Ophthalmic preparation and use thereof

Abstract

The present invention relates to an ophthalmic preparation and the use thereof. Specifically, the present invention relates to a pilocarpine ophthalmic preparation and the use thereof in the treatment of ocular diseases. The pilocarpine ophthalmic preparation provided in the present invention has the beneficial effects of a good stability and low ocular irritation.

Description

An ophthalmic preparation and its uses Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to an ophthalmic preparation and its uses. Background Technology

[0002] Presbyopia is an age-related visual impairment caused by a gradual decrease in the eye's physiological accommodation, leading to progressive difficulty in near vision. Its pathogenesis involves a gradual weakening of the lens's elasticity and a decline in the ciliary muscle's contractile ability with age, along with a series of changes in other eye tissues. This results in a decline in the eye's accommodative function, causing difficulty in near vision, the need for increased reading light intensity, and easy eye strain. Currently, treatment methods for presbyopia mainly include optical correction, surgical correction, and drug therapy.

[0003] Drug treatment for presbyopia primarily relies on two mechanisms of action: one is to produce a pinhole effect through pupillary constriction, increasing visual depth; the other is to improve lens elasticity to achieve a fundamental cure. Currently, there are no commercially available drugs that completely cure presbyopia by improving lens elasticity. Currently approved drugs that exert their therapeutic effect through pupillary constriction include the FDA-approved pilocarpine hydrochloride eye drops Vuity and Qlosi. The multi-dose packaged Vuity contains benzalkonium chloride as an antibacterial agent, has a pH of 3.5-5.5, and causes significant eye discomfort after ocular administration, leading to poor patient compliance. Common adverse reactions to Vuity in clinical trials include conjunctival hyperemia and eye irritation. Phase III clinical trials showed that the probability of eye irritation and pain was higher than that in the control group (George O. Waring IV, MD; Francis W. Price Jr, MD; David Wirta, MD; et al. Safety and Efficacy of AGN-190584 in Individuals With Presbyopia The GEMINI 1 Phase 3 Randomized Clinical Trial[J].JAMA Ophthalmol,2022,140(4):363-371; Shane Kannarr, Sherif M El-Harazi, Majid Moshirfar, et al. Safety and Efficacy of Twice-Daily Pilocarpine HCl in Presbyopia:The Virgo Phase 3,Randomized,Double-Masked,Controlled Study[J].Am J Ophthalmol,2023,253:189-200.). The pH value of single-dose Qlosi is 5.1-6.1. To ensure stability, Qlosi needs to be stored at 2-8°C.

[0004] The molecular structure of pilocarpine is shown below.

[0005] This structure contains a five-membered lactone ring segment, which is chemically unstable. It readily hydrolyzes and opens in neutral or slightly alkaline aqueous environments, leading to a decrease in pilocarpine content and an increase in related impurities, thus affecting the quality and efficacy of drugs using pilocarpine as the active pharmaceutical ingredient. Furthermore, the hydrolysis of pilocarpine intensifies significantly with increasing solution pH. Neutral solutions prepared using conventional formulations exhibit poor stability when stored at room temperature. Current technologies primarily inhibit pilocarpine hydrolysis by lowering the solution pH and storage temperature.

[0006] Chinese patent application CN117243906A discloses an ophthalmic preparation and its preparation method. To improve the stability of pilocarpine, this patent application divides the preparation into two parts: a solid tablet and a liquid. The pilocarpine is made into a solid tablet to avoid hydrolysis problems encountered during storage in solution. When used, the tablet is added to the liquid to immediately prepare eye drops. The disadvantage of this invention is that it is difficult to ensure strict aseptic requirements for ophthalmic medication when using tablet compression technology to prepare solid tablets, and the risk of microbial contamination during long-term use is relatively high. Chinese patent CN115089587B discloses a compound pilocarpine composition, its preparation process, and application method. While maintaining the original therapeutic effect of pilocarpine, it reduces side effects by combining it with brimonidine tartrate to lower the concentration of pilocarpine. The disadvantage of this invention is that it requires the combined use of two active ingredients to lower the concentration of pilocarpine to overcome its side effects, posing a challenge to patients. Summary of the Invention

[0007] To overcome the problems of eye irritation, pain, and stability in existing pilocarpine ophthalmic preparations, this invention provides an ophthalmic preparation characterized by comprising a first solution and a second solution. The first solution contains 0.1%-3.0% (w / v) of pharmaceutically acceptable pilocarpine salt and optionally an osmotic pressure regulator; the second solution contains a pH buffer and an osmotic pressure regulator; the volume ratio of the first solution to the second solution is 1:10 to 10:1; the first solution and the second solution are mixed immediately before use to form a homogeneous mixed solution, the pH of which is about 5.0 to about 8.0.

