Pharmaceutical compositions containing pilocarpine, methods of preparation, uses, ophthalmic formulations

Abstract

The application discloses a kind of pilocarpine-containing pharmaceutical composition, preparation method, application, ophthalmic preparation.The pharmaceutical composition includes pilocarpine or its pharmaceutically acceptable salt, substance A and solvent;The mass percentage of the pilocarpine or its pharmaceutically acceptable salt is 0.40-1.25%;The substance A is one or more of camphor, menthol, ethylenediaminetetraacetic acid, cyclodextrin, carboxymethyl chitosan, carbomer, sodium hyaluronate and polyvinyl alcohol;Percentage refers to the mass percentage in pharmaceutical composition, and the sum of the mass percentage of each component in the pharmaceutical composition is 100%.The pharmaceutical composition in the application can allow lower concentration of pilocarpine to achieve better therapeutic effect in clinical correction presbyopia and mild hyperopia, avoid adverse reactions caused by high concentration of pilocarpine.

Description

[0001] This application claims priority to Chinese patent application CN202510568536.1, filed on April 30, 2025. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to a pharmaceutical composition containing pilocarpine, its preparation method, its application, and an ophthalmic preparation. Background Technology

[0003] Presbyopia, also known as age-related farsightedness, is a relatively common progressive eye disease that typically appears in middle age (around 40 years old). Its prevalence and severity increase with age. Currently, nearly a quarter of the global population is affected by presbyopia, and by 2030, due to population aging, there will be approximately 2.1 billion people with presbyopia worldwide. According to the "2023 China Presbyopia Population Insight Report," 56.9% of China's population aged 35 and above has presbyopia, reaching 390 million people. Current research suggests that the mechanism of presbyopia is the decline of the eye's accommodative function. A typical characteristic of patients is weakened accommodative vision, caused by the hardening of the lens, which increases the difficulty of changing its shape, making it difficult to focus near objects clearly on the retina. This results in patients being unable to accurately see near objects, thus reducing their quality of life.

[0004] Presbyopia treatment currently falls into two main categories: optical correction and surgical treatment. Wearing reading glasses is the most common and convenient correction method. Since the prescription of reading glasses changes with age, patients need regular eye exams and replacement lenses with the appropriate prescription. In addition, bifocal or multifocal glasses and contact lenses offer diverse correction options for presbyopia patients. For presbyopia patients whose physical condition permits and who meet the surgical indications, surgical treatments such as corneal refractive surgery and lens refractive surgery can be performed under the guidance of a doctor. Given the limitations of the above treatment methods, exploring a safe, non-invasive, and reversible presbyopia treatment plan is particularly important, aiming to effectively improve patients' reading vision and accommodative ability. Drug therapy, represented by pilocarpine, has shown promising application prospects in the treatment of presbyopia.

[0005] Hyperopia, a type of refractive error, refers to a condition where, in a relaxed state, parallel light rays, after passing through the eye's refractive system, focus behind the retina. Hyperopia occurs when the eye's refractive power is insufficient or the eyeball's anteroposterior diameter is relatively short. Both hyperopia and presbyopia share the characteristic of focusing light rays behind the retina, resulting in blurred vision. Therefore, methods that increase the eye's refractive power or increase depth of field are effective in correcting low-grade hyperopia and presbyopia.

[0006] Pilocarpine, an M-cholinergic receptor agonist, works by stimulating the contraction of the pupillary sphincter, resulting in a pupillary constriction effect. This enhances depth of field and improves near and intermediate vision, showing some efficacy in the clinical treatment of presbyopia and mild hyperopia. Simultaneously, it induces accommodative spasm, causing ciliary muscle contraction and suspensory ligament relaxation. The lens, due to its elasticity, becomes more convex, making near vision clearer. This pupillary constriction is similar to the narrowing of a camera aperture, enhancing the eye's ability to focus on near objects and thus alleviating presbyopia symptoms. While the mechanism of action of pilocarpine may contribute to its effectiveness in treating presbyopia, the concentration used is a crucial factor. High concentrations may increase the risk of irritation, including systemic reactions such as muscle tremors, nausea, difficulty breathing, asthma, and excessive sweating, as well as local ocular reactions such as blurred vision, dim vision, changes in near or far vision, conjunctival congestion, and eye pain.

[0007] Therefore, the potential efficacy and safety issues of pilocarpine have become a hot topic in new drug development. In 2019, Allergan published a patent (CN112272558A) for a composition of 1.0 to 1.5% w / v pilocarpine hydrochloride. Vuity eye drops, the first eye drop approved by the U.S. Food and Drug Administration (FDA) for the treatment of presbyopia in 2021, has 1.25% pilocarpine hydrochloride as its main ingredient. This eye drop takes effect within 15 minutes and its effect lasts for 6 hours. It improves near and intermediate vision by constricting the pupil, enhancing depth of field without interfering with distance vision, thereby improving presbyopia. In 2017, Orasis Pharmaceuticals filed a patent (CN109803652A) containing pilocarpine or a pharmaceutically acceptable salt thereof at concentrations of 0.01% (w / w or w / v) to 0.4% (w / w or w / v) and a pharmaceutically acceptable carrier, providing eye drops and formulations comprising kits or implants of ophthalmic pharmaceutical compositions suitable for implantation in the eye or surrounding tissues of a subject. This patent significantly reduces the therapeutic concentration of pilocarpine, but its application forms include sustained-release formulations and implantation in the eye or surrounding tissues of a subject, resulting in poor clinical compliance and higher risks. Implantation sites include the subconjunctival space, nasolacrimal duct, or vitreous body of the subject. In October 2023, the FDA approved Qlosi 0.4% pilocarpine hydrochloride eye drops for the treatment of presbyopia in adults, representing the lowest concentration currently available for improving near vision without affecting distance vision in presbyopic patients. Two Phase 3 clinical trials (NEAR-1 and NEAR-2) showed that after 8 days of treatment, it significantly improved near vision under distance correction (DCNVA) by three or more lines, with distance vision loss of less than one line. In 2021, the Center for Drug Evaluation of the National Medical Products Administration of China approved the Phase 3 new drug clinical trial application for ARVN003 for the treatment of presbyopia. ARVN003, introduced by Jimu Biotechnology, uses a micro-dose delivery device to instantly and precisely deliver as low as 8µL of 2% pilocarpine to the eye, greatly reducing the total exposure of pilocarpine to the eye and minimizing the risk of drug or preservative exposure due to overdose. The experimental group achieved significant improvement in near vision 2 hours after administration.

[0008] It is evident that strict control of drug concentration and dosage is crucial in the application of pilocarpine for treating presbyopia and mild hyperopia. For existing marketed products, high drug concentrations may increase the risk of adverse reactions, such as impaired night vision or greater irritation to ocular tissues. Therefore, Jimu Company utilizes devices for precise micro-dose administration to control the total dosage. On the other hand, lower concentrations may require riskier administration methods such as injection or implantation, increasing clinical risks. In conclusion, exploring more possible safe and effective application concentrations will provide more options for clinical application.

[0009] Therefore, given the current situation that high-concentration pilocarpine formulations have a high risk of adverse reactions and low-concentration formulations may require special devices in clinical applications, how to provide a composition of pilocarpine that can further improve its efficacy in treating presbyopia and hyperopia without the need for special devices is a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0010] The technical problem to be solved by the present invention is to overcome the defects of existing technologies in the clinical application of pilocarpine, which are either poorly effective in low-concentration formulations or require special devices for low-concentration formulations. The present invention provides a pharmaceutical composition containing pilocarpine, a preparation method, an application, and an ophthalmic formulation.

[0011] The purpose of this invention is to provide a pharmaceutical composition containing pilocarpine, its preparation method, application, and ophthalmic formulation. By using appropriate concentrations of borneol, menthol, or substance A (substance A is selected from one or more of ethylenediaminetetraacetic acid, cyclodextrin, carboxymethyl chitosan, carbomer, sodium hyaluronate, and polyvinyl alcohol), the miotic effect of pilocarpine is enhanced, thereby improving the corrective effect of pilocarpine in correcting presbyopia and mild hyperopia. The pharmaceutical composition of this invention allows for the use of lower concentrations of pilocarpine in clinical practice to achieve superior therapeutic effects in correcting presbyopia and mild hyperopia, avoiding the adverse reactions associated with high concentrations of pilocarpine.

[0012] The inventors of this invention have creatively achieved therapeutic effects comparable to higher concentrations of pilocarpine by adding appropriate concentrations of borneol, menthol, or substance A (substance A is selected from one or more of ethylenediaminetetraacetic acid, cyclodextrin, carboxymethyl chitosan, carbomer, sodium hyaluronate, and polyvinyl alcohol) to the drug formulation. This reduces the potential risks associated with the clinical application of high-concentration pilocarpine preparations. In other words, this invention enhances the miotic effect of pilocarpine by combining borneol, menthol, or substance A (substance A is selected from one or more of ethylenediaminetetraacetic acid, cyclodextrin, carboxymethyl chitosan, carbomer, sodium hyaluronate, and polyvinyl alcohol) with pilocarpine, thus achieving the therapeutic effect of low-concentration pilocarpine for presbyopia and mild hyperopia.

[0013] In this invention, the pharmaceutical composition may have a miotic effect, which is superior to using pilocarpine alone or its pharmaceutically acceptable salt.

[0014] In this invention, the pharmaceutical composition can be used to treat presbyopia and mild hyperopia, and its effect is superior to using pilocarpine alone or its pharmaceutically acceptable salt.

[0015] This invention provides a pharmaceutical composition that satisfies any one of the following conditions i-iii: i. The pharmaceutical composition comprises pilocarpine or a pharmaceutically acceptable salt thereof, borneol, and a solvent; The mass percentage of pilocarpine or its pharmaceutically acceptable salt is 0.40-1.25%; The mass percentage of the borneol is 0.03-0.05%; ii. The pharmaceutical composition comprises pilocarpine or a pharmaceutically acceptable salt thereof, menthol, and a solvent; The mass percentage of pilocarpine or its pharmaceutically acceptable salt is 0.40-1.25%; The menthol content is 0.03-0.20% by mass. iii. The pharmaceutical composition comprises pilocarpine or a pharmaceutically acceptable salt thereof, substance A, and a solvent; The mass percentage of pilocarpine or its pharmaceutically acceptable salt is 0.40-1.25%; The substance A is selected from one or more of ethylenediaminetetraacetic acid, cyclodextrin, carboxymethyl chitosan, carbomer, sodium hyaluronate, and polyvinyl alcohol; The mass percentage of the ethylenediaminetetraacetic acid is 0.005-0.05%; The mass percentage of the cyclodextrin is 0.5-1.5%; The carboxymethyl chitosan has a mass percentage of 0.25-1%; The carbomer content is 0.05-0.5% by mass; The sodium hyaluronate has a mass percentage of 0.1-0.45%; The polyvinyl alcohol has a mass percentage of 0.5-3%; Percentage refers to the mass percentage of a pharmaceutical composition, where the sum of the mass percentages of all components in the pharmaceutical composition is 100%.

[0016] In this invention, the pilocarpine is a cholinergic muscarinic agonist represented by the following chemical structure: .

[0017] In this invention, the pharmaceutically acceptable salt of pilocarpine can be in a conventional salt form in the art, such as pilocarpine hydrochloride or pilocarpine nitrate.

[0018] In this invention, the borneol can be conventional borneol in the art, such as natural borneol (dextral borneol), borneol (synthetic borneol), and artemisia argyi (levorotatory borneol) as specified in the 2020 edition of the Chinese Pharmacopoeia. All three varieties can be used as traditional Chinese medicine borneol.

[0019] In some embodiments of the present invention, the borneol refers to borneol sources that comply with the 2020 edition of the Chinese Pharmacopoeia, such as any one of natural borneol (dextral borneol), borneol (synthetic borneol), and artemisia argyi (levorotatory borneol).

[0020] In some embodiments of the present invention, the borneol is selected from one or more of natural borneol (dextral borneol), synthetic borneol (synthetic borneol), and borneol (levorotatory borneol), such as natural borneol and / or synthetic borneol.

[0021] In some embodiments of the present invention, the borneol is selected from one or more of dextrorotatory borneol, synthetic borneol, and levorotatory borneol.

[0022] In some embodiments of the present invention, the mass percentage of pilocarpine or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 0.40-1.00%, for example 0.40-0.99%, also for example 0.50-0.99%, further for example 0.70-0.99% or 0.50-0.90%, and even more for example 1.00%, 0.50%, 0.55%, 0.75% or 0.90%.

[0023] In some embodiments of the present invention, the pilocarpine or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at a mass percentage of 0.40-0.90%, for example 0.50-0.90%, 0.55-0.90%, or 0.75-0.90%.

[0024] In some embodiments of the present invention, the pilocarpine or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at a mass percentage of 1.00-1.25%, for example 1.00%, 1.10% or 1.25%.

