Ophthalmic pharmaceutical composition, application and preparation thereof

Abstract

The present invention relates to an ophthalmic pharmaceutical composition comprising pilocarpine phenylacetate or pilocarpine phenylacetic acid derivative salt and an alpha receptor agonist or a pharmaceutically acceptable salt thereof. The pharmaceutical composition can effectively prolong the drug action time, the overall action effect is smoother and more stable, the eye hyperemia and redness phenomena are effectively improved, and the administration irritation is reduced.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical compositions, and in particular to ophthalmic pharmaceutical compositions, uses and preparations thereof. Background Art

[0002] The pupil is an important window to the eye, responsible for regulating the brightness of light transmission. Light passes through the lens and enters the retina at the back of the eye. The size of the pupil diameter is affected by many factors at different times in this process. With age, usually from 40 to 65 years old, there is a loss of accommodation function, which causes patients to need more light to read, squint to see close objects, and hold reading materials farther away. These are some of the first signs of presbyopia. The importance of pupil size and the limitations of human anatomy have inspired people to pay attention to the various methods, surgeries and drug options for correcting presbyopia.

[0003] Pupil size is influenced by both parasympathetic (constriction) and sympathetic (dilation) pathways. The pupil is controlled by two sets of muscles that function in antagonistic ways - when the pupillary sphincter contracts, the pupil constricts; when the pupillary dilator contracts, the pupil dilates. Pupillary responses at close range are thought to contribute to increased depth of field for near vision, with a smaller pupil providing a wider range than a larger pupil. Pupillary responses involve both reflexive and voluntary movements, and the size of a patient's pupil affects the level of chromatic and spherical aberration experienced, ultimately affecting subjective visual perception.

[0004] Pupil size is an important consideration when choosing a treatment option for presbyopia, including multifocal contact lenses, refractive surgery, and / or medication.

[0005] Typically, miotics work by contracting the ciliary muscle, which shrinks the trabecular meshwork, increasing aqueous humor outflow and reducing intraocular pressure. Miotic eye drops act on the pupillary sphincter, causing the pupil to constrict, creating a pinhole effect that improves depth of field without accommodative distance blur.

[0006] In November 2021, the U.S. Food and Drug Administration (FDA) approved the ophthalmic drug Vuity (mydriatic drug, pilocarpine HCl, 1.25% eye drops) developed by Allergan, a subsidiary of Abbvie, for the treatment of presbyopia. This is the world's first topical eye drops for presbyopia. As an M-cholinergic receptor agonist, it is dropped into both eyes once a day for less than 8 hours, which cannot meet the daily eye use time requirements. Patients treated with Vuity have improved near and medium-distance vision, and long-distance vision is not affected.

[0007] However, as the first presbyopia medication, Vuity's duration of action and comfort of use need to be improved. Summary of the invention

[0008] In view of the problems existing in the prior art, the present invention provides an ophthalmic drug composition, which can prolong the miosis effect time of the eye, reduce the congestion of the eye, and effectively improve the irritation of drug administration.

[0009] The purpose of the present invention is achieved through the following technical solutions:

[0010] An ophthalmic pharmaceutical composition comprising pilocarpine phenylacetate or a derivative salt thereof as shown in the following formula (I); and an alpha receptor agonist or a pharmaceutically acceptable salt thereof;

[0011]

[0012] Wherein R1, R2, R3, R4, R5 are the same or different and are independently selected from hydrogen, C 1-6 Alkyl, halogen, cyano, -COOR', -NR'R", R', R" are the same or different, each independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-10 membered heterocyclyl;

[0013] Wherein Ra and Rb are the same or different and are independently selected from hydrogen, C 1-6 Alkyl, halogen, cyano, C 3-10 Cycloalkyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-10 membered heterocyclyl;

[0014] The C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-10 membered heterocyclyl are optionally substituted by one, two or more of the following groups: oxo, thioxo, halogen, cyano, -NR'R", -COOH, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 Cycloalkyl, C 6-14 Aryl, 5-14 membered heteroaryl.

[0015] In some embodiments, R1, R2, R3, R4, and R5 are the same or different and are independently selected from hydrogen, C 1-6 Alkyl, halogen, -COOR', R" is independently selected from H, C 1-6 alkyl.

[0016] In some embodiments, R1, R2, R3, R4, and R5 are the same or different, and are independently selected from hydrogen, methyl, ethyl, isopropyl, chlorine, fluorine, and bromine.

[0017] In some embodiments, Ra and Rb are the same or different and are independently selected from hydrogen, C 1-6 Alkyl, halogen, cyano, preferably hydrogen, C 1-6 alkyl.

[0018] In some embodiments, R1, R2, R3, R4, and R5 are the same or different, and at least 2 of them are selected from hydrogen, preferably 3 or 4 are selected from hydrogen.

[0019] In some embodiments, the compound of formula (I) is selected from the following compounds:

[0020]

[0021]

[0022] In some embodiments, the compound represented by formula (I) is prepared by the following method:

[0023]

[0024] wherein Ra, Rb, R1, R2, R3, R4, and R5 have the same meanings as described above.

[0025] The composition of the present invention comprises an ophthalmically acceptable medium, which includes but is not limited to an ophthalmic pharmaceutical carrier, a pH buffer, a pH adjuster, and a combination thereof.