[0008] In some embodiments, the pH value of the first solution in the ophthalmic preparation of the present invention is about 2.0-5.0; preferably, the pH value of the first solution is about 3.0-5.0; more preferably, the pH value of the first solution is about 3.5-4.5; even more preferably, the pH value of the first solution is about 4.0-4.5. In some specific embodiments, the pH value of the first solution in the ophthalmic preparation of the present invention is about 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0.

[0009] In some embodiments, the first solution of the ophthalmic formulation of the present invention does not contain a pH buffer.

[0010] In some embodiments, the first solution of the ophthalmic preparation of the present invention comprises 0.5%-3% (w / v), preferably 0.5%-2.5% (w / v) of pharmaceutically acceptable pilocarpine salt, and 0.1%-5.0% (w / v), preferably 0.1%-1.5% (w / v), more preferably 0.3%-1.0% (w / v) of an osmotic pressure regulator, and does not contain a pH buffer. In some embodiments, the first solution of the ophthalmic preparation of the present invention comprises 0.5%-2.5% (w / v) of pharmaceutically acceptable pilocarpine salt, and 0.3%-1.0% (w / v) of an osmotic pressure regulator, and does not contain a pH buffer. In some embodiments, the first solution of the ophthalmic preparation of the present invention comprises 0.5%-2.5% (w / v) of pharmaceutically acceptable pilocarpine salt, and 0.3%-1.0% (w / v) of an osmotic pressure regulator, with the balance being water for injection.

[0011] In some embodiments, the second solution of the ophthalmic preparation of the present invention has a pH value of about 5.0-9.0; preferably, the pH value of the second solution is about 6.0-8.5; more preferably, the pH value of the second solution is about 6.0-8.0. In some specific embodiments, the pH value of the second solution of the ophthalmic preparation of the present invention is about 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, or 9.0.

[0012] In some embodiments, the second solution of the ophthalmic preparation of the present invention comprises 0.1%-5.0% (w / v) of a pH buffer, preferably 0.1%-3.0% (w / v) of a pH buffer, more preferably 1.0%-2.0% (w / v) of a pH buffer; and 0.1%-5.0% of an osmotic pressure regulator, preferably 0.1%-3.0% of an osmotic pressure regulator, more preferably 0.1%-1.0% of an osmotic pressure regulator. In some embodiments, the second solution of the ophthalmic preparation of the present invention comprises 1.0%-2.0% (w / v) of a pH buffer and 0.1%-1.0% of an osmotic pressure regulator, with the balance being water for injection.

[0013] In some embodiments, the pharmaceutically acceptable salts of pilocarpine contained in the ophthalmic formulations of the present invention include, but are not limited to, pilocarpine hydrochloride, pilocarpine hydrobromide, pilocarpine sulfate, pilocarpine hydrogen sulfate, pilocarpine phosphate, pilocarpine hydrogen phosphate, pilocarpine dihydrogen phosphate, pilocarpine nitrate, pilocarpine tartrate, pilocarpine fumarate, pilocarpine salicylate, pilocarpine malate, pilocarpine citrate, pilocarpine oxalate, pilocarpine methanesulfonate, pilocarpine formate, pilocarpine acetate, and pilocarpine hydrochloride. Pilocarpine succinate, pilocarpine maleate, pilocarpine citrate, pilocarpine benzoate, pilocarpine cinnamate, pilocarpine mandelate, pilocarpine ethanesulfonate, pilocarpine p-toluenesulfonate, pilocarpine lactate, pilocarpine nicotinate, pilocarpine lauryl sulfate, pilocarpine naphthalenesulfonate, pilocarpine camphorsulfonate, pilocarpine gluconate, pilocarpine glucuronate, pilocarpine oleate, pilocarpine palmitate, pilocarpine stearate, pilocarpine dihydroxynaphthalate, pilocarpine trifluoroacetate. In some preferred embodiments, the pharmaceutically acceptable salts of pilocarpine contained in the ophthalmic formulations of the present invention include, but are not limited to, pilocarpine hydrochloride, pilocarpine hydrobromide, pilocarpine sulfate, pilocarpine hydrogen sulfate, pilocarpine phosphate, pilocarpine hydrogen phosphate, pilocarpine dihydrogen phosphate, pilocarpine nitrate, pilocarpine tartrate, pilocarpine fumarate, pilocarpine salicylate, pilocarpine malate, pilocarpine citrate, pilocarpine oxalate, pilocarpine formate, pilocarpine acetate, pilocarpine succinate, pilocarpine maleate, and pilocarpine trifluoroacetate. In some preferred embodiments, the pharmaceutically acceptable salts of pilocarpine contained in the ophthalmic formulations of the present invention include, but are not limited to, pilocarpine hydrochloride, pilocarpine hydrobromide, pilocarpine sulfate, pilocarpine hydrogen sulfate, pilocarpine phosphate, pilocarpine hydrogen phosphate, pilocarpine dihydrogen phosphate, pilocarpine nitrate, pilocarpine formate, and pilocarpine acetate. In some preferred embodiments, the pharmaceutically acceptable salts of pilocarpine contained in the ophthalmic formulations of the present invention include, but are not limited to, pilocarpine hydrochloride, pilocarpine hydrobromide, pilocarpine sulfate, pilocarpine hydrogen sulfate, pilocarpine phosphate, pilocarpine hydrogen phosphate, pilocarpine dihydrogen phosphate, and pilocarpine nitrate. In some more preferred embodiments, the pharmaceutically acceptable salts of pilocarpine contained in the ophthalmic formulations of the present invention include, but are not limited to, pilocarpine hydrochloride and pilocarpine nitrate.