[0025] In some embodiments of the present invention, the pilocarpine or a pharmaceutically acceptable salt thereof is pilocarpine hydrochloride, wherein the pilocarpine hydrochloride is present in the pharmaceutical composition at a mass percentage of 0.50-0.99%, for example 0.70-0.99% or 0.50-0.90%, or even for example 0.50%, 0.75% or 0.90%.

[0026] In some embodiments of the present invention, the pilocarpine or its pharmaceutically acceptable salt is pilocarpine nitrate, wherein the pilocarpine nitrate is present in the pharmaceutical composition at a mass percentage of 0.50-0.99%, for example 0.70-0.99% or 0.50-0.90%, or even for example 0.55%, 0.50%, 0.75% or 0.90%.

[0027] In some embodiments of the present invention, the borneol in the pharmaceutical composition is 0.04-0.05% by mass, or 0.03-0.04%.

[0028] In some embodiments of the present invention, the pilocarpine or a pharmaceutically acceptable salt thereof (e.g., pilocarpine hydrochloride) is present in the pharmaceutical composition at a mass percentage of 0.75%, and the borneol is present in the pharmaceutical composition at a mass percentage of 0.03-0.05%.

[0029] In some embodiments of the present invention, the pilocarpine or a pharmaceutically acceptable salt thereof (e.g., pilocarpine hydrochloride) is present in the pharmaceutical composition at a mass percentage of 0.90%, and the borneol is present in the pharmaceutical composition at a mass percentage of 0.03-0.05% (e.g., 0.03%, 0.04%, or 0.05%).

[0030] In some embodiments of the present invention, the pilocarpine or a pharmaceutically acceptable salt thereof (e.g., pilocarpine hydrochloride) is present in the pharmaceutical composition at a mass percentage of 0.50%, and the borneol is present in the pharmaceutical composition at a mass percentage of 0.03-0.05% (e.g., 0.03%, 0.04%, or 0.05%).

[0031] In some embodiments of the present invention, the pilocarpine or a pharmaceutically acceptable salt thereof (e.g., pilocarpine nitrate) is present in the pharmaceutical composition at a mass percentage of 0.55%, and the borneol is present in the pharmaceutical composition at a mass percentage of 0.03%.

[0032] In some embodiments of the present invention, the mass ratio of pilocarpine or its pharmaceutically acceptable salt to borneol is (3.0-35.0):1, for example (5.0-35.0):1, also for example (10.0-35.0):1, and further for example 25.0:1, 15.0:1, 30.0:1, 22.5:1, 18.0:1, 16.7:1, 12.5:1, 10.0:1 or 18.3:1.

[0033] In some embodiments of the present invention, the pilocarpine or its pharmaceutically acceptable salt is pilocarpine hydrochloride, and the mass ratio of the pilocarpine hydrochloride to the borneol is (10.0-30.0):1, for example 25.0:1, 15.0:1, 30.0:1, 22.5:1, 18.0:1, 16.7:1, 12.5:1 or 10.0:1.

[0034] In some embodiments of the present invention, the pilocarpine or its pharmaceutically acceptable salt is pilocarpine nitrate, and the mass ratio of the pilocarpine nitrate to the borneol is (10.0-30.0):1, for example 18.3:1.

[0035] In this invention, the menthol can be conventional menthol in the art, such as, according to the 2025 edition of the Chinese Pharmacopoeia, menthol is derived from the plant *Mentha haplocalyx* (Lamiaceae). Mentha haplocalyx It is obtained by steam distillation, freezing and recrystallization of fresh stems and leaves of Briq.

[0036] In this invention, menthol, also known as menthol, is a terpene organic compound with the chemical formula C. 10 H 20 O, CAS No. 89-78-1 (DL), 15356-60-2 (D), 2216-51-5 (L).

[0037] In this invention, the menthol may be natural menthol, or menthol obtained by natural extraction or chemical / biosynthesis.

[0038] In this invention, the content of menthol is calculated based on the content of pure menthol.

[0039] In some embodiments of the present invention, the menthol is present in the pharmaceutical composition at a mass percentage of 0.03-0.05% or 0.05-0.20%, for example 0.03%, 0.05%, 0.07%, 0.1% or 0.2%.

[0040] In some embodiments of the present invention, the pilocarpine or a pharmaceutically acceptable salt thereof (e.g., pilocarpine hydrochloride) is present in the pharmaceutical composition at a mass percentage of 0.75%, and the menthol is present in the pharmaceutical composition at a mass percentage of 0.03-0.20%, such as 0.03%, 0.05%, 0.07%, 0.1%, or 0.2%.

[0041] In some embodiments of the present invention, the pilocarpine or a pharmaceutically acceptable salt thereof (e.g., pilocarpine hydrochloride) is present in the pharmaceutical composition at a mass percentage of 0.90%, and the menthol is present in the pharmaceutical composition at a mass percentage of 0.03-0.20%, for example 0.03%, 0.04%, 0.05%, 0.07%, 0.10%, or 0.20%, or even 0.03-0.05% or 0.05-0.20%.

[0042] In some embodiments of the present invention, the pilocarpine or a pharmaceutically acceptable salt thereof (e.g., pilocarpine hydrochloride) is present in the pharmaceutical composition at a mass percentage of 0.50%, and the menthol is present in the pharmaceutical composition at a mass percentage of 0.03-0.20%, for example 0.03%, 0.04%, 0.05%, 0.07%, 0.10%, or 0.20%, or even 0.03-0.05% or 0.05-0.20%.

[0043] In some embodiments of the present invention, the mass ratio of pilocarpine or its pharmaceutically acceptable salt to menthol is (1.0-35.0):1, for example (2.0-30.0):1, also for example (2.5-30.0):1, and further for example 2.5:1, 3.75:1, 4.5:1, 5.0:1, 7.5:1, 9.0:1, 10.0:1, 10.7:1, 15.0:1, 18.0:1, 25.0:1, or 30.0:1.

[0044] In some embodiments of the present invention, the pilocarpine or its pharmaceutically acceptable salt is pilocarpine hydrochloride, and the mass ratio of the pilocarpine hydrochloride to the menthol is (1.0-35.0):1, for example (2.0-30.0):1, also for example (2.5-30.0):1, and further for example 2.5:1, 3.75:1, 4.5:1, 5.0:1, 7.5:1, 9.0:1, 10.0:1, 10.7:1, 15.0:1, 18.0:1, 25.0:1 or 30.0:1.

[0045] In some embodiments of the present invention, substance A is selected from ethylenediaminetetraacetic acid, cyclodextrin, carboxymethyl chitosan, carbomer, sodium hyaluronate, or polyvinyl alcohol.

[0046] In this invention, EDTA refers to ethylenediaminetetraacetic acid (EDTA), whose CAS number is 60-00-4.

[0047] In some embodiments of the present invention, the ethylenediaminetetraacetic acid is present in the pharmaceutical composition at a mass percentage of 0.01-0.05%, for example, 0.01% or 0.05%.

[0048] In some embodiments of the present invention, the mass ratio of pilocarpine or its pharmaceutically acceptable salt to ethylenediaminetetraacetic acid is (15.0-150.0):1, for example 15.0:1, 75.0:1 or 150.0:1.

[0049] In some embodiments of the present invention, the pilocarpine or a pharmaceutically acceptable salt thereof (e.g., pilocarpine hydrochloride) is present in the pharmaceutical composition at a mass percentage of 0.75%, and the ethylenediaminetetraacetic acid is present in the pharmaceutical composition at a mass percentage of 0.005-0.05%, for example 0.005%, 0.01%, or 0.05%.

[0050] In this invention, cyclodextrin refers to a series of cyclic oligosaccharides generated from linear starch under the action of cyclodextrin glucosyltransferase produced by Bacillus, which typically contains 6 to 12 D-glucan units.

[0051] In some embodiments of the present invention, the cyclodextrin is selected from β-cyclodextrin or β-cyclodextrin derivatives, such as hydroxypropyl-β-cyclodextrin.

[0052] In some embodiments of the present invention, the hydroxypropyl-β-cyclodextrin is available from Bidex Pharmaceuticals, catalog number: BD44359.

[0053] In some embodiments of the present invention, the cyclodextrin is present in the pharmaceutical composition at a mass percentage of 0.8-1.2%, for example, 1.0%.

[0054] In some embodiments of the present invention, the mass ratio of pilocarpine or its pharmaceutically acceptable salt to the cyclodextrin is (0.5-1.0):1, for example 0.75:1.

[0055] In some embodiments of the present invention, the pilocarpine or a pharmaceutically acceptable salt thereof (e.g., pilocarpine hydrochloride) is present in the pharmaceutical composition at a mass percentage of 0.75%, and the cyclodextrin is present in the pharmaceutical composition at a mass percentage of 1.0%.

[0056] In this invention, the carboxymethyl chitosan refers to the product in which the hydroxyl or amino groups in the molecular structure of chitosan (a positively charged linear polysaccharide, obtained from chitin through partial or complete deacetylation reaction, such as a natural linear polysaccharide composed of glucosamine and N-acetylglucosamine) are replaced by carboxymethyl (-CH2COOH).

[0057] In some embodiments of the present invention, the degree of carboxymethyl substitution (DS) of the carboxymethyl chitosan is >90%.

[0058] In some embodiments of the present invention, the carboxymethyl chitosan is available from Aladdin, catalog number: C304738.

[0059] In some embodiments of the present invention, the carboxymethyl chitosan is present in the pharmaceutical composition at a mass percentage of 0.4-0.6%, for example, 0.5%.

[0060] In some embodiments of the present invention, the mass ratio of pilocarpine or its pharmaceutically acceptable salt to the carboxymethyl chitosan is (0.5-2.0):1, for example 1.5:1.

[0061] In some embodiments of the present invention, the pilocarpine or a pharmaceutically acceptable salt thereof (e.g., pilocarpine hydrochloride) is present in the pharmaceutical composition at a mass percentage of 0.75%, and the carboxymethyl chitosan is present in the pharmaceutical composition at a mass percentage of 0.5%.

[0062] In this invention, carbomer refers to the trade name of cross-linked polyacrylic acid polymer (generic name: carboxyvinyl polymer), whose molecular backbone is polymerized from acrylic acid monomers and contains a large number of hydrophilic carboxyl groups (-COOH).

[0063] In some embodiments of the present invention, the carbomer is selected from one or more of carbomer 407, carbomer 934, carbomer 974 and carbomer 980, such as carbomer 934.

[0064] In some embodiments of the present invention, the viscosity of the carbomer is 20,000-40,000 mPa·s.

[0065] In some embodiments of the present invention, the carbomer in the pharmaceutical composition is 0.1-0.3% by mass, for example 0.2%.

[0066] In some embodiments of the present invention, the mass ratio of pilocarpine or its pharmaceutically acceptable salt to carbomer is (1.0-5.0):1, for example 3.75:1.

[0067] In some embodiments of the present invention, the pilocarpine or a pharmaceutically acceptable salt thereof (e.g., pilocarpine hydrochloride) is present in the pharmaceutical composition at a mass percentage of 0.75%, and the carbomer is present in the pharmaceutical composition at a mass percentage of 0.2%.

[0068] In this invention, sodium hyaluronate is the sodium salt of hyaluronic acid. It is a naturally occurring linear anionic polysaccharide composed of repeating D-glucuronic acid and N-acetylglucosamine disaccharide units linked by β-1,3 and β-1,4 glycosidic bonds.

[0069] In some embodiments of the present invention, the molecular weight of the sodium hyaluronate is 400,000 to 1,000,000.

[0070] In some embodiments of the present invention, the sodium hyaluronate was purchased from Shanghai Yuanye Biotechnology Co., Ltd., product number: S24592.

[0071] In some embodiments of the present invention, the sodium hyaluronate in the pharmaceutical composition is 0.2-0.4% by mass, for example 0.3%.

[0072] In some embodiments of the present invention, the mass ratio of pilocarpine or its pharmaceutically acceptable salt to sodium hyaluronate is (1.0-5.0):1, for example 2.5:1.

[0073] In some embodiments of the present invention, the pilocarpine or a pharmaceutically acceptable salt thereof (e.g., pilocarpine hydrochloride) is present in the pharmaceutical composition at a mass percentage of 0.75%, and the carbomer is present in the pharmaceutical composition at a mass percentage of 0.2%.

[0074] In this invention, the polyvinyl alcohol refers to polyvinyl alcohol with the chemical formula [C2H4O]. n .

[0075] In some embodiments of the present invention, the polyvinyl alcohol was purchased from Aladdin, product number: P139545.

[0076] In some embodiments of the present invention, the degree of alcoholysis of the polyvinyl alcohol is 85.0-90.0 mol%.

[0077] In some embodiments of the present invention, the viscosity of the polyvinyl alcohol is 20.0-30.0 mPa·s.