[0026] Preferably, the ophthalmically acceptable medium further comprises a preservative, an osmotic pressure regulator, or a combination thereof.

[0027] In some specific embodiments, the preservative is selected from any one of benzoic acid esters, parabens, and benzalkonium bromide, or a combination of two or more thereof.

[0028] In some specific embodiments, the pH buffer is selected from a buffer system consisting of an acid and a salt selected from tartaric acid, sodium tartrate, oxalic acid, sodium oxalate, citric acid, sodium citrate, disodium ethylenediaminetetraacetate, acetic acid, sodium acetate, boric acid, sodium borate, phosphoric acid, disodium hydrogen phosphate, and sodium dihydrogen phosphate.

[0029] In some specific embodiments, the pH adjuster is selected from sodium hydroxide or hydrochloric acid.

[0030] In some specific embodiments, the osmotic pressure regulator is at least one of sodium chloride, calcium chloride or potassium chloride.

[0031] In some specific embodiments, the effective amount of pilocarpine phenylacetic acid salt or pilocarpine phenylacetic acid derivative salt is 0.01-5% (w / w or w / v), preferably 0.1-3% (w / w or w / v), more preferably 0.5-2% (w / w or w / v).

[0032] In some embodiments, the concentration of the pilocarpine phenylacetic acid salt or the pilocarpine phenylacetic acid derivative salt is 1-30 mg / ml, such as 5-25 mg / ml, such as 8-19 mg / ml.

[0033] In some embodiments, the effective amount of the α receptor agonist or a pharmaceutically acceptable salt thereof is 0.01-2% (w / w or w / v), preferably 0.05-1% (w / w or w / v), and more preferably 0.1-0.5% (w / w or w / v).

[0034] In some embodiments, the concentration of the alpha receptor agonist or a pharmaceutically acceptable salt thereof is 0.5-5 mg / ml, such as 0.8-4 mg / ml, such as 1-3 mg / ml.

[0035] In some embodiments, the pH adjuster adjusts the pH of the composition to 3.0-7.0, preferably 3.5-5.5, and more preferably 4.0-5.0.

[0036] In some preferred embodiments, the pilocarpine phenylacetic acid derivative salt is pilocarpine methylphenylacetate.

[0037] In some preferred embodiments, the methylphenyl acetate is at least one of p-methylphenyl acetate, m-methylphenyl acetate or o-methylphenyl acetate.

[0038] In some preferred embodiments, the methylphenyl acetate is p-methylphenyl acetate.

[0039]

[0040] In some specific embodiments, the alpha receptor agonist is at least one of brimonidine, aceclidine, or phentolamine.

[0041] In some preferred embodiments, the alpha receptor agonist is brimonidine.

[0042] In some preferred embodiments, the alpha receptor agonist is brimonidine tartrate.

[0043] In some preferred embodiments, the composition includes pilocarpine p-toluene acetate, brimonidine tartrate, boric acid, sodium citrate, sodium chloride, and sodium hydroxide / hydrochloric acid to adjust the pH to no more than 7.

[0044] In some embodiments, the composition includes the following components at the following concentrations:

[0045] 5-25 mg / ml of pilocarpine phenylacetate or its derivative salt represented by formula (I), 0.8-4 mg / ml of α receptor agonist or its pharmaceutically acceptable salt, 0.1-20 mg / ml of pH buffer, 0.1-3.0 mg / ml of osmotic pressure regulator and pH regulator are appropriately adjusted to pH not exceeding 7.

[0046] In some specific embodiments, the composition comprises the following components in concentrations: 5-25 mg / ml pilocarpine p-toluene acetate, 0.5-5 mg / ml brimonidine tartrate, 2-20 mg / ml boric acid, 0.1-1.0 mg / ml sodium citrate, 0.1-3.0 mg / ml sodium chloride and an appropriate amount of a pH adjuster to adjust the pH to no more than 7.

[0047] As an example, the composition includes the following components in concentrations: 18.3 or 9.15 mg / ml pilocarpine p-toluene acetate, 2 mg / ml brimonidine tartrate, 10 mg / ml boric acid, 0.3 mg / ml sodium citrate, 0.8 mg / ml sodium chloride, and a pH adjuster in an amount not exceeding 7.

[0048] The present invention also provides use of the ophthalmic pharmaceutical composition as described above in the preparation of a medicament for treating and / or preventing eye diseases or disorders and related diseases or conditions.

[0049] As used herein, an "ocular disorder" is an ailment or condition that affects or involves the eye, a part or region of the eye, and includes, for example: aphakia; pseudophakia; astigmatism; blepharospasm; cataracts; conjunctival disease; conjunctivitis; corneal disease; corneal ulcer; dry eye syndrome; eyelid disease; tear apparatus disease; tear duct obstruction; myopia; presbyopia; pupil disorders; refractive power disorders and strabismus; glaucoma; choroidal neovascularization, acute macular neuroretinopathy, macular edema (such as cystoid macular edema and diabetic macular edema), Behcet's disease, retinal disorders, diabetic retinopathy, Retinopathy (including proliferative diabetic retinopathy), retinal artery occlusive disease, central retinal vein occlusion, uveitic retinal disease, retinal detachment; eye trauma affecting the posterior eye site or location; posterior eye disorders caused by or affected by ocular laser treatment; posterior eye disorders caused by or affected by photodynamic therapy; photocoagulation; radiation retinopathy; epiretinal membrane disorders; branch retinal vein occlusion; anterior ischemic optic neuropathy; non-retinopathy diabetic retinopathy, pigmentary retinitis, etc. In general, the eye includes the eyeball and the tissues and fluids that make up the eyeball, the muscles around the eye (such as the oblique muscles and rectus muscles), parts of the optic nerve located in or near the eyeball, and surrounding tissues (such as the tear glands and eyelids).