[0014] In some embodiments, the osmotic pressure regulator in the ophthalmic formulation of the present invention is selected from one or more of sodium chloride, mannitol, potassium chloride, sodium sulfate, potassium sulfate, glycerin, sorbitol, glucose, propylene glycol, and boric acid. In some preferred embodiments, the osmotic pressure regulator is selected from one or more of sodium chloride or boric acid.

[0015] In some embodiments, the pH buffer in the ophthalmic formulation of the present invention is selected from one or more of citric acid, sodium citrate, potassium citrate, boric acid, borax, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, acetic acid, sodium acetate, citric acid, sodium citrate, tartaric acid, sodium tartrate, hydrochloric acid, phosphoric acid, sodium hydroxide, and potassium hydroxide. In some preferred embodiments, the pH buffer is selected from one or more of citric acid, sodium citrate, potassium citrate, boric acid, borax, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, sodium hydroxide, and potassium hydroxide. In some preferred embodiments, the pH buffer is selected from one or more of citric acid, sodium citrate, boric acid, borax, sodium dihydrogen phosphate, disodium hydrogen phosphate, hydrochloric acid, and sodium hydroxide.

[0016] In some embodiments, the pH value of the solution obtained by mixing the first solution and the second solution in the ophthalmic formulation of the present invention is about 5.5 to about 7.5; preferably, the pH value of the solution obtained by mixing the first solution and the second solution is about 6.0 to about 7.0; more preferably, the pH value of the solution obtained by mixing the first solution and the second solution is about 6.0 to about 6.5. In some specific embodiments, the pH value of the solution obtained by mixing the first solution and the second solution is about 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, or 7.5.

[0017] In some embodiments, the osmotic pressure of the solution obtained by mixing the first solution and the second solution in the ophthalmic formulation of the present invention is about 260 to about 320 mOsm; preferably, the osmotic pressure of the solution obtained by mixing the first solution and the second solution is about 290 to about 310; more preferably, the osmotic pressure of the solution obtained by mixing the first solution and the second solution is about 300.

[0018] In some embodiments, the ophthalmic formulations of the present invention may not contain any antibacterial agents. In some embodiments, the ophthalmic formulations of the present invention may not contain any antibacterial agents selected from the following: benzalkonium chloride, benzalkonium bromide, methylparaben, parabens (e.g., methylparaben, ethylparaben, propylparaben, butylparaben), benzyl alcohol, phenethyl alcohol, and sorbic acid (ester).

[0019] In some embodiments, the ophthalmic formulation of the present invention comprises:

[0020] 1) A first solution; the first solution comprises:

[0021] i) 0.5% to 2.5% (w / v) pilocarpine hydrochloride or pilocarpine nitrate;

[0022] ii) 0.3%-1.0% (w / v) sodium chloride;

[0023] iii) The remainder is water for injection;

[0024] 2) A second solution; the second solution comprises:

[0025] i) 1.0%-2.0% (w / v) pH buffer;

[0026] ii) 0.1%-1.0% sodium chloride;

[0027] iii) The remainder is water for injection;

[0028] The pH value of the solution obtained by mixing the first solution and the second solution is approximately 6.0 to approximately 7.0.

