Pharmaceutical composition containing dextimolol maleate, and preparation method, pharmaceutical preparation and application thereof

Abstract

The invention provides a pharmaceutical composition containing dextimolol maleate. The pharmaceutical composition is prepared from the following components: dextimolol maleate, a high polymer material, an osmotic pressure regulator, a bacteriostatic agent, a stabilizer, a pH regulator and water for injection. Compared with levotimolol maleate, the dextimolol maleate in the pharmaceutical composition disclosed by the invention is smaller in side effect, and compared with eye drops, the pharmaceutical composition serving as an ophthalmic gel preparation has the advantages of small irritation, longer drug effect maintenance time and the like.

Description

Technical Field

[0001] The present invention relates to the field of medicines, and in particular to a pharmaceutical composition comprising dextimolol maleate, a preparation method thereof, a pharmaceutical preparation and use thereof. Background Art

[0002] Glaucoma is an eye disease associated with increased intraocular pressure, which in turn threatens and damages the function of the optic nerve. Clinically, the treatment effect is mainly achieved by reducing intraocular pressure. Since local administration is more targeted and has fewer systemic side effects, ocular administration is the first choice for glaucoma treatment. Commonly used intraocular pressure-lowering drugs include beta-blockers (such as timolol and betaxolol), prostaglandins (such as bimatoprost and travoprost), etc. Among them, beta-blockers are currently the most commonly used intraocular pressure-lowering drugs.

[0003] Timolol (timolol, timolol) is the most commonly used drug for glaucoma treatment. Timolol has optical isomers, namely, levo-timolol (S-type, L-type) and dextro-timolol (R-type, D-type). The main active ingredient of the currently widely used timolol maleate ophthalmic preparation is levo-timolol. Since glaucoma drugs need to be used repeatedly for a long time, and levo-timolol is similar to propranolol and can block β1 and β2 receptors, it is easy to cause systemic cardiovascular side effects such as bradycardia (Ma Aiping and Xie Huiyun, Journal of Drug Epidemiology, 2000, 9(4): 213) and bronchospasm (Yang Jinbiao, Journal of Modern Integrated Traditional Chinese and Western Medicine, 2007, 16(24): 3516).

[0004] In 1981, Chiou GCY found that dextro-timolol (D-type) also has the effect of lowering intraocular pressure, but its β-receptor blocking effect is much weaker than that of L-type (Liu HK, Chiou GCY. Experimental eye research, 1981, 32 (5): 583-92). At the therapeutic dose for glaucoma, it does not cause cardiovascular side effects caused by β-receptor blocking like L-type (Chiou GCY. Current Eye Research, 1982 / 1983, 2: 507). Therefore, dextro-timolol has obvious clinical advantages in the treatment of glaucoma.

[0005] Compared with levo-timolol, dextro-timolol is more difficult to synthesize. At present, only dextro-timolol maleate eye drops (trade name: Dilijian) produced by Hebei Yongguang Pharmaceutical Co., Ltd. are clinically used for the treatment of glaucoma and ocular hypertension. Eye drops have the advantages of rapid onset, but they are easily lost with tears after administration, have a short retention time in the eye, and are affected by blinking, which leads to large fluctuations in the dosage. Multiple administrations are required to improve bioavailability to achieve therapeutic effects. In addition, due to the high fluidity of eye drops, the drug is easily introduced into the body through the nasolacrimal duct, causing cardiovascular side effects.

[0006] The gel preparation is a semi-solid state with a hydrophilic polymer as the matrix, and has the advantages of: (1) prolonging the retention time in the eye and improving the bioavailability of the drug; (2) good biocompatibility; (3) no sticky feeling in the preparation and good patient compliance. At present, some Chinese patents have also disclosed related ophthalmic gel preparations, such as CN100413505C, CN114073670B, and CN102178644B, but their active ingredients are all L-timolol. Therefore, it is particularly important to develop a preparation for treating glaucoma with good therapeutic effect, long retention time in the eye, and less side effects. Summary of the invention

[0007] In view of the problems existing in the prior art, the object of the present invention is to provide a pharmaceutical composition comprising dextrotimolol maleate, wherein the active ingredient is dextrotimolol maleate, and the pharmaceutical composition has a comparable glaucoma treatment effect to that of timolol maleate (levorotatory), but has less cardiovascular side effects and higher safety for long-term administration. Moreover, the pharmaceutical composition comprising dextrotimolol maleate of the present invention is non-irritating to the eyes as an ophthalmic gel preparation, has a longer retention time, and has better efficacy.

[0008] The technical scheme of the pharmaceutical composition containing dexamolol maleate of the present invention is as follows:

[0009] A pharmaceutical composition comprising dextrotimolol maleate, wherein the components and dosages of the pharmaceutical composition are as follows:

[0010]

[0011] According to the pharmaceutical composition containing dextrotimolol maleate of the present invention, the components and dosages of the pharmaceutical composition are as follows:

[0012]

[0013] According to the pharmaceutical composition containing dextrotimolol maleate of the present invention, the components and dosages of the pharmaceutical composition are as follows:

[0014]

[0015] According to the pharmaceutical composition comprising dextimolol maleate of the present invention, wherein:

[0016] The polymer material is selected from one or more of carbomer, poloxamer, polycarbophil, cellulose derivatives, poly-N-isopropylacrylamide, chitosan, hyaluronic acid, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol, sodium alginate, xanthan gum, and gellan gum;

[0017] The osmotic pressure regulator is selected from one or more of glycerol, mannitol, sodium chloride, sorbitol, glucose and propylene glycol;

[0018] The antibacterial agent is selected from one or more of sodium benzoate, benzalkonium chloride, benzalkonium bromide, phenylethyl alcohol, benzyl alcohol, methylparaben, phenoxyethanol, and methylparaben;

[0019] The stabilizer is selected from EDTA and / or EDTA-2Na;

[0020] The pH regulator is selected from one or more of sodium hydroxide, potassium hydroxide, triethanolamine, ethanolamine, borax, boric acid, hydrochloric acid, acetic acid, sulfuric acid, phosphate, citric acid, and sodium citrate.

[0021] According to the pharmaceutical composition comprising dextimolol maleate of the present invention, wherein:

[0022] The polymer material is selected from carbomer, and the carbomer is selected from one or more of carbomer 934, carbomer 940, carbomer 941, carbomer 971, carbomer 973, carbomer 980 and carbomer 981, preferably carbomer 940 and / or carbomer 980; and / or

[0023] The polymer material is selected from cellulose derivatives, including but not limited to one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, carboxymethyl cellulose, sodium methylcellulose, sodium carboxymethyl cellulose, preferably hydroxypropyl methylcellulose; preferably, the hydroxypropyl methylcellulose is selected from one or more of hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose E4M and hydroxypropyl methylcellulose E10M, preferably hydroxypropyl methylcellulose K4M and / or hydroxypropyl methylcellulose E4M; and / or

[0024] The polymer material is selected from poloxamer, and the poloxamer is one or more of poloxamer 407, poloxamer 188 and poloxamer 338, preferably poloxamer 407 and / or poloxamer 188; and / or

[0025] The polymer material is selected from polycarbophil; and / or

[0026] The polymer material is selected from gellan gum.

[0027] According to the pharmaceutical composition comprising