[0050] In some preferred embodiments, the eye disease or disorder is selected from glaucoma, cataract, intraocular lens, aphakia, astigmatism, blepharospasm, conjunctivitis, corneal disease, corneal edema, corneal ulcer, dry eye, eyelid disease, tear duct disease, tear duct obstruction, pupil disorder, refractive disorder and strabismus, myopia, hyperopia, presbyopia, pupil disorder.

[0051] In some preferred embodiments, the eye disease or disorder is selected from myopia, hyperopia, presbyopia, preferably presbyopia.

[0052] The present invention also provides use of the ophthalmic pharmaceutical composition as described above in preparing a medicament for miosis.

[0053] The present invention also provides an ophthalmic preparation comprising the ophthalmic pharmaceutical composition as described above.

[0054] In some specific embodiments, the ophthalmic preparation is in the form of any one of an emulsion, eye drops, eye ointment, sustained-release microspheres, intraocular sustained-release implants, and ocular sustained-release films.

[0055] In some specific embodiments, the ophthalmic preparation is eye drops.

[0056] In some preferred embodiments, the pH of the eye drop solution is 3.0-7.0, preferably pH 3.5-5.5, and more preferably pH 4.0-5.0.

[0057] Definitions and Description of Terms Throughout this application, the term "comprising" should be interpreted as having an open-ended meaning. That is, the term should be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a method, the term "comprising" means that the method includes at least the recited steps, but may include additional steps. When used in the context of a composition, the term "comprising" means that the composition includes at least the recited features or components, but may also include additional features or components.

[0058] As used herein, the recording of a numerical range of a variable is intended to convey that the variable can be equal to any value within the range. Thus, for an inherently discrete variable, the variable can be equal to any integer value within the numerical range, including the endpoints of the range. Similarly, for an inherently continuous variable, the variable can be equal to any real value within the numerical range, including the endpoints of the range. As an example, a variable described as having a value of 0-2 can be 0, 1, or 2 for an inherently discrete variable, and 0.0, 0.1, 0.01, 0.001, or any other real value as an inherently continuous variable.

[0059] "Halogen" refers to fluorine, chlorine, bromine or iodine. Preferably, halogen is fluorine, chlorine or bromine.

[0060] “C 1-6 "Alkyl" is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl. More particularly, the radical has 1, 2 or 3 carbon atoms ("C 1-3 "alkyl"), for example methyl, ethyl, n-propyl or isopropyl.

[0061] “C 1-6 "Alkoxy" refers to the group -OC 1-6 Alkyl, the C 1-6 Alkyl has the same meaning as defined above.

[0062] “C 1-6 "Alkylthio" is understood to mean -SC 1-6 Alkyl, the C 1-6 Alkyl has the same meaning as defined above.

[0063] “C 3-10 "Cycloalkyl" is understood to mean a saturated, monovalent, monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 3-10 The cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as a decalin ring.

[0064] “C 6-14The term "aryl" is understood to mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 "aryl"), for example anthracenyl.

[0065] “5-14 membered heteroaryl” is understood to include monovalent mono-, bi- or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and which contain 1 to 5, preferably 1 to 3 heteroatoms which are each independently selected from N, O and S and which, in addition, in each case may be benzo-fused. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl and the like; or azinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like.

[0066] "3-10 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3 heteroatoms selected from N, O and S. The heterocyclyl may be attached to the rest of the molecule via any of the carbon atoms or the nitrogen atom, if present. In particular, the heterocyclyl may include, but is not limited to, a 4-membered ring such as azetidinyl, oxetanyl; a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclyl may be benzo-fused. The heterocyclic group may be bicyclic, for example, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The ring containing the nitrogen atom may be partially unsaturated, i.e., it may contain one or more double bonds, for example, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, for example, but not limited to, dihydroisoquinolinyl.

[0067] Compared with the prior art, the advantages of the present invention are:

[0068] (1) The ophthalmic pharmaceutical composition of the present invention can effectively prolong the duration of drug efficacy, and the overall effect is more gentle and stable, and it can effectively improve the phenomenon of eye congestion and redness, and reduce the irritation of administration. The miotic effect intensity of the pilocarpine phenylacetic acid derivative salt and brimonidine composition of the present invention at 5 hours is significantly stronger than the miotic effect intensity of the pilocarpine hydrochloride and brimonidine composition at 4 hours, and the drug efficacy duration is long and the effect is stable. Moreover, the miotic effect intensity of the pilocarpine phenylacetic acid derivative salt and brimonidine composition of the present invention at 5 hours is also significantly stronger than the miotic effect intensity of the pilocarpine nitrate and brimonidine composition at 5 hours.