[0029] In some embodiments, the ophthalmic formulation of the present invention comprises:

[0030] 1) A first solution; the first solution comprises:

[0031] i) 0.5% to 2.5% (w / v) pilocarpine hydrochloride or pilocarpine nitrate;

[0032] ii) 0.3%-1.0% (w / v) sodium chloride;

[0033] iii) The remainder is water for injection;

[0034] 2) A second solution; the second solution comprises:

[0035] i) 1.0%-2.0% (w / v) disodium hydrogen phosphate or sodium citrate;

[0036] ii) 0.1%-1.0% sodium chloride;

[0037] iii) Appropriate amount of hydrochloric acid;

[0038] iv) Optionally, sodium hyaluronate;

[0039] v) Remaining water for injection;

[0040] The pH value of the solution obtained by mixing the first solution and the second solution is approximately 6.0 to approximately 7.0.

[0041] In some embodiments, the pH of the first solution in the ophthalmic formulation of the present invention is about 3.5 to about 4.5, the pH of the second solution is about 6.0 to about 8.5, and the pH of the solution obtained by mixing the first solution and the second solution is about 6.0 to about 7.0.

[0042] In some embodiments, the pH of the first solution in the ophthalmic formulation of the present invention is about 4.0 to about 4.5, the pH of the second solution is about 6.0 to about 8.0, and the pH of the solution obtained by mixing the first solution and the second solution is about 6.0 to about 6.5.

[0043] In some embodiments, the volume ratio of the first solution to the second solution in the ophthalmic preparation of the present invention is 1:10 to 10:1; preferably, the volume ratio of the first solution to the second solution is 1:5 to 5:1; more preferably, the volume ratio of the first solution to the second solution is 1:3 to 3:1; even more preferably, the volume ratio of the first solution to the second solution is 1:2 to 2:1; most preferably, the volume ratio of the first solution to the second solution is about 1:1.

[0044] In some embodiments, the first solution and the second solution of the ophthalmic preparation of the present invention are stored separately and mixed to form a homogeneous mixed solution before use.

[0045] In some embodiments, the ophthalmic formulation of the present invention is a multi-dose formulation or a single-dose formulation. In some embodiments, the ophthalmic formulation of the present invention is a single-dose formulation.

[0046] In some embodiments, the ophthalmic preparation of the present invention is a multi-chamber eye drop, characterized in that the eye drop comprises a first solution and a second solution, as defined herein; the body of the multi-chamber container includes a first chamber and a second chamber, the first chamber being in communication with an outlet, and a sealed portion (i.e., a false weld) between the first and second chambers. The second solution is placed in the first chamber, and the first solution is placed in the second chamber. During application, without any specific auxiliary device, the first or second chamber is pressurized by, for example, manual pressure applied with one hand, increasing the internal pressure of the chamber, thereby opening the false weld and allowing the first and second chambers to communicate with each other, mixing the first and second solutions contained in the two chambers together. Furthermore, manual pressure application does not damage the tail of the multi-chamber container, preventing undesirable leakage of the container contents from the tail. Then, the cap at the front end of the outlet is twisted off, opening the outlet, allowing the resulting mixed solution to be squeezed out drop by drop from the outlet.

[0047] In some embodiments, the present invention provides a method for preparing the ophthalmic formulation of the present invention, comprising:

[0048] Prepare a first solution by mixing pilocarpine pharmaceutical salt, an osmotic pressure regulator, and water for injection in the proportions described herein; prepare a second solution by mixing a pH buffer, an osmotic pressure regulator, and water for injection in the proportions described herein.

[0049] The first and second solutions are filtered through a microporous membrane; then...

[0050] The filtered first and second solutions are dispensed into two chambers of a multi-chamber container. When in use, the first and second solutions are mixed by manually applying pressure to open the gap between the two chambers.

[0051] In some embodiments, the present invention provides a method for preparing an ophthalmic formulation, comprising:

[0052] Prepare a first solution by mixing pilocarpine hydrochloride or pilocarpine nitrate, sodium chloride, and water for injection in the proportions described herein; prepare a second solution by mixing sodium citrate, sodium chloride, hydrochloric acid, and water for injection, or sodium dihydrogen phosphate, sodium chloride, hydrochloric acid, and water for injection in the proportions described herein.

[0053] The first and second solutions are filtered through a microporous membrane; then...

[0054] The first solution and the second solution are dispensed into two chambers of a multi-chamber container. When in use, the first solution and the second solution are mixed by manually applying pressure to open the gap between the two chambers.

[0055] In some implementations, the microporous membrane used for filtration has a pore size of 0.15 to 0.45 μm, preferably about 0.22 μm.

[0056] In some embodiments, the present invention provides a method for preventing or treating eye diseases, comprising administering a therapeutically effective amount of the ophthalmic preparation described herein to an individual in need. In some embodiments, the eye diseases described herein include, but are not limited to, presbyopia, hyperopia, mydriasis, accommodative esotropia, and astigmatism.

