A pharmaceutical composition, a preparation method thereof, use thereof, and an ophthalmic preparation

Abstract

The application discloses a kind of pharmaceutical composition and preparation method, application, ophthalmic preparation thereof.The pharmaceutical composition is composed of 0.70-0.90% (w / w) of pilocarpine hydrochloride, pH regulator, osmotic pressure regulator and solvent, w / w refers to the mass percentage in the pharmaceutical composition;Percentage refers to the mass percentage in pharmaceutical composition, the sum of the mass percentage of each component in the pharmaceutical composition is 100%.The application determines the change of 0.40-1.00% pilocarpine hydrochloride for pupil diameter, further determines the mydriatic effect of the concentration range, can be administered in a simple manner with 0.70-0.90% lower concentration in clinic, obtain good curative effect, while avoiding adverse reactions caused by high concentration and high dose and the medication risk caused by the administration mode of injection implantation of too low concentration.

Description

[0001] This application claims priority to Chinese patent application CN202510568538.0, 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, 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 after passing through the refractive system. 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 becomes more convex due to its elasticity, 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 and mild hyperopia, 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 / w or w / v pilocarpine hydrochloride. Vuity eye drops, the first eye drops 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. These eye drops take effect within 15 minutes and the effect lasts for 6 hours. They improve 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) for pilocarpine or a pharmaceutically acceptable salt thereof, comprising concentrations of 0.01% (w / w or w / v) to 0.4% (w / w or w / v) and a pharmaceutically acceptable carrier, to provide eye drop formulations and formulations comprising kits or implants of ophthalmic pharmaceutical compositions suitable for implantation in the eye or surrounding tissues of a subject. Its application forms include sustained-release formulations and implantation in the eye or surrounding tissues of a subject. 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 the therapeutic effect of any drug depends on appropriate dosage, administration site, drug concentration, and frequency of administration. A complex and non-linear relationship exists between therapeutic effect and drug concentration. It is not difficult to see that strict control of drug concentration and dosage is crucial in the application of pilocarpine for treating presbyopia and mild hyperopia. However, discovering the differences in the effects of different drug concentrations and dosages is not straightforward. For example, patent CN 117084977A discloses that pilocarpine, when used in combination with a specific ratio of sodium hyaluronate, can better lower intraocular pressure; however, when sodium hyaluronate is not added, the onset time of pilocarpine's pressure-lowering effect is delayed, the intensity of the effect is reduced, and the duration of the effect is shortened. For example, patent CN104093404B discloses that 0.5-1.5% pilocarpine needs to be used in combination with α-stimulatory agonists with imidazoline groups or COX-2 selective nonsteroidal anti-inflammatory agents to effectively treat presbyopia and mild hyperopia; however, when pilocarpine is used alone, its improvement effect is small and its duration of action is short. Both of these patents show that pilocarpine requires special excipients or other drug combinations to exhibit sufficient therapeutic effect, but do not conduct in-depth and detailed research on its own characteristics of action.

[0009] For existing marketed products, high drug concentrations may increase the risk of adverse reactions, such as impaired night vision or greater irritation to eye tissues. Therefore, Jimu utilizes devices for precise micro-dose administration to control the total dosage. On the other hand, lower concentrations may require higher-risk administration methods such as injection or implantation, increasing clinical risks. Therefore, currently, both investigational and marketed products strictly define their application concentrations to ensure clinical efficacy while avoiding adverse reactions associated with high-concentration formulations. In conclusion, exploring more possible safe and effective application concentrations will provide more options for clinical applications.

[0010] Most drugs can exist in multiple different salt forms of the same active ingredient. Although they have the same active ingredient, each salt form should still be considered a different chemical entity with its own unique chemical and biological properties, resulting in differences in the chemical efficacy and safety of these drugs.