[0078] In some embodiments of the present invention, the degree of hydrolysis of the polyvinyl alcohol is 85.0-90.0 mol%, and the viscosity is 20.0-30.0 mPa.s.

[0079] In some embodiments of the present invention, the polyvinyl alcohol is present in the pharmaceutical composition at a mass percentage of 1.0-2.0%, for example, 1.4%.

[0080] In some embodiments of the present invention, the mass ratio of pilocarpine or its pharmaceutically acceptable salt to the polyvinyl alcohol is (0.1-3.0):1, for example 0.54:1.

[0081] In some embodiments of the present invention, the pilocarpine or a pharmaceutically acceptable salt thereof (e.g., pilocarpine hydrochloride) is present in the pharmaceutical composition at a mass percentage of 0.75%, and the polyvinyl alcohol is present in the pharmaceutical composition at a mass percentage of 1.4%.

[0082] In some embodiments of the present invention, the solvent is water for injection.

[0083] In some embodiments of the present invention, the pharmaceutical composition further includes one or more pharmaceutically acceptable excipients, such as pH adjusters and / or osmotic pressure regulators.

[0084] In some embodiments of the present invention, the pharmaceutical composition further includes a pH adjuster.

[0085] In some embodiments of the present invention, the pH adjuster is sodium hydroxide or HCl, or for example, a 0.1 mol / L sodium hydroxide solution or a 0.1 mol / L HCl solution.

[0086] In some embodiments of the present invention, when the solvent is water, the pH adjuster may be used together with part of the solvent, such as hydrochloric acid solution.

[0087] In some embodiments of the present invention, the pH of the pharmaceutical composition may be 4.5-5.5, for example 5.0-5.5.

[0088] In some embodiments of the present invention, the amount of pH adjuster used is the amount used to adjust the pH of the pharmaceutical composition to 4.5-5.5.

[0089] In some embodiments of the present invention, the pharmaceutical composition further includes an osmotic pressure regulator.

[0090] In some embodiments of the present invention, the osmotic pressure regulator is one or more of sodium chloride, glucose, sucrose, mannitol and glycerol, such as sodium chloride.

[0091] In some embodiments of the present invention, the osmotic pressure of the pharmaceutical composition may be 289-310 mOsm / L.

[0092] In some embodiments of the present invention, the amount of the osmotic pressure regulator is the amount used to adjust the osmotic pressure of the pharmaceutical composition to 289-310 mOsm / L.

[0093] In some embodiments of the present invention, pilocarpine or a pharmaceutically acceptable salt thereof is the sole active ingredient in the pharmaceutical composition that produces a miotic effect.

[0094] In some embodiments of the present invention, the pharmaceutical composition further includes one or more of preservatives, thickeners, suspending agents, surfactants, and chelating agents.

[0095] In this invention, the pharmaceutical composition can be used as an ophthalmic preparation.

[0096] In this invention, the dosage form of the ophthalmic preparation can be a conventional dosage form in the art, such as conventional ophthalmic dosage forms in the art, or ophthalmic liquid preparations or ophthalmic semi-solid preparations.

[0097] The ophthalmic liquid preparation may be an eye drop, an eye wash, an ophthalmic suspension, or an intraocular injection solution.

[0098] The ophthalmic semi-solid preparation may be an ointment, ophthalmic cream, or ophthalmic gel.

[0099] In this invention, the ophthalmic preparation can be formed into an eye drop, an ophthalmic gel, or an ophthalmic suspension.

[0100] The present invention also provides a method for preparing the pharmaceutical composition, which includes the following steps: mixing the components in the pharmaceutical composition to obtain the final product.

[0101] In some embodiments of the present invention, the method for preparing the pharmaceutical composition includes the following steps: The pharmaceutical composition is prepared by mixing pilocarpine or its pharmaceutically acceptable salt, borneol, menthol or substance A, and the solvent. When the pharmaceutical composition further includes a pH adjuster and / or an osmotic pressure adjuster, the pharmaceutical composition is prepared by mixing pilocarpine or a pharmaceutically acceptable salt thereof, "the borneol, the menthol or the substance A", the solvent, the pH adjuster and the osmotic pressure adjuster. When the pharmaceutical composition further includes one or more of a preservative, a thickener, a suspending agent, a surfactant, and a chelating agent, the pharmaceutical composition is obtained by mixing pilocarpine or a pharmaceutically acceptable salt thereof, "the borneol, the menthol, or substance A", the solvent, and "one or more of the preservative, the thickener, the suspending agent, the surfactant, and the chelating agent".

[0102] In some embodiments of the present invention, the solvent is selected from water for injection.

[0103] In some embodiments of the present invention, the method for preparing the pharmaceutical composition includes the following steps: The pharmaceutical composition is prepared by mixing the pilocarpine or a pharmaceutically acceptable salt thereof, "the borneol, the menthol or substance A", and water for injection.

[0104] In some embodiments of the present invention, the method for preparing the pharmaceutical composition includes the following steps: (1) The osmotic pressure regulator and the solvent (e.g., water for injection) are mixed to prepare mixture 1; (2) Mix the borneol or the menthol with solvent 2 to obtain mixture 2; (3) Mix the mixture 1 and the mixture 2 to obtain the mixture 3; (4) Mix the pilocarpine or its pharmaceutically acceptable salt with the mixture 3 to obtain the mixture 4; (5) Adjust the pH of the mixture 4 to 4.5-5.5 to obtain the drug composition.

[0105] In this invention, the order of steps (1) and (2) is not limited.

[0106] The solvent 2 may be a conventional solvent in the art that can dissolve menthol, such as ethanol, or ethanol with a volume fraction of 95%.

[0107] The amount of solvent 2 used can be the conventional amount used in the art, generally an amount that can dissolve borneol or menthol, and an appropriate amount is sufficient.

[0108] In some embodiments of the present invention, the method for preparing the pharmaceutical composition includes the following steps: S1: Mix the pilocarpine or its pharmaceutically acceptable salt with the solvent (e.g., water for injection) to prepare mixture 5; S2: Mix the borneol or menthol with solvent 2 to obtain mixture 2; S3: Mix the mixture 2 and the mixture 5 to obtain the pharmaceutical composition; The order of steps S1 and S2 is not limited.

[0109] In some embodiments of the present invention, the method for preparing the pharmaceutical composition includes the following steps: (1) Mix the osmotic pressure regulator, the solvent and substance A to prepare mixture 6; (2) Mix the pilocarpine or its pharmaceutically acceptable salt with the mixture 6 to prepare the mixture 7; (3) Adjust the pH of the mixture 7 to 4.5-5.5 to obtain the drug composition.

[0110] In some embodiments of the present invention, the method for preparing the pharmaceutical composition includes the following steps: (1) The solvent and substance A are mixed to obtain mixture 8; (2) The osmotic pressure regulator and the mixture 8 are mixed to obtain the mixture 9; (3) Mix the pilocarpine or its pharmaceutically acceptable salt with the mixture 9 to obtain the mixture 10; (4) Adjust the pH of the mixture 10 to 4.5-5.5 to obtain the drug composition.

[0111] In some embodiments of the present invention, the mixing temperature during the preparation of the mixture 6 is 50-80°C, for example 60-80°C.

[0112] In some embodiments of the present invention, the pharmaceutical composition is further subjected to sterilization post-treatment, for example, by filtration sterilization using a 0.22 μm filter membrane.

[0113] In this invention, the pharmaceutical composition can be used as an ophthalmic preparation.

[0114] The present invention also provides an ophthalmic formulation comprising the pharmaceutical composition.

[0115] In some embodiments of the present invention, the ophthalmic formulation further includes one or more pharmaceutically acceptable excipients.

[0116] In this invention, the pharmaceutically acceptable excipients may be selected based on the dosage form that the pharmaceutical composition can be formed into.

[0117] In some embodiments of the present invention, the pharmaceutically acceptable excipient is selected from one or more of preservatives, thickeners, suspending agents, surfactants, and chelating agents.

[0118] In this invention, the pharmaceutically acceptable excipients do not contain solvents.

[0119] In this invention, the dosage form of the ophthalmic preparation can be a conventional dosage form in the art, such as conventional ophthalmic dosage forms in the art, and also, for example, ophthalmic liquid preparations, ophthalmic semi-solid preparations, ophthalmic solid preparations, etc.

[0120] The ophthalmic liquid preparation may be an eye drop, an eye wash, an ophthalmic suspension, or an intraocular injection solution.

[0121] The ophthalmic semi-solid preparation may be an ointment, ophthalmic cream, or ophthalmic gel.

[0122] The ophthalmic solid dosage form may be an ophthalmic film, an ophthalmic pill, or an intraocular insertion.

[0123] In this invention, the ophthalmic preparation can be formed into an eye drop, an ophthalmic gel, or an ophthalmic suspension.

[0124] The present invention also provides the use of the pharmaceutical composition and / or the ophthalmic preparation in the preparation of a medicament for treating presbyopia and / or hyperopia.

[0125] The present invention also provides the use of borneol, menthol or substance A as a miotic enhancer of pilocarpine or a pharmaceutically acceptable salt thereof; Substance A is selected from one or more of ethylenediaminetetraacetic acid, cyclodextrin, carboxymethyl chitosan, carbomer, sodium hyaluronate, and polyvinyl alcohol.

[0126] The borneol can be the borneol described above.

[0127] The menthol may be the menthol described above.

[0128] Wherein, substance A may be substance A as described above.

[0129] The present invention also provides the use of borneol, menthol or substance A as a presbyopia and / or hyperopia treatment promoter of pilocarpine or a pharmaceutically acceptable salt thereof; Substance A is selected from one or more of ethylenediaminetetraacetic acid, cyclodextrin, carboxymethyl chitosan, carbomer, sodium hyaluronate, and polyvinyl alcohol.

[0130] The borneol can be the borneol described above.

[0131] The menthol may be the menthol described above.

[0132] Wherein, substance A may be substance A as described above.

[0133] The present invention also provides the use of borneol, menthol or substance A in the preparation of a medicament for treating presbyopia and / or hyperopia; Substance A is selected from one or more of ethylenediaminetetraacetic acid, cyclodextrin, carboxymethyl chitosan, carbomer, sodium hyaluronate, and polyvinyl alcohol.

[0134] The borneol can be the borneol described above.

[0135] The menthol may be the menthol described above.

[0136] Wherein, substance A may be substance A as described above.

[0137] In this invention, presbyopia refers to the phenomenon where, with age, the lens gradually hardens and loses elasticity, and the ciliary muscle gradually reduces its function, resulting in a decline in the eye's accommodative ability and difficulty in clearly focusing near objects on the retina.

[0138] In this invention, farsightedness refers to the condition where, in a relaxed state, parallel light rays from a distance focus behind the retina after passing through the eye's refractive system. This is typically manifested as blurred vision at a distance and even more blurred vision at close range.

[0139] In this invention, the hyperopia can be mild hyperopia, i.e., low hyperopia, with a hyperopia degree < +3.00DS.

[0140] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0141] The reagents and raw materials used in this invention are all commercially available.

[0142] The positive and progressive effects of this invention are as follows: This invention comprises a pharmaceutical composition containing pilocarpine and borneol, menthol, or substance A (substance A is selected from one or more of ethylenediaminetetraacetic acid, cyclodextrin, carboxymethyl chitosan, carbomer, sodium hyaluronate, and polyvinyl alcohol). By using appropriate concentrations of borneol, menthol, or substance A (substance A is selected from one or more of ethylenediaminetetraacetic acid, cyclodextrin, carboxymethyl chitosan, carbomer, sodium hyaluronate, and polyvinyl alcohol), the miotic effect of pilocarpine is enhanced, thereby improving the corrective effect of pilocarpine in correcting presbyopia and mild hyperopia. The pharmaceutical composition of this invention allows for the use of lower concentrations of pilocarpine in clinical practice to achieve superior therapeutic effects in correcting presbyopia and mild hyperopia, avoiding the adverse reactions associated with high concentrations of pilocarpine. Attached Figure Description

[0143] Figure 1 Comparison of pupil diameter changes after combined use of 0.75% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.03% menthol, and 0.75% pilocarpine hydrochloride.

[0144] Figure 2 Comparison of pupil diameter changes after combined use of 0.75% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.05% menthol, and 0.75% pilocarpine hydrochloride.

[0145] Figure 3 Comparison of pupil diameter changes after combined use of 0.75% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.07% menthol, and 0.75% pilocarpine hydrochloride.

[0146] Figure 4 Comparison of pupil diameter changes after combined use of 0.75% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.1% menthol, and 0.75% pilocarpine hydrochloride.

[0147] Figure 5Comparison of pupil diameter changes after combined use of 0.75% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.2% menthol, and 0.75% pilocarpine hydrochloride.

[0148] Figure 6 Comparison of pupil diameter changes after combined use of 0.75% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.01% menthol, and 0.75% pilocarpine hydrochloride.