[0057] In some embodiments, the ophthalmic preparations described herein can be used for the prevention or treatment of eye diseases. In some embodiments, the eye diseases described herein include, but are not limited to, presbyopia, hyperopia, pupillary dilation, accommodative esotropia, and astigmatism.

[0058] Beneficial effects: The ophthalmic preparation of the present invention stores a first solution containing the active drug pilocarpine and a second solution containing other excipients in two separate chambers. They are mixed into a homogeneous solution before use. Compared with the already marketed Vuity, this not only overcomes the problem of long-term stable storage of pilocarpine, but also reduces the irritation to the eyes due to the significantly weakened acidity of the mixed solution.

[0059] Secondly, the aqueous solution of pilocarpine itself presents an acidic environment, which improves the storage stability of pilocarpine at room temperature in the absence of a pH buffer. Surprisingly, this invention reveals that, compared to the case where a pH buffer is added, the stability of pilocarpine in the first solution is actually higher when no pH buffer is added.

[0060] Furthermore, both the first and second solutions use osmotic pressure regulators to adjust the osmotic pressure to be isotonic with the tear fluid. Compared to adjusting the osmotic pressure of only one solution, this design can avoid the direct instillation of solutions with too low or too high osmotic pressure in the first chamber into the eye due to improper use causing the weld to fail to open, thus preventing eye irritation. Attached Figure Description

[0061] Figure 1: An example of a multi-chamber eye drop container according to this application; Detailed Implementation

[0062] definition

[0063] As used in this specification, unless the context indicates otherwise, the following words and phrases are generally intended to have the meanings set forth below.

[0064] As used herein, the terms “comprising” or “including” mean that a structure or process includes the described components or steps, but does not exclude other components or steps.

[0065] As used herein, the term "about" refers to a common range of error for a corresponding value that is readily known to those skilled in the art. Values ​​or parameters described herein in the manner of "about" include the value or parameter itself.

[0066] As used herein, the term "multi-chamber" refers to those described in international patent application PCT / CN2024 / 075262, which includes not only the two chambers exemplified in the specific embodiments, but also the more chambers, such as three or more, that can be readily conceived by those skilled in the art based on the disclosure of this invention and specific requirements.

[0067] Example

[0068] Example 1: Acid-base stability of pilocarpine

[0069] Weigh appropriate amounts of citric acid and sodium citrate, and dissolve them in water for injection to prepare buffer solutions with pH values ​​of 3.0, 3.6, 4.0, 4.4, 5.0, and 6.0, respectively. Weigh appropriate amounts of sodium dihydrogen phosphate and disodium hydrogen phosphate, and dissolve them in water for injection to prepare a buffer solution with pH 7.0. Take 100 ml of each buffer solution with different pH values, and add 0.5 g of pilocarpine hydrochloride to each to prepare a pilocarpine hydrochloride solution with a final concentration of 0.5% (w / v). Incubate the solutions at room temperature, 40°C, and 60°C for 0 or 30 days, respectively, and conduct stability studies by measuring the content of relevant impurities. The results showed that when the pH of the buffer solution was between 4.4 and 7.0, pilocarpine hydrochloride was unstable and significantly degraded after being placed at 40℃ and 60℃ for 30 days, with a significant increase in the content of related impurities. When the pH of the buffer solution was between 3.0 and 4.0, or when water for injection was used instead of the buffer solution as the solvent, pilocarpine hydrochloride showed better stability, with no significant degradation after being placed at 40℃ and 60℃ for 30 days, and a significant decrease in the increase in the content of related impurities (as shown in Table 1).

[0070] Table 1

[0071] Example 2: Preparation of the pilocarpine preparation of the present invention

[0072] According to the prescription dosage in Table 2, sodium chloride and pilocarpine hydrochloride were added to water for injection and completely dissolved, then diluted to volume to obtain the first solution. According to the prescription dosage in Table 2, sodium hyaluronate (if available), disodium hydrogen phosphate or sodium citrate (pH buffer), and sodium chloride were completely dissolved in water for injection. An appropriate amount of dilute hydrochloric acid was added to adjust the pH to the target value, and the solution was diluted to volume to obtain the second solution. The first and second solutions were filtered separately through a 0.22 μm microporous membrane. After filtration, the second solution was first filled into the first chamber 3 near the outlet 5 of the double-chamber container 1, which is sealed at the nozzle end. The first chamber was then loosely sealed by welding before the first solution was filled into the second chamber 4, and the second chamber was sealed. During application, no specific auxiliary device is required. For example, manual pressure applied with one hand increases the internal pressure of either the first chamber 3 or the second chamber 4, opening the weak weld 2 and allowing the first chamber 3 and the second chamber 4 to connect. The first and second solutions contained in the two chambers then mix together. Furthermore, manual pressure application does not damage the tail 7 of the multi-chamber container, preventing undesirable leakage of the container contents. Next, the cap 6 at the front end of the outlet 5 is twisted off, opening the outlet 5 and allowing the resulting mixed solution to be squeezed out dropwise from the outlet 5 (as shown in Figure 1).