[0011] Overall, the application of pilocarpine at different concentrations and in different salt forms in the treatment of presbyopia represents a key scientific issue that requires further investigation. Therefore, how to administer pilocarpine clinically at lower concentrations in a convenient manner while maintaining its efficacy is a pressing technical problem that needs to be solved in this field. Summary of the Invention

[0012] The technical problem to be solved by the present invention is to overcome the defects of the prior art in the clinical application of pilocarpine, such as high risk of adverse reactions at high concentrations, the need for special devices, specific excipients, or combination with other drugs for low concentrations, and to provide a pharmaceutical composition, its preparation method, application, and ophthalmic preparation.

[0013] The technical problem this invention aims to solve is to provide a safe and effective treatment for presbyopia. This invention explores suitable concentrations of pilocarpine to ensure efficacy while reducing common adverse reactions associated with high concentrations of pilocarpine in clinical application. The pilocarpine used in this invention is in the form of its hydrochloride salt, specifically comprising pilocarpine hydrochloride at concentrations of 0.70% (w / w or w / v) to 0.90% (w / w or w / v), and may also include one or more pharmaceutically acceptable excipients (e.g., pH adjusters, osmotic pressure adjusters). It can be applied in common formulations such as eye drops, ophthalmic gels, and ointments.

[0014] Pilocarpine nitrate is a salt formed from pilocarpine and nitric acid, while pilocarpine hydrochloride is a salt formed from pilocarpine and hydrochloric acid. Chemically, pilocarpine nitrate contains nitrate ions (NO3). - Pilocarpine hydrochloride contains chloride ions (Cl...). - Both have similar mechanisms of action, but differ in their specific intensity and effects.

[0015] Therefore, the purpose of this invention is to determine the effect of 0.40-1.00% pilocarpine hydrochloride on pupil diameter, and further determine the miotic effect within this concentration range, so as to achieve good efficacy in clinical administration at a lower concentration and in a simpler manner, while avoiding the adverse reactions caused by high concentrations and high doses, as well as the medication risks caused by injection or implantation for excessively low concentrations.

[0016] The present invention provides a pharmaceutical composition comprising 0.70-0.90 w / w % pilocarpine hydrochloride and a solvent, where w / w refers to the mass percentage of the pharmaceutical composition.

[0017] Pilocarpine hydrochloride is the sole active ingredient in the pharmaceutical composition.

[0018] 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%.

[0019] The present invention provides a pharmaceutical composition comprising 0.70-0.90% (w / w) of pilocarpine hydrochloride, a pH adjuster, an osmotic pressure adjuster, and a solvent, wherein w / w refers to the mass percentage in the pharmaceutical composition;

[0020] 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%.

[0021] In this invention, the CAS number of the pilocarpine hydrochloride is 54-71-7, abbreviated as PH.

[0022] In some embodiments of the present invention, the amount of pilocarpine hydrochloride is 0.70-0.80%, for example 0.75%.

[0023] In some embodiments of the present invention, the amount of pilocarpine hydrochloride is 0.80-0.90%, for example 0.90%.

[0024] In some embodiments of the present invention, the amount of pilocarpine hydrochloride is 0.75-0.90%.

[0025] In some embodiments of the present invention, the pH adjuster is sodium hydroxide or hydrogen chloride.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] In some embodiments of the present invention, the osmotic pressure of the pharmaceutical composition may be 289-310 mOsm / L.

[0031] 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.

[0032] In some embodiments of the present invention, the solvent is water for injection.

[0033] In one embodiment of the present invention, the pharmaceutical composition comprises 0.75% pilocarpine hydrochloride, a pH adjuster, an osmotic pressure adjuster, and a solvent, where w / w refers to the mass percentage in the pharmaceutical composition.

[0034] The pH of the pharmaceutical composition is 4.5 to 5.5;

[0035] The osmotic pressure of the pharmaceutical composition is 289-310 mOsm / L.

[0036] In one embodiment of the present invention, the pharmaceutical composition comprises 0.90% pilocarpine hydrochloride, a pH adjuster, an osmotic pressure adjuster, and a solvent, where w / w refers to the mass percentage in the pharmaceutical composition.

[0037] The pH of the pharmaceutical composition is 4.5 to 5.5;

[0038] The osmotic pressure of the pharmaceutical composition is 289-310 mOsm / L.