[0149] Figure 7 Comparison of pupil diameter changes after combined use of 0.75% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.02% menthol, and 0.75% pilocarpine hydrochloride.

[0150] Figure 8 Comparison of pupil diameter changes after combined use of 0.90% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.03% menthol, and 0.90% pilocarpine hydrochloride.

[0151] Figure 9 Comparison of pupil diameter changes after combined use of 0.90% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.05% menthol, and 0.90% pilocarpine hydrochloride.

[0152] Figure 10 Comparison of pupil diameter changes after combined use of 0.90% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.1% menthol, and 0.90% pilocarpine hydrochloride.

[0153] Figure 11 Comparison of pupil diameter changes after combined use of 0.90% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.2% menthol, and 0.90% pilocarpine hydrochloride.

[0154] Figure 12 Comparison of pupil diameter changes after combined use of 0.90% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.01% menthol, and 0.90% pilocarpine hydrochloride.

[0155] Figure 13 Comparison of pupil diameter changes after combined use of 0.90% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.02% menthol, and 0.90% pilocarpine hydrochloride.

[0156] Figure 14 Comparison of pupil diameter changes after combined use of 0.50% pilocarpine hydrochloride, 1.00% pilocarpine hydrochloride, 0.05% menthol, and 0.50% pilocarpine hydrochloride.

[0157] Figure 15 Comparison of pupil diameter changes after combined use of 0.50% pilocarpine hydrochloride, 1.00% pilocarpine hydrochloride, 0.1% menthol, and 0.50% pilocarpine hydrochloride.

[0158] Figure 16 Comparison of pupil diameter changes after combined use of 0.50% pilocarpine hydrochloride, 1.00% pilocarpine hydrochloride, 0.2% menthol, and 0.50% pilocarpine hydrochloride.

[0159] Figure 17 Comparison of pupil diameter changes after combined use of 0.50% pilocarpine hydrochloride, 1.00% pilocarpine hydrochloride, 0.01% menthol, and 0.50% pilocarpine hydrochloride.

[0160] Figure 18 Comparison of pupil diameter changes after combined use of 0.75% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.005% EDTA, and 0.75% pilocarpine hydrochloride.

[0161] Figure 19 Comparison of pupil diameter changes after combined use of 0.75% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.01% EDTA, and 0.75% pilocarpine hydrochloride.

[0162] Figure 20 Comparison of pupil diameter changes after administration of 0.75% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.05% EDTA, and 0.75% pilocarpine hydrochloride.

[0163] Figure 21 Comparative graph showing the changes in pupil diameter after using 0.75% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 1.0% cyclodextrin, and 0.75% pilocarpine hydrochloride in combination.

[0164] Figure 22 A comparison of pupil diameter changes after combining 0.75% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.5% carboxymethyl chitosan, and 0.75% pilocarpine hydrochloride.

[0165] Figure 23 A comparison of pupil diameter changes after combining 0.75% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.003% benzalkonium chloride, and 0.75% pilocarpine hydrochloride.

[0166] Figure 24Comparison of pupil diameter changes after combined use of 0.75% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.2% carbomer, and 0.75% pilocarpine hydrochloride.

[0167] Figure 25 Comparison of pupil diameter changes after combined use of 0.75% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.3% sodium hyaluronate, and 0.75% pilocarpine hydrochloride.

[0168] Figure 26 Comparison of pupil diameter changes after combined use of 0.75% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 1.4% PVA, and 0.75% pilocarpine hydrochloride.

[0169] Figure 27 Comparison of pupil diameter changes after combined use of 0.75% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.03% borneol, and 0.75% pilocarpine hydrochloride.

[0170] Figure 28 Comparative graph showing the changes in pupil diameter after using 0.75% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.05% borneol, and 0.75% pilocarpine hydrochloride in combination.

[0171] Figure 29 Comparative graph showing the changes in pupil diameter after using 0.75% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.01% borneol, and 0.75% pilocarpine hydrochloride in combination.

[0172] Figure 30 Comparative graph showing the changes in pupil diameter after using 0.75% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.02% borneol, and 0.75% pilocarpine hydrochloride in combination.

[0173] Figure 31 Comparative graph showing the changes in pupil diameter after combined use of 0.90% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.03% borneol, and 0.90% pilocarpine hydrochloride.

[0174] Figure 32 Comparative graph showing the changes in pupil diameter after combined use of 0.90% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.04% borneol, and 0.90% pilocarpine hydrochloride.

[0175] Figure 33 A comparison of pupil diameter changes after the combined use of 0.90% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.05% borneol, and 0.90% pilocarpine hydrochloride.

[0176] Figure 34 Comparative graph showing the changes in pupil diameter after combined use of 0.50% pilocarpine hydrochloride, 1.00% pilocarpine hydrochloride, 0.03% borneol, and 0.50% pilocarpine hydrochloride.

[0177] Figure 35 Comparative graph showing the changes in pupil diameter after using 0.50% pilocarpine hydrochloride, 1.00% pilocarpine hydrochloride, 0.04% borneol, and 0.50% pilocarpine hydrochloride in combination.

[0178] Figure 36 Comparative graph showing the changes in pupil diameter after using 0.50% pilocarpine hydrochloride, 1.00% pilocarpine hydrochloride, 0.05% borneol, and 0.50% pilocarpine hydrochloride in combination.

[0179] Figure 37 Comparative graph showing the changes in pupil diameter after combined use of 0.55% pilocarpine nitrate, 1.10% pilocarpine nitrate, 0.03% borneol, and 0.55% pilocarpine nitrate.

[0180] Figure 38 A comparison of pupil diameter changes after combining 0.75% pilocarpine hydrochloride, 1.25% pilocarpine hydrochloride, 0.40% polyethylene glycol borneol, and 0.75% pilocarpine hydrochloride. Detailed Implementation

[0181] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0182] In the following embodiments and comparative examples: Pilocarpine Hydrochloride: CAS No.: 54-71-7, abbreviated as PH; Pilocarpine Nitrate: CAS No.: 148-72-1, abbreviated as PN; Menthol: CAS No.: 1490-04-6 (natural menthol, the main component is L-menthol) or 89-78-1 (L-menthol obtained by natural extraction or chemical / biosynthesis), Menthol, abbreviated as Men; Ethylene diaminetetraacetic acid (EDTA): CAS No.: 60-00-4; Hydroxypropyl-β-cyclodextrin: CAS No.: 128446-35-5, 2-Hydroxypropyl-β-cyclodextrin, abbreviated as HP-β-CD, molecular formula is C 63 H 112 O 42 Purchased from Bid Pharmaceuticals, product number: BD44359; Carboxymethyl chitosan: CAS: 83512-85-0; degree of carboxymethyl substitution (DS) > 90%; purchased from Aladdin, catalog number: C304738; Benzalkonium chloride: CAS No.: 8001-54-5, molecular formula is C 17 H 30 ClN; Carbomer 934: CAS: 9007-20-9; Viscosity: 20000-40000 mPa·s; Sodium hyaluronate: CAS No.: 9067-32-7, molecular weight: 400,000-1,000,000; purchased from Shanghai Yuanye Biotechnology Co., Ltd., product number: S24592; Polyvinyl alcohol: CAS No.: 9002-89-5, Polyvinyl alcohol, abbreviated as PVA; degree of alcoholysis: 85.0-90.0 mol%, viscosity: 20.0-30.0 mPa.s; purchased from Aladdin, product number: P139545.

[0183] In this invention, the degree of alcoholysis refers to the molar percentage (%) of hydroxyl groups in the product after the alcoholysis reaction relative to the original groups. This indicator reflects the extent to which acetate groups are replaced by hydroxyl groups during the alcoholysis of polyvinyl acetate.

[0184] In this invention, the menthol is derived from the mint plant (Mentha haplocalyx). Mentha haplocalyx Menthol is obtained from the fresh stems and leaves of *Briquette* through steam distillation, freezing, and recrystallization. For example, according to the 2025 edition of the Chinese Pharmacopoeia, menthol can be derived from either peppermint or peppermint oil.

[0185] Borneol (CAS No. 507-70-0), abbreviated as Bor, refers to any one of natural borneol (dextral borneol), synthetic borneol, and artemisia argyi (levorotatory borneol). All three varieties can be used as traditional Chinese medicine borneol according to the regulations under the borneol section of the Chinese Pharmacopoeia. Natural Borneol (D-rotary Borneol): This product is derived from camphor trees (Cinnamomum camphora), a plant belonging to the Lauraceae family. Cinnamomum camphora(L.)Presl is made from fresh branches and leaves through extraction and processing; Borneol (synthetic borneol): This product is a colorless, transparent or white translucent flaky, brittle crystal; it has a fragrant odor and a pungent, cool taste; it is volatile, and when ignited, it produces thick smoke and a luminous flame; Artemisia argyi (L-carnitine borneol): This product is made from Artemisia argyi, a plant of the Asteraceae family. Blumea balsamifera Crystals made from the fresh leaves of (L.) DC.

[0186] In the following examples and comparative examples, the borneol used is natural borneol.

[0187] Polyethylene glycol: CAS: 25322-68-3, Polyethylene glycol 400, abbreviated as PEG400.

[0188] In the following examples and comparative examples, the menthol content is calculated based on the content of pure menthol.

[0189] In the following examples and comparative examples, the mass percentage of pilocarpine salt is calculated based on the actual mass of pilocarpine salt.

[0190] Unless otherwise specified, the percentages % in the following examples and comparative examples refer to the percentage by mass in the composition (e.g., eye drops).

[0191] Unless otherwise specified, the 289-310 mOsm / L in the following examples and comparative examples refers to the osmotic pressure of the eye drops being 289-310 mOsm / L.

[0192] The present application will be further described in detail below through examples and comparative examples.

[0193] [Examples 1-5, Comparative Examples 1-4]

[0194] 1) Preparation of eye drops

[0195] Prepare 100 mL samples of Examples 1-5 and Comparative Examples 1-4 according to the weight percentages listed in Table 1. Add an appropriate amount of the prescribed sodium chloride to approximately 80 mL of sterile water for injection and stir to dissolve. Dissolve different weights of natural menthol (Menthol) in an appropriate amount of pharmaceutical ethanol (95% ethanol), then transfer it to the above solution. Add different masses of pilocarpine hydrochloride (pH), stir to dissolve, and add 0.1 mol / L sodium hydroxide or 0.1 mol / L hydrochloric acid solution to adjust the pH to 4.5-5.5. Then, bring the volume to 100 mL with water for injection. Filter sterilize using a 0.22 μm filter membrane and fill into 5 mL eye drop bottles.

[0196] Table 1. Components of experimental drugs in different groups

[0197] Note: "—" indicates that it has not been added.

[0198] 2) Effect of menthol on the miotic effect of 0.75% pilocarpine

[0199] The efficacy of the drug was studied using New Zealand rabbits. A single dose was administered, and pupil diameter was used as the indicator to evaluate the formulations of Examples 1-5 and Comparative Examples 1-4. Each group consisted of 12 New Zealand white rabbits (2.5-3.0 kg), half male and half female. The experiment used a self-comparison method between the left and right sides of the same animal. 100 μL of the eye drops from Examples 1-5 and Comparative Examples 1-4 were instilled into the conjunctival sac of the right eye of each rabbit. The eyelid was then gently closed for 10 seconds to allow sufficient contact between the drug and the cornea. Simultaneously, 100 μL of physiological saline was instilled into the left eye as a control. Pupil diameter was recorded at time zero (before administration) as the pre-administration measurement. All animal experiments were conducted under standard lighting conditions after acclimatization to room temperature. The pupil diameter measured before administration was recorded as the time-zero measurement. Pupil diameter (unit: mm) was measured using a pupil ruler at 0.2 h, 0.3 h, 0.5 h, 0.8 h, 1.0 h, 2.0 h, and 4.0 h after drug administration. The measurements were recorded and photographed. The pupil diameter changes at different time points were calculated based on the value at time zero. The results are shown in Table 2. Figure 1 , Figure 2 , Figure 3 , Figure 4 , Figure 5 , Figure 6 , Figure 7 .

[0200] The method for calculating the change in pupil diameter at different time points is: pupil diameter measured at time zero - pupil diameter at the measurement time point. The blank control, physiological saline, has no effect on pupil diameter.

[0201] According to Table 2, Figure 1 , Figure 2 , Figure 3 , Figure 4 , Figure 5 , Figure 6 , Figure 7The results showed that pH values ​​within the 0.75%–1.25% concentration range had a significant miotic effect, with the miotic effect at 0.75% pH being significantly lower than that at 1.25% pH (p < 0.05). Combining 0.75% pH with 0.03%, 0.05%, 0.07%, 0.1%, and 0.2% menthol significantly increased the intensity and duration of the miotic effect after 0.2 hours (p < 0.05), and showed no significant difference compared to the miotic effect at 1.25% pH (p > 0.05). Therefore, this indicates that 0.03%–0.2% menthol significantly enhances the miotic effect of 0.75% pilocarpine, and combining 0.03%–0.2% menthol significantly enhances the miotic effect of 0.75% pilocarpine to the 1.25% pH level.

