all known sterilization methods, including filtration through 0.22-micron filters, heat sterilization, autoclaving and irradiation (e.g. gamma, electron beam or microwave treatment).

[0044] Due to the stability achieved in this way, the formulations according to the invention can be filled into sterile single-dose or multi-dose containers made of polyethylene (PE), polypropylene (PP), or low-density polyethylene (LDPE) using the blow-fill-seal (BFS) process. The BFS process is a state-of-the-art, aseptic manufacturing method in which the container is formed, filled, and sealed in a fully automated process.

[0045] The BFS process begins with the extrusion of a molten plastic preform, which is immediately blown into the desired container shape. While the material is still in a malleable state, it is sterilely filled with the ophthalmic formulation. The container is then hermetically sealed and cooled in a controlled manner to ensure product integrity.

[0046] The formulations according to the invention can be provided in various packaging formats, including single-dose containers and multi-dose containers. Single-dose containers typically have a filling volume of 0.2 mL to 1.0 mL, particularly for preservative-free formulations for single use. Multi-dose containers typically have a filling volume of 2 mL to 150 mL and can be equipped with sterile dropper tips or special valve systems to prevent contamination and facilitate dosing.

[0047] The composition of the ophthalmic formulation is advantageously chosen to withstand the temperature and pressure requirements of the BFS process without significant degradation of active ingredients (e.g., less than 5 wt%, less than 3 wt%, less than 2 wt%, less than 1 wt%).

[0048] Another aspect of the present invention relates to a liquid ophthalmic composition comprising atropine or a pharmaceutically acceptable salt thereof, at least one buffering agent, at least one tonic agent, and water, wherein atropine or a pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.001 wt.% to 0.1 wt.%, the at least one buffering agent is present in the composition in a concentration of 0.5 mM to 50 mM, the at least one tonic agent is present in the composition in a concentration of 100 mM to 500 mM, and wherein the composition has a pH of 4.0 to 6.0.

[0049] In one embodiment, the composition consists of atropine or a pharmaceutically acceptable salt thereof, at least one buffering agent, at least one tonic agent, and water, wherein atropine or a pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.005 wt.% to 0.07 wt.%, the at least one buffering agent is present in the composition in a concentration of 1 mM to 10 mM, the at least one tonic agent is present in the composition in a concentration of 100 mM to 200 mM, and wherein the composition has a pH of 4.0 to 6.0.

[0050] In one embodiment, the composition consists of atropine or a pharmaceutically acceptable salt thereof, at least one buffering agent, at least one tonic agent, and water, wherein atropine or a pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.01% to 0.05% by weight, the at least one buffering agent is present in the composition in a concentration of 1 mM to 5 mM, the at least one tonic agent is present in the composition in a concentration of 125 mM to 175 mM, and wherein the composition has a pH of 4.5 to 5.0, preferably a pH of 4.7 to 4.9.

[0051] In one embodiment, the composition consists of atropine sulfate in an amount of 0.01 wt.% to 0.05 wt.%, citric acid in a concentration of 1 mM to 5 mM, sodium chloride in a concentration of 125 mM to 175 mM, and water, and has a pH of 4.5 to 5.0, preferably a pH of 4.7 to 4.9.

[0052] Another aspect of the present invention relates to the composition according to the invention as disclosed herein for use in the treatment or prevention of the progression of myopia. Examples

[0053] The following examples illustrate the present invention. They are intended to aid in understanding the invention and should not be interpreted as limiting the scope of the invention in any way. Example 1 - General manufacturing process of an aqueous atropine composition

[0054] The compositions according to the invention can be obtained as follows: For preparation, the desired amount of sterile water, for example 90% of the final volume, is first placed in a sterile beaker. Then, the desired amount of sodium chloride, citric acid, and atropine sulfate is added and completely dissolved with continuous stirring. The pH of the mixture is then adjusted to the desired pH value with a 1 M sodium hydroxide solution or a 1 M hydrochloric acid solution. After reaching the desired pH value, the volume is made up with sterile water to the final atropine concentration. The solution is then sterilized by sterile filtration through a 0.22 µm filter. Example 2 - Atropine composition according to the invention

[0055] First, 900 mL of sterile water were placed in a sterile beaker. Then, 0.1 g of atropine sulfate was completely dissolved under continuous stirring. Next, 0.63 g of citric acid and 8.8 g of sodium chloride were added. The pH of the mixture was then adjusted to 4.8 using either a 1 M sodium hydroxide solution or a 1 M hydrochloric acid solution. Once the desired pH was reached, the volume was made up to one liter with sterile water. The solution was then sterilized by sterile filtration through a 0.22 µm filter. Example 3 - Bearing stability

[0056] To determine the storage stability of the formulations according to the invention, the atropine composition from Example 2 (0.1 mg / mL atropine sulfate) was stored at 25°C / 60% relative humidity, 30°C / 65% relative humidity, and 40°C / 75% relative humidity, and the tropic acid content was determined. The sample volume was 0.3 mL, and the samples were stored in polyethylene containers (Purell 1840H).

