Compound pharmaceutical composition for treating presbyopia, preparation method therefor, use thereof, and formulation thereof

Abstract

Provided are a compound pharmaceutical composition for treating presbyopia, a preparation method therefor, use thereof, and a formulation thereof, which belong to the technical field of medicines. The compound pharmaceutical composition comprises the following components in mass concentration: 0.1%-1.25% of a muscarinic M3 receptor agonist, 0.01%-0.1% of an α-adrenergic receptor agonist, and 0.001%-0.01% of pirenoxine or a pharmaceutically acceptable salt thereof, with a pH range of 3.5-4.5. The compound pharmaceutical composition ameliorates presbyopia and myopia vision in a short period of time while delaying the progression of presbyopia from the pathogenic cause, and can also reduce side effects such as red eyes caused by drug factors, thereby alleviating visual fatigue and improving the quality of life.

Description

A compound pharmaceutical composition for the treatment of presbyopia, its preparation method, application and formulation thereof.

[0001] Priority claim: This invention claims priority to Chinese Patent Application No. 202510145584X, filed on February 10, 2025, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of pharmaceutical technology, specifically relating to a compound pharmaceutical composition for the treatment of presbyopia, its preparation method, application, and formulation. Background Technology

[0003] The onset of presbyopia is mainly related to the decline in the lens's focusing ability. Lens autofocus is a mechanism that enables the eye to adjust its refractive ability, allowing people to see near objects clearly. The lens focuses primarily in three ways: (1) ciliary muscle contraction, reducing ciliary band tension and increasing lens thickness; (2) pupillary constriction; and (3) convergence of the two eyeballs. With age, the human eye's lens gradually ages (due to lens protein oxidation, denaturation, abnormal cell metabolism, etc.) and hardens, limiting its thickness changes and weakening its autofocus ability, leading to presbyopia.

[0004] In November 2021, the FDA approved the first drug for the treatment of presbyopia: 1.25% pilocarpine hydrochloride eye drops (brand name: Vuity). Pilocarpine hydrochloride is an M-cholinergic receptor agonist that acts on the iris sphincter muscle, constricting the pupil, increasing focusing depth, and improving near and intermediate visual acuity. Simultaneously, pilocarpine hydrochloride eye drops may also constrict the ciliary muscle, allowing the eye to achieve a better state for near vision. As the first drug for the treatment of presbyopia, pilocarpine has been developed for combination therapy with various drugs, such as nonsteroidal anti-inflammatory drugs, sedative antihistamines, M-cholinergic receptor antagonists, corticosteroids, and alpha-adrenergic receptor agonists, to exert a synergistic effect in treating presbyopia or to reduce the side effects caused by pilocarpine. However, these treatments primarily work by producing a pinhole effect through pupil constriction, treating presbyopia but do not address the pathological cause of lens aging and hardening, and therefore cannot slow the progression of presbyopia.

[0005] Pirenoxine is currently used clinically for the treatment of age-related cataracts. Simultaneously, pirenoxine has a strong affinity for water-soluble proteins in the lens, can improve abnormal metabolism of aromatic amino acids, inhibit the production of quinone compounds, and suppress their oxidative, denaturing, and opacifying effects on soluble proteins in the lens. Scientific Reports (DOI:10.1038 / s41598-017-07208-6) reported that pirenoxine can be used to treat presbyopia, but there are no studies on the combined use of pirenoxine with other drugs for the treatment of presbyopia.

[0006] On the other hand, the product information for 1.25% pilocarpine hydrochloride eye drops (trade name: Vuity) indicates that Vuity has a greater than 5% probability of causing conjunctival hyperemia, leading to red eyes, and in severe cases, allergic conjunctivitis. Brimonidine tartrate, as an α-adrenergic receptor agonist, selectively constricts intraocular veins, increases oxygen supply to surrounding tissues, relieves red eyes, and has no rebound hyperemia or rapid reaction side effects. Chinese patent CN 115089587 B discloses a compound pilocarpine composition and its preparation process and application method, including pilocarpine nitrate, disodium edetate, polyvinyl alcohol, an osmotic pressure regulator, benzalkonium chloride, brimonidine tartrate, and sodium citrate. While maintaining the original therapeutic effect of pilocarpine, the addition of brimonidine tartrate reduces the concentration of pilocarpine to decrease side effects. However, it does not address the pathological cause of lens aging and hardening, and cannot slow the progression of presbyopia. Summary of the Invention