[0202] According to Table 2, Figure 6 , Figure 7 The results showed that the miotic effect of 0.01% or 0.02% menthol combined with 0.75% menthol alone was not significantly different from that of 0.75% menthol alone (p>0.05), indicating that 0.01%~0.02% menthol concentration had no significant effect on the miotic effect of pilocarpine hydrochloride.

[0203] Table 2

[0204] Note: # Compared with Comparative Example 1, there was a significant difference (p<0.05); Compared with Comparative Example 2, there was a significant difference (p<0.05).

[0205] [Examples 6-9, Comparative Examples 1, 5-7]

[0206] 1) Preparation of eye drops

[0207] Prepare 100 mL of each of Examples 6-9 and Comparative Examples 1 and 5-7 according to the weight percentages listed in Table 3. Add an appropriate amount of the prescribed sodium chloride to approximately 80 mL of sterile water for injection and stir to dissolve. Dissolve different weights of natural menthol in an appropriate amount of pharmaceutical ethanol (95% ethanol), then transfer it to the above solution. Add the active pharmaceutical ingredient pH, stir to dissolve, and add 0.1 mol / L sodium hydroxide or 0.1 mol / L hydrochloric acid solution to adjust the pH to 4.5-5.5. Then, bring the volume to 100 mL with water for injection. Filter sterilize using a 0.22 μm filter membrane and fill into 5 mL eye drop bottles.

[0208] Table 3 Composition of experimental drugs in different groups

[0209] Note: "-" indicates that it has not been added.

[0210] 2) Effect of menthol on the miotic effect of 0.9% pilocarpine hydrochloride

[0211] The efficacy of the eye drops (Examples 6-9 and Comparative Examples 1, 5-7) was evaluated using New Zealand rabbits as the research subjects. A single dose was administered, and pupil diameter was used as the indicator. Twelve New Zealand white rabbits (2.5-3.0 kg) were used in each group, with half male and half female. The experiment employed a self-comparison method between the left and right sides of the same animal. 100 μL of the eye drops (Examples 6-9 and Comparative Examples 1, 5-7) were instilled into the conjunctival sac of the right eye of each rabbit. The eyelid was then gently closed for 10 seconds to allow sufficient contact between the drug and the cornea. Simultaneously, 100 μL of physiological saline was instilled into the left eye as a control. Pupil diameter was recorded at time zero (before administration). All animal experiments were conducted under standard lighting conditions after acclimatization to room temperature. Pupil diameter measurements taken before administration were recorded as time zero. Pupil diameter (unit: mm) was measured using a pupil ruler at 0.2 h, 0.3 h, 0.5 h, 0.8 h, 1.0 h, 2.0 h, and 4.0 h after drug administration. The measurements were recorded and photographed. The pupil diameter changes at different time points were calculated based on the value at time zero. The results are shown in Table 4. Figure 8 , Figure 9 , Figure 10 , Figure 11 , Figure 12 , Figure 13 .

[0212] According to Table 4, Figure 8 , Figure 9 , Figure 10 , Figure 11 , Figure 12 , Figure 13 The results showed that pH levels within the 0.90%-1.25% concentration range had a significant miotic effect, with the miotic effect at 0.90% pH being significantly lower than that at 1.25% pH (p<0.05). The combined use of 0.03%, 0.05%, 0.1%, or 0.2% menthol at 0.9% pH significantly increased the intensity and duration of the miotic effect (p<0.05), and showed no significant difference compared to the miotic effect of 1.25% pilocarpine hydrochloride (p>0.05). This indicates that 0.03%-0.2% menthol concentrations can significantly improve the miotic effect at 0.9% pH, and that 0.03%-0.2% menthol concentrations can significantly enhance the miotic effect at 0.9% pH to reach the corresponding 1.25% pH level.

[0213] According to Table 4, Figure 12 , Figure 13The results showed that the miotic effect of 0.01% or 0.02% menthol combined with 0.9% menthol was not significantly different from that of 0.9% menthol alone (p>0.05), indicating that 0.01%~0.02% menthol concentration had no significant effect on the miotic effect of pilocarpine hydrochloride.

[0214] Table 4

[0215] Note: # Compared with Comparative Example 1, there was a significant difference (p<0.05). Compared with Comparative Example 5, there was a significant difference (p<0.05).

[0216] [Examples 10-12, Comparative Examples 8-10]

[0217] 1) Preparation of eye drops

[0218] Prepare 100 mL samples of Examples 10-12 and Comparative Examples 8-10 according to the weight percentages listed in Table 5. Add the prescribed amount of sodium chloride to approximately 80 mL of sterile water for injection and stir to dissolve. Dissolve different weights of natural menthol in an appropriate amount of ethanol (95% ethanol), then transfer it to the above solution. Add the active pharmaceutical ingredient pH, stir to dissolve, and add 0.1 mol / L sodium hydroxide or 0.1 mol / L hydrochloric acid solution to adjust the pH to 4.5-5.5. Then, bring the volume to 100 mL with water for injection. Filter sterilize using a 0.22 μm filter membrane and fill into 5 mL eye drop bottles.

[0219] Table 5. Components of experimental drugs in different groups

[0220] 2) Effect of menthol on the miotic effect of 0.5% pilocarpine hydrochloride

[0221] Following the experimental conditions described in "The Effect of Menthol on the Miotic Constriction of 0.75% Pilocarpine," the effect of menthol on the miotic constriction of 0.5% pilocarpine hydrochloride was evaluated. The results are shown in Table 6. Figure 14 , Figure 15 , Figure 16 , Figure 17 .

[0222] From Table 6, Figure 14 , Figure 15 , Figure 16 , Figure 17The results showed that 0.5%-1.0% pH had a miotic effect, and the miotic effect of 0.5% pH was significantly lower than that of 1% pH (p<0.05). When combined with 0.05-0.2% menthol, the intensity and duration of the miotic effect significantly increased (p<0.05), and there was no significant difference compared to the miotic effect of 1% pH (p>0.05). This indicates that 0.05%-0.2% menthol can significantly enhance the miotic effect of 0.5% pH to achieve the same miotic therapeutic effect as 1% pH, and that 0.05%-0.2% menthol can significantly enhance the miotic effect of 0.5% pH to achieve the same level as 1% pH.

[0223] According to Table 6, Figure 17 The results showed that the miotic effect of 0.01% menthol combined with 0.5% menthol was not significantly different from that of 0.5% menthol alone (p>0.05), indicating that 0.01% menthol had no significant effect on the miotic effect of pilocarpine hydrochloride.

[0224] Table 6

[0225] Note: # Compared with Comparative Example 8, there was a significant difference (p<0.05); Compared with Comparative Example 9, there was a significant difference (p<0.05).

[0226] [Examples 13-15, Comparative Examples 1-2]

[0227] 1) Preparation of eye drops

[0228] Prepare 100 mL samples of Examples 13-15 and Comparative Examples 1-2 according to the weight percentages listed in Table 7. Place 80 mL of sterile water for injection in a 100 mL round-bottom flask and heat to 60°C. Slowly add the prescribed amount of EDTA, and after complete dissolution, add the prescribed amount of sodium chloride and stir to dissolve. After cooling the solution to room temperature, add 0.75 g of the active pharmaceutical ingredient (pH), stir to dissolve, and add 0.1 mol / L sodium hydroxide or 0.1 mol / L hydrochloric acid solution to adjust the pH to 4.5-5.5. Then, bring the volume to 100 mL with water for injection. Filter sterilize using a 0.22 μm filter membrane and fill into 5 mL eye drop bottles.

[0229] Table 7. Components of experimental drugs in different groups

[0230] 2) Effect of EDTA on the miotic effect of 0.75% pH

[0231] Following the experimental conditions described in "The Effect of Menthol on the Miotic Constriction of 0.75% Pilocarpine," the effect of EDTA on the miotic constriction of 0.75% pH was evaluated. The results are shown in Table 8. Figure 18 , Figure 19 , Figure 20 .

[0232] Table 8

[0233] Note: # Compared with Comparative Example 1, there was a significant difference (p<0.05). Compared with Comparative Example 2, there was a significant difference (p<0.05).

[0234] From Table 8, Figure 18 , Figure 19 , Figure 20 The results showed that 0.75% pH had a certain miotic effect, but it was significantly lower than that of 1.25% pH (p<0.05). When 0.75% pH was used in combination with EDTA in the concentration range of 0.005%-0.05%, the miotic effect of pH was significantly increased after 0.2 hours (p<0.05), and there was no significant difference in miotic effect compared with 1.25% pH (p>0.05). When used in combination with 0.005% EDTA, there was no significant difference compared with 0.75% alone before 0.5 hours, but the miotic intensity of pH was significantly increased after 0.5 hours. Therefore, it is indicated that the combined use of 0.005-0.05% EDTA can significantly enhance the effect of 0.75% pilocarpine to the level of 1.25% pH.

[0235] [Example 16, Comparative Examples 1-2]

[0236] 1) Preparation of eye drops

[0237] Prepare 100 mL samples of Example 16 and Comparative Examples 1-2 according to the weight percentages listed in Table 9. Place 80 mL of sterile water for injection in a 100 mL round-bottom flask, heat to 60°C, slowly add 1.0 g of HP-β-CD, and after complete dissolution, add the prescribed amount of sodium chloride and stir to dissolve. After cooling the above solution to room temperature, add 0.75 g of the active pharmaceutical ingredient pH, stir to dissolve, add 0.1 mol / L sodium hydroxide or 0.1 mol / L hydrochloric acid solution to adjust the pH to 4.5-5.5, and then bring the volume to 100 mL with water for injection. Filter sterilize using a 0.22 μm filter membrane and fill into 5 mL eye drop bottles.

[0238] Table 9. Components of experimental drugs in different groups

[0239] 2) Effect of HP-β-CD on the miotic effect of 0.75% pH

[0240] Following the experimental conditions described in "2. Effect of Menthol on the Miotic Constriction of 0.75% Pilocarpine," the effect of HP-β-CD on the miotic constriction of 0.75% pH was evaluated. The results are shown in Table 10. Figure 21 .

[0241] Table 10

[0242] Note: # Compared with Comparative Example 1, there was a significant difference (p<0.05). Compared with Comparative Example 2, there was a significant difference (p<0.05).

[0243] From Table 10, Figure 21 The results showed that 0.75% pH had a certain miotic effect, but it was significantly lower than that of 1.25% pH (p<0.05). When 0.75% pH was combined with 1.0% cyclodextrin, the miotic effect of pH was significantly increased after 0.2 hours (p<0.05), and there was no significant difference in miotic effect compared to 1.25% pH (p>0.05). Therefore, it is indicated that the combined use of 1.0% cyclodextrin can significantly enhance the effect of 0.75% pilocarpine to the level of 1.25% pH.

[0244] [Example 17, Comparative Examples 1-2]

[0245] 1) Preparation of eye drops

[0246] Prepare 100 mL samples of Example 17 and Comparative Examples 1-2 according to the weight percentages listed in Table 11. Place 80 mL of sterile water for injection in a 100 mL round-bottom flask, heat to 60°C, slowly add 0.5 g of carboxymethyl chitosan, and after complete dissolution, add the prescribed amount of sodium chloride and stir to dissolve. After cooling the solution to room temperature, add 0.75 g of the active pharmaceutical ingredient (pH), stir to dissolve, add 0.1 mol / L sodium hydroxide or 0.1 mol / L hydrochloric acid solution to adjust the pH to 4.5-5.5, and then bring the volume to 100 mL with water for injection. Filter sterilize using a 0.22 μm filter membrane and fill into 5 mL eye drop bottles.

[0247] Table 11 Components of Experimental Drugs in Different Groups

[0248] 2) Effect of carboxymethyl chitosan on the miotic effect at 0.75% pH

[0249] Following the experimental conditions described in "The Effect of Menthol on the Miotic Constriction of 0.75% Pilocarpine," the effect of carboxymethyl chitosan on the miotic constriction of 0.75% pH was evaluated. The results are shown in Table 12. Figure 22 .

[0250] Table 12

[0251] Note: # Compared with Comparative Example 1, there was a significant difference (p<0.05). Compared with Comparative Example 2, there was a significant difference (p<0.05).

[0252] From Table 12, Figure 22 The results showed that 0.75% pH had a certain miotic effect, but it was significantly lower than that of 1.25% pH (p<0.05). When 0.75% pH was used in combination with 0.5% carboxymethyl chitosan, the miotic effect of pH was significantly increased after 0.2 hours (p<0.05), and there was no significant difference in miotic effect compared to 1.25% pH (p>0.05). Therefore, it is indicated that the combined use of 0.5% carboxymethyl chitosan can significantly enhance the effect of 0.75% pilocarpine to the level of 1.25% pH.