[0069] (2) The combination of the half-concentration pilocarpine phenylacetic acid derivative salt and brimonidine of the present invention prolongs the duration of miosis in rabbits by at least 1 hour compared with the combination of the full-concentration pilocarpine hydrochloride and brimonidine. Since the dose of pilocarpine is halved, its side effects are also reduced, and the medicinal safety is improved. After the half-concentration pilocarpine phenylacetic acid derivative salt and brimonidine combination is administered, there is almost no congestion in the rabbit's eyes. BRIEF DESCRIPTION OF THE DRAWINGS

[0070] Figure 1 This is a graph showing changes in pupil congestion in rabbits using the eye drop solution 1 of Example 1 of the present invention;

[0071] Figure 2This is a diagram showing changes in pupil congestion in rabbits using the eye drop solution 2 of Example 2 of the present invention;

[0072] Figure 3 This is a graph showing changes in pupil congestion in rabbits after the eye drop solution 4 of Example 4 of the present invention was applied. DETAILED DESCRIPTION

[0073] The present invention is described in detail below in conjunction with the accompanying drawings and specific embodiments.

[0074] Preparation Example 1 Preparation of Pilocarpine

[0075]

[0076] At room temperature, pilocarpine nitrate (30.00 g, 0.11 mol, 1.0 eq) was dissolved in H2O (60 mL), 1 mol / L NaHCO3 aqueous solution (121.6 mL, 0.12 mol, 1.1 eq) was added dropwise, and stirred at room temperature for 30 min. HPLC monitored the reaction to be complete, 90 mL of dichloromethane was added to the reaction solution and stirred for 15 min, the mixture was allowed to stand for separation, and the organic phase was collected. The aqueous phase was extracted three times with 90 mL of DCM. The organic phases were combined, washed with 60 mL×1 H2O, 60 mL×1 saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, and the filtrate was collected. Drying under reduced pressure gave a colorless liquid, i.e., pilocarpine (21.88 g, yield: 95.0%).

[0077] Preparation Example 2 Preparation of m-Toluphenylacetate

[0078]

[0079] At room temperature, pilocarpine (5.00 g, 24 mmol, 1.0 eq) was dissolved in EtOH (15 mL), 3-methylphenylacetic acid (3.61 g, 24 mmol, 1.0 eq) was added, and the mixture was stirred at room temperature for 1 hour. HPLC showed that the reaction was complete, the solvent was dried, and the residue was stored at -20 ° C overnight. A white solid was obtained, and the obtained solid was slurried with 16 ml of n-hexane for 1 hour, filtered, and the filter cake was collected and dried under reduced pressure to obtain a white solid, namely m-methylphenylacetate (8.42 g, yield: 97.8%).

[0080] 1H NMR (400 MHz, deuterated DMSO) δ7.53 (s, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.09–7.01 (m, 3H), 6.73 (s, 1H), 4.21 (dd, J = 8.9, 5.8 Hz, 1H), 3.96 (dd, J = 9.0, 3.1 Hz, 1H), 3.54 (s, 3H), 3.51 (s, 2H), 2.9 0–2.80(m,1H),2.73(dd,J=15.4,7.3Hz,1H),2.66(dd,J=15.6,4.3Hz,1H),2.35(dd,J=15 .6,11.4Hz,1H),2.29(s,3H),172–1.65(m,1H),1.59–1.46(m,1H),1.02(t,J=7.4Hz,3H).

[0081] Preparation Example 3 Preparation of p-Toluene Acetate

[0082]

[0083] At room temperature, pilocarpine (5.00 g, 24 mmol, 1.0 eq) was dissolved in EtOH (15 mL), 4-methylphenylacetic acid (3.61 g, 24 mmol, 1.0 eq) was added, and stirred at room temperature for 1 hour. HPLC showed that the reaction was complete, the solvent was dried, and the residue was stored at -20 ° C overnight. A white solid was obtained, and the obtained solid was slurried with 16 ml of n-hexane for 1 hour, filtered, and the filter cake was collected and dried under reduced pressure to obtain a white solid, i.e., p-methylphenylacetate (8.40 g, yield: 97.6%).

[0084] 1 H NMR (400 MHz, deuterated DMSO) δ7.54 (s, 1H), 7.17–7.09 (m, 4H), 6.73 (s, 1H), 4.21 (dd, J=8.9, 5.8 Hz, 1H), 3.96 (dd, J=9.0, 3.1 Hz, 1H), 3.54 (s, 3H), 3.50 (s, 2H), 2.90–2.80 (m, 1 H),2.73(dd,J=15.2,7.5Hz,1H),2.66(dd,J=15.6,4.3Hz,1H),2.36(dd,J=15.6,11 .4Hz,1H),2.28(s,3H),1.75–1.62(m,1H),1.59–1.46(m,1H),1.02(t,J=7.4Hz,3H).

[0085] Example 1

[0086] Eye drop solution 1:

[0087] Table 1

[0088]

[0089] Take a certain amount of pilocarpine p-toluene acetate, brimonidine tartrate, boric acid, sodium citrate, sodium chloride, and an appropriate amount of sodium hydroxide / hydrochloric acid (to adjust the pH) to prepare an eye drop solution with the component contents shown in the above table.