[0007] To address the aforementioned technical problems, this invention provides a compound pharmaceutical composition for the treatment of presbyopia, its preparation method, application, and formulation. This invention rapidly improves myopia-related vision in presbyopia through the pinhole effect of pupil constriction, while simultaneously inhibiting lens aging and hardening through mechanisms such as anti-oxidation and anti-degeneration, thus slowing the progression of presbyopia and significantly increasing the duration of lens elasticity maintenance in the elderly, thereby improving visual acuity. Furthermore, by combining the drugs, it reduces drug-induced side effects such as conjunctival congestion and red eyes, greatly improving the quality of life for the elderly.

[0008] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0009] In a first aspect, the present invention provides a compound pharmaceutical composition for the treatment of presbyopia, comprising the following components in mass concentrations: 0.1%-1.25% muscarinic choline M3 receptor agonist, 0.01%-0.1% α-adrenergic receptor agonist, and 0.001%-0.01% pirenoxine or a pharmaceutically acceptable salt thereof.

[0010] Furthermore, the compound pharmaceutical composition further includes the following components at mass concentrations: 0.001%-2% excipients, 0.01%-2% osmotic pressure regulators, 0.01%-0.05% stabilizers, and 0.1%-1.1% pH buffers.

[0011] Preferably, the compound pharmaceutical composition comprises the following components in mass concentrations: 0.3%-1.25% muscarinic choline M3 receptor agonist, 0.02%-0.03% α-adrenergic receptor agonist, and 0.004%-0.006% pirenoxine or a pharmaceutically acceptable salt thereof.

[0012] Preferably, the compound pharmaceutical composition comprises the following components in mass concentrations: 0.3%-1.25% muscarinic choline M3 receptor agonist, 0.025% α-adrenergic receptor agonist, and 0.005% pirenoxine or a pharmaceutically acceptable salt thereof.

[0013] Preferably, the compound pharmaceutical composition further comprises the following components in mass concentrations: 1%-2% excipient, 1%-2% osmotic pressure regulator, 0.01%-0.02% stabilizer, and 1%-1.1% pH buffer.

[0014] Furthermore, the muscarinic M3 receptor agonist comprises at least one of the following compounds or pharmaceutically acceptable salts thereof: pilocarpine, pilocarpine alkaloid, acetylcholine, clobetacholine, and carbacholine.

[0015] Preferably, the muscarinic choline M3 receptor agonist is pilocarpine or a pharmaceutically acceptable salt thereof, or a combination thereof.

[0016] Preferably, the muscarinic choline M3 receptor agonist is pilocarpine hydrochloride.

[0017] Further, the α-adrenergic receptor agonist comprises at least one of the following compounds or pharmaceutically acceptable salts thereof: brimonidine, aprotinin, oxaclonidine, oxymetazoline, naphazoline, tetrahydrozoline, tramazoline, xylometazoline, cilerazoline, methoxyamine, midodrine, metaraminol, phenylephrine, amiflunomide, SDZ-NVI-085, dexmedetomidine, guanifacin, guanethidine, guanoxabine, tinosoxabine, methyldopa, epinephrine, methylnorepinephrine, norepinephrine, or lofexidine.

[0018] Preferably, the α-adrenergic receptor agonist is brimonidine or a pharmaceutically acceptable salt thereof, or a combination thereof.

[0019] Preferably, the α-adrenergic receptor agonist is brimonidine tartrate.

[0020] Preferably, the pyrenoxine or its pharmaceutically acceptable salt is pyrenoxine.

[0021] Further, the excipients include at least one of the following: polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, carnosine derivative, sodium hyaluronate, ectoine, cellulose derivative, polysorbate 20, polysorbate 80, sorbitan monolaurate, poloxamer, carbomer, castor oil, polyethylene glycol, and polyvinylpyrrolidone.

[0022] Furthermore, the carnosine derivative includes at least one of carnosine, N-acetylcarnosine, and desiccant carnosine.