[0253] [Example 18, Comparative Examples 1-2]

[0254] 1) Preparation of eye drops

[0255] Prepare 100 mL samples of Example 18 and Comparative Examples 1-2 according to the weight percentages listed in Table 13. Place 80 mL of sterile water for injection in a 100 mL round-bottom flask, heat to 60°C, slowly add 0.003 g of benzalkonium chloride, and after complete dissolution, add the prescribed amount of sodium chloride and stir to dissolve. After cooling the solution to room temperature, add 0.75 g of the active pharmaceutical ingredient (pH), stir to dissolve, add 0.1 mol / L sodium hydroxide or 0.1 mol / L hydrochloric acid solution to adjust the pH to 4.5-5.5, and then bring the volume to 100 mL with water for injection. Filter sterilize using a 0.22 μm filter membrane and fill into 5 mL eye drop bottles.

[0256] Table 13 Components of Experimental Drugs in Different Groups

[0257] 2) Effect of benzalkonium chloride on the miotic effect of 0.75% pH

[0258] Following the experimental conditions described in "The Effect of Menthol on the Miotic Constriction of 0.75% Pilocarpine," the effect of benzalkonium chloride on the miotic constriction of 0.75% pH was evaluated. The results are shown in Table 14. Figure 23 .

[0259] Table 14

[0260] Note: # Compared with Comparative Example 1, there was a significant difference (p<0.05). Compared with Comparative Example 2, there was a significant difference (p<0.05).

[0261] From Table 14, Figure 23 The results showed that 0.75% pH had a certain miotic effect, but it was significantly lower than that of 1.25% pH (p<0.05). The combination of 0.75% pH and 0.003% benzalkonium chloride did not show a significant difference in miotic effect compared to using 0.75% pH alone (p>0.05). Therefore, overall, 0.003% benzalkonium chloride had no significant effect on the miotic effect of 0.75% pH.

[0262] Existing technology reports indicate that benzalkonium chloride can act as a penetration enhancer by disrupting the protection provided by the tear film and the mucus layer on the corneal surface (e.g., references: Mahaling, B., & Katti, DS (2016). Understanding the influence of surface properties of nanoparticles and penetration enhancers for improving bioavailability in eye tissues in vivo. International Journal of Pharmaceutics, 501(1-2), 1-9; Pescina, S., Carra, F., Padula, C., Santi, P., & Nicoli, S. (2016). Effect of pH and penetration enhancers on cysteamine stability and trans-corneal transport. European Journal of Pharmaceutics and Biopharmaceutics, 107, 171-179). Therefore, while benzalkonium chloride may have some penetration enhancer effect, it may not necessarily effectively promote intraocular drug absorption.

[0263] [Example 19, Comparative Examples 1-2]

[0264] 1) Preparation of eye drops

[0265] Prepare 100 mL samples of Example 19 and Comparative Examples 1-2 according to the weight percentages listed in Table 15. Place 80 mL of sterile water for injection in a 100 mL round-bottom flask, heat to 60°C, slowly add 0.2 g of carbomer 934, and after complete dissolution, add the prescribed amount of sodium chloride and stir to dissolve. After cooling the solution to room temperature, add 0.75 g of the active pharmaceutical ingredient (pH), stir to dissolve, add 0.1 mol / L sodium hydroxide or 0.1 mol / L hydrochloric acid solution to adjust the pH to 4.5-5.5, and then bring the volume to 100 mL with water for injection. Filter sterilize using a 0.22 μm filter membrane and fill into 5 mL eye drop bottles.

[0266] Table 15. Components of experimental drugs in different groups

[0267] 2) Effect of Carbomer 934 on the miotic effect of 0.75% pH

[0268] Following the experimental conditions described in "2. Effect of Menthol on the Miotic Effect of 0.75% Pilocarpine," the effect of carbomer on the miotic effect of 0.75% pH was evaluated. The results are shown in Table 16. Figure 24 .

[0269] Table 16

[0270] Note: # Compared with Comparative Example 1, there was a significant difference (p<0.05). Compared with Comparative Example 2, there was a significant difference (p<0.05).

[0271] From Table 16, Figure 24 The results showed that 0.75% pH had a certain miotic effect, but it was significantly lower than that of 1.25% pH (p<0.05). When 0.75% pH was used in combination with 0.2% carbomer 934, the miotic effect of pH was significantly increased after 0.2 hours (p<0.05), and there was no significant difference in miotic effect compared to 1.25% pH (p>0.05). Therefore, it is indicated that the combined use of 0.2% carbomer 934 can significantly enhance the effect of 0.75% pilocarpine to the level of 1.25% pH.

[0272] [Example 20, Comparative Examples 1-2]

[0273] 1) Preparation of eye drops

[0274] Prepare 100 mL samples of Example 20 and Comparative Examples 1-2 according to the weight percentages listed in Table 17. Take 80 mL of sterile water for injection and place it in a 100 mL round-bottom flask. Heat to 60°C, slowly add 0.3 g of sodium hyaluronate, and after complete dissolution, add the prescribed amount of sodium chloride and stir to dissolve. After cooling the above solution to room temperature, add 0.75 g of the active pharmaceutical ingredient (pH), stir to dissolve, add 0.1 mol / L sodium hydroxide or 0.1 mol / L hydrochloric acid solution to adjust the pH to 4.5-5.5, and then bring the volume to 100 mL with water for injection. Filter sterilize using a 0.22 μm filter membrane and fill into 5 mL eye drop bottles.

[0275] Table 17 Components of Experimental Drugs in Different Groups

[0276] 2) Effect of sodium hyaluronate on the miotic effect of 0.75% pH solution

[0277] Following the experimental conditions described in "The Effect of Menthol on the Miotic Constriction of 0.75% Pilocarpine," the effect of carbomer on the miotic constriction of 0.75% pH was evaluated. The results are shown in Table 18. Figure 25 .

[0278] Table 18

[0279] Note: # Compared with Comparative Example 1, there was a significant difference (p<0.05). Compared with Comparative Example 2, there was a significant difference (p<0.05).

[0280] From Table 18, Figure 25 The results showed that 0.75% pH had a certain miotic effect, but it was significantly lower than that of 1.25% pH (p<0.05). When 0.75% pH was used in combination with 0.3% sodium hyaluronate, the miotic effect of pH was significantly increased after 0.2 hours (p<0.05), and there was no significant difference in miotic effect compared to 1.25% pH (p>0.05). Therefore, it is indicated that the combined use of 0.3% sodium hyaluronate can significantly enhance the effect of 0.75% pilocarpine to the level of 1.25% pH.

[0281] [Example 21, Comparative Examples 1-2]

[0282] 1) Preparation of eye drops

[0283] Prepare 100 mL of each of Example 21 and Comparative Examples 1-2 according to the weight percentages listed in Table 19. Place 80 mL of sterile water for injection in a 100 mL round-bottom flask, heat to 80°C, and slowly add 1.4 g of polyvinyl alcohol (PVA). After complete dissolution, add the prescribed amount of sodium chloride and stir to dissolve. After cooling the solution to room temperature, add 0.75 g of the active pharmaceutical ingredient (pH), stir to dissolve, and add 0.1 mol / L sodium hydroxide or 0.1 mol / L hydrochloric acid solution to adjust the pH to 4.5-5.5. Then, bring the volume to 100 mL with water for injection. Filter sterilize using a 0.22 μm filter membrane and fill into 5 mL eye drop bottles.

[0284] Table 19. Components of Experimental Drugs in Different Groups

[0285] 2) Effect of PVA on the miotic effect of 0.75% pH

[0286] Following the experimental conditions described in "The Effect of Menthol on the Miotic Constriction of 0.75% Pilocarpine," the effect of PVA on the miotic constriction of 0.75% pH was evaluated. The results are shown in Table 20. Figure 26 .

[0287] Table 20

[0288] Note: # Compared with Comparative Example 1, there was a significant difference (p<0.05). Compared with Comparative Example 2, there was a significant difference (p<0.05).

[0289] From Table 20, Figure 26 The results showed that 0.75% pH had a certain miotic effect, but it was significantly lower than that of 1.25% pH (p<0.05). When 0.75% pH was used in combination with 1.4% polyvinyl alcohol, the miotic effect of pH was significantly increased after 0.2 hours (p<0.05), and there was no significant difference in miotic effect compared to 1.25% pH (p>0.05). Therefore, it is indicated that the combined use of 1.4% polyvinyl alcohol can significantly enhance the effect of 0.75% pilocarpine to the level of 1.25% pH.

[0290] Stimulation test

[0291] Ocular irritation was assessed using the Draize test, with a single dose administered to evaluate the formulations of Examples 1-21 and Comparative Examples 3-4. Each group consisted of 12 New Zealand white rabbits (2.5-3.0 kg), half male and half female, using a self-comparison method. 100 μL of the eye drops from Examples 1-21 and Comparative Examples 3-4 were instilled into the conjunctival sac of each rabbit's right eye. Before administration, the condition of the cornea, iris, and conjunctiva of each rabbit was observed and recorded; rabbits with existing lesions or inflammation were excluded. A self-control method was used, administering 100 μL of the different formulations to the conjunctival sac of the rabbit's right eye, while the left eye received physiological saline as a blank control. After administration, the rabbit's eye was passively closed for 8-10 seconds. Ocular tissue reactions (cornea, iris, and conjunctiva) were observed and recorded at 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, and 72 h after administration. As shown in Table 21, the cornea, iris, and conjunctiva were scored using the Draize eye irritation test scoring criteria, and the eye irritation of the eye drops was determined according to the evaluation criteria in Table 22. The evaluation results are shown in Table 23.

[0292] Table 21. Scoring of the modified Draize test for assessing the severity of ocular lesions.

[0293] Table 22 Evaluation levels of eye irritation

[0294] Table 23 Results of a single ocular irritation assessment using the modified Draize test

[0295] After applying eye drops to rabbit eyes in Examples 1-21 and Comparative Examples 3-4, parameters such as ocular tissue were observed externally under standard lighting conditions. The scoring results after observation are shown in Table 23. Scores for parameters such as cornea, conjunctiva, iris, edema, and secretions after using the eye drops are presented.

[0296] Conclusion: No ocular irritation was observed. After a single dose, the animals were in good condition, with no corneal opacity, normal iris, conjunctival hyperemia, ocular edema, or discharge.

[0297] Examples 22-23, Comparative Examples 11-14

[0298] 1) Preparation of eye drops

[0299] Prepare 100 mL of each of Examples 22-23 and Comparative Examples 11-14 according to the weight percentages listed in Table 24. Add an appropriate amount of the prescribed sodium chloride to approximately 80 mL of sterile water for injection and stir to dissolve. Dissolve different weights of natural borneol (Bor) in an appropriate amount of pharmaceutical ethanol (95% ethanol), then transfer it to the above solution. Add different masses of pilocarpine hydrochloride (pH), stir to dissolve, and add 0.1 mol / L sodium hydroxide or 0.1 mol / L hydrochloric acid solution to adjust the pH to 4.5-5.5. Then, bring the volume to 100 mL with water for injection. Filter sterilize using a 0.22 μm filter membrane and fill into 5 mL eye drop bottles.

[0300] Table 24. Components of experimental drugs in different groups

[0301] Note: "-" indicates no addition; 289-310 mOsm / L refers to the osmotic pressure of the eye drops being 289-310 mOsm / L.

[0302] 2) Effect of borneol on the miotic effect of 0.75% pilocarpine

[0303] The efficacy of the drug was studied using New Zealand rabbits. A single dose was administered, and pupil diameter was used as the indicator to evaluate the formulations of Examples 22-23 and Comparative Examples 11-14. Each group consisted of 12 New Zealand white rabbits (2.5-3.0 kg), half male and half female. The experiment used a self-comparison method between the left and right sides of the same animal. 100 μL of the eye drops from Examples 22-23 and Comparative Examples 11-14 were instilled into the conjunctival sac of the right eye of each rabbit. The eyelid was then gently closed for 10 seconds to allow sufficient contact between the drug and the cornea. Simultaneously, 100 μL of physiological saline was instilled into the left eye as a control. Pupil diameter was recorded at time zero (before administration) as the pre-administration measurement. All animal experiments were conducted under standard lighting conditions after acclimatization to room temperature. The pupil diameter measured before administration was recorded as the time-zero measurement. Pupil diameter (unit: mm) was measured using a pupil ruler at 0.2 h, 0.3 h, 0.5 h, 0.8 h, 1.0 h, 2.0 h, and 4.0 h after drug administration. The measurements were recorded and photographed. The pupil diameter changes at different time points were calculated based on the value at time zero. The results are shown in Table 25. Figure 27 , Figure 28 , Figure 29 , Figure 30 .