[0090] Example 2

[0091] Eye Drop Solution 2:

[0092] Table 2

[0093]

[0094] Take a certain amount of pilocarpine p-toluene acetate, brimonidine tartrate, boric acid, sodium citrate, sodium chloride, and an appropriate amount of sodium hydroxide / hydrochloric acid (to adjust the pH) to prepare an eye drop solution with the component contents shown in the above table.

[0095] Example 3

[0096] Eye Drop Solution 3:

[0097] Table 3

[0098]

[0099] Take a certain amount of pilocarpine hydrochloride, brimonidine tartrate, boric acid, sodium citrate, sodium chloride, and an appropriate amount of sodium hydroxide / hydrochloric acid (to adjust the pH) to prepare an eye drop solution with the component contents shown in the above table.

[0100] Example 4

[0101] Eye Drop Solution 4:

[0102] Table 4

[0103]

[0104] Take a certain amount of pilocarpine p-toluene acetate, boric acid, sodium citrate, sodium chloride, and an appropriate amount of sodium hydroxide / hydrochloric acid (to adjust the pH) to prepare an eye drop solution with the component contents shown in the above table.

[0105] Example 5

[0106] Eye Drop Solution 5:

[0107] Table 5

[0108] Raw materials Component content Pilocarpine Nitrate 13.8mg / ml (10.6mg / ml as pilocarpine) Boric acid 10mg / ml Sodium Citrate 0.3mg / ml Sodium chloride 0.8mg / ml Sodium hydroxide / hydrochloric acid Moderate pH 4.5

[0109] Take a certain amount of pilocarpine nitrate, boric acid, sodium citrate, sodium chloride, and an appropriate amount of sodium hydroxide / hydrochloric acid (to adjust the pH) to prepare an eye drop solution with the component contents shown in the above table.

[0110] Example 6

[0111] (I) Efficacy test

[0112] (1) Experimental animals

[0113] Species and strain: New Zealand rabbit

[0114] Level: General

[0115] Source: Qinglongshan Animal Breeding Farm, Jiangning District, Nanjing

[0116] Production license number: SCXK (Su) 2016-0008

[0117] Animal age: about 90 days old at the time of administration

[0118] Animal weight: about 2.5-5.0 kg at the time of administration

[0119] Animal gender: All are male

[0120] Feed: rabbit pellet feed.

[0121] Rearing conditions: air-conditioned room, temperature 18-26℃, relative humidity 40%-70%.

[0122] (2) Test methods

[0123] 1) Route of administration

[0124] Each rabbit was administered the drug by eye drops (pipette) in the left eye, and the administration volume was 100 μL.

[0125] 2) Experimental arrangements

[0126] Number of animals: 4 rabbits / group of eye drops;

[0127] Dosage cycle: single dose;

[0128] Measurement indicators and time points:

[0129] Intensity and duration of action: The pupil diameter of the left eye of rabbits was measured before administration, at 15min, 0.5h, 3h, 4h, and 5h. Each rabbit was measured 3 times at each time point.

[0130] Stimulus: Accompanying inspection.

[0131] (2) Test results

[0132] Percentage change of pupil diameter after drug administration % = (pupil diameter after drug administration - pupil diameter before drug administration) / pupil diameter before drug administration * 100%

[0133] The results of each rabbit at each time point were expressed as the average of three measurements.

[0134] Table 6: Monitoring of pupil changes in rabbits administered eye drop solution 1

[0135]

[0136]

[0137] Table 7: Monitoring of pupil changes in rabbits administered eye drop solution 2

[0138]

[0139] Table 8: Monitoring of pupil changes in rabbits after administration of eye drop solution 3

[0140]

[0141] Table 9: Monitoring of pupil changes in rabbits after administration of eye drop solution 4

[0142]

[0143]

[0144] Table 10: Monitoring of pupil changes in rabbits after administration of eye drop solution 5

[0145]

[0146] Combined with the data of comparison tables 6-8, eye drop solution 1 is 18.3 mg / ml pilocarpine p-methylphenyl acetate (10.6 mg / ml in terms of pilocarpine) + 2 mg / ml brimonidine tartrate eye drop solution, eye drop solution 2 is 9.15 mg / ml pilocarpine p-methylphenyl acetate (5.3 mg / ml in terms of pilocarpine) + 2 mg / ml brimonidine tartrate eye drop solution, and eye drop solution 3 is 12.5 mg / ml pilocarpine hydrochloride (10.6 mg / ml in terms of pilocarpine) + 2 mg / ml brimonidine tartrate eye drop solution. Eye drop solution 1 and eye drop solution 2 still have miotic effect on rabbits after 5 hours, and the percentage of miotic change is about 10%, while the miotic effect of eye drop solution 3 on rabbits tends to disappear after 5 hours, and there is basically no miotic effect. It indicates that the miotic effect intensity of the pilocarpine phenylacetic acid derivative salt and brimonidine combination of the present invention at 5 hours is significantly stronger than that of the pilocarpine hydrochloride and brimonidine combination at 5 hours, the pharmacodynamic effect lasts for a long time, and the effect is stable.