[0039] 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;

[0040] For example, the pharmaceutical composition is obtained by mixing pilocarpine hydrochloride, the pH adjuster, the osmotic pressure adjuster, and the solvent.

[0041] In some embodiments of the present invention, the method for preparing the pharmaceutical composition includes the following steps:

[0042] The osmotic pressure regulator and the solvent are mixed to prepare mixture 1;

[0043] Mix the pilocarpine hydrochloride and the mixture 1 to obtain mixture 2;

[0044] The pH of the mixture 2 is adjusted to 4.5-5.5 to obtain the pharmaceutical composition.

[0045] 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.

[0046] The present invention also provides an ophthalmic formulation comprising the aforementioned pharmaceutical composition and one or more pharmaceutically acceptable excipients.

[0047] In this invention, the pharmaceutically acceptable excipients can be selected based on the dosage form that the ophthalmic preparation can be formed into.

[0048] 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.

[0049] The ophthalmic liquid preparation can be an eye drop, an eye wash, an ophthalmic suspension, or an intraocular injection solution.

[0050] The ophthalmic semi-solid preparation may be an ointment, ophthalmic cream, or ophthalmic gel.

[0051] The ophthalmic solid dosage form may be an ophthalmic film, an ophthalmic pill, or an intraocular insertion.

[0052] In this invention, the dosage form of the ophthalmic preparation may be eye drops, ophthalmic gel, or ophthalmic suspension.

[0053] The present invention also provides the use of the pharmaceutical composition and / or the ophthalmic preparation in the preparation of a medicament for correcting presbyopia and / or hyperopia.

[0054] 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.

[0055] The present invention also provides the application of an ophthalmic preparation containing pilocarpine hydrochloride in the preparation of a drug for correcting presbyopia and / or hyperopia, wherein the concentration of pilocarpine hydrochloride in the ophthalmic preparation containing pilocarpine hydrochloride is 0.70-0.90%, and the percentage refers to the mass percentage in the ophthalmic preparation containing pilocarpine hydrochloride.

[0056] In the ophthalmic preparation containing pilocarpine hydrochloride, pilocarpine hydrochloride is the sole active ingredient.

[0057] The present invention also provides the use of an ophthalmic preparation containing pilocarpine hydrochloride in the preparation of a drug for treating presbyopia and / or hyperopia, wherein the concentration of pilocarpine hydrochloride in the ophthalmic preparation containing pilocarpine hydrochloride is 0.70-0.90%, and the percentage refers to the mass percentage in the ophthalmic preparation containing pilocarpine hydrochloride.

[0058] In the ophthalmic preparation containing pilocarpine hydrochloride, pilocarpine hydrochloride is the sole active ingredient.

[0059] In some embodiments of the present invention, the amount of pilocarpine hydrochloride is 0.70-0.80%, for example 0.75%.

[0060] In some embodiments of the present invention, the amount of pilocarpine hydrochloride is 0.80-0.90%, for example 0.90%.

[0061] In some embodiments of the present invention, the amount of pilocarpine hydrochloride is 0.75-0.90%.

[0062] 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.

[0063] 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 condition is typically characterized by blurred vision at a distance and even more blurred vision at close range.

[0064] In this invention, the hyperopia can be mild hyperopia, i.e., low hyperopia, with a hyperopia degree < +3.00DS.

[0065] In this invention, an active ingredient refers to a biologically active component in a drug or other product that can exert the expected therapeutic effect or other function.

[0066] 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.

[0067] The reagents and raw materials used in this invention are all commercially available.

[0068] The positive and progressive effects of this invention are as follows:

[0069] This invention has determined the effect of 0.40-1.00% pilocarpine hydrochloride on pupil diameter, and further determined the miotic effect of this concentration range. In clinical practice, it can be administered at a lower concentration of 0.70-0.90% in a simple manner to achieve good therapeutic effects, while avoiding the adverse reactions caused by high concentrations and high doses, as well as the medication risks caused by injection or implantation of too low concentrations. Attached Figure Description

[0070] Figure 1 The graph shows a comparison of pupil diameter changes after administration of pilocarpine hydrochloride (PH) at concentrations of 1.25%, 1.00%, 0.75%, and 0.90%.