[0023] Preferably, the carnosine derivative is N-acetylcarnosine.

[0024] Furthermore, the osmotic pressure regulator includes at least one of potassium chloride, calcium chloride, sodium chloride, magnesium chloride, glycerol, mannitol, and glucose.

[0025] Furthermore, the stabilizer comprises at least one of disodium edetate, ethylenediaminetetraacetic acid, disodium dehydrated ethylenediaminetetraacetic acid, and disodium ethylenediaminetetraacetic acid.

[0026] Preferably, the stabilizer is disodium edetate.

[0027] Preferably, the pH buffer comprises at least one of citrate, borate, acetate, and phosphate.

[0028] Preferably, the borate is boric acid and borax.

[0029] Preferably, the compound pharmaceutical composition further includes a pH adjuster, which includes at least one of hydrochloric acid, sulfuric acid, sodium hydroxide, and potassium hydroxide.

[0030] In the above-described scheme, the compound pharmaceutical composition comprises one or more active ingredients formulated in an aqueous solution. Optionally or additionally, the compound pharmaceutical composition can be formulated into a solution, suspension, oil, emulsion, gel, ointment, cream, powder, as well as long-acting or sustained-release formulations, or other types of solid or semi-solid compositions for topical administration. The administration method can be selected from eye drops, sprays, smears / patches, implantation, etc.

[0031] Secondly, the present invention provides a method for preparing a compound pharmaceutical composition, comprising the following steps:

[0032] S1. Dissolve the excipients, osmotic pressure regulators, pH buffers and stabilizers in water to obtain an excipient solution;

[0033] S2. Add the muscarinic M3 receptor agonist and the α-adrenergic receptor agonist to the excipient solution in step S1 to dissolve them, adjust the pH value, and obtain solution L2.

[0034] S3. Filter and sterilize the solution L2 from step S2 to obtain a sterile mixed solution;

[0035] S4. After sterilization, pirenoxine or its pharmaceutically acceptable salt is aseptically added to the aseptic mixed solution in step S3.

[0036] or

[0037] The method for preparing the compound pharmaceutical composition is characterized by comprising the following steps:

[0038] (1) Dissolve polysorbate 80, osmotic pressure regulator, pH buffer and stabilizer in water to obtain excipient solution;

[0039] (2) Dissolve the prescribed amount of oxaliplatin M3 receptor agonist and α-adrenergic receptor agonist in the excipient solution of step (1) to obtain solution L;

[0040] (3) Dissolve pyrenoxine in castor oil and add it to solution L from step (2) to emulsify and obtain emulsion 1;

[0041] (4) Add glycerin to the emulsion in step (3) and stir well to obtain emulsion 2;

[0042] (5) Disperse carbomer in water for injection and sterilize it to obtain a carbomer solution;

[0043] (6) After sterilization and filtration, the emulsion 2 from step (4) is added to the carbomer solution from step (5) and stirred evenly to obtain the final product.

[0044] Furthermore, the preparation method also includes homogenizing the drug solution obtained in step S4 under high pressure or dispersing it under high shear, and then filling it using aseptic blow-fill-seal technology.

[0045] Preferably, the water in steps S1 and (1) is water for injection.

[0046] Preferably, the pH adjustment in step S2 uses hydrochloric acid and sodium hydroxide.

[0047] Thirdly, the present invention provides a formulation comprising the above-described compound pharmaceutical composition and pharmaceutically acceptable excipients.

[0048] Fourthly, the present invention provides the use of a compound pharmaceutical composition in the preparation of a drug for treating, delaying and improving presbyopia.