[0073] Table 2

[0074] Example 3: Study on physicochemical properties

[0075] The pH value of the first solution of the ophthalmic preparation prepared in this invention varies with the concentration of pilocarpine hydrochloride. The pH value of the second solution can be adjusted by adding an appropriate amount of hydrochloric acid. Mixing the first and second solutions yields a homogeneous solution with a pH value of approximately 6.3. The osmotic pressure of the prepared first solution, second solution, and their mixture is very close to that of human tears (Table 3).

[0076] Table 3

[0077] Example 4: Stability of the pilocarpine preparation of the present invention

[0078] The 0.3%, 0.4%, and 1.25% samples and the control (formulations shown in Table 4) prepared in Example 2 of this invention were placed at 60°C, 25°C / 40%RH, and 40°C / 25%RH for several days or months, respectively. The first solution was mixed with the second solution, and the stability was studied by measuring the content of relevant impurities in the mixture. The pH value of the first solution in the control group was approximately 4.0, and the pH value of the mixture obtained after mixing the first and second solutions was approximately 6.5. The results showed that the increase in the content of relevant impurities pilocarpine acid and / or pilocarpine isocarpine in the 0.3%, 0.4%, and 1.25% samples was less than that of the marketed product Vuity and the control, indicating that the pilocarpine preparation of this invention has higher stability (as shown in Table 5).

[0079] Table 4

[0080] Table 5

[0081] The 0.3% and 1.25% samples prepared in Example 2 were stored at 25°C / 40%RH and 40°C / 25%RH for 3 months, respectively, and the sterility test still met the requirements. Compared with the method in patent CN117243906A, which uses tableting technology to prepare solid tablets of pilocarpine to improve its stability, the pilocarpine preparation of this invention can ensure a sterile environment during storage, and is safe and effective (as shown in Table 6).

[0082] Table 6

[0083] Example 5: Ocular irritation test of the pilocarpine preparation of the present invention.

[0084] 1. Laboratory animals

[0085] Dutch rabbits (standard grade), 3-5 months old, purchased from Pizhou City Dongfang Breeding Co., Ltd.; 12 rabbits, both male and female, divided into 3 groups of 4 rabbits each;

[0086] 2. Experimental Samples

[0087] Ophthalmic formulations in 0.3% and 1.25% strengths prepared in Example 2 of this invention;

[0088] Vuity, 1.25% (5ml: 62.5mg, calculated as pilocarpine hydrochloride), purchased from AbbVie Inc.;

[0089] Sodium chloride injection (0.9%), commercially available, manufactured by Hunan Kelun Pharmaceutical Co., Ltd.

[0090] 3. Experimental Methods and Results

[0091] Slit-lamp examination was performed on both eyes of each animal within 24 hours prior to the experiment to ensure that the rabbit eyes showed no signs of irritation or corneal and conjunctival damage. During the experiment, the lower eyelid of the animal's right eye was gently pulled back to expose the conjunctival sac. Using a micropipette of appropriate volume, 50 μL of each formulation was instilled into the conjunctival sac of the right eye of each group of rabbits. The same amount of physiological saline was instilled into the left eye as a negative control. After administration, the eyelid was gently closed for about 10 seconds. The 0.3% ophthalmic formulation was administered twice daily at 50 μL each time for 14 consecutive days; the 1.25% ophthalmic formulation was administered once daily at 50 μL each time for 14 consecutive days. Slit-lamp examination was performed before each administration and at 1, 2, 4, 24, 48, and 72 hours after the last administration. Corneal, iris, and conjunctival hyperemia, conjunctival edema, and conjunctival secretions were observed with a slit lamp and scored according to the ocular irritation reaction scoring criteria (Table 7).

[0092] Table 7 Scoring Standards for Ocular Irritation Reactions

[0093] The scores for corneal, iris, conjunctival hyperemia, conjunctival edema, and conjunctival secretions were summed to obtain the total score for eye irritation symptoms for each animal at each time point. Based on the eye irritation symptom scores, the mean total score for each observation time point and each group of animals was calculated, and the degree of eye irritation for each time point and each group of animals was determined according to the criteria in Table 8.