[0057] The tropical acid content was determined by HPLC according to Ph. Eur. 2.2.29 “Liquid chromatography” as follows: HPLC with diode array detector (DAD); DAD 190 - 300 nm. Column: Silica Gel C8, 150 x 4.6 mm, 5 µm. Mobile Phase A: Mixture of 830 mL buffer solution with 170 mL acetonitrile and 2.0 mL phosphoric acid. Mobile Phase B: Acetonitrile. Retention time of tropical acid: 7.7 min.

[0058] Tables 1 to 3 below show the content of tropic acid (hydrolytic degradation product of atropine) in the samples over time under different storage conditions. Table 1: 0.1 mg / mL atropine sulfate at 25°C / 60% relative humidity Months 0 3 6 9 12 18 24 36 Tropical acid [%] nd* 0,08 0,17 0,25 0,38 0,49 0,67 1,00 * not detected Table 2: 0.1 mg / mL atropine sulfate at 30°C / 65% relative humidity Months 0 3 6 9 12 Tropical acid [%] nd* 0,16 0,32 0,46 0,73 * not detected Table 3: 0.1 mg / mL atropine sulfate at 40°C / 75% relative humidity Months 0 3 6 Tropical acid [%] nd* 0,48 1,03 * not detected

[0059] As can be seen from Tables 1 to 3, the compositions according to the invention are surprisingly stable and have a high storage life, despite the low atropine concentration.

[0060] It is obvious to those skilled in the art that these embodiments and elements represent only examples of a multitude of possibilities. Therefore, the embodiments shown here should not be understood as limiting these features and configurations. Any possible combination and configuration of the described features can be chosen within the scope of the invention.

Claims

[1] A liquid ophthalmic composition comprising atropine or a pharmaceutically acceptable salt thereof, at least one buffering agent and at least one tonic agent, wherein Atropine or a pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.001% to 0.1% by weight. that at least one buffering agent is present in the composition at a concentration of 0.5 mM to 50 mM, that at least one tonic agent is present in the composition at a concentration of 100 mM to 500 mM, the composition has a pH value of 4.0 to 6.

0. [2] The composition according to claim 1, wherein the pharmaceutically acceptable salt of atropine is atropine sulfate. [3] The composition according to claim 1 or 2, wherein atropine or a pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.005 wt.% to 0.07 wt.%, preferably 0.01 wt.% to 0.05 wt.%. [4] The composition according to any one of claims 1 to 3, wherein the at least one buffering agent is selected from the group consisting of carboxylic acids, phosphates, amino acids and combinations thereof. [5] The composition according to any one of claims 1 to 4, wherein the at least one buffering agent is citric acid. [6] The composition according to any one of claims 1 to 5, wherein the at least one buffer agent is present in a concentration of 1 mM to 10 mM, preferably from 1 mM to 5 mM. [7] The composition according to any one of claims 1 to 6, wherein the at least one tonic agent is a pharmaceutically acceptable salt. [8] The composition according to any one of claims 1 to 7, wherein the at least one tonic agent is sodium chloride. [9] The composition according to any one of claims 1 to 8, wherein the composition has a pH value of 4.5 to 5.

0. [10] The composition according to any one of claims 1 to 9, wherein the composition has a pH value of 4.7 to 4.

9. [11] The composition according to any one of claims 1 to 10, wherein the composition comprises: Atropine sulfate in an amount of 0.01% w / w to 0.05% w / w, Citric acid in a concentration of 1 mM to 10 mM, preferably from 1 mM to 5 mM, and Sodium chloride at a concentration of 100 mM to 200 mM, preferably from 125 mM to 175 mM. [12] The composition according to any one of claims 1 to 11, wherein the composition is free of preservatives, viscosity modifiers and chelators. [13] A liquid ophthalmic composition consisting of atropine or a pharmaceutically acceptable salt thereof, at least one buffering agent, at least one tonic agent and water wherein Atropine or a pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.001% to 0.1% by weight. that at least one buffering agent is present in the composition at a concentration of 0.5 mM to 50 mM, that at least one tonic agent is present in the composition at a concentration of 100 mM to 500 mM, and the composition has a pH value of 4.0 to 6.

0. [14] The composition according to claim 13, wherein atropine or a pharmaceutically acceptable salt thereof is present in the composition in an amount of 0.005 wt.% to 0.07 wt.%, preferably 0.01 wt.% to 0.05 wt.%. [15] The composition according to one of claims 13 to 14, wherein the at least one buffering agent is selected from the group consisting of carboxylic acids, phosphates, amino acids and combinations thereof, preferably wherein the at least one buffering agent is citric acid, and / or wherein the at least one tonic agent is a pharmaceutically acceptable salt, preferably wherein the at least one tonic agent is sodium chloride. [16] The composition according to any one of claims 13 to 15, wherein the at least one buffer agent is present in a concentration of 1 mM to 10 mM, preferably from 1 mM to 5 mM. [17] The composition according to any one of claims 13 to 16, wherein the composition has a pH of 4.5 to 5.0, preferably a pH of 4.7 to 4.

9. [18] A composition according to any one of claims 1 to 17 for use in the treatment or prevention of myopia.