[0049] The beneficial effects of this invention are as follows:

[0050] The present invention utilizes a combination of a muscarinic M3 receptor agonist, an α-adrenergic receptor agonist, and pirenoxine or a pharmaceutically acceptable salt thereof, which work synergistically to allow the compound pharmaceutical composition to act on the iris sphincter, constrict the pupil, and enable the eye to focus on near objects, thus improving myopia vision. Simultaneously, it acts on the lens, inhibiting its hardening due to oxidative damage and other factors, thus slowing the progression of presbyopia. Furthermore, it constricts intraocular veins, alleviating symptoms such as conjunctival redness caused by drug factors. This invention can improve myopia vision in presbyopia in a short time, while simultaneously slowing the progression of presbyopia from its pathogenic perspective; it also reduces side effects such as redness caused by drug factors, alleviates eye fatigue, and improves quality of life. Detailed Implementation

[0051] To make the objectives, technical solutions, and advantages of this invention clearer, the invention is described with reference to the following specific embodiments, but is by no means limited thereto. The following descriptions are preferred embodiments of the invention and are merely for illustrative purposes; they should not be construed as limiting the invention. It should be noted that any modifications, equivalent substitutions, and improvements made within the spirit and principles of this invention should be included within the scope of protection of this invention. This invention does not limit the source of the raw materials used; unless otherwise specified, the raw materials used in this invention are all commercially available products commonly used in this technical field.

[0052] I. Examples and Comparative Examples

[0053] The bill of materials for Examples 1-7 is shown in Table 1.

[0054] Table 1

[0055] Example 8: A pyrenoxine compound emulsion composition. The material list for Example 8 is shown in Table 2.

[0056] Table 2

[0057] The bill of materials for Comparative Examples 1-2 is shown in Table 3.

[0058] Table 3

[0059] The preparation methods of Examples 1-7 and Comparative Examples 1-2 are as follows:

[0060] (1) Add the prescribed amount of excipients, osmotic pressure regulators, pH buffers and stabilizers to water for injection and stir until completely dissolved;

[0061] (2) Add the prescribed amount of muscarinic M3 receptor agonist and α-adrenergic receptor agonist to the excipient solution in step (1), stir until completely dissolved, and adjust the pH value.

[0062] (3) Filter the solution from step (2) through a 0.22 μm filter to obtain a sterile mixed solution;

[0063] (4) After being sterilized by irradiation, pirenoxine or its pharmaceutically acceptable salt is aseptically added to the aseptic mixed solution in step (3);

[0064] (5) The drug solution from step (4) is homogenized under high pressure or dispersed under high shear, and then filled using aseptic blow-fill-seal technology.

[0065] The preparation method of Example 8 is as follows:

[0066] (1) Dissolve the prescribed amount of polysorbate 80, osmotic pressure regulator, pH buffer and stabilizer in water for injection to obtain excipient solution;

[0067] (2) Dissolve the prescribed amount of alkaloid M3 receptor agonist and α-adrenergic receptor agonist in the excipient solution of step (1);

[0068] (3) Dissolve the prescribed amount of pyrenoxine in castor oil and add it to the solution in step (2), and emulsify it by high shear or high pressure homogenization;

[0069] (4) Slowly add the prescribed amount of glycerin to the emulsion in step (3) and stir until well mixed;

[0070] (5) Disperse the prescribed amount of carbomer in water for injection and sterilize by moist heat.

[0071] (6) After the emulsion from step (4) is sterilized by filtration through a 0.22μm filter cartridge, it is added to the solution from step (5), and the volume is adjusted to the prescribed amount and stirred evenly.

[0072] (7) The mixed emulsion from step (6) is filled using aseptic blow-fill-seal technology to obtain the final product.

[0073] II. Stability Testing

[0074] Examples 3, 4, and Comparative Examples 1-2 were placed at 40°C for 1 month. The bromonidine impurity G (CAS: 1216379-05-3), pilocarpine impurity A (CAS: 28958-85-2), pilocarpine impurity B (CAS: 2700080-55-1), and pyrenoxine impurity (pyrenoxine degradation impurity) were detected by HPLC, and their stability was compared. The results are shown in Table 4.

[0075] Table 4

[0076] The commonly used stable pH range for pilocarpine hydrochloride eye drops is 3.5-5.5, for brimonidine tartrate eye drops it is 5.5-8.0, and for pirenoxine suspension eye drops it is 3.4-4.0. This invention maintains a pH range of 3.5-4.5, ensuring the stability of the compound drug composition even at pH values ​​below 5.5 and above 4.0. Furthermore, it further narrows the pH range within the commonly used range for pilocarpine hydrochloride, ensuring the stability of pilocarpine hydrochloride in the compound system.

[0077] The pH of Comparative Example 1 was 3.0, and its impurity growth level was significantly higher than that of Examples 3-4.

[0078] The results showed that, at 40°C, the samples with added N-acetylcarnosine in Examples 3-4 had significantly lower impurity growth levels than the samples without added N-acetylcarnosine (Comparative Example 2). The addition of N-acetylcarnosine in this invention can significantly improve stability.

[0079] III. Combinations of active ingredients at different concentrations

[0080] The initial mass concentrations of the active components in Examples 3 and 6-7 were measured, and the results are shown in Table 5.

[0081] Table 5

[0082] The results showed that there were no significant differences in the related substances of the active ingredient compositions at different concentrations, and they had similar properties.

[0083] Therefore, the stability data in Example 3 also demonstrate that other combinations of active ingredients at different concentrations have similar stability.

[0084] IV. Treatment Effects of Presbyopia

[0085] Fifteen subjects were randomly divided into three groups. One group received 1.25% pilocarpine hydrochloride eye drops (trade name: Treatment included one group receiving 0.005% pirenoxine eye drops (trade name: Treatment: One group received the treatment described in Example 5. From day 1 to day 14, subjects randomly assigned to receive the active treatment received the drug daily in each eye for 14 days.

[0086] Before administration on day 1 of treatment, and one hour after administration on days 7 and 14 of treatment, visual acuity was tested using an international near vision chart. The results are as follows:

[0087] The evaluation results are shown in Table 6.

[0088] Table 6

[0089] Continuous administration of marketed drugs After 7 days of treatment, visual acuity improved by an average of 2 lines; continued use of marketed medications After 7 days of treatment, visual acuity increased by an average of 0.4 lines; after 7 days of continuous treatment with the drug in Example 5, visual acuity increased by an average of 2.8 lines.

[0090] Continuous administration of marketed drugs After 14 days of treatment, visual acuity improved by an average of 2 lines; continued use of marketed medications After 14 days of treatment, visual acuity increased by an average of 0.6 lines; after 14 days of continuous treatment with the drug in Example 5, visual acuity increased by an average of 3 lines.

[0091] Example 5 of the present invention shows a significantly better effect on improving vision than [previous invention]. Groups and Group. Results showed that the compound drug composition of this invention, compared to 1.25% pilocarpine hydrochloride eye drops and... In this group, the effect of improving myopia vision in patients with presbyopia was more obvious, and the effect of vision improvement gradually increased during continuous drug treatment.

[0092] The results of this invention suggest that the combined use of pirenoxine and pilocarpine hydrochloride may, in long-term drug treatment, delay the aging process of the lens and enhance the effect of pilocarpine hydrochloride in improving presbyopia and myopia by pupil constriction. Thus, while reducing the concentration of pilocarpine hydrochloride, its effect on improving vision may not be reduced or may even be enhanced, further reducing drug side effects and drug costs.

[0093] V. Eye Irritation - Conjunctival Hyperemia Test

[0094] Evaluation method: Ten rabbits were randomly divided into two groups. The rabbits in each group were given eye drops according to the method described in Example 5 and 1.25% pilocarpine eye drops, respectively. The left eye was used as the control eye, and the degree of conjunctival hyperemia in the test eye was observed at different time points after drug administration.

[0095] The evaluation criteria are shown in Table 7.

[0096] Table 7

[0097] The evaluation results are shown in Table 8.

[0098] Table 8

[0099] The table shows the names of marketed drugs administered to the 5 test rabbits: Subsequently, four rabbits developed conjunctival congestion, which returned to normal within 10-30 minutes. When Example 5 of this invention was applied to five test rabbits, only two rabbits developed conjunctival congestion, and it returned to normal within 10 minutes. Therefore, the eye drops of Example 5 are superior to... It has fewer side effects of eye irritation.

[0100] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A compound pharmaceutical composition for the treatment of presbyopia, characterized in that: The product comprises the following components in mass concentrations: 0.1%-1.25% muscarinic choline M3 receptor agonist, 0.01%-0.1% α-adrenergic receptor agonist, and 0.001%-0.01% pirenoxine or a pharmaceutically acceptable salt thereof; The pH range of the compound pharmaceutical composition is 3.5-4.

5.

2. The compound pharmaceutical composition according to claim 1, characterized in that: The muscarinic M3 receptor agonist comprises at least one of the following compounds or pharmaceutically acceptable salts thereof: pilocarpine, pilocarpine alkaloid, acetylcholine, clobetacholine, or carbacholine; preferably pilocarpine hydrochloride.

3. The compound pharmaceutical composition according to claim 1, characterized in that: The α-adrenergic receptor agonist comprises at least one of the following compounds or pharmaceutically acceptable salts thereof: brimonidine, apradilidine, oxaclonidine, oxymetazoline, naphazoline, tetrahydrozoline, tramazoline, xylometazoline, cilerazoline, methoxyamine, midodrine, metaraminol, phenylephrine, amiflunidine, SDZ-NVI-085, dexmedetomidine, guanifacin, guanethidine, guanoxabine, tetrodoxabenzyl, methyldopa, epinephrine, methylnorepinephrine, norepinephrine, or lofexidine; preferably brimonidine tartrate.

4. The compound pharmaceutical composition according to claim 1, characterized in that: The pyrenoxine or its pharmaceutically acceptable salt is preferably pyrenoxine.

5. The compound pharmaceutical composition according to any one of claims 1-4, characterized in that: It also includes the following components at mass concentrations: excipients 0.001%-2%, osmotic pressure regulators 0.01%-2%, stabilizers 0.01%-0.05%, and pH buffers 0.1%-1.1%.

6. The compound pharmaceutical composition according to claim 5, characterized in that: The excipient is at least one of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, carnosine derivative, sodium hyaluronate, ectoine, cellulose derivative, polysorbate 20, polysorbate 80, sorbitan monolaurate, poloxamer, carbomer, castor oil, polyethylene glycol, or polyvinylpyrrolidone.

7. The compound pharmaceutical composition according to claim 5, characterized in that: The osmotic pressure regulator is at least one of potassium chloride, calcium chloride, sodium chloride, magnesium chloride, glycerol, mannitol, and glucose; and / or The stabilizer is at least one selected from disodium edetate, ethylenediaminetetraacetic acid, disodium dehydrated ethylenediaminetetraacetic acid, and disodium ethylenediaminetetraacetic acid; and / or The pH buffer is at least one of borate, citrate, phosphate, and acetate.

8. A method for preparing the compound pharmaceutical composition according to any one of claims 1-7, characterized in that, Includes the following steps: S1. Dissolve the excipients, osmotic pressure regulators, pH buffers and stabilizers in water to obtain an excipient solution; S2. Add the muscarinic M3 receptor agonist and the α-adrenergic receptor agonist to the excipient solution in step S1 to dissolve them, adjust the pH value, and obtain solution L2. S3. Filter the solution L2 from step S2 to remove bacteria and obtain a sterile mixed solution. S4. After sterilization, pirenoxine or its pharmaceutically acceptable salt is aseptically added to the aseptic mixed solution in step S3. or The method for preparing the compound pharmaceutical composition is characterized by comprising the following steps: (1) Dissolve polysorbate 80, osmotic pressure regulator, pH buffer and stabilizer in water to obtain excipient solution; (2) Dissolve the alkaloid M3 receptor agonist and the α-adrenergic receptor agonist in the excipient solution of step (1) to obtain solution L; (3) Dissolve pyrenoxine in castor oil and add it to solution L from step (2) to emulsify and obtain emulsion 1; (4) Add glycerin to the emulsion in step (3) and stir well to obtain emulsion 2; (5) Disperse carbomer in water for injection and sterilize it to obtain a carbomer solution; (6) After sterilization and filtration, the emulsion 2 from step (4) is added to the carbomer solution from step (5) and stirred evenly to obtain the final product.

9. A formulation, characterized in that, It includes the compound pharmaceutical composition according to any one of claims 1-7 or the compound pharmaceutical composition prepared by the preparation method according to claim 8, as well as pharmaceutically acceptable excipients.

10. The use of the compound pharmaceutical composition according to any one of claims 1-7 or the compound pharmaceutical composition prepared by the preparation method according to claim 8 in the preparation of a drug for treating, delaying and improving presbyopia.

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