[0094] Table 8 Evaluation and Scoring Standards for Ocular Irritation Reactions

[0095] The ocular irritation data of each group of animals were statistically analyzed according to the scoring criteria, and the results are shown in Table 9. In Example 2, the 0.3% and 1.25% formulations, as well as the negative control group (physiological saline), showed no irritation, but Vuity showed mild irritation after administration. This indicates that the pilocarpine ophthalmic formulation of the present invention, due to the near-neutral pH value of the mixture of the first and second solutions and the easier pH balancing after instillation with a small amount of pH buffer, can reduce the irritation of the solution and improve the patient's experience.

[0096] Table 9 Results of eye irritation tests

Claims

1. An ophthalmic preparation, characterized in that, The mixture comprises a first solution and a second solution, the first solution comprising 0.1%-3.0% (w / v) of pharmaceutically acceptable pilocarpine salt and optional osmotic pressure regulator; the second solution comprising a pH buffer and an osmotic pressure regulator; the volume ratio of the first solution to the second solution being 1:10 to 10:1; the first solution and the second solution being mixed immediately before use to form a homogeneous mixture having a pH of about 5.0 to about 8.

0.

2. The ophthalmic preparation according to claim 1, characterized in that, The first solution has a pH value of about 2.0-5.0; preferably, the first solution has a pH value of about 3.0-5.0; more preferably, the first solution has a pH value of about 3.5-4.5; even more preferably, the first solution has a pH value of about 4.0-4.

5.

3. The ophthalmic preparation according to claim 1, characterized in that, The first solution contains 0.5%-3% (w / v), preferably 0.5% to 2.5% (w / v) of medicinal salt of pilocarpine, and 0.1%-5.0% (w / v), preferably 0.1%-1.5% (w / v), more preferably 0.3%-1.0% (w / v) of an osmotic pressure regulator.

4. The ophthalmic preparation according to claim 1, characterized in that, The first solution does not contain a pH buffer.

5. The ophthalmic preparation according to claim 1, characterized in that, The second solution has a pH value of about 5.0-9.0; preferably, the second solution has a pH value of about 6.0-8.5; more preferably, the second solution has a pH value of about 6.0-8.

0.

6. The ophthalmic preparation according to claim 1, characterized in that, The second solution contains 0.1%-5.0% (w / v), preferably 0.1%-3.0% (w / v), more preferably 1.0%-2.0% (w / v) of a pH buffer; and 0.1%-5.0%, preferably 0.1%-3.0%, more preferably 0.1%-1.0% of an osmotic pressure regulator.

7. The ophthalmic preparation according to any one of claims 1-6, characterized in that, The osmotic pressure regulator is selected from one or more of sodium chloride, mannitol, potassium chloride, sodium sulfate, potassium sulfate, glycerol, sorbitol, glucose, propylene glycol, and boric acid.

8. The ophthalmic preparation according to any one of claims 1-6, characterized in that, The pH buffer is selected from one or more of the following: citric acid, sodium citrate, potassium citrate, boric acid, borax, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, acetic acid, sodium acetate, citric acid, sodium citrate, tartaric acid, sodium tartrate, hydrochloric acid, phosphoric acid, sodium hydroxide, and potassium hydroxide.

9. The ophthalmic preparation according to any one of claims 1-6, characterized in that, The medicinal salts of pilocarpine are selected from pilocarpine hydrochloride, pilocarpine hydrobromide, pilocarpine sulfate, pilocarpine hydrogen sulfate, pilocarpine phosphate, pilocarpine hydrogen phosphate, pilocarpine dihydrogen phosphate, pilocarpine nitrate, pilocarpine tartrate, pilocarpine fumarate, pilocarpine salicylate, pilocarpine malate, pilocarpine citrate, pilocarpine oxalate, pilocarpine methanesulfonate, pilocarpine formate, pilocarpine acetate, pilocarpine succinate, pilocarpine maleate, and pilocarpine hydrochloride. Pilocarpine citrate, pilocarpine benzoate, pilocarpine cinnamate, pilocarpine mandelate, pilocarpine ethanesulfonate, pilocarpine p-toluenesulfonate, pilocarpine lactate, pilocarpine nicotinate, pilocarpine lauryl sulfate, pilocarpine naphthalenesulfonate, pilocarpine camphorsulfonate, pilocarpine gluconate, pilocarpine glucuronate, pilocarpine oleate, pilocarpine palmitate, pilocarpine stearate, pilocarpine dihydroxynaphthalate, pilocarpine trifluoroacetate; preferably, the pilocarpine is pharmaceutically acceptable. The salt is selected from pilocarpine hydrochloride, pilocarpine hydrobromide, pilocarpine sulfate, pilocarpine hydrogen sulfate, pilocarpine phosphate, pilocarpine hydrogen phosphate, pilocarpine dihydrogen phosphate, pilocarpine nitrate, pilocarpine tartrate, pilocarpine fumarate, pilocarpine salicylate, pilocarpine malate, pilocarpine citrate, pilocarpine oxalate, pilocarpine formate, pilocarpine acetate, pilocarpine succinate, pilocarpine maleate, and pilocarpine trifluoroacetate; more preferably, the pilocarpine... The medicinally usable salts of pilocarpine are selected from pilocarpine hydrochloride, pilocarpine hydrobromide, pilocarpine sulfate, pilocarpine hydrogen sulfate, pilocarpine phosphate, pilocarpine hydrogen phosphate, pilocarpine dihydrogen phosphate, pilocarpine nitrate, pilocarpine formate, and pilocarpine acetate; more preferably, the medicinally usable salts of pilocarpine are selected from pilocarpine hydrochloride, pilocarpine hydrobromide, pilocarpine sulfate, pilocarpine hydrogen sulfate, pilocarpine phosphate, pilocarpine hydrogen phosphate, pilocarpine dihydrogen phosphate, and pilocarpine nitrate.