[0304] According to Table 25, Figure 27 , Figure 28The results showed that borneol at concentrations between 0.75% and 1.25% had a significant miotic effect, with the miotic effect at 0.75% pH being significantly lower than that at 1.25% pH (p < 0.05). Combining borneol at 0.75% pH with 0.03% or 0.05% concentrations significantly increased the intensity and duration of the miotic effect (p < 0.05), but showed no significant difference compared to the miotic effect at 1.25% pH (p > 0.05). Therefore, it is concluded that borneol at concentrations of 0.03%–0.05% can significantly enhance the miotic effect of 0.75% pilocarpine, and that borneol at concentrations of 0.03%–0.05% can significantly enhance the miotic effect of 0.75% pilocarpine to the level of 1.25% pH.

[0305] According to Table 25, Figure 29 , Figure 30 The results showed that the miotic effect of 0.01% or 0.02% borneol was not significantly different from that of 0.75% borneol alone (p>0.05), indicating that 0.01%~0.02% borneol had no significant effect on the miotic effect of pilocarpine hydrochloride.

[0306] Table 25

[0307] Note: # Compared with Comparative Example 11, there was a significant difference (p<0.05); Compared with Comparative Example 12, there was a significant difference (p<0.05).

[0308] Examples 24-26, Comparative Examples 11 and 15

[0309] 1) Preparation of eye drops

[0310] Prepare 100 mL of each of the example and comparative samples according to the weight percentages listed in Table 26. Add an appropriate amount of the prescribed sodium chloride to approximately 80 mL of sterile water for injection and stir to dissolve. Dissolve different weights of natural borneol in an appropriate amount of pharmaceutical ethanol (95% ethanol), then transfer it to the above solution. Add the active pharmaceutical ingredient pH, stir to dissolve, and add 0.1 mol / L sodium hydroxide or 0.1 mol / L hydrochloric acid solution to adjust the pH to 4.5-5.5. Then, bring the volume to 100 mL with water for injection. Filter the solution through a 0.22 μm filter membrane for sterilization and fill into 5 mL eye drop bottles.

[0311] Table 26 Composition of Experimental Drugs in Different Groups

[0312] Note: "-" indicates that it has not been added.

[0313] 2) Effect of borneol on the miotic effect of 0.9% pilocarpine hydrochloride

[0314] The efficacy of the eye drops in Examples 24-26, Comparative Examples 11, and Comparative Examples 15 was evaluated using a single-dose administration and pupil diameter as the indicator. Each group consisted of 12 New Zealand white rabbits (2.5-3.0 kg), half male and half female, and the experiment used a self-comparison method between the left and right sides of the same animal. 100 μL of the eye drops from Examples 24-26, Comparative Examples 11, or Comparative Examples 15 were instilled into the conjunctival sac of the right eye of each rabbit, and the eyelid was gently closed for 10 seconds to allow sufficient contact between the drug and the cornea. Simultaneously, 100 μL of physiological saline was instilled into the left eye as a control. Pupil diameter was recorded at time zero (before administration) as the pre-administration measurement. All animal experiments were conducted under standard lighting conditions after acclimatization to room temperature. The pupil diameter measured before administration was recorded as the time-zero value. Pupil diameter (unit: mm) was measured using a pupil ruler at 0.2 h, 0.3 h, 0.5 h, 0.8 h, 1.0 h, 2.0 h, and 4.0 h after drug administration. The measurements were recorded and photographed. The pupil diameter changes at different time points were calculated based on the value at time zero. The results are shown in Table 27. Figure 31 , Figure 32 , Figure 33 .

[0315] According to Table 27, Figure 31 , Figure 32 , Figure 33 The results showed that pH levels within the 0.90%-1.25% concentration range had a significant miotic effect, with the miotic effect at 0.90% pH being significantly lower than that at 1.25% pH (p<0.05). The combined use of 0.03%, 0.04%, or 0.05% borneol at 0.9% pH significantly increased the intensity and duration of the miotic effect (p<0.05), and showed no significant difference compared to the miotic effect of 1.25% pilocarpine hydrochloride (p>0.05). This indicates that 0.03%-0.05% borneol significantly enhances the miotic effect at 0.9% pH, and that 0.03%-0.05% borneol significantly improves the miotic effect at 0.9% pH to reach the corresponding 1.25% pH level.

[0316] Table 27

[0317] Note: # Compared with Comparative Example 11, there was a significant difference (p<0.05). Compared with Comparative Example 15, there was a significant difference (p<0.05).

[0318] Examples 27-29, Comparative Examples 16 and 17

[0319] 1) Preparation of eye drops

[0320] Prepare 100 mL of each of the example and comparative samples according to the weight percentages listed in Table 28. Add the prescribed amount of sodium chloride to approximately 80 mL of sterile water for injection and stir to dissolve. Dissolve different weights of natural borneol in an appropriate amount of ethanol (95% ethanol), then transfer it to the above solution. Add the active pharmaceutical ingredient pH, stir to dissolve, and add 0.1 mol / L sodium hydroxide or 0.1 mol / L hydrochloric acid solution to adjust the pH to 4.5-5.5. Then, bring the volume to 100 mL with water for injection. Filter the solution through a 0.22 μm filter membrane for sterilization and fill into 5 mL eye drop bottles.

[0321] Table 28 Components of Experimental Drugs in Different Groups

[0322] 2) Effect of borneol on the miotic effect of 0.5% pilocarpine hydrochloride

[0323] Referring to the experimental conditions in "2) Effect of Borneol on the Miotic Effect of 0.75% Pilocarpine," the effect of borneol on the miotic effect of 0.5% pilocarpine hydrochloride was evaluated. The results are shown in Table 29. Figure 34 , Figure 35 , Figure 36 .

[0324] From Table 29, Figure 34 , Figure 35 , Figure 36 The results showed that 0.5%-1.0% pH had a miotic effect, and the miotic effect of 0.5% pH was significantly lower than that of 1% pH (p<0.05). When combined with 0.03-0.05% borneol, the miotic effect of 0.5% pH remained unchanged before 0.8 hours, but the intensity and duration of the effect significantly increased from 1 to 4 hours (p<0.05), and there was no significant difference in miotic effect between 0.03%-0.05% and 1% pH after 1 hour (p>0.05). This indicates that 0.03%-0.05% borneol can significantly enhance the miotic effect of 0.5% pH 1 hour after administration, and the miotic effect of 0.03%-0.05% borneol can significantly enhance the miotic effect of 0.5% pH to the same level as that of 1% pH 1 hour after administration.

[0325] Table 29

[0326] Note: # Compared with Comparative Example 16, there was a significant difference (p<0.05); Compared with Comparative Example 17, there was a significant difference (p<0.05).

[0327] Example 30, Comparative Examples 18 and 19

[0328] 1) Preparation of Pilocarpine Nitrate Eye Drops

[0329] Pilocarpine Nitrate (PN) eye drops were prepared according to the proportions shown in Table 30 and the preparation conditions of the eye drops in Examples 22-23. The efficacy test was conducted with reference to the experimental conditions in "2) Effect of Borneol on the miotic effect of 0.75% Pilocarpine".

[0330] Table 30 Components of Experimental Drugs in Different Groups

[0331] Note: "-" indicates that it has not been added.

[0332] 2) Effect of borneol on the miotic effect of 0.55% PN

[0333] Referring to the experimental conditions in "2) Effect of Borneol on the Miotic Effect of 0.75% Pilocarpine", the effect of borneol on the miotic effect of 0.55% PN was evaluated. The results are shown in Table 31. Figure 37 .

[0334] From Table 31, Figure 37 The results showed that 0.55% PN had a certain miotic effect, but it was significantly lower than that of 1.1% PN (p<0.05). The combination of 0.55% PN and 0.03% borneol significantly enhanced the miotic effect of this PN concentration (p<0.05), and after 0.3 hours of administration, there was no significant difference in miotic effect between the 1.10% PN group and the 0.55% PN + 0.03% borneol group (p>0.05). This indicates that 0.03% borneol can enhance the miotic effect of 0.55% PN, and that 0.03% borneol can enhance the miotic effect of 0.55% PN to the level of 1.1% PN.

[0335] Table 31

[0336] Note: # Compared with Comparative Example 18, there was a significant difference (p<0.05); Compared with Comparative Example 19, there was a significant difference (p<0.05).

[0337] Example 31, Comparative Examples 11-12

[0338] 1) Preparation of eye drops

[0339] Prepare 100 mL samples of Example 31 and Comparative Examples 11-12 according to the weight percentages listed in Table 32. Take 80 mL of sterile water for injection and place it in a 100 mL round-bottom flask. Heat to 60°C, slowly add 0.4 g of polyethylene glycol 400, and after complete dissolution, add the prescribed amount of sodium chloride and stir to dissolve. After cooling the above solution to room temperature, add 0.75 g of the active pharmaceutical ingredient pH, stir to dissolve, add 0.1 mol / L sodium hydroxide or 0.1 mol / L hydrochloric acid solution to adjust the pH to 4.5-5.5, and then bring the volume to 100 mL with water for injection. Filter sterilize using a 0.22 μm filter membrane and fill into 5 mL eye drop bottles.

[0340] Table 32 Components of Experimental Drugs in Different Groups

[0341] 2) Effect of polyethylene glycol 400 on the miotic effect of 0.75% pH

[0342] Referring to the experimental conditions in "2) Effect of Borneol on the Miotic Effect of 0.75% Pilocarpine", the effect of polyethylene glycol on the miotic effect of 0.75% pH was evaluated. The results are shown in Table 33. Figure 38 .

[0343] Table 33

[0344] Note: # Compared with Comparative Example 11, there was a significant difference (p<0.05). Compared with Comparative Example 12, there was a significant difference (p<0.05).

[0345] From Table 33, Figure 38 The results showed that 0.75% pH had a certain miotic effect, but it was significantly lower than that of 1.25% pH (p<0.05). When 0.75% pH was used in combination with 0.4% PEG, the miotic effect of pH was significantly enhanced at 0.2 hours (p<0.05), but there was no significant difference in miotic effect between 0.75% pH and 0.75% pH alone after 0.2 hours (p>0.05). Therefore, 0.4% PEG can only enhance the miotic effect of pH in a short period of time, and overall has no significant effect on the miotic effect of 0.75% pH.

[0346] Stimulation test

[0347] Ocular irritation was assessed using the Draize test, with a single dose administered to evaluate the formulations of Examples 22-31 and Comparative Examples 13-14. Each group consisted of 12 New Zealand white rabbits (2.5-3.0 kg), half male and half female, using a self-comparison method. 100 μL of the eye drops from Examples 22-31 and Comparative Examples 13-14 were instilled into the conjunctival sac of each rabbit's right eye. Before administration, the condition of the cornea, iris, and conjunctiva of each rabbit was observed and recorded; rabbits with existing lesions or inflammation were excluded. A self-control method was used, administering 100 μL of the different formulations to the conjunctival sac of the right eye of each rabbit, while the left eye received physiological saline as a blank control. After administration, the rabbit's eyes were passively closed for 8-10 seconds. Ocular tissue reactions (cornea, iris, and conjunctiva) were observed and recorded at 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, and 72 h after administration. As shown in Table 34, the cornea, iris, and conjunctiva were scored using the Draize eye irritation test scoring criteria, and the eye irritation of the eye drops was determined according to the evaluation criteria in Table 35. The evaluation results are shown in Table 36.

[0348] Table 34 Scoring of the Modified Draize Test for Assessing the Severity of Ocular Lesions

[0349] Table 35 Evaluation levels of eye irritation

[0350] Table 36 Results of a single ocular irritation assessment using the modified Draize test

[0351] After applying eye drops to rabbit eyes in Examples 22-31 and Comparative Examples 13-14, parameters such as ocular tissue were observed externally under standard lighting conditions. The scoring results after observation are shown in Table 36. Scores for parameters such as cornea, conjunctiva, iris, edema, and secretions after using the eye drops are presented.

[0352] Conclusion: No ocular irritation was observed. After a single dose, the animals were in good condition, with no corneal opacity, normal iris, conjunctival hyperemia, ocular edema, or discharge.

Claims

1. A pharmaceutical composition, characterized in that, The pharmaceutical composition satisfies any one of the following conditions i-iii: i. The pharmaceutical composition comprises pilocarpine or a pharmaceutically acceptable salt thereof, borneol, and a solvent; The mass percentage of pilocarpine or its pharmaceutically acceptable salt is 0.40-1.25%; The mass percentage of the borneol is 0.03-0.05%; ii. The pharmaceutical composition comprises pilocarpine or a pharmaceutically acceptable salt thereof, menthol, and a solvent; The mass percentage of pilocarpine or its pharmaceutically acceptable salt is 0.40-1.25%; The menthol content is 0.03-0.20% by mass. iii. The pharmaceutical composition comprises pilocarpine or a pharmaceutically acceptable salt thereof, substance A, and a solvent; The mass percentage of pilocarpine or its pharmaceutically acceptable salt is 0.40-1.25%; The substance A is selected from one or more of ethylenediaminetetraacetic acid, cyclodextrin, carboxymethyl chitosan, carbomer, sodium hyaluronate, and polyvinyl alcohol; The mass percentage of the ethylenediaminetetraacetic acid is 0.005-0.05%; The mass percentage of the cyclodextrin is 0.5-1.5%; The carboxymethyl chitosan has a mass percentage of 0.25-1%; The carbomer content is 0.05-0.5% by mass; The sodium content of the hyaluronic acid is 0.1-0.45% by mass; The polyvinyl alcohol has a mass percentage of 0.5-3%; The percentages in conditions i-iii refer to the mass percentages in the pharmaceutical composition, where the sum of the mass percentages of all components in the pharmaceutical composition is 100%.

2. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition described herein satisfies one or more of the following conditions: (1) The pharmaceutically acceptable salt of pilocarpine is pilocarpine hydrochloride or pilocarpine nitrate; Preferably, the pilocarpine hydrochloride is present in the pharmaceutical composition at a mass percentage of 0.50-0.99%, for example 0.70-0.99% or 0.50-0.90%, or even for example 0.50%, 0.75% or 0.90%. Preferably, the pilocarpine nitrate in the pharmaceutical composition is 0.50-0.99% by mass, for example 0.70-0.99% or 0.50-0.90%, or even 0.55%; (2) The borneol is selected from one or more of natural borneol, synthetic borneol and artemisia, such as natural borneol and / or synthetic borneol; the borneol is selected from one or more of dextrorotatory borneol, synthetic borneol and levorotatory borneol; (3) The mass ratio of the pilocarpine or its pharmaceutically acceptable salt to the borneol is (8.0-42.0):1, for example (8.0-35.0):1, also for example (10.0-35.0):1, and even more for example 25.0:1, 15.0:1, 30.0:1, 22.5:1, 18.0:1, 16.7:1, 12.5:1, 10.0:1 or 18.3:1; (4) The mass percentage of the pilocarpine or its pharmaceutically acceptable salt in the pharmaceutical composition is 0.40-1.00%, preferably 0.40-0.99%, for example 0.50-0.99%, also for example 0.70-0.99% or 0.50-0.90%, and even more for example 1.00%, 0.50%, 0.55%, 0.75% or 0.90%; Alternatively, the pilocarpine or a pharmaceutically acceptable salt thereof may be present in the pharmaceutical composition at a mass percentage of 0.40-0.90%, for example, 0.50-0.90%, 0.55-0.90%, or 0.75-0.90%. Alternatively, the pilocarpine or a pharmaceutically acceptable salt thereof may be present in the pharmaceutical composition at a mass percentage of 1.00-1.25%, for example, 1.00%, 1.10%, or 1.25%. (5) The borneol in the pharmaceutical composition is 0.04-0.05% by mass, or 0.03-0.04% by mass; For example, the mass percentage of pilocarpine or its pharmaceutically acceptable salt in the pharmaceutical composition is 0.75%, and the mass percentage of borneol in the pharmaceutical composition is 0.03-0.05%. Alternatively, the pilocarpine or a pharmaceutically acceptable salt thereof constitutes 0.90% by mass in the pharmaceutical composition, and the borneol constitutes 0.03-0.05% by mass in the pharmaceutical composition. Alternatively, the pilocarpine or a pharmaceutically acceptable salt thereof constitutes 0.50% by mass in the pharmaceutical composition, and the borneol constitutes 0.03-0.05% by mass in the pharmaceutical composition. Alternatively, the pilocarpine or a pharmaceutically acceptable salt thereof constitutes 0.55% by mass in the pharmaceutical composition, and the borneol constitutes 0.03% by mass in the pharmaceutical composition. (6) Substance A is selected from ethylenediaminetetraacetic acid, cyclodextrin, carboxymethyl chitosan, carbomer, sodium hyaluronate or polyvinyl alcohol; (7) The menthol mentioned is from the Lamiaceae plant peppermint (Mentha haplocalyx). Mentha haplocalyx It is obtained by steam distillation, freezing and recrystallization of fresh stems and leaves of Briq. ; (8) The menthol in the pharmaceutical composition is 0.03%-0.05% or 0.05-0.20% by mass, for example, 0.03%, 0.05%, 0.07%, 0.1% or 0.2%; For example, the mass percentage of pilocarpine or its pharmaceutically acceptable salt in the pharmaceutical composition is 0.75%, and the mass percentage of menthol in the pharmaceutical composition is 0.03-0.20%, such as 0.03%, 0.05%, 0.07%, 0.1%, or 0.2%. For example, the pilocarpine or a pharmaceutically acceptable salt thereof constitutes 0.90% by mass in the pharmaceutical composition, and the menthol constitutes 0.03-0.20% by mass in the pharmaceutical composition, for example, 0.03%, 0.04%, 0.05%, 0.07%, 0.10%, or 0.20%, or even 0.05-0.20%; For example, the pilocarpine or its pharmaceutically acceptable salt constitutes 0.50% by mass in the pharmaceutical composition, and the menthol constitutes 0.03-0.20% by mass in the pharmaceutical composition, such as 0.03%, 0.04%, 0.05%, 0.07%, 0.10%, or 0.20%, or even 0.05-0.20%; (9) The ethylenediaminetetraacetic acid in the pharmaceutical composition is 0.01-0.05% by mass, for example, 0.01% or 0.05%; For example, the pilocarpine or a pharmaceutically acceptable salt thereof constitutes 0.75% by mass in the pharmaceutical composition, and the ethylenediaminetetraacetic acid constitutes 0.005-0.05% by mass in the pharmaceutical composition, for example, 0.005%, 0.01%, or 0.05%. (10) The cyclodextrin is selected from β-cyclodextrin or β-cyclodextrin derivatives, such as hydroxypropyl-β-cyclodextrin; (11) The cyclodextrin in the pharmaceutical composition is 0.8-1.2% by mass, for example 1.0%; For example, the pilocarpine or a pharmaceutically acceptable salt thereof constitutes 0.75% by mass in the pharmaceutical composition, and the cyclodextrin constitutes 1.0% by mass in the pharmaceutical composition. (12) The degree of carboxymethyl substitution of the carboxymethyl chitosan is >90%; (13) The carboxymethyl chitosan constitutes 0.4-0.6% by mass in the pharmaceutical composition, for example, 0.5%; For example, the mass percentage of pilocarpine or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 0.75%, and the mass percentage of carboxymethyl chitosan in the pharmaceutical composition is 0.5%. (14) The viscosity of the carbomer is 20,000-40,000 mPa·s; (15) The carbomer in the pharmaceutical composition is 0.1-0.3% by mass, for example 0.2%; For example, the pilocarpine or a pharmaceutically acceptable salt thereof constitutes 0.75% by mass in the pharmaceutical composition, and the carbomer constitutes 0.2% by mass in the pharmaceutical composition. (16) The sodium hyaluronate in the pharmaceutical composition is 0.2-0.4% by mass, for example 0.3%; For example, the pilocarpine or a pharmaceutically acceptable salt thereof constitutes 0.75% by mass in the pharmaceutical composition, and the carbomer constitutes 0.2% by mass in the pharmaceutical composition. (17) The degree of hydrolysis of the polyvinyl alcohol is 85.0-90.0 mol%, and / or the viscosity of the polyvinyl alcohol is 20.0-30.0 mPa·s; (18) The polyvinyl alcohol in the pharmaceutical composition is 1.0-2.0% by mass, for example 1.4%; For example, the pilocarpine or a pharmaceutically acceptable salt thereof constitutes 0.75% by mass in the pharmaceutical composition, and the polyvinyl alcohol constitutes 1.4% by mass in the pharmaceutical composition. (19) The mass ratio of the pilocarpine or its pharmaceutically acceptable salt to the menthol is (1.0-35.0):1, for example (2.0-30.0):1, also for example (2.5-30.0):1, and even more for example 2.5:1, 3.75:1, 4.5:1, 5.0:1, 7.5:1, 9.0:1, 10.0:1, 10.7:1, 15.0:1, 18.0:1, 25.0:1 or 30.0:1; (20) The mass ratio of the pilocarpine or its pharmaceutically acceptable salt to the ethylenediaminetetraacetic acid is (15.0-150.0):1, for example 15.0:1, 75.0:1 or 150.0:1; (21) The mass ratio of the pilocarpine or its pharmaceutically acceptable salt to the cyclodextrin is (0.5-1.0):1, for example 0.75:1; (22) The mass ratio of the pilocarpine or its pharmaceutically acceptable salt to the carboxymethyl chitosan is (0.5-2.0):1, for example 1.5:1; (23) The carbomer is selected from one or more of carbomer 407, carbomer 934, carbomer 974 and carbomer 980, for example carbomer 934; (24) The mass ratio of the pilocarpine or its pharmaceutically acceptable salt to the carbomer is (1.0-5.0):1, for example 3.75:1; (25) The mass ratio of the pilocarpine or its pharmaceutically acceptable salt to the polyvinyl alcohol is (0.1-3.0):1, for example 0.54:1; (26) The solvent is water for injection; (27) The pH of the pharmaceutical composition is 4.5-5.5, for example 5.0-5.5; (28) The osmotic pressure of the pharmaceutical composition is 289-310 mOsm / L; (29) The pilocarpine or a pharmaceutically acceptable salt thereof is the sole active ingredient in the pharmaceutical composition that produces a miotic effect; and, (30) The molecular weight of the sodium hyaluronate is 400,000 to 1,000,000.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that, The pharmaceutical composition further includes one or more pharmaceutically acceptable excipients, such as: The pharmaceutical composition may also include a pH adjuster; The pharmaceutical composition may also include an osmotic pressure regulator; The pharmaceutical composition may also include one or more of the following: preservatives, thickeners, suspending agents, surfactants, and chelating agents.

4. The pharmaceutical composition according to claim 3, characterized in that, The pharmaceutical composition described herein satisfies one or more of the following conditions: (1) The pH adjuster is sodium hydroxide or HCl; (2) The amount of pH adjuster used is the amount used to adjust the pH of the pharmaceutical composition to 4.5-5.5; (3) The osmotic pressure regulator is one or more of sodium chloride, glucose, sucrose, mannitol, and glycerol, for example, sodium chloride; and, (4) The amount of the osmotic pressure regulator is the amount used to adjust the osmotic pressure of the pharmaceutical composition to 289-310 mOsm / L.

5. A method for preparing a pharmaceutical composition according to any one of claims 1-4, characterized in that, It includes the following steps: mixing the components in the pharmaceutical composition to obtain the final product; For example, the pharmaceutical composition is prepared by mixing pilocarpine or its pharmaceutically acceptable salt, borneol, menthol or substance A, and the solvent. When the pharmaceutical composition further includes a pH adjuster and / or an osmotic pressure regulator, the pharmaceutical composition is prepared by mixing pilocarpine or a pharmaceutically acceptable salt thereof, the borneol, the menthol or substance A, the solvent, the pH adjuster and the osmotic pressure regulator. When the pharmaceutical composition further includes one or more of a preservative, a thickener, a suspending agent, a surfactant, and a chelating agent, the pharmaceutical composition is obtained by mixing pilocarpine or a pharmaceutically acceptable salt thereof, "the borneol, the menthol, or substance A", the solvent, and "one or more of the preservative, the thickener, the suspending agent, the surfactant, and the chelating agent".

6. An ophthalmic preparation, characterized in that, It comprises the pharmaceutical composition as described in any one of claims 1-4; The ophthalmic preparation may be a liquid ophthalmic preparation or a semi-solid ophthalmic preparation. The ophthalmic liquid preparation may be an eye drop, an eye wash, an ophthalmic suspension, or an intraocular injection solution; The ophthalmic semi-solid preparation may be an ointment, ophthalmic cream, or ophthalmic gel.

7. The use of a pharmaceutical composition according to any one of claims 1-4 and / or an ophthalmic preparation according to claim 6 in the preparation of a medicament for treating presbyopia and / or hyperopia.

8. The use of borneol, menthol, or substance A as a miotic enhancer of pilocarpine or a pharmaceutically acceptable salt thereof; The borneol may be the borneol as described in claim 1 or 2; The menthol may be the menthol as described in claim 1 or 2; The substance A is the substance A as described in claim 1 or 2.

9. The use of borneol, menthol, or substance A as a presbyopia and / or hyperopia treatment promoter of pilocarpine or a pharmaceutically acceptable salt thereof; The borneol may be the borneol as described in claim 1 or 2; The menthol may be the menthol as described in claim 1 or 2; The substance A is the substance A as described in claim 1 or 2.

10. The use of borneol, menthol, or substance A in the preparation of a medicament for treating presbyopia and / or hyperopia; The borneol may be the borneol as described in claim 1 or 2; The menthol may be the menthol as described in claim 1 or 2; The substance A is the substance A as described in claim 1 or 2.

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