[0147] Eye drop solution 2 has a pilocarpine content equivalent to half the concentration of eye drop solution 1 and eye drop solution 3. Compared with eye drop solution 1, although the effect of eye drop solution 2 is slightly reduced at 5 hours, it still has a significant intensity of action, and is partially superior to the effect of eye drop solution 3 at 4 hours. This indicates that the combination of half-concentration pilocarpine phenylacetic acid derivative salt and brimonidine of the present invention prolongs the duration of miosis in rabbits by at least 1 hour compared with full-concentration pilocarpine hydrochloride and brimonidine. And because the dose of pilocarpine is halved, its side effects are also reduced, and the medicinal safety is improved. The test results of the above eye drops 1, 2 and 4 are shown in Figure 1-3 .contrast Figure 1 and Figure 2 It can be seen that after the administration of the medicinal combination of half-concentration pilocarpine p-methylphenylacetate and brimonidine to rabbits, there was almost no congestion in the rabbits' eyes.

[0148] Comparing the data in Table 6 and Table 9, 15 minutes after administration, the percentage changes in miosis of eye drop solution 1 and eye drop solution 4 were similar, but 3 hours after administration, the average percentage change in miosis of eye drop solution 1 remained at about 25%, while the percentage change in miosis of eye drop solution 4 was about 7%. 4 hours after administration, eye drop solution 4 had basically no miotic effect on rabbits, while eye drop solution 1 still maintained an average miotic percentage of 14% 5 hours after administration. This indicates that the addition of brimonidine tartrate to pilocarpine p-methylphenyl acetate eye drops can effectively prolong the duration of drug efficacy, and the overall effect is more gentle and stable. At the same time, compared Figure 1 and Figure 3 It can be seen that the addition of brimonidine can also effectively improve the early congestion and redness of the rabbit's eyes.

[0149] Comparing the data in Tables 6 and 10, it can be seen that 15 minutes after administration, the percentage changes of miosis in eye drop solution 1 and eye drop solution 5 are similar, but 3 hours after administration, the average percentage change of miosis in eye drop solution 1 remains at about 25%, while the percentage change of miosis in eye drop solution 5 is about 16%. After 5 hours of administration, eye drop solution 5 has basically no miotic effect on rabbits, while eye drop solution 1 still maintains an average miotic percentage of 14% after 5 hours of administration. This indicates that the miotic effect intensity of the pilocarpine phenylacetic acid derivative salt and brimonidine combination of the present invention at 5 hours is significantly stronger than the miotic effect intensity of the pilocarpine nitrate and brimonidine combination at 5 hours, the pharmacodynamic effect lasts for a long time, and the effect is stable.

[0150] The statistical difference (P value) of the miotic effect of the above-mentioned embodiment preparations was calculated by T-test method, and the results are shown in the following table:

[0151] Table 11 Group number Before administration 15min 0.5h 3h 4h 5h Example 1 VS Example 3 - 0.0888 0.4543 0.2453 0.0035 0.0000 Example 1 VS Example 5 - 0.4394 0.6805 0.0494 0.0010 0.0000 Example 1 VS Example 4 - 0.3722 0.0063 0.0008 0.0002 -

[0152] It can be seen from the statistical data in the above table that the statistical difference P values ​​of the pilocarpine p-methylphenyl acetate & brimonidine composition of the present invention and pilocarpine hydrochloride & brimonidine and pilocarpine nitrate & brimonidine at 4 hours and 5 hours are all less than 0.05, which is significantly different, that is, the pilocarpine p-methylphenyl acetate & brimonidine composition of the present invention has a significant mydriasis effect relative to the composition of pilocarpine hydrochloride & brimonidine and pilocarpine nitrate & brimonidine.

[0153] Example 7

[0154] Organization distribution data test:

[0155] Twelve Dutch rabbits (male) were randomly divided into four groups (distribution group 1, distribution group 2, distribution group 3, and distribution group 4), with three animals in each group. Eye drops (the concentration of pilocarpine p-methylphenylacetic acid was 18.3 mg / mL; the concentration of pilocarpine hydrochloride was 12.5 mg / mL, and both contained the same amount of pilocarpine) were administered to the left eye (OS) and the right eye (OD) of each group of animals, 50 μL / eye, that is, the dose of pilocarpine p-methylphenylacetic acid was 1.83 mg (0.915 mg / eye), and the amount of pilocarpine hydrochloride was 1.25 mg (0.625 mg / eye). Blood samples and ocular tissues were collected from each group of animals at 0.25h, 1h, 2h, and 4h after administration. The concentration of pilocarpine in rabbit plasma and ocular tissues was analyzed using a validated LC-MS / MS method.

[0156] (1) Blood sample processing:

[0157] Before blood collection, place the blood collection tube with EDTA-K2 in an ice box filled with crushed ice; add the collected blood to the blood collection tube, manually invert it several times, and temporarily store it in an ice box filled with crushed ice. Centrifuge it at 2000g for 10 minutes at 4℃ within 2 hours. Transfer the centrifuged plasma to a centrifuge tube with a new label, and then store it below -60℃. During the blood sample transportation process, use an ice box filled with crushed ice. After sample collection, use the WatsonLIMS7.5 system to manage the samples.