10. The ophthalmic preparation according to any one of claims 1-9, characterized in that, The pH value of the mixed solution is from about 5.5 to about 7.5; preferably, the pH value of the mixed solution is from about 6.0 to about 7.0; more preferably, the pH value of the mixed solution is from about 6.0 to about 6.

5.

11. The ophthalmic preparation according to any one of claims 1-10, characterized in that, The osmotic pressure of the mixed solution is about 260 to about 320 mOsm; preferably, the osmotic pressure of the mixed solution is about 290 to about 310; more preferably, the osmotic pressure of the mixed solution is about 300.

12. The ophthalmic preparation according to any one of claims 1-11, characterized in that, The ophthalmic preparation does not contain antibacterial agents.

13. The ophthalmic preparation according to claim 1, characterized in that, The first solution contains 0.5% to 2.5% (w / v) pilocarpine hydrochloride or pilocarpine nitrate and 0.3% to 1.0% (w / v) sodium chloride, with the balance being water for injection; the second solution contains 1.0% to 2.0% (w / v) pH buffer, 0.1% to 1.0% sodium chloride, with the balance being water for injection; the pH of the solution obtained by mixing the first solution and the second solution is about 6.0 to about 7.

0.

14. The ophthalmic preparation according to claim 1, characterized in that, The volume ratio of the first solution to the second solution is 1:5 to 5:1; preferably, the volume ratio of the first solution to the second solution is 1:3 to 3:1; more preferably, the volume ratio of the first solution to the second solution is 1:2 to 2:1; most preferably, the volume ratio of the first solution to the second solution is about 1:

1.

15. The ophthalmic preparation according to claim 1, characterized in that, The ophthalmic preparation is filled in a multi-chamber container, the body (1) of which is composed of at least two chambers including a first chamber (3) and a second chamber (4). The first chamber (3) is connected to the outlet (5), and the second chamber (4) is connected to the first chamber (3) through a sealing part (2), but they are not connected to each other. The first solution is filled in the second chamber (4), and the second solution is filled in the first chamber (3).

16. The ophthalmic preparation according to claim 15, characterized in that, When the outer wall of the first chamber (3) and / or the second chamber (4) is subjected to external force, causing the sealing part (2) to detach irreversibly, the first chamber (3) and the second chamber (4) are connected to each other, and the first solution and the second solution are mixed together.

17. The ophthalmic preparation according to any one of claims 1-16, characterized in that, The ophthalmic preparation is a multi-dose preparation or a single-dose preparation; preferably, the ophthalmic preparation is a single-dose preparation.

18. The ophthalmic preparation according to any one of claims 1-17, used in a medicament for the prevention or treatment of an ophthalmic disease, wherein the ophthalmic disease is selected from presbyopia, hyperopia, mydriasis, accommodative esotropia, and astigmatism.

19. Use of the ophthalmic preparation according to any one of claims 1-17 in the preparation of a medicament for the prevention or treatment of an ophthalmic disease, wherein the ophthalmic disease is selected from presbyopia, hyperopia, mydriasis, accommodative esotropia, and astigmatism.

20. A method for preventing or treating an ophthalmic disease, comprising administering a therapeutically effective amount of an ophthalmic preparation according to any one of claims 1-17 to an individual in need, wherein the ophthalmic disease is selected from presbyopia, hyperopia, mydriasis, accommodative esotropia, and astigmatism.

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