Composition and use thereof in preparing medicine for treating presbyopia

Abstract

The present invention relates to a composition and the use of the composition in preparing a medicine for treating eye diseases. The composition comprises 0.5-1.5% by weight of a muscarinic acetylcholine receptor M3 agonist; 0.005-0.5% by weight of naphazoline, a pharmaceutically acceptable salt thereof, or a combination thereof; and 0.1-1% by weight of ketorolac tromethamine. The composition enhances the effect of a muscarinic acetylcholine receptor M3 agonist such as a pilocarpine active ingredient in treating presbyopia, while effectively and significantly reducing or even eliminating the side effects caused by the pilocarpine active ingredient.

Description

Technical Field

[0001] The present invention relates to the field of medicine. Specifically, the present invention relates to a composition, in particular an ophthalmic preparation, preferably an eye drop or an eye spray, and use of the composition in preparing a medicament for treating eye diseases such as presbyopia. Background Art

[0002] The human eye has normal refractive power and central axis length. It is possible to see distant objects immediately through the optical system of the eye by passively contracting the light through the muscle. The focusing mechanism of human and primate eyes is caused by the contraction of the ciliary muscle of the eye, which causes changes in the shape and position of the lens. Starting from childhood, the lens begins to gradually lose the ability to change shape and position due to the contraction of the ciliary muscle. From the perspective of optometry, hyperopia requires increased refractive power to see more clearly. When the age is around 40, presbyopia will occur with age, that is, normal eyes cannot focus on nearby objects (40 cm or less from the eye) in a comfortable way, which is usually called presbyopia in China.

[0003] In the eye, the ciliary muscle is under the control of the parasympathetic nervous system. The sympathetic nervous system plays a secondary (regulatory) role via its α and β receptors. One of the therapeutic mechanisms of presbyopia is to regulate the relaxation of the iris and the effect of the sphincter that can change the pupil diameter. The iris sphincter is mainly under the control of the parasympathetic nerves via muscarinic receptors. M3 cholinergic receptor agonists can increase the contraction of the ciliary muscle and thus increase the refractive power of the eye. Therefore, it is possible to regulate conditions such as presbyopia, mild hyperopia and irregular astigmatism, hyperopic accommodative esotropia and glaucoma. Such receptor agonists mainly include acetylcholine, bethanechol, carbachol, pilocarpine or pilocarpine.

[0004] At present, the treatment of presbyopia is mainly based on M3 cholinergic receptor agonists, among which pilocarpine is the main active ingredient. It has been used as a single drug for the treatment of presbyopia and mild hyperopia, but has not received very satisfactory results, because the local concentration below 0.5% has little effect on the mediation and is ineffective, while the concentration above 0.5% is intolerable due to side effects such as red eyes, eye pain, migraine and headache. In addition, when the concentration of pilocarpine is sufficient to effectively improve hyperopia, this myopia of the eye causes a significant decrease in the distance vision of the eye (Gilmartin et al., 1995, Ophthalmic and Physiological Optics, Pergamon Press, Oxford, GB, 15 (5): 475-479). In the current treatment scheme, there is no scheme that can achieve satisfactory treatment effects and solve the side effects of red eyes, eye pain, migraine and headache caused by the use of pilocarpine. The present invention can effectively alleviate the above-mentioned side effects caused by the use of pilocarpine on the basis of being able to achieve satisfactory treatment effects.

[0005] Application CN112272558A (application number 201980037652.3) of Allegan Corporation of the United States discloses an eye drop composition containing only pilocarpine hydrochloride as an active ingredient for the treatment of presbyopia. The pilocarpine hydrochloride eye drop composition contains about 1.25% w / v of pilocarpine hydrochloride, about 1.0% w / v of boric acid, about 0.015% w / v of sodium citrate dihydrate, about 0.08% w / v of sodium chloride, and about 0.0075% w / v of benzalkonium chloride. The results of clinical trials conducted on the eye drops of the composition showed that the administration of pilocarpine at a concentration of ≥1% and <1.5% was most effective for improving the reading ability of presbyopic patients, and the incidence of adverse reactions did not increase significantly.

[0006] The pilocarpine hydrochloride eye drop composition contains only one active ingredient, pilocarpine hydrochloride, and the incidence of side effects is only not significantly increased, and there are no other active ingredients to suppress the side effects caused by the use of pilocarpine hydrochloride. The side effects such as red eyes, eye pain, migraine and headache are caused by the use of pilocarpine, and other targeted active ingredients need to be used to suppress them one by one, so that the incidence of these adverse reactions can be significantly reduced.

[0007] Application CN104093404A (application number 201280056271.8) of Allegan Corporation of the United States discloses a compound preparation composition comprising an M3 cholinergic receptor agonist, oxymetazoline, and an NSAID (nonsteroidal anti-inflammatory drug) for treating presbyopia. The composition comprises 0.5% to 1.5% w / w of a muscarinic acetylcholine receptor M3 agonist, 0.02% to 0.1% w / w of oxymetazoline, and an NSAID with COX-2 selectivity (including one or more of meloxicam, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, nimesulide, etodolac, and nabumetone). Used for treating presbyopia, mild hyperopia, irregular astigmatism, hyperopic accommodative esotropia, or for enhancing or strengthening the delay, reversal, or modification of the aging process of the lens and its surrounding tissues in a subject.

[0008] The compound preparation composition has oxymetazoline and nonsteroidal anti-inflammatory drugs added to the side effects caused by using pilocarpine, which can effectively alleviate these side effects. Oxymetazoline is an alpha receptor agonist with an imidazoline group, which has the effect of contracting blood vessels, and is therefore used to alleviate the symptoms of red eyes. NSAIDs with COX-2 selectivity (its patent includes one or more of meloxicam, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, nimesulide, etodolac and nabumetone) can selectively inhibit COX-2, that is, can inhibit the cyclooxygenase-2 of the product to produce prostaglandins, and then inhibit the development of inflammation. Although the NSAIDs included in the patent can resist inflammation, it can not achieve obvious effects on alleviating the headache caused by using pilocarpine. Therefore, although it can have a certain effect of alleviating side effects, it has not yet reached an ideal state.

[0009] Therefore, there is still a need for pilocarpine eye drop compositions that can maintain or even enhance the effect of the pilocarpine active ingredient in treating presbyopia while effectively and significantly reducing or even eliminating the side effects caused by the pilocarpine active ingredient. Summary of the invention

[0010] Technical issues

[0011] One object of the present invention is to provide a composition, wherein the effect of pilocarpine active ingredients in treating presbyopia can be synergistically enhanced.

[0012] Another object of the present invention is to provide a composition which can enhance the efficacy of pilocarpine while significantly reducing the side effects caused by pilocarpine.

[0013] Another object of the present invention is to provide use of the above composition in preparing a medicament for treating eye diseases such as presbyopia.

[0014] Technical means to solve technical problems

[0015] In view of the above technical problems, the present inventors conducted intensive studies and obtained the following findings, thereby completing the present invention.

[0016] Specifically, the present invention can be achieved as follows.

[0017] 1. A composition comprising, relative to the total weight of the composition:

[0018] 0.5-1.5% by weight of a muscarinic acetylcholine receptor M3 agonist;

[0019] 0.005-0.5% by weight of naphazoline, a pharmaceutically acceptable salt thereof, or a combination thereof; and

[0020] 0.1-1% by weight of ketorolac tromethamine.

[0021] 2. The composition according to claim 1, wherein the composition is an ophthalmic preparation, preferably eye drops or eye sprays.

[0022] 3. A composition as described in any one of items 1-2, wherein the muscarinic acetylcholine receptor M3 agonist comprises at least one selected from the following: acetylcholine, bethanechol, carbachol, oxotremorine, pilocarpine, pilocarpine, a pharmaceutically acceptable salt thereof, or a combination thereof;

[0023] Preferably, the muscarinic acetylcholine receptor M3 agonist comprises at least one selected from the following: pilocarpine, a pharmaceutically acceptable salt thereof, or a combination thereof;

[0024] Preferably, the muscarinic acetylcholine receptor M3 agonist is pilocarpine, pilocarpine hydrochloride, pilocarpine nitrate, or a combination thereof, preferably pilocarpine nitrate.

[0025] 4. A composition as described in any one of items 1-3, wherein the pharmaceutically acceptable salt of naphazoline is naphazoline hydrochloride.

[0026] 5. A composition as described in any one of items 1 to 4, wherein the composition comprises water, preferably water for injection, as a liquid carrier.

[0027] 6. A composition as described in any one of items 1 to 5, wherein the composition does not include an antibacterial agent.

[0028] 7. The composition of any one of items 1 to 6, wherein the composition does not include an alpha receptor agonist having an imidazoline group other than naphazoline, a pharmaceutically acceptable salt thereof, or a combination thereof.

[0029] 8. The composition of claim 7, wherein the composition does not include an alpha receptor agonist other than naphazoline, a pharmaceutically acceptable salt thereof, or a combination thereof.

[0030] 9. The composition of any one of items 1-8, wherein the composition does not include other active pharmaceutical ingredients (API) other than the muscarinic acetylcholine receptor M3 agonist, naphazoline, a pharmaceutically acceptable salt thereof, or a combination thereof, and ketorolac tromethamine.

[0031] 10. A composition as described in any one of items 1-9, wherein the composition does not include sodium chloride.

[0032] 11. A composition as described in any one of items 1 to 10, wherein the composition has a pH of 3.0-8.5 at room temperature, preferably the composition has a pH of 4.0-6.0 at room temperature, preferably the composition has a pH of 4.5-5.5 at room temperature.

[0033] 12. The composition of item 1, wherein the composition further comprises an osmotic pressure regulator, preferably, the osmotic pressure regulator is present in an amount of 0.1-2.0% relative to the total weight of the composition.

[0034] 13. A composition as described in claim 12, wherein the osmotic pressure regulator comprises one or more selected from the following: propylene glycol, glycerol, sodium chloride, glycerol, glucose, boric acid, borax.

[0035] 14. The composition of item 13, wherein the osmotic pressure regulator is boric acid, preferably 0.5 to 1.5% by weight of boric acid relative to the total weight of the composition.

[0036] 15. A composition according to any one of items 1 to 14, wherein the composition further comprises a surfactant;

[0037] Preferably, the surfactant is 0.1 to 1% by weight relative to the total weight of the composition;

[0038] Preferably, the surfactant comprises one or more selected from the following: polyoxyethylene (20) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polysorbate 80, Span, poloxamer, propylene glycol, tyloxapol, nonoxynol ether;

[0039] Preferably, the surfactant is polyoxyethylene (40) hydrogenated castor oil.

[0040] 16. A composition as described in any one of items 1 to 15, wherein the composition further comprises a stabilizer;

[0041] Preferably, the stabilizer comprises one or more selected from the following: disodium edetate, EDTA, sodium bisulfite,

[0042] Preferably, the stabilizer is 0.005-0.05% by weight of sodium citrate relative to the total weight of the composition, and / or 0.005-0.05% by weight of disodium edetate relative to the total weight of the composition.

[0043] 17. The composition of any one of items 1 to 16, wherein the composition further comprises a pH adjuster;

[0044] Preferably, the pH adjuster includes one or more selected from the following: acids such as citric acid, phosphoric acid, acetic acid, and hydrochloric acid, and bases such as sodium hydroxide and potassium hydroxide.

[0045] 18. A composition as described in any one of items 1 to 17, wherein the pH adjusting agent comprises:

[0046] 0-0.1% by weight of citric acid relative to the total weight of the composition and / or 0-0.1% by weight of sodium hydroxide relative to the total weight of the composition.

[0047] 19. A composition according to any one of items 1 to 18, wherein the composition comprises:

[0048] 0.5-1.5% by weight of pilocarpine nitrate;

[0049] 0.005-0.5% by weight of naphazoline and / or naphazoline hydrochloride;

[0050] 0.1-1% by weight of ketorolac tromethamine;

[0051] 0.5-1.5% by weight of boric acid;

[0052] 0.005-0.05% by weight of sodium citrate;

[0053] 0.005-0.05% by weight of disodium edetate;

[0054] 0.1-1% by weight of polyoxyethylene (40) hydrogenated castor oil;

[0055] 0-0.1% by weight of citric acid;

[0056] 0 to 0.1% by weight of sodium hydroxide; and

[0057] The balance is water for injection.

[0058] 20. Use of the composition according to any one of items 1 to 19 in the preparation of a medicament for treating eye diseases such as presbyopia.

[0059] Technical Effects

[0060] The present inventors surprisingly found that when a muscarinic acetylcholine receptor M3 agonist such as a pilocarpine active ingredient is used in combination with naphazoline or a pharmaceutically acceptable salt thereof (such as hydrochloride) and ketorolac tromethamine in a specific amount, there is a synergistic effect between naphazoline or a pharmaceutically acceptable salt thereof such as hydrochloride and ketorolac tromethamine, which synergistically improves the efficacy of the composition, and can significantly reduce or even eliminate the side effects such as red eyes, eye pain, migraine and headache caused by the muscarinic acetylcholine receptor M3 agonist such as a pilocarpine active ingredient while effectively treating presbyopia. For example, by using naphazoline or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) and ketorolac tromethamine in combination, the composition of the present invention can achieve a better effect of treating presbyopia when using a lower amount of a muscarinic acetylcholine receptor M3 agonist such as a pilocarpine active ingredient, and / or achieve lower side effects (red eyes, eye pain, migraine and headache, etc.) when using a higher amount of a muscarinic acetylcholine receptor M3 agonist such as a pilocarpine active ingredient, and / or prolong the effective duration of action in treatment (obtain a sustained and effective therapeutic effect over a longer period of time) relative to the eye drop composition of the prior art. In addition, the composition of the present invention has good drugability.

[0061] The independent and dependent claims set out particular and preferred features of the invention. Features from the dependent claims may be combined with features from the independent claim or other dependent claims as appropriate.

[0062] The present invention will now be further described. In the following paragraphs, different aspects of the present invention are defined in more detail. Unless clearly indicated to the contrary, each aspect so defined can be combined with any other aspect or aspects. Especially, any feature or statement that is indicated as preferred or advantageous can be combined with any other feature or statement that is indicated as preferred or advantageous. DETAILED DESCRIPTION

[0063] When describing the present invention, the terms used are to be interpreted in accordance with the following definitions, unless the context dictates otherwise.

[0064] As used herein, the expression "pharmaceutically acceptable salt" refers to an inorganic acid salt or an organic acid salt, wherein the inorganic acid may be, for example, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid and perchloric acid; the organic acid may be, for example, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphor, camphorsulfonate, cyclopentyl propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, iodide, 2-hydroxyethylsulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like.

[0065] Herein, “naphazoline hydrochloride” is sometimes described as “naphazoline hydrochloride”, which can be used interchangeably; and “pilocarpine nitrate” is sometimes described as “pilocarpine nitrate”, which can be used interchangeably.

[0066] Unless otherwise defined, all terms (including technical and scientific terms) used in disclosing the present invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0067] In the following paragraphs, different aspects of the present invention are defined in more detail. Unless explicitly indicated to the contrary, each aspect so defined can be combined with any other aspect or aspects. In particular, any feature that is indicated as preferred or advantageous can be combined with any other feature or features that are indicated as preferred or advantageous.

[0068] References to "one embodiment" or "an embodiment" throughout this specification mean that the specific features, structures, or characteristics described in conjunction with the embodiment are included in at least one embodiment of the present invention. Therefore, the phrases "in one embodiment" or "in one embodiment" appearing in different places throughout this specification do not necessarily all refer to the same embodiment, but may all refer to the same embodiment. In addition, in one or more embodiments, the specific features, structures, or characteristics may be combined in any suitable manner as will be apparent to those skilled in the art from the present disclosure. In addition, although some embodiments described herein include some features included in other embodiments, other features included in the other embodiments are not included, but the combination of features of different embodiments is intended to be within the scope of the present invention and form different embodiments, as will be understood by those skilled in the art. For example, in the appended claims and the following statements, any of the embodiments may be used in any combination.

[0069] The term "comprising" as used herein is synonymous with "including" or "containing", and is inclusive or open-ended and does not exclude additional, unrecited members, elements, or method steps. It will be appreciated that the term "comprising" as used herein includes the term "consisting of".

[0070] The recitation of numerical ranges by endpoints includes all integers and, where appropriate, fractions encompassed in the range (e.g., 1 to 5 may include 1, 2, 3, 4 when referring to, for example, the number of elements, and may also include 1.5, 2, 2.75, and 3.80 when referring to, for example, a metric). The recitation of endpoints also includes the endpoint values ​​themselves (e.g., 1.0-5.0 includes both 1.0 and 5.0). Any numerical range recited herein is intended to include all subranges encompassed therein.

[0071] In this document, when referring to a numerical value, unless otherwise specified, the numerical value mentioned should be understood to disclose the numerical value itself, and also cover the numerical value and the variation of + / -10% or less, preferably + / -5% or less, more preferably + / -1% or less from the numerical value, as long as such variation is suitable for making in the disclosed invention.

[0072] The present invention will be described in detail below. Unless explicitly indicated to the contrary, each statement and embodiment of the present invention so defined can be combined with any other statement and / or embodiment. In particular, any feature indicated as preferred or advantageous can be combined with any other feature or features or statements indicated as preferred or advantageous. In this regard, the present invention is particularly obtained by any one of the following numbered statements and embodiments or any combination of one or more of them with any other aspects and / or embodiments.

[0073] A first aspect of the present invention relates to a composition comprising:

[0074] Muscarinic acetylcholine receptor M3 agonist;

[0075] Naphazoline, a pharmaceutically acceptable salt thereof, or a combination thereof, and

[0076] Ketorolac tromethamine.

[0077] In one embodiment, the composition is an ophthalmic preparation, preferably an eye drop or an eye spray.

[0078] In one embodiment, the muscarinic acetylcholine receptor M3 agonist is present in an amount by weight of 0.5 to 1.5%, such as 0.50%, 0.51%, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65%, 0.66%, 0.67%, 0.68%, 0.69%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, 131%, 132%, 133%, 134%, 135%, 136%, 137%, 138%, 139%, 140%, 141%, 142%, 143%, 144%, 145%, 146%, 147%, 148%, 149%, 150%, 8%, 0.69%, 0.70%, 0.71%, 0.72%, 0.73%, 0.74%, 0.75%, 0.76%, 0.77%, 0.78%, 0.79%, 0.80%, 0.81%, 0.82%, 0.83%, 0.84%, 0.85%, 0.86%, 0.87%, 0.88%, 0.89%, 0.90%, 0.91%, 0.92%, 0.93%, 0.94%, 0.95%, 0.96% , 0.97%, 0.98%, 0.99%, 1.00%, 1.01%, 1.02%, 1.03%, 1.04%, 1.05%, 1.06%, 1.07%, 1.08%, 1.09%, 1.10%, 1.11%, 1.12%, 1.13%, 1.14%, 1.15%, 1.16%, 1.17%, 1.18%, 1.19%, 1.20%, 1.21%, 1.22%, 1.23%, 1.24%, 1 .25%, 1.26%, 1.27%, 1.28%, 1.29%, 1.30%, 1.31%, 1.32%, 1.33%, 1.34%, 1.35%, 1.36%, 1.37%, 1.38%, 1.39%, 1.40%, 1.41%, 1.42%, 1.43%, 1.44%, 1.45%, 1.46%, 1.47%, 1.48%, 1.49%, 1.50%, or a range limited by any two of them.

[0079] In one embodiment, the muscarinic acetylcholine receptor M3 agonist includes at least one selected from the group consisting of acetylcholine, bethanechol, carbachol, oxotremorine, pilocarpine, pilocarpine, a pharmaceutically acceptable salt thereof, or a combination thereof.

[0080] In one embodiment, the muscarinic acetylcholine receptor M3 agonist is pilocarpine, a pharmaceutically acceptable salt thereof, or a combination thereof.

[0081] In one embodiment, the muscarinic acetylcholine receptor M3 agonist is pilocarpine, pilocarpine hydrochloride, pilocarpine nitrate, or a combination thereof, preferably pilocarpine nitrate.

[0082] In one embodiment, naphazoline, a pharmaceutically acceptable salt thereof, or a combination thereof is present in an amount by weight of 0.005-0.5%, such as 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.013%, 0.014%, 0.015%, 0.016%, 0.017%, 0.018%, 0.019%, 0.020%, 0.021%, 0.022%, 0.023%, 0.024%, 0.025%, 0.026%, 0.027%, 0.028%, 0.029%, 0.030%, 0.031%, 0.032%, 0.033%, 0.034%, 0.035%, 0.036%, 0.037%, 0.038%, 0.039%, 0.040%, 0.041%, 0.042%, 0.043%, 0.044%, 0.045%, 0.046%, 0.047%, 0.048%, 0.049%, 0.050%, 0.051%, 0.052%, 0.053%, 0.054%, 0.055%, 0.056%, 0.057%, 0.058%, 0.059%, 0.060%, 0.061%, 0.062%, 0.063%, 0.064%, 0.065%, 0.066%, 0.067%, 0.068%, 0.069%, 0.070%, 0.071%, 0.031%, 0.032%, 0.033%, 0.034%, 0.035%, 0.036%, 0.037%, 0.038%, 0.039%, 0.040%, 0.041%, 0.042%, 0.043%, 0.044%, 0.045%, 0.046%, 0.047%, 0.048%, 0 .049%, 0.050%, 0.051%, 0.052%, 0.053%, 0.054%, 0.055%, 0.056%, 0.057%, 0.058%, 0.059%, 0.060%, 0.061%, 0.062%, 0.063%, 0.064%, 0.065%, 0.066%, 0.067%, 0.068%, 0.069%, 0.070%, 0.071%, 0.072%, 0.073%, 0.074%, 0.075%, 0.076%, 0.077%, 0.078%, 0.079%, 0.080%, 0.081%, 0.082%, 0.083%, 0.084 %, 0.085%, 0.086%, 0.087%, 0.088%, 0.089%, 0.090%, 0.091%, 0.092%, 0.093%, 0.094%, 0.095%, 0.096%, 0.097%, 0.098%, 0.099%, 0.100%, 0.105%, 0.11 0%, 0.115%, 0.120%, 0.125%, 0.130%, 0.135%, 0.140%, 0.145%, 0.150%, 0.155%, 0.160%, 0.165%, 0.170%, 0.175%, 0.180%, 0.185%, 0.190%, 0.195%, 0.2 00%, 0.205%, 0.210%, 0.215%, 0.220%, 0.225%, 0.230%, 0.235%, 0.240%, 0.245%, 0.250%, 0.255%, 0.260%, 0.265%, 0.270%, 0.275%, 0.280%, 0.285%, 0.290%, 0.295%, 0.300%, 0.305%, 0.310%, 0.315%, 0.320%, 0.325%, 0.330%, 0.335%, 0.340%, 0.345%, 0.350%, 0.355%, 0.360%, 0.365%, 0.370%, 0.375%, 0.380%, 0.385%, 0.390%, 0.395%, 0.400 %, 0.405%, 0.410%, 0.415%, 0.420%, 0.425%, 0.430%, 0.435%, 0.440%, 0.445%, 0.450%, 0.455%, 0.460%, 0.465%, 0.470%, 0.475%, 0.480%, 0.485%, 0.490%, 0.495%, 0.500%, or a range defined by any two of them.

[0083] In one embodiment, the pharmaceutically acceptable salt of naphazoline is naphazoline hydrochloride.

[0084] In one embodiment, ketorolac tromethamine is present in an amount by weight of 0.1-1%, such as 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51%, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65%, 0.66%, 0.67%, 0.68%, 0.69%, 0.70%, 0.71%, 0.72%, 0.73%, 0.74%, 0.75%, 0.76%, 0.77%, 0.78%, 0.79%, 0.80%, .27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51%, 0.52 %, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65%, 0.66%, 0.67%, 0.68%, 0.69%, 0.70%, 0.71%, 0.72%, 0.73%, 0.74%, 0.75%, 0.76%, 0.77%, 0.78%, 0.79%, 0.80%, 0.81%, 0.82%, 0.83%, 0.84%, 0.85%, 0.86%, 0.87%, 0.88%, 0.89%, 0.90%, 0.91%, 0.92%, 0.93%, 0.94%, 0.95%, 0.96%, 0.97%, 0.98%, 0.99%, 1.00%, or a range limited by any two of them.

[0085] In one embodiment, the composition does not include a bacteriostatic agent.

[0086] In one embodiment, the composition does not include an alpha receptor agonist having an imidazoline group other than naphazoline, a pharmaceutically acceptable salt thereof, or a combination thereof.

[0087] In one embodiment, the composition does not include an alpha receptor agonist other than naphazoline, a pharmaceutically acceptable salt thereof, or a combination thereof.

[0088] In one embodiment, the composition comprises no active pharmaceutical ingredients (API) other than the muscarinic acetylcholine receptor M3 agonist, naphazoline, a pharmaceutically acceptable salt thereof, or a combination thereof, and ketorolac tromethamine.

[0089] In one embodiment, the composition comprises water, preferably water for injection, as the liquid carrier.

[0090] In one embodiment, the composition may further include a surfactant.

[0091] In one embodiment, the surfactant includes one or more selected from the following: polyoxyethylene (20) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polysorbate 80, Span, poloxamer, propylene glycol, tyloxapol, and nonoxynol ether.

[0092] In one embodiment, the surfactant (e.g., polyoxyethylene (40) hydrogenated castor oil) is present in an amount of 0.1 to 1% relative to the total weight of the composition, such as 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51% , 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65%, 0.66%, 0.67%, 0.68%, 0.69%, 0.70%, 0.71%, 0.72%, 0.73%, 0.74%, 0.75%, 0.76%, 0.77 %, 0.78%, 0.79%, 0.80%, 0.81%, 0.82%, 0.83%, 0.84%, 0.85%, 0.86%, 0.87%, 0.88%, 0.89%, 0.90%, 0.91%, 0.92%, 0.93%, 0.94%, 0.95%, 0.96%, 0.97%, 0.98%, 0.99%, 1.00%, or a range limited by any two of them.

[0093] In one embodiment, the composition may further include an osmotic pressure regulator.

[0094] In one embodiment, the osmotic pressure regulator includes one or more selected from the following: propylene glycol, glycerol, sodium chloride, glycerol, glucose, boric acid, borax.

[0095] In one embodiment, the osmotic pressure regulator is present in an amount of 0.1-2.0% relative to the total weight of the composition, such as 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.55%, 0.60%, 0.65%, 0.70%, 0.75%, 0.80%, 0.85%, 0.90%, 0.95%, 1.00%, 1.05%, 1.10%, 1.15%, 1.20%, 1.25%, 1.30%, 1.35%, 1.40%, 1.45%, 1.50%, 1.55%, 1.60%, 1.65%, 1.70%, 1.75%, 1.80%, 1.85%, 1.90%, 1.95%, 2.00%, or a range limited by any two of them.

[0096] In one embodiment, the osmotic pressure regulator includes or is boric acid, and the amount of boric acid present relative to the total weight of the composition is 0.5-1.5%, such as 0.50%, 0.51%, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65%, 0.66%, 0.67%, 0.68%, 0.69%, 0.70%, 0.71%, 0.72%, 0.73%, 0.74%, 0.75%, 0.76%, 0.77%, 0.78%, 0.79%, 0.80%, 0.81%, 0.82%, 0.83%, 0.84%, 0.85%, 0.86%, 0.87%, 0.88%, 0.89%, 0.90%, 0.91%, 0.92%, 0.93%, 0.94%, 0.95%, 0.96%, 0. .97%, 0.98%, 0.99%, 1.00%, 1.01%, 1.02%, 1.03%, 1.04%, 1.05%, 1.06%, 1.07%, 1.08%, 1.09%, 1.10%, 1.11%, 1.12%, 1.13%, 1.14%, 1.15%, 1.16%, 1.17%, 1.18%, 1.19%, 1.20%, 1.21%, 1.22%, 1.23%, 1.24%, 1. 25%, 1.26%, 1.27%, 1.28%, 1.29%, 1.30%, 1.31%, 1.32%, 1.33%, 1.34%, 1.35%, 1.36%, 1.37%, 1.38%, 1.39%, 1.40%, 1.41%, 1.42%, 1.43%, 1.44%, 1.45%, 1.46%, 1.47%, 1.48%, 1.49%, 1.50%, or a range limited by any two of them.

[0097] In one embodiment, the osmotic pressure regulator may further include propylene glycol, and the amount of propylene glycol relative to the total weight of the composition is 0.1-1%, for example 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51%, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65%, 0.66%, 0.67%, 0.68%, 0.69%, 0.70%, 0.71%, 0.72%, 0.73%, 0.74%, 0.75%, 0.76%, 0.77%, 0.78%, 0.79%, 0.80%, 6%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51%, 0. .52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65%, 0.66%, 0.67%, 0.68%, 0.69%, 0.70%, 0.71%, 0.72%, 0.73%, 0.74%, 0.75%, 0.76%, 0.77% , 0.78%, 0.79%, 0.80%, 0.81%, 0.82%, 0.83%, 0.84%, 0.85%, 0.86%, 0.87%, 0.88%, 0.89%, 0.90%, 0.91%, 0.92%, 0.93%, 0.94%, 0.95%, 0.96%, 0.97%, 0.98%, 0.99%, 1.00%, or a range limited by any two of them.

[0098] In one embodiment, the composition may further include a stabilizer.

[0099] In one embodiment, the stabilizer comprises one or more selected from the following: disodium edetate, EDTA, sodium bisulfite.

[0100] In one embodiment, the stabilizer (e.g., edetate disodium) is present in an amount of 0.005-0.05%, such as 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.013%, 0.014%, 0.015%, 0.016%, 0.017%, 0.018%, 0.019%, 0.020%, 0.021%, 0.022%, 0.023%, 0.024%, 0.025%, 0.026%, 0.027%, 0.028%, 0.029%, 0.030%, 0.031%, 0.032%, 0.033%, 0.034%, 0.035%, 0.036%, 0.037%, 0.038%, 0.039%, 0.040%, 0.041%, 0.042%, 0.043%, 0.044%, 0.045%, 0.046%, 0.047%, 0.048%, 0.049%, 0.050%, 0.051%, 0.052%, 0.053%, 0.054%, 0.055%, 0.056%, 0.057%, 0.058%, 0.059%, 0.060%, 0.061%, 0.062%, 0.063%, 0.064%, 0.065%, 0.066%, 0.067%, 0.068%, 0.069%, 0. 0.025%, 0.026%, 0.027%, 0.028%, 0.029%, 0.030%, 0.031%, 0.032%, 0.033%, 0.034%, 0.035%, 0.036%, 0.037%, 0.038%, 0.039%, 0.040%, 0.041%, 0.042%, 0.043%, 0.044%, 0.045%, 0.046%, 0.047%, 0.048%, 0.049%, 0.050%, or a range limited by any two of them.

[0101] In one embodiment, the composition may further include a pH buffer.

[0102] In one embodiment, the pH buffer comprises one or more selected from the group consisting of: phosphate, citrate.

[0103] In one embodiment, the pH buffer (e.g., sodium citrate) is present in an amount of 0.005-0.05%, such as 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.013%, 0.014%, 0.015%, 0.016%, 0.017%, 0.018%, 0.019%, 0.020%, 0.021%, 0.022%, 0.023%, 0.024%, 0.025%, 0.026%, 0.027%, 0.028%, 0.029%, 0.030%, 0.031%, 0.032%, 0.033%, 0.034%, 0.035%, 0.036%, 0.037%, 0.038%, 0.039%, 0.040%, 0.041%, 0.042%, 0.043%, 0.044%, 0.045%, 0.046%, 0.047%, 0.048%, 0.049%, 0.050%, 0.051%, 0.052%, 0.053%, 0.054%, 0.055%, 0.056%, 0.057%, 0.058%, 0.059%, 0.060%, 0.061%, 0.062%, 0.063%, 0.064%, 0.065%, 0.066%, 0.067%, 0 0.025%, 0.026%, 0.027%, 0.028%, 0.029%, 0.030%, 0.031%, 0.032%, 0.033%, 0.034%, 0.035%, 0.036%, 0.037%, 0.038%, 0.039%, 0.040%, 0.041%, 0.042%, 0.043%, 0.044%, 0.045%, 0.046%, 0.047%, 0.048%, 0.049%, 0.050%, or a range limited by any two of them.

[0104] In one embodiment, the composition may further include a pH adjuster.

[0105] In one embodiment, the pH adjuster includes one or more selected from the following: acids such as citric acid, phosphoric acid, acetic acid, and hydrochloric acid, and bases such as sodium hydroxide and potassium hydroxide.

[0106] In one embodiment, the pH adjuster is present in an amount of 0 to 0.5%, such as 0%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.2%, 0.21%, 0.22%, 0.2 3%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.3%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.4%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.5%, or a range limited by any two of them.

[0107] In one embodiment, the pH adjuster comprises citric acid, and the amount of citric acid present relative to the total weight of the composition is 0-0.1%, for example, 0%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, or a range defined by any two thereof.

[0108] In one embodiment, the pH adjuster comprises sodium hydroxide, and the amount of sodium hydroxide present relative to the total weight of the composition is 0-0.1%, for example, 0%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, or a range defined by any two thereof.

[0109] In one embodiment, the content of the pH adjuster (e.g., citric acid and / or sodium hydroxide) is such that the composition has the following pH at room temperature: 3.0-8.5, for example, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8. .2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, or a range limited by any two of them.

[0110] In one embodiment, the pharmaceutical composition can have a pH of 3.0-8.5 at room temperature, e.g., 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, or a range limited by any two thereof.

[0111] In one embodiment, the pharmaceutical composition has a pH of 3.0-7.0, preferably 3.5-6.5, preferably 4.0-6.0, preferably 4.5-5.5, such as 5.0 at room temperature.

[0112] In one embodiment, the composition comprises:

[0113] 0.5-1.5% by weight of pilocarpine nitrate;

[0114] 0.005-0.5% by weight of naphazoline and / or naphazoline hydrochloride;

[0115] 0.1-1% by weight of ketorolac tromethamine;

[0116] 0.1-1% polyoxyethylene (40) hydrogenated castor oil;

[0117] 0.5-1.5% by weight of boric acid;

[0118] 0.005-0.05% by weight of sodium citrate;

[0119] 0.005-0.05% by weight of disodium edetate;

[0120] 0-0.1% by weight of citric acid;

[0121] 0 to 0.1% by weight of sodium hydroxide; and

[0122] The balance is water for injection.

[0123] The second aspect of the present invention relates to the use of the above composition in the preparation of a medicament for treating eye diseases.

[0124] In one embodiment, the eye disease includes presbyopia, mild hyperopia, irregular astigmatism, hyperopic accommodative esotropia, and glaucoma; preferably, the eye disease is presbyopia.

[0125] As used herein, an "eye disorder" is a condition, disease or disorder that affects or involves the eye or a part or region of the eye, including the eyeball and the tissues and fluids that make up the eyeball, the muscles around the eye (such as the oblique and rectus muscles), and parts of the optic nerve in or adjacent to the eyeball. Examples of eye disorders include presbyopia and mild hyperopia, irregular astigmatism, hyperopic accommodative esotropia, and glaucoma.

[0126] The present inventors surprisingly found that when a muscarinic acetylcholine receptor M3 agonist such as a pilocarpine active ingredient is used in combination with naphazoline or a pharmaceutically acceptable salt thereof (such as hydrochloride) and ketorolac tromethamine in a specific amount, there is a synergistic effect between naphazoline hydrochloride and ketorolac tromethamine, which synergistically improves the efficacy, significantly reduces the side effects, and has good drugability. While effectively treating presbyopia, the side effects such as red eyes, eye pain, migraine and headache caused by a muscarinic acetylcholine receptor M3 agonist such as a pilocarpine active ingredient can be more significantly reduced or even eliminated. For example, by using naphazoline or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) and ketorolac tromethamine in combination, the composition of the present invention can, relative to the eye drop compositions of the prior art: achieve a better effect in treating conjunctivitis while using a lower amount of a muscarinic acetylcholine receptor M3 agonist such as a pilocarpine-type active ingredient, and / or achieve lower side effects (red eyes, eye pain, migraine, headache, etc.) while using a higher amount of a muscarinic acetylcholine receptor M3 agonist such as a pilocarpine-type active ingredient, and / or prolong the effective duration of the therapeutic effect (obtain a sustained and effective therapeutic effect over a longer period of time).

[0127] The composition of the present invention can achieve a sustained and effective presbyopia treatment effect within an ideal time, can effectively relieve the red eyes and headaches caused by pilocarpine, greatly enhances the medication compliance of elderly patients, and while solving the existing drug compatibility problem, can further reduce the irritation of the composition to the eyes of presbyopic patients after removing the antibacterial agent.

[0128] The above is only an exemplary embodiment of the present invention. It should be noted that, for those skilled in the art, improvements can be made without departing from the inventive concept of the present invention, but these all belong to the protection scope of the present invention.

[0129] Example

[0130] Test 1

[0131] The pharmaceutical solutions were prepared as shown in Table 1-1-1, and the efficacy test and irritation test were carried out.

[0132] Table 1-1-1: Ingredients of different groups

[0133]

[0134] Preparation: Prepare 1L of each sample of the example and comparative example according to the weight percentage listed in Table 4-1-1. Take sodium citrate, disodium edetate, and boric acid, add them to about 800ml of water, and stir to dissolve; then add polyoxyethylene 40 hydrogenated castor oil, and stir to dissolve; then add pilocarpine nitrate, naphazoline hydrochloride, and ketorolac tromethamine, respectively, stir to dissolve, adjust the pH to 5.0, and add water to 1L.

[0135] Test 1-1: Efficacy test

[0136] Rabbits were used for drug efficacy test, and the pupil diameter was used as an indicator to evaluate the above four preparations. 20 rabbits were randomly divided into 4 groups, and 50 μL of the test solution of Example 1, Comparative Example 1, Comparative Example 2 and Comparative Example 3 were applied to the right eyes of the test rabbits according to the groups. The pupil transverse diameter (unit: mm) was measured with an anterior segment optical coherence tomography scanner (anterior segment OCT, Domei, CASIA2) at different time points after administration, and the average diameter of each group was calculated as the pupil diameter result in the table below.

[0137] The results are as follows:

[0138] Table 1-1-2: Pupil diameter results after drug administration (mm)

[0139]

[0140]

[0141] According to the test results in Table 1-1-2, the pupil diameter reduction values ​​of Example 1 and Comparative Examples 1 to 3 after administration compared with those before administration can be calculated.

[0142] Table 1-1-3: Pupil diameter reduction value after drug administration (mm)

[0143]

[0144] Through further calculation, it can be known that compared with Comparative Example 1 using only pilocarpine nitrate, the changes in the pupil diameter reduction value after administration in Comparative Example 2 using pilocarpine nitrate and naphazoline hydrochloride, Comparative Example 3 using pilocarpine nitrate and ketorolac tromethamine, and Example 1 using pilocarpine nitrate, naphazoline hydrochloride, and ketorolac tromethamine in combination.

[0145] Table 1-1-4: Changes in pupil diameter reduction after administration compared to Comparative Example 1 (mm)

[0146]

[0147] According to the above calculation results, we can know that:

[0148] (Comparative Example 1)

[0149] In Comparative Example 1, only pilocarpine nitrate was used, wherein the pupil diameter of the rabbit eye was significantly reduced 15 minutes after administration compared with that before administration (the pupil diameter reduction value at 15 minutes reached 3.47), and then the reduction amplitude of the pupil diameter of the rabbit eye gradually decreased (the pupil diameter reduction value at 120 minutes was reduced to 2.23; the pupil diameter reduction value at 240 minutes was reduced to 1.57; the pupil diameter reduction value at 300 minutes was reduced to 1.36), and the pupil diameter of the rabbit eye was almost completely restored 5.5 hours after administration (the pupil diameter reduction value at 330 minutes was reduced to 0.19), that is, the efficacy of reducing the pupil diameter of the rabbit eye was almost completely lost 5.5 hours after administration;

[0150] (Comparative Example 2)

[0151] In Comparative Example 2, pilocarpine nitrate and naphazoline hydrochloride were used, wherein:

[0152] - 15 minutes after administration, the value of the reduction in rabbit pupil diameter was -0.35 compared to Comparative Example 1 using only pilocarpine nitrate (i.e., the efficacy of pilocarpine nitrate in reducing the rabbit pupil diameter was weakened).

[0153] - The change in the pupil diameter of rabbit eyes 2 hours after administration was -0.25 compared with Comparative Example 1 using only pilocarpine nitrate,

[0154] - The change in the pupil diameter of rabbit eyes 4 hours after administration was -0.35 compared with Comparative Example 1 using only pilocarpine nitrate,

[0155] - The change in the pupil diameter of rabbit eyes 5 hours after administration was -0.20 compared with Comparative Example 1 using only pilocarpine nitrate,

[0156] - The change in the pupil diameter of rabbits at 5.5 hours after administration was -0.03 compared with Comparative Example 1 using only pilocarpine nitrate,

[0157] - The change in the pupil diameter of rabbit eyes 6 hours after administration was -0.19 compared with Comparative Example 1 using only pilocarpine nitrate,

[0158] It can be seen that when naphazoline hydrochloride was used alone, the efficacy of pilocarpine nitrate was weakened within 5.5 hours after administration;

[0159] (Comparative Example 3)

[0160] In Comparative Example 3, pilocarpine nitrate and ketorolac tromethamine were used, wherein:

[0161] - 15 minutes after administration, the value of the reduction in rabbit pupil diameter was -0.42 compared with Comparative Example 1 using only pilocarpine nitrate (i.e., the efficacy of pilocarpine nitrate in reducing the rabbit pupil diameter was weakened).

[0162] - The change in the pupil diameter of rabbit eyes 2 hours after administration was -0.15 compared with Comparative Example 1 using only pilocarpine nitrate,

[0163] - The change in the pupil diameter reduction value of rabbit eyes 4 hours after administration was +0.33 compared with Comparative Example 1 using only pilocarpine nitrate (i.e., the efficacy of pilocarpine nitrate in reducing the pupil diameter of rabbit eyes was enhanced),

[0164] - The change in the pupil diameter of rabbit eyes 5 hours after administration was +0.08 compared with Comparative Example 1 using only pilocarpine nitrate,

[0165] - The change in the pupil diameter of rabbit eyes at 5.5 hours after administration was +1.19 compared to Comparative Example 1 using only pilocarpine nitrate,

[0166] - The change in the pupil diameter of rabbit eyes 6 hours after administration was +1.02 compared with Comparative Example 1 using only pilocarpine nitrate,

[0167] It can be seen that when ketorolac tromethamine is used alone, the efficacy of pilocarpine nitrate is weakened within 2 hours after administration, and the efficacy of pilocarpine nitrate is enhanced to a certain extent within 4 to 6 hours after administration;

[0168] (Example 1)

[0169] In Example 1, pilocarpine nitrate, naphazoline hydrochloride, and ketorolac tromethamine were used in combination, wherein:

[0170] - 15 minutes after administration, the change in the pupil diameter of rabbits was -0.18 compared with Comparative Example 1 using only pilocarpine nitrate, which was significantly better than the sum of the effects of naphazoline hydrochloride alone and ketorolac tromethamine alone (Comparative Example 2 + Comparative Example 3), i.e. -0.77.

[0171] - The change in the value of the reduction in the pupil diameter of the rabbit eye 2 hours after administration was +0.04 compared with Comparative Example 1 using only pilocarpine nitrate (i.e., the efficacy of pilocarpine nitrate in reducing the pupil diameter of the rabbit eye was enhanced), which was significantly better than the sum of the effects of naphazoline hydrochloride used alone and ketorolac tromethamine used alone (Comparative Example 2 + Comparative Example 3), i.e., -0.40.

[0172] - The change in the pupil diameter of rabbits 4 hours after administration was +0.44 compared with Comparative Example 1 using only pilocarpine nitrate, which was significantly better than the sum of the effects of naphazoline hydrochloride alone and ketorolac tromethamine alone (Comparative Example 2 + Comparative Example 3), i.e. -0.02,

[0173] - The change in the pupil diameter of rabbits 5 hours after administration was +0.38 compared with Comparative Example 1 using only pilocarpine nitrate, which was significantly better than the sum of the effects of naphazoline hydrochloride alone and ketorolac tromethamine alone (Comparative Example 2 + Comparative Example 3), i.e. -0.12,

[0174] - 5.5 hours after administration, the change in the pupil diameter of rabbits was +1.33 compared with Comparative Example 1 using only pilocarpine nitrate, which was significantly better than the sum of the effects of naphazoline hydrochloride alone and ketorolac tromethamine alone (Comparative Example 2 + Comparative Example 3), i.e., +1.16.

[0175] - The change in the pupil diameter of rabbits 6 hours after administration was +1.28 compared with Comparative Example 1 using only pilocarpine nitrate, which was superior to the sum of the effects of naphazoline hydrochloride alone and ketorolac tromethamine alone (Comparative Example 2 + Comparative Example 3), i.e., +1.21.

[0176] It can be seen that the combined use of naphazoline hydrochloride and ketorolac tromethamine can significantly enhance the efficacy of pilocarpine nitrate, and the enhanced effect is significantly better than the sum of the effects of naphazoline hydrochloride alone and ketorolac tromethamine alone within 6 hours after administration.

[0177] The above results show that the combined use of naphazoline hydrochloride and ketorolac tromethamine has an obvious synergistic effect in enhancing the efficacy.

[0178] Test 1-2: Conjunctival hyperemia degree comparison test

[0179] The efficacy test was conducted on rabbits, and the above four preparations were evaluated with the degree of conjunctival congestion as an index. 20 rabbits were randomly divided into 4 groups, and 1 drop of the test solution of Example 1, Comparative Example 1, Comparative Example 2 and Comparative Example 3 was applied to the right eyes of the test rabbits according to the groups. The degree of conjunctival congestion of the administered eyes was observed at different time points after administration, and the evaluation criteria for the degree of congestion are shown in the following table:

[0180] Table 1-2-1 Degree of congestion

[0181]

[0182] The results are as follows:

[0183] Table 1-2-2: Example 1 Group

[0184]

[0185] Table 1-2-3: Comparative Example 1

[0186]

[0187] Table 1-2-4: Comparative Example 2

[0188]

[0189]

[0190] Table 1-2-5: Comparative Example 3

[0191]

[0192] According to the above test results, we can know that:

[0193] In Comparative Example 1, only pilocarpine nitrate was used, and 5 animals showed mild to moderate conjunctival congestion 1 minute after administration, and the duration lasted up to 30 minutes;

[0194] In Comparative Example 2, pilocarpine nitrate and naphazoline hydrochloride were used, wherein:

[0195] - The average value of conjunctival hyperemia at 1 minute after administration was reduced by 0.8 (0.6-1.4) compared with Comparative Example 1 in which only pilocarpine nitrate was used.

[0196] - The average value of conjunctival hyperemia at 2 minutes after administration was reduced by 1.0 (0.6-1.6) compared with Comparative Example 1 in which only pilocarpine nitrate was used,

[0197] - The mean value of the conjunctival hyperemia at 5 minutes after administration was reduced by 1.0 (0.2-1.2) compared with Comparative Example 1 using only pilocarpine nitrate, and

[0198] - Conjunctival hyperemia completely disappeared 10 minutes after administration.

[0199] It can be seen that the use of naphazoline hydrochloride alone can reduce the side effects of pilocarpine nitrate to a certain extent;

[0200] In Comparative Example 3, pilocarpine nitrate and ketorolac tromethamine were used, wherein:

[0201] - The average value of conjunctival hyperemia at 1 minute after administration was reduced by 0.4 (1.0-1.4) compared with Comparative Example 1 in which only pilocarpine nitrate was used,

[0202] - The average value of conjunctival hyperemia at 2 minutes after administration was reduced by 0.8 (0.8-1.6) compared with Comparative Example 1 in which only pilocarpine nitrate was used.

[0203] - The mean value of the degree of conjunctival hyperemia 5 minutes after administration was reduced by 0.6 (0.6-1.2) compared with Comparative Example 1 using only pilocarpine nitrate, and

[0204] - Conjunctival hyperemia completely disappeared 10 minutes after administration.

[0205] It can be seen that the use of ketorolac tromethamine alone can reduce the side effects of pilocarpine nitrate to a certain extent;

[0206] In Example 1, pilocarpine nitrate, naphazoline hydrochloride, and ketorolac tromethamine were used in combination, wherein:

[0207] - The average value of conjunctival hyperemia at 1 minute after administration was reduced by 1.2 (0.2-1.4) compared with Comparative Example 1 in which only pilocarpine nitrate was used.

[0208] - The mean value of the conjunctival hyperemia at 2 minutes after administration was reduced by 1.4 (0.2-1.6) compared with Comparative Example 1 in which only pilocarpine nitrate was used, and

[0209] - Conjunctival hyperemia completely disappears within 5 minutes after administration, and

[0210] - After administration, only mild conjunctival hyperemia (severity: 1) occurred, and moderate conjunctival hyperemia (severity: 2) did not occur, which was significantly better than any of Comparative Examples 2 and 3.

[0211] - The degree of conjunctival hyperemia at each time point was lower than that of Comparative Examples 2 and 3.

[0212] - The number of animals with conjunctival hyperemia was lower than that of Comparative Examples 2 and 3.

[0213] It can be seen that by using naphazoline hydrochloride and ketorolac tromethamine in combination, the side effects of pilocarpine nitrate can be significantly reduced while the efficacy of pilocarpine nitrate is synergistically enhanced, and the enhancing effect is better than the effect of using naphazoline hydrochloride alone and the effect of using ketorolac tromethamine alone, and the effect of reducing side effects is better than the effect of using naphazoline hydrochloride alone and the effect of using ketorolac tromethamine alone.

[0214] The above results show that the combined use of naphazoline hydrochloride and ketorolac tromethamine can enhance the efficacy of pilocarpine nitrate and significantly reduce the side effects caused by pilocarpine nitrate.

[0215] Test 1-3: Pain comparison test:

[0216] In order to actually understand the pain caused by the above four preparations, we conducted an experiential test on humans. 20 people were randomly divided into 4 groups, and one drop of the test solution of Example 1, Comparative Example 1, Comparative Example 2, and Comparative Example 3 was applied to the right eye of the subjects according to the groups. The pain level was observed at different time points after administration, and the pain level evaluation criteria are shown in the following table:

[0217] Table 1-3-1 Pain Degree

[0218] Severity Description

[0219] 0 Normal: No pain.

[0220] 1 Mild: Mild pain, usually intermittent, does not interfere with eye use.

[0221] 2 Moderate: Persistent pain that interferes with normal eye use and requires drug intervention.

[0222] 3 Severe: Persistent severe pain that is unresponsive to drug intervention.

[0223] The results are as follows:

[0224] Table 1-3-2: Example 1 Group

[0225]

[0226] Table 1-3-3: Comparative Example 1

[0227]

[0228] Table 1-3-4: Comparative Example 2

[0229]

[0230] Table 1-3-5: Comparative Example 3

[0231]

[0232] According to the above test results, we can know that:

[0233] In Comparative Example 1, only pilocarpine nitrate was used, and 5 subjects experienced mild to moderate pain 1 minute after administration, which lasted for 60 minutes;

[0234] In Comparative Example 2, pilocarpine nitrate and naphazoline hydrochloride were used, wherein:

[0235] - The average value of pain level 1 minute after administration was reduced by 0.4 (1.2-1.6) compared with Comparative Example 1 in which only pilocarpine nitrate was used,

[0236] - The average value of pain intensity 2 minutes after administration was reduced by 0.6 (1.0-1.6) compared with Comparative Example 1 in which only pilocarpine nitrate was used,

[0237] - The average value of pain level 5 minutes after administration was reduced by 0.4 (0.8-1.2) compared with Comparative Example 1 using only pilocarpine nitrate,

[0238] The average value of pain level 10 minutes after administration was reduced by 0.4 (0.4-0.8) compared with Comparative Example 1 in which only pilocarpine nitrate was used.

[0239] The average value of pain level at 30 minutes after administration was reduced by 0.4 (0.2-0.6) compared with Comparative Example 1 using only pilocarpine nitrate, and

[0240] - The pain completely disappeared 30 minutes after administration.

[0241] It can be seen that the use of naphazoline hydrochloride alone can reduce the side effects of pilocarpine nitrate to a certain extent;

[0242] In Comparative Example 3, pilocarpine nitrate and ketorolac tromethamine were used, wherein:

[0243] - The average value of pain intensity 1 minute after administration was reduced by 1.2 (0.4-1.6) compared with Comparative Example 1 in which only pilocarpine nitrate was used,

[0244] - The average value of pain intensity 2 minutes after administration was reduced by 1.2 (0.4-1.6) compared with Comparative Example 1 in which only pilocarpine nitrate was used,

[0245] - The average value of pain level 5 minutes after administration was reduced by 0.8 (0.4-1.2) compared with Comparative Example 1 using only pilocarpine nitrate,

[0246] The average value of pain level 10 minutes after administration was reduced by 0.6 (0.2-0.8) compared with Comparative Example 1 using only pilocarpine nitrate, and

[0247] - The pain completely disappeared within 10 minutes after administration.

[0248] It can be seen that the use of ketorolac tromethamine alone can reduce the side effects of pilocarpine nitrate to a certain extent;

[0249] In Example 1, pilocarpine nitrate, naphazoline hydrochloride, and ketorolac tromethamine were used in combination, wherein:

[0250] - The average value of pain intensity 1 minute after administration was reduced by 1.4 (0.2-1.6) compared with Comparative Example 1 in which only pilocarpine nitrate was used,

[0251] - The average value of pain intensity 2 minutes after administration was reduced by 1.4 (0.2-1.6) compared with Comparative Example 1 using only pilocarpine nitrate, and

[0252] - The pain disappears completely within 5 minutes after administration, and

[0253] - After administration, only mild pain (severity level 1) occurred, and moderate pain (severity level 2) did not occur, which was significantly better than any of Comparative Examples 2 and 3.

[0254] - The pain level at each time point was lower than that of Comparative Examples 2 and 3.

[0255] - The number of people experiencing pain was lower than that of Comparative Examples 2 and 3.

[0256] It can be seen that by using naphazoline hydrochloride and ketorolac tromethamine in combination, the side effects of pilocarpine nitrate can be significantly reduced while the efficacy of pilocarpine nitrate is synergistically enhanced, and the enhancing effect is better than the effect of using naphazoline hydrochloride alone and the effect of using ketorolac tromethamine alone, and the effect of reducing side effects is better than the effect of using naphazoline hydrochloride alone and the effect of using ketorolac tromethamine alone.

[0257] The above results show that the combined use of naphazoline hydrochloride and ketorolac tromethamine can enhance the efficacy of pilocarpine nitrate and significantly reduce the side effects caused by pilocarpine nitrate.

[0258] Test 2

[0259] As shown in Table 2-1-1, the pharmaceutical solution was prepared in the same manner as in Test 1, and the efficacy test was performed.

[0260] Table 2-1-1: Examples of different pilocarpine concentrations

[0261]

[0262]

[0263] Test 2-1: Efficacy test

[0264] The above five preparations were evaluated by using rabbits for efficacy test with pupil diameter as an index. Thirty rabbits were randomly divided into five groups, and one drop of each test solution of Examples 1 to 5 was applied to the right eyes of the test rabbits according to the groups. The transverse pupil diameter was measured by an anterior segment optical coherence tomography (OCT) scanner at different time points after administration.

[0265] The results are as follows:

[0266] Table 2-1-2: Pupil diameter results after drug administration (mm)

[0267]

[0268] The pupil diameter reduction value after drug administration was further calculated compared with that before drug administration.

[0269] Table 2-1-3: Pupil diameter reduction after drug administration (mm)

[0270]

[0271] According to the above test results, we can know that:

[0272] In Example 1, 1 wt% of pilocarpine nitrate, 0.05 wt% of naphazoline hydrochloride and 0.5 wt% of ketorolac tromethamine were used, and the pupil diameter of the rabbit eye was significantly reduced 15 minutes after administration, and then the pupil diameter slowly recovered, and the drug effect was still there 6 hours after administration;

[0273] In Example 2, naphazoline hydrochloride and ketorolac tromethamine were used at the same concentrations as in Example 1, but pilocarpine nitrate was reduced to 0.5%. The change in rabbit eye diameter after administration was substantially the same as in Example 1.

[0274] In Example 3, naphazoline hydrochloride and ketorolac tromethamine were used at the same concentrations as in Example 1, but the pilocarpine nitrate was reduced to 0.1%. After administration, the reduction in the pupil diameter of the rabbit eye decreased compared to that in Example 1, and the pupil diameter of the rabbit eye was completely restored after 4 hours.

[0275] In Example 4, naphazoline hydrochloride and ketorolac tromethamine were used at the same concentrations as in Example 1, but the pilocarpine nitrate was increased to 1.5%. The change in rabbit eye diameter after administration was substantially the same as in Example 1;

[0276] In Example 5, naphazoline hydrochloride and ketorolac tromethamine were used at the same concentrations as in Example 1, but the pilocarpine nitrate was increased to 3%. The diameter of the rabbit eye remained extremely reduced 6 hours after administration.

[0277] The above test results show that: when 0.5-1.5% pilocarpine nitrate is used, the desired clinical effect can be achieved, and the synergistic effect of naphazoline hydrochloride and ketorolac tromethamine in terms of drug efficacy is shown. In addition, when 0.1% pilocarpine nitrate is used, the requirements for clinical use cannot be met, and when 3% pilocarpine nitrate is used, the requirements for clinical use are also not met. Therefore, in the present invention, it is preferred to use pilocarpine nitrate in a concentration range of 0.5-1.5%.

[0278] Test 2-2:

[0279] As shown in Table 2-2-1, the liquid medicine was prepared in the same manner as in Test 1-1, and the irritation test was carried out.

[0280] Table 2-2-1: Examples of different naphazoline concentrations and ketorolac tromethamine concentrations

[0281]

[0282]

[0283] The irritation test was conducted on rabbits, and the above 9 preparations were evaluated with the degree of conjunctival congestion as an index. 45 rabbits were randomly divided into 9 groups, and 1 drop of each test solution of Examples 1, 6 to 13 was applied to the right eyes of the test rabbits according to the groups. The degree of conjunctival congestion of the administered eyes was observed at different time points after administration, and the evaluation criteria for the degree of congestion are shown in Table 1-2-2.

[0284] The results are as follows:

[0285] Table 2-2-2: Example 1 Group

[0286]

[0287] Table 2-2-3: Example 6 Group

[0288]

[0289] Table 2-2-4: Example 7 Group

[0290]

[0291]

[0292] Table 2-2-5: Example 8 Group

[0293]

[0294] Table 2-2-6: Example 9 Group

[0295]

[0296] Table 2-2-7: Example 10 Group

[0297]

[0298] Table 2-2-8: Example 11 Group

[0299]

[0300] Table 2-2-9: Example 12 Group

[0301]

[0302] Table 2-2-10: Example 13 Group

[0303]

[0304] According to the above test results, we can know that:

[0305] In Example 1, 1 wt% pilocarpine nitrate, 0.05 wt% naphazoline hydrochloride, and 0.5 wt% ketorolac tromethamine were used, and 2 of the 5 animals showed mild conjunctival hyperemia 1 min after administration, which disappeared 2 min later. This test result was consistent with the results in Test 1-2.

[0306] In Example 6, the same concentrations of pilocarpine nitrate and ketorolac tromethamine as in Example 1 were used, but the concentration of naphazoline hydrochloride was reduced to 0.005% by weight, wherein 3 out of 5 animals experienced mild conjunctival hyperemia after administration, which disappeared after 2 minutes. The test results were substantially the same as those in Example 1;

[0307] In Example 7, the same concentrations of pilocarpine nitrate and ketorolac tromethamine as in Example 1 were used, but the concentration of naphazoline hydrochloride was reduced to 0.0005% by weight, and 4 out of 5 animals experienced mild to moderate conjunctival hyperemia after administration, which lasted for 30 minutes. This test result was significantly inferior to that of Example 1;

[0308] In Example 8, the same concentrations of pilocarpine nitrate and ketorolac tromethamine as in Example 1 were used, but the concentration of naphazoline hydrochloride was increased to 0.5% by weight, and 2 of the 5 animals showed mild to moderate conjunctival hyperemia, which disappeared after 2 minutes. The test results were substantially the same as those in Example 1.

[0309] In Example 9, the same concentrations of pilocarpine nitrate and ketorolac tromethamine as in Example 1 were used, but the concentration of naphazoline hydrochloride was increased to 5% by weight, and 3 of the 5 animals showed mild to moderate conjunctival hyperemia, which disappeared after 2 minutes. This test result was inferior to that of Example 1;

[0310] In Example 10, the same concentrations of pilocarpine nitrate and naphazoline hydrochloride as in Example 1 were used, but the ketorolac tromethamine was reduced to 0.1% by weight, wherein 2 of the 5 animals experienced mild conjunctival hyperemia after administration, which disappeared after 2 minutes. The test results were substantially the same as those in Example 1;

[0311] In Example 11, the same concentrations of pilocarpine nitrate and naphazoline hydrochloride as in Example 1 were used, but the ketorolac tromethamine was reduced to 0.01% by weight, wherein 4 out of 5 animals experienced mild conjunctival hyperemia after administration, and the duration of the phenomenon reached more than 10 minutes, and the test results were inferior to those of Example 1;

[0312] In Example 12, the same concentrations of pilocarpine nitrate and naphazoline hydrochloride as in Example 1 were used, but the ketorolac tromethamine was increased to 1% by weight, wherein 3 out of 5 animals developed mild conjunctival hyperemia after administration, which disappeared after 2 minutes. The test results were substantially the same as those in Example 6;

[0313] In Example 13, the same concentrations of pilocarpine nitrate and naphazoline hydrochloride as in Example 1 were used, but the ketorolac tromethamine was increased to 10% by weight, wherein 5 animals all experienced mild to moderate conjunctival congestion after administration, and the duration of the phenomenon reached more than 30 minutes. The test results were inferior to those of Example 1.

[0314] The above test results show that when naphazoline hydrochloride in a concentration range of 0.005 to 0.5% is used in combination with pilocarpine nitrate and ketorolac tromethamine, a good irritation reduction effect can be achieved. In addition, when 0.0005% by weight of naphazoline hydrochloride is used, the irritation reduction effect is insufficient. In addition, when 5% by weight of naphazoline hydrochloride is used, the irritation reduction effect is weakened. Therefore, in the present invention, naphazoline hydrochloride in a concentration range of 0.005 to 0.5% is preferably used.

[0315] In addition, the above test results also show that: when 0.1-1% concentration of ketorolac tromethamine is used in combination with pilocarpine nitrate and naphazoline hydrochloride, a good irritation reduction effect can be achieved. In addition, when 0.01% by weight of ketorolac tromethamine is used, the irritation reduction effect is insufficient. In addition, when 10% by weight of ketorolac tromethamine is used, the irritation reduction effect is insufficient. Therefore, in the present invention, it is preferred to use 0.1-1% concentration of ketorolac tromethamine.

[0316] Test 3

[0317] As shown in Table 3-1, other α receptor agonists and nonsteroidal anti-inflammatory drugs (NSAIDs) were used to prepare pharmaceutical solutions in the same manner as in Test 1-1, and the efficacy test and irritation test were performed.

[0318] Table 3-1: Examples of use of other α-agonists and nonsteroidal anti-inflammatory drugs

[0319]

[0320]

[0321] It should be noted that, in the above examples, drug precipitation occurred in Comparative Examples 4 and 8 during preparation, that is, the drugability of diclofenac and pilocarpine nitrate was poor, and therefore Comparative Examples 4 and 8 were not prepared into final preparations.

[0322] The efficacy and irritation tests were conducted on rabbits to evaluate the six preparations obtained in Example 1, Comparative Examples 5 to 7, and Comparative Examples 9 to 10. Thirty rabbits were randomly divided into six groups, and one drop of the test solution of Example 1, Comparative Examples 5 to 7, and Comparative Examples 9 to 10 was applied to the right eyes of the test rabbits according to the groups.

[0323] Test 3-1: Efficacy test

[0324] Taking the pupil diameter of the drug-treated rabbit eyes as an indicator, the transverse pupil diameter was measured using anterior segment optical coherence tomography (anterior segment OCT) at different time points after drug administration.

[0325] The results are as follows:

[0326] Table 3-2: Pupil diameter results after drug administration (mm)

[0327]

[0328] According to the above test results, we can know that:

[0329] In Example 1, 1 wt% of pilocarpine nitrate, 0.05 wt% of naphazoline hydrochloride, and 0.5 wt% of ketorolac tromethamine were used. The pupil diameter of the rabbit eye was significantly reduced 15 minutes after administration, and then the pupil diameter slowly recovered. The drug effect was still there 6 hours after administration. The test results were consistent with those of Test 1-1.

[0330] Comparative Example 5 used the same concentrations of pilocarpine nitrate and naphazoline hydrochloride as in Example 1, and used 0.5% by weight of pranoprofen instead of ketorolac tromethamine. The test results of the change in rabbit eye diameter after administration were significantly inferior to those of Example 1.

[0331] Comparative Example 6 used the same concentration of pilocarpine nitrate as in Example 1, and used 0.05% by weight of oxymetazoline hydrochloride instead of naphazoline hydrochloride, and used 0.5% by weight of pranoprofen instead of ketorolac tromethamine. The test results of the change in rabbit eye diameter after administration were significantly inferior to those of Example 1.

[0332] Comparative Example 7 used the same concentrations of pilocarpine nitrate and naphazoline hydrochloride as in Example 1, and used 0.5 wt % of pranoprofen instead of ketorolac tromethamine. The test results of the change in rabbit eye diameter after administration were significantly inferior to those of Example 1.

[0333] Comparative Examples 9 and 10 used other M3 receptor agonists, and the results showed that none of them could achieve the effect achieved by pilocarpine nitrate.

[0334] The above pharmacodynamic test results show that only when ketorolac tromethamine and naphazoline hydrochloride are used in combination, a synergistic effect can be produced in terms of drug efficacy. When other α receptor agonists or non-steroidal anti-inflammatory drugs are used, the synergistic effect cannot be produced, or even the preparation cannot be made into a drug.

[0335] Test 3-2: Irritation test

[0336] Taking the degree of conjunctival congestion as an indicator, the degree of conjunctival congestion of the administered eye was observed at different time points after administration. The evaluation criteria for the degree of congestion are shown in Table 1-2-1.

[0337] The results are as follows:

[0338] Table 3-3: Example 1 Group

[0339]

[0340] Table 3-4: Comparative Example 5

[0341]

[0342]

[0343] Table 3-5: Comparative Example 6

[0344]

[0345] Table 3-6: Comparative Example 7

[0346]

[0347] Table 3-7: Comparative Example 9

[0348]

[0349] Table 3-8: Comparative Example 10

[0350]

[0351] According to the above test results, we can know that:

[0352] In Example 1, pilocarpine nitrate, naphazoline hydrochloride, and ketorolac tromethamine were used in combination, and one of the five animals developed mild conjunctival hyperemia 1 minute after administration, which disappeared 2 minutes later. This test result was consistent with that of Experiment 1-2;

[0353] In Comparative Example 5, pilocarpine nitrate and naphazoline hydrochloride were used, and pranoprofen was used instead of ketorolac tromethamine. Four of the five animals developed mild conjunctival congestion after administration, which lasted for 30 minutes. This test result was significantly inferior to that of Example 1.

[0354] In Comparative Example 6, pilocarpine nitrate was used, and oxymetazoline hydrochloride was used instead of naphazoline hydrochloride, and pranoprofen was used instead of ketorolac tromethamine. Three of the five animals developed mild to moderate congestion after administration, which lasted for 30 minutes. This test result was significantly inferior to that of Example 1.

[0355] Comparative Example 7 used pilocarpine nitrate and naphazoline hydrochloride, and 0.5% by weight of pranoprofen was used instead of ketorolac tromethamine. Three of the five animals developed mild congestion after administration, which lasted for 30 minutes. This test result was significantly inferior to that of Example 1.

[0356] Comparative Examples 9 and 10 used other M3 receptor agonists instead of pilocarpine nitrate. The results showed that 4 out of 5 animals in each of the two groups experienced mild to moderate congestion after administration, which lasted for 30 minutes. This test result was significantly inferior to that of Example 1.

[0357] The above irritation test results show that only when naphazoline hydrochloride and ketorolac tromethamine are used in combination, a synergistic effect can be produced to minimize the irritation caused by pilocarpine nitrate, and the optimal side effect reduction effect of pilocarpine nitrate is achieved. In addition, when other α receptor agonists such as oxymetazoline hydrochloride or other non-steroidal anti-inflammatory drugs such as diclofenac and pranoprofen are used, the side effect reduction effect of pilocarpine nitrate is obviously insufficient, that is, no synergistic effect can be produced, or even no preparation can be made into a medicine.

[0358] Test 4

[0359] Table 4-1: Examples of using other muscarinic acetylcholine receptor M3 agonists

[0360]

[0361] As shown in Table 4-1, other muscarinic acetylcholine receptor M3 agonists were used to prepare pharmaceutical solutions in the same manner as in Test 1-1, and the efficacy test and irritation test were performed.

[0362] In addition, from the viewpoint of using the same molar number of pilocarpine, the case of using 1.25% of pilocarpine hydrochloride and the case of using 1.38% of pilocarpine nitrate is equivalent to the case of using 1.1% of pilocarpine.

[0363] When conducting the efficacy test and the irritation test, 20 rabbits were randomly divided into 4 groups, and one drop of the test solution of Examples 14 to 16 was applied to the right eyes of the test rabbits according to the groups.

[0364] Test 4-1: Efficacy test

[0365] The pupil diameter was used as an indicator for pharmacodynamic verification. The transverse pupil diameter was measured using anterior segment optical coherence tomography (OCT) at different time points after administration.

[0366] Compared with before administration, the transverse diameter of pupils decreased after administration, and the results were as follows:

[0367] Table 4-2: Pupil diameter reduction results after drug administration (mm)

[0368]

[0369]

[0370] Test 4-2: Irritation test

[0371] The irritation was verified by taking the degree of conjunctival congestion as an indicator. The degree of conjunctival congestion of the administered eye was observed at different time points after administration. The evaluation criteria for the degree of congestion are shown in Table 1-2-2.

[0372] The results are as follows:

[0373] Table 4-3: Example 14 Group

[0374]

[0375] Table 4-4: Example 15 Group

[0376]

[0377] Table 4-5: Example 16 Group

[0378]

[0379] Table 4-6: Example 17 Group

[0380]

[0381] Table 4-7: Example 18 Group

[0382]

[0383] The test results of Examples 14-16 above show that when the same molar number of pilocarpine is used in the present invention, the technical effect of the present invention can be achieved when the components of the optional concentrations are used within the specific concentration ranges of naphazoline hydrochloride (%) and ketorolac tromethamine (%).

[0384] The test results of Examples 16 to 18 above show that when other pharmaceutically acceptable salts of pilocarpine are used instead of pilocarpine nitrate, the technical effects of the present invention can also be achieved. When pilocarpine nitrate is used, the pharmacodynamic effect can be superior to that of other salts and the same safety can be achieved.

Claims

1. A composition comprising, relative to the total weight of the composition: 0.5-1.5% by weight of a muscarinic acetylcholine receptor M3 agonist, wherein the muscarinic acetylcholine receptor M3 agonist is pilocarpine, pilocarpine hydrochloride, pilocarpine nitrate, or a combination thereof; 0.005 to 0.5% by weight of naphazoline hydrochloride; and 0.1~1% by weight of ketorolac tromethamine.

2. The composition of claim 1, wherein the composition is an ophthalmic preparation.

3. The composition according to claim 1 or 2, wherein the composition is eye drops or eye sprays.

4. The composition of claim 1 or 2, wherein the muscarinic acetylcholine receptor M3 agonist is pilocarpine nitrate.

5. The composition of claim 1 or 2, wherein the composition comprises water as a liquid carrier.

6. The composition of claim 1 or 2, wherein the composition comprises water for injection as a liquid carrier.

7. The composition of claim 1 or 2, wherein the composition does not include a bacteriostatic agent.

8. The composition of claim 1 or 2, wherein the composition does not include an alpha receptor agonist having an imidazoline group other than naphazoline hydrochloride.

9. The composition of claim 1 or 2, wherein the composition does not include an alpha receptor agonist other than naphazoline hydrochloride.

10. The composition of claim 1 or 2, wherein the composition does not comprise other active pharmaceutical ingredients other than the muscarinic acetylcholine receptor M3 agonist, naphazoline hydrochloride, and ketorolac tromethamine.

11. The composition of claim 1 or 2, wherein the composition does not include sodium chloride.

12. The composition of claim 1 or 2, wherein the composition has a pH of 3.0-8.5 at room temperature.

13. The composition of claim 1 or 2, wherein the composition has a pH of 4.0-6.0 at room temperature.

14. The composition of claim 1 or 2, wherein the composition has a pH of 4.5-5.5 at room temperature.

15. The composition of claim 1 or 2, wherein the composition further comprises an osmotic pressure regulator.

16. The composition of claim 15, wherein the amount of the osmotic pressure regulator relative to the total weight of the composition is 0.1-2.0%.

17. The composition of claim 15, wherein the osmotic pressure regulator comprises one or more selected from the group consisting of propylene glycol, glycerol, sodium chloride, glucose, boric acid, and borax.

18. The composition of claim 1 or 2, wherein the composition further comprises boric acid.

19. The composition of claim 1 or 2, wherein the composition further comprises: The amount of boric acid is 0.5-1.5% by weight relative to the total weight of the composition.

20. The composition of claim 1 or 2, wherein the composition further comprises a surfactant.

21. The composition of claim 20, wherein the surfactant is present in an amount of 0.1 to 1% by weight relative to the total weight of the composition.

22. The composition of claim 20, wherein the surfactant comprises one or more selected from the group consisting of polyoxyethylene (20) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polysorbate 80, Span, poloxamer, propylene glycol, tyloxapol, and nonoxynol ether.

23. The composition of claim 20, wherein the surfactant is polyoxyethylene (40) hydrogenated castor oil.

24. The composition of claim 1 or 2, wherein the composition further comprises a stabilizer.

25. The composition of claim 24, wherein the stabilizer comprises one or more selected from the group consisting of disodium edetate, EDTA, sodium bisulfite.

26. The composition of claim 1 or 2, wherein the composition further comprises: 0.005-0.05% by weight of sodium citrate relative to the total weight of the composition, and / or 0.005-0.05% by weight of disodium edetate relative to the total weight of the composition.

27. The composition of claim 1 or 2, wherein the composition further comprises a pH adjusting agent.

28. The composition of claim 27, wherein the pH adjuster comprises one or more selected from the group consisting of citric acid, phosphoric acid, acetic acid, hydrochloric acid, sodium hydroxide, and potassium hydroxide.

29. The composition of claim 1 or 2, wherein the composition further comprises: 0-0.1% by weight of citric acid relative to the total weight of the composition and / or 0-0.1% by weight of sodium hydroxide relative to the total weight of the composition.

30. The composition of claim 1 or 2, wherein the composition comprises: 0.5-1.5% by weight of pilocarpine nitrate; 0.005-0.5% by weight of naphazoline hydrochloride; 0.1-1% by weight of ketorolac tromethamine; 0.5-1.5% by weight of boric acid; 0.005-0.05% by weight of sodium citrate; 0.005-0.05% by weight of disodium edetate; 0.1-1% by weight of polyoxyethylene (40) hydrogenated castor oil; 0-0.1% by weight of citric acid; 0-0.1% by weight of sodium hydroxide; and The balance is water for injection.

31. Use of the composition according to any one of claims 1 to 30 in the preparation of a medicament for treating presbyopia.

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