[0071] Figure 2 The graph shows a comparison of pupil diameter changes after administration of pilocarpine hydrochloride (PH) at concentrations of 1.25%, 1.00%, 0.60%, and 0.50%.

[0072] Figure 3 Comparison of pupil diameter changes after administration of pilocarpine nitrate (PN) at concentrations of 1.10% and 1.38% and pilocarpine hydrochloride (PH) at concentrations of 1.00% and 1.25%.

[0073] Figure 4A comparison of pupil diameter changes after administration of 0.83% pilocarpine nitrate (PN) and 0.75% pilocarpine hydrochloride (PH). Detailed Implementation

[0074] 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.

[0075] Pilocarpine Hydrochloride: CAS No.: 54-71-7, abbreviated as PH;

[0076] Pilocarpine Nitrate: CAS No.: 148-72-1, abbreviated as PN.

[0077] In the following examples and comparative examples, the mass percentage of pilocarpine salt is calculated based on the actual mass of pilocarpine salt.

[0078] Unless otherwise specified, the percentages % in the following examples and comparative examples refer to the mass percentage (w / w) or volume percentage (w / v) in the composition (e.g., eye drops).

[0079] 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.

[0080] The present application will be further described in detail below through examples and comparative examples.

[0081] Examples 1-4, Comparative Examples 1-2

[0082] 1. Preparation of eye drops

[0083] Prepare 100 mL samples of the examples and comparative examples according to the weight percentages listed in Table 1. Accurately weigh the corresponding amount of sodium chloride and add it to approximately 80 mL of sterile water for injection, stirring to dissolve. Then add 0.5–1.25 g of the active pharmaceutical ingredient pilocarpine hydrochloride (pH) according to Table 1, stirring to dissolve. Continue to 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 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.

[0084] Table 1. Composition of different groups of preparations

[0085]

[0086] 2. Study on the miotic effect of eye drops at different pH concentrations

[0087] The efficacy of the ophthalmic preparations described in Examples 1-4 and Comparative Examples 1-2 was evaluated using New Zealand white rabbits as the research subjects. A single dose was administered, and pupil diameter was used as the indicator. Seventy-two New Zealand white rabbits (2.5-3.0 kg), half male and half female, were randomly divided into six groups of 12 rabbits each. The experiment used a self-comparison method between the left and right sides of the same animal. 100 μL of the ophthalmic drops from Examples 1-4 and Comparative Examples 1-2 were instilled into the conjunctival sac of the right eye of each rabbit, and then 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. All animal experiments were conducted under standard lighting conditions after acclimatization to room temperature. The pupil diameter was measured before administration and recorded as the zero-time value. Pupil diameter (unit: mm) was measured using a pupillometer 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 pupillary changes at different time points were calculated based on the value at time zero. The results are shown in [Table missing]. Figure 1 , Figure 2 Table 2.

[0088] 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.

[0089] Table 2. Changes in pupil diameter at different time points after drug administration

[0090]

[0091] * 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).

[0092] according to Figure 1 , Figure 2 As shown in Table 2, pH concentrations in the range of 1.0%-1.25% exhibit a significant miotic effect (Comparative Examples 1-2), and the intensity of this effect is dose-dependent within this concentration range. pH concentrations of 0.75%-0.9% also show a significant miotic effect (Examples 3-4), and their intensity is not significantly different from that of pH concentration 1.0% (p>0.05). pH concentrations of 0.5%-0.6% also show a miotic effect (Examples 1-2), but their intensity is significantly lower than that of pH concentration 1.0% (p<0.05). Therefore, pH concentrations in the range of 0.75%-0.9% can achieve a miotic effect equivalent to that of pH concentration 1.0%.