[0158] (2) Ocular tissue collection and processing

[0159] After euthanasia of Dutch rabbits in each group, both eyeballs were quickly removed at the corresponding time points. The eyeballs were placed on ice, and the conjunctiva (bulbar conjunctiva), aqueous humor, cornea, iris, lacrimal gland, retina, sclera, lower eyelid (including facial conjunctiva and surrounding soft tissue), lens, and vitreous body were separated. The above tissues were stored below -60°C for future use. The separation operation was performed on ice.

[0160] After sampling, each eye tissue was taken of appropriate size and placed in a pre-weighed homogenizer tube. After weighing again, an appropriate volume of diluent (50% (v / v) acetonitrile water was added, so that the final diluent volume and tissue mass ratio was 4:1 (mL:g). An appropriate amount of magnetic beads was placed in each homogenizer, homogenized on a homogenizer, and centrifuged at 3200g for 15 minutes at 4C. The supernatant after centrifugation was transferred to a centrifuge tube with a new label and diluted 4 times with a blank biological matrix (Dutch rabbit eye tissue homogenate supernatant). The sample processing and transfer should be carried out on an ice box filled with crushed ice and then stored below -60°C. The samples were managed using the Watson LIMS7.5 system.

[0161] (3) Sample analysis and testing

[0162] All samples need to be completely thawed in an ice box filled with crushed ice (if frozen samples) and mixed before sampling. Prepare samples and use a validated LC-MS / MS method to detect the concentration of pilocarpine in tissue samples.

[0163] Table 12

[0164]

[0165] Peak concentration Cmax (ng / g):

[0166] Cornea: "a" represents the corneal Cmax concentration range of 0<Cmax≤2000ng / g;

[0167] “aa” represents the corneal Cmax concentration range of 2000<Cmax≤4000ng / g;

[0168] “aaa” means the corneal Cmax concentration range is 4000<Cmax≤6000ng / g;

[0169] “aaaa” represents the corneal Cmax concentration range of >6000 ng / g;

[0170] Conjunctiva: “b” represents the conjunctival Cmax concentration range of 0<Cmax≤500ng / g;

[0171] “bb” represents the conjunctival Cmax concentration range of 500<Cmax≤1000ng / g;

[0172] “bbb” represents the conjunctival Cmax concentration range of >1000 ng / g;

[0173] Iris: “c” represents the iris Cmax concentration range of 0<Cmax≤5000ng / g;

[0174] “cc” represents the iris Cmax concentration range of 5000<Cmax≤10000ng / g;

[0175] “ccc” represents the iris Cmax concentration range of 10000<Cmax≤15000ng / g;

[0176] “cccc” represents the iris Cmax concentration range of >15000 ng / g;

[0177] Plasma: "d" represents the plasma Cmax concentration range of 0<Cmax≤100ng / g;

[0178] “dd” represents the plasma Cmax concentration range of 100<Cmax≤1000ng / g;

[0179] “ddd” represents the plasma Cmax concentration range of >1000 ng / g;

[0180] Area under the plasma concentration-time curve AUC (ng / g . hr):

[0181] Cornea: "A" represents the corneal AUC range of 0<AUC≤5000ng / g . hr;

[0182] "AA" means the corneal AUC concentration range is 5000<AUC≤10000ng / g . hr;

[0183] "AAA" means the corneal AUC concentration range is >10000hr . ng / g;

[0184] Conjunctiva: "B" represents the conjunctiva AUC concentration range of 0<AUC≤1000ng / g . hr;

[0185] "BB" means the conjunctival AUC concentration range is 1000<AUC≤5000ng / g . hr;

[0186] "BBB" means the conjunctival AUC concentration range is >5000hr . ng / g;

[0187] Iris: "C" represents the iris AUC concentration range of 0<AUC≤10000ng / g . hr;

[0188] "CC" represents the iris AUC concentration range of 10000<AUC≤50000ng / g . hr;

[0189] "CCC" represents the iris AUC concentration range of 50000<AUC≤100000ng / g . hr;

[0190] "CCCC" means the iris AUC concentration range is >100000ng / g . hr;

[0191] Plasma: "D" represents the plasma AUC concentration range of 0<AUC≤100ng / g . hr;

[0192] "DD" means the plasma AUC concentration range is 100<AUC≤1000ng / g . hr;

[0193] "DDD" means the plasma AUC concentration range is >1000ng / g . hr.

[0194] In summary, the composition of the present invention has a higher drug concentration and exposure in the target tissue iris than pilocarpine hydrochloride & brimonidine, and therefore has a significantly better miotic effect.

[0195] The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. An ophthalmic pharmaceutical composition, characterized in that: It comprises pilocarpine phenylacetate or its derivative salt as shown in the following formula (I); and an alpha receptor agonist or a pharmaceutically acceptable salt thereof; Wherein R1, R2, R3, R4, R5 are the same or different and are independently selected from hydrogen, C 1-6 Alkyl, halogen, cyano, -COOR', -NR'R", R', R" are the same or different, each independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-10 membered heterocyclyl; Wherein Ra and Rb are the same or different and are independently selected from hydrogen, C 1-6 Alkyl, halogen, cyano, C 3-10 Cycloalkyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-10 membered heterocyclyl; The C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-10 membered heterocyclyl are optionally substituted by one, two or more of the following groups: oxo, thioxo, halogen, cyano, -NR'R", -COOH, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 Cycloalkyl, C 6-14 Aryl, 5-14 membered heteroaryl.