[0093] 3. Irritation test of eye drops at different concentrations

[0094] Ocular irritation tests were conducted using the Draize test, with 12 New Zealand white rabbits (2.5-3.0 kg) per group, half male and half female. Before administration, the cornea, iris, and conjunctiva of each rabbit were observed and recorded. Healthy rabbits were selected for the test. A self-controlled method was used, administering 100 μL of different formulations to the lower conjunctival sac of the right eye according to Table 1, 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 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 48h, and 72h after administration. As shown in Table 3, the cornea, iris, and conjunctiva were scored using the Draize ocular irritation test scoring criteria, and the ocular irritation of the eye drops was determined according to the evaluation criteria in Table 4.

[0095] Table 3. Scoring of the modified Draize test for assessing the severity of ocular lesions.

[0096]

[0097] Table 4 Evaluation levels of eye irritation

[0098]

[0099] Table 5. Results of a single ocular irritation assessment using the modified Draize test.

[0100]

[0101] After applying eye drops to rabbit eyes in Examples 1-4, ocular tissue parameters were observed externally under standard lighting conditions. The scoring results are shown in Table 5. Scores were given for parameters such as cornea, conjunctiva, iris, edema, and secretions after eye drop application. Results: No ocular irritation was observed in any of the four groups. This indicates that after a single administration within the 0.5%-0.9% concentration range, the animals were in good condition, with no corneal opacity, normal iris, no conjunctival hyperemia, and no ocular edema or secretions; no adverse reactions occurred.

[0102] Examples 3 and 5, Comparative Examples 1-4

[0103] 4. Comparative Study on the Miotic Effects of Different Salt Forms of Pilocarpine

[0104] Prepare eye drops according to the method shown in Table 6, as described in Experiment 1. Preparation of Eye Drops. All pilocarpine concentrations are by mass percentage: 0.75% pilocarpine hydrochloride (PH) and 0.83% pilocarpine nitrate (PN) are equimolar; 1.1% PN and 1.0% PH are equimolar; 1.25% PH and 1.38% PN are equimolar.

[0105] Table 6. Components of Experimental Drugs in Different Groups

[0106]

[0107] Note: "-" indicates that the drug was not added.

[0108] The efficacy of the drug was tested on New Zealand white rabbits using a single-dose administration method. The pupil diameter was used as an indicator to evaluate the formulations of Examples 3, 5, and Comparative Examples 1-4. Seventy-two New Zealand white rabbits (2.5-3.0 kg), half male and half female, were randomly divided into six groups of 12 rabbits each. 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 3, 5, or Comparative Examples 1-4 were instilled into the conjunctival sac of the right eye of each rabbit. The eyelid was then gently closed for 8-10 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. The pupil diameter was recorded at zero (before use) as the pre-administration measurement. All animal experiments were conducted under standard lighting conditions after acclimatization to room temperature. Pupil diameter (unit: mm) was measured using a pupil ruler before administration and at 0.2 h, 0.3 h, 0.5 h, 0.8 h, 1.0 h, 2.0 h, and 4.0 h after administration. The measurements were recorded and photographed. The average diameter for each group was calculated. The results are shown below. Figure 3 , Figure 4 And Table 7.

[0109] Table 7. Changes in pupil diameter at different time points after drug administration

[0110]

[0111] # Compared with Comparative Example 3 (1.1% PN), there was a significant difference (p<0.05); * Compared with Example 5 (0.83% PN), there was a significant difference (p<0.05); + Compared with Comparative Example 4 (1.38% PN), there was a significant difference (p<0.05);

[0112] Depend on Figure 3As shown in Table 7, the miotic effect of 1.1% PN was significantly higher than that of 1.0% pH at an equimolar concentration within the range of 0.3h-1.0h. However, there was no significant difference in miotic effect between 1.38% PN and 1.25% pH at 4h. This indicates that even at equimolar concentrations, the effects of different salt forms of pilocarpine are not entirely the same, therefore the miotic characteristics of different salt forms cannot be derived through simple deduction.

[0113] Depend on Figure 4 As shown in Table 7, the 0.75% pH solution had a faster onset of action and higher potency than the corresponding molar concentration of 0.83% PN within 0.5 hours. The miotic effect of 0.75% pH was slightly higher than that of 0.83% PN, indicating that the miotic potency of different salt forms of pilocarpine may vary. Therefore, the characteristics of the miotic effect of different salt forms cannot be derived through simple deduction. Exploring the specific potency and effects of different salt forms of pilocarpine has significant scientific and clinical value.

Claims

1. A pharmaceutical composition, characterized in that, It includes 0.70-0.90 w / w % pilocarpine hydrochloride and a solvent, where w / w refers to the mass percentage in the pharmaceutical composition; Pilocarpine hydrochloride is the sole active ingredient in the pharmaceutical composition. 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%.

2. The pharmaceutical composition according to claim 1, characterized in that, The amount of pilocarpine hydrochloride used is 0.70-0.80%, for example, 0.75%; Alternatively, the amount of pilocarpine hydrochloride used is 0.80-0.90%, for example, 0.90%; Alternatively, the amount of pilocarpine hydrochloride used is 0.75-0.90%; And / or, the pH of the pharmaceutical composition is 4.5-5.5, for example 5.0-5.5; And / or, the osmotic pressure of the pharmaceutical composition is 289-310 mOsm / L; And / or, the pharmaceutical composition further includes a pH adjuster and / or an osmotic pressure adjuster; And / or, the solvent is water for injection.

3. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition comprises 0.70-0.90 w / w % pilocarpine hydrochloride, a pH adjuster, an osmotic pressure adjuster, and the solvent.

4. The pharmaceutical composition according to claim 2, characterized in that, The pH adjuster is sodium hydroxide or hydrogen chloride; And / or, the osmotic pressure regulator is one or more of sodium chloride, glucose, sucrose, mannitol and glycerol, such as sodium chloride.

5. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition comprises 0.75% pilocarpine hydrochloride, a pH adjuster, an osmotic pressure adjuster, and a solvent, where w / w refers to the mass percentage in the pharmaceutical composition; the pH of the pharmaceutical composition is 4.5-5.5; and the osmotic pressure of the pharmaceutical composition is 289-310 mOsm / L. Alternatively, the pharmaceutical composition comprises 0.90% pilocarpine hydrochloride, a pH adjuster, an osmotic pressure adjuster, and a solvent, where w / w refers to the mass percentage in the pharmaceutical composition; the pH of the pharmaceutical composition is 4.5-5.5; and the osmotic pressure of the pharmaceutical composition is 289-310 mOsm / L.

6. A method for preparing the pharmaceutical composition, characterized in that, It includes the following steps: mixing the components of the pharmaceutical composition as described in any one of claims 1-5 to obtain the product; For example, the product is obtained by mixing pilocarpine hydrochloride, the pH adjuster, the osmotic pressure adjuster, and the solvent as described in any one of claims 1-5.

7. An ophthalmic preparation, characterized in that, It comprises the pharmaceutical composition of any one of claims 1-5 and one or more pharmaceutically acceptable excipients.

8. The ophthalmic preparation as described in claim 7, characterized in that, The dosage form of the ophthalmic preparation is eye drops, ophthalmic gel, or ophthalmic suspension.

9. The use of a pharmaceutical composition according to any one of claims 1-5 and / or an ophthalmic preparation according to any one of claims 7-8 in the preparation of a medicament for treating presbyopia and / or hyperopia.

10. The use of an ophthalmic preparation containing pilocarpine hydrochloride in the preparation of a medicament for treating presbyopia and / or hyperopia, wherein the concentration of pilocarpine hydrochloride in the ophthalmic preparation containing pilocarpine hydrochloride is 0.70-0.90%, and the percentage refers to the mass percentage in the ophthalmic preparation containing pilocarpine hydrochloride. In the ophthalmic preparation containing pilocarpine hydrochloride, pilocarpine hydrochloride is the sole active ingredient. Optionally, the amount of pilocarpine hydrochloride used is 0.70-0.80%, for example, 0.75%; Optionally, the amount of pilocarpine hydrochloride used is 0.80-0.90%, for example, 0.90%; Optionally, the amount of pilocarpine hydrochloride used is 0.75-0.90%.

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