2. The ophthalmic pharmaceutical composition according to claim 1, characterized in that: The R1, R2, R3, R4, and R5 are the same or different and are independently selected from hydrogen, C 1-6 Alkyl, halogen, -COOR', R" is independently selected from H, C 1-6 alkyl.

3. The ophthalmic pharmaceutical composition according to claim 1, characterized in that: The compound of formula (I) is selected from the following compounds: 。 4. The ophthalmic pharmaceutical composition according to claim 1, characterized in that: The composition comprises an ophthalmically acceptable medium, wherein the ophthalmically acceptable medium is selected from one of an ophthalmic pharmaceutical carrier, a pH buffer, a pH adjuster, and a combination thereof; Preferably, the ophthalmically acceptable medium further comprises a preservative, an osmotic pressure regulator, or a combination thereof.

5. The ophthalmic pharmaceutical composition according to claim 4, characterized in that: The preservative is selected from any one of benzoic acid esters, p-hydroxybenzoic acid esters, and benzalkonium bromide, or a combination of two or more thereof. Preferably, the pH buffer is selected from a buffer system consisting of an acid and a salt selected from tartaric acid, sodium tartrate, oxalic acid, sodium oxalate, citric acid, sodium citrate, disodium edetate, acetic acid, sodium acetate, boric acid, sodium borate, phosphoric acid, disodium hydrogen phosphate, and sodium dihydrogen phosphate. Preferably, the pH adjuster is selected from sodium hydroxide or hydrochloric acid. Preferably, the osmotic pressure regulator is at least one of sodium chloride, calcium chloride or potassium chloride.

6. The ophthalmic pharmaceutical composition according to any one of claims 1 to 5, characterized in that: The compound represented by formula (I) is selected from methylphenyl acetate, and the methylphenyl acetate is at least one of p-methylphenyl acetate, m-methylphenyl acetate or o-methylphenyl acetate. Preferably, the methylphenyl acetate is p-methylphenyl acetate. Preferably, the α receptor agonist is at least one of brimonidine, aceclidine or phentolamine.

7. The ophthalmic pharmaceutical composition according to any one of claims 1 to 6, characterized in that: The composition includes pilocarpine p-toluene acetate, brimonidine tartrate, boric acid, sodium citrate, sodium chloride, and sodium hydroxide / hydrochloric acid to adjust the pH to not more than 7. Preferably, the composition comprises the following components in the following concentrations: 5-25 mg / ml of pilocarpine phenylacetate or its derivative salt represented by formula (I), 0.8-4 mg / ml of α receptor agonist or its pharmaceutically acceptable salt, 0.1-20 mg / ml of pH buffer, 0.1-3.0 mg / ml of osmotic pressure regulator and pH regulator are appropriately adjusted to pH not exceeding 7. Also preferably, the composition comprises the following components in concentrations: 5-25 mg / ml pilocarpine p-toluene acetate, 0.5-5 mg / ml brimonidine tartrate, 2-20 mg / ml boric acid, 0.1-1.0 mg / ml sodium citrate, 0.1-3.0 mg / ml sodium chloride and a pH adjuster in an appropriate amount to adjust the pH to no more than 7.

8. Use of the ophthalmic pharmaceutical composition according to any one of claims 1 to 7 in the preparation of a medicament for treating and / or preventing ocular diseases or disorders and related diseases or conditions; or use of the ophthalmic pharmaceutical composition in the preparation of a miotic medicament.

9. The use according to claim 8, characterized in that The "eye disorder" is an ailment or condition that affects or involves the eye, part or region of the eye, including, for example: aphakia; pseudophakia; astigmatism; blepharospasm; cataracts; conjunctival disease; conjunctivitis; corneal disease; corneal ulcer; dry eye syndrome; eyelid disease; tear apparatus disease; tear duct obstruction; myopia; presbyopia; pupil disorders; refractive power disorders and strabismus; glaucoma; choroidal neovascularization, acute macular neuroretinopathy, macular edema, Behcet's disease, retinal disorders, diabetic retinopathy lesions, retinal artery occlusive disease, central retinal vein occlusion, uveitic retinal disease, retinal detachment; ocular trauma affecting a point or location in the posterior eye; posterior eye conditions caused by or affected by ocular laser treatment; posterior eye conditions caused by or affected by photodynamic therapy; photocoagulation; radiation retinopathy; epiretinal membrane disorders; branch retinal vein occlusion; anterior ischemic optic neuropathy; non-retinopathy diabetic retinopathy, retinitis pigmentosa. Preferably, the eye disease or disorder is selected from glaucoma, cataract, intraocular lens, aphakia, astigmatism, blepharospasm, conjunctivitis, corneal disease, corneal edema, corneal ulcer, dry eye, eyelid disease, tear duct disease, tear duct obstruction, pupil disorder, refractive disorder and strabismus, myopia, hyperopia, presbyopia, pupil disorder.

10. An ophthalmic preparation comprising the ophthalmic pharmaceutical composition according to any one of claims 1 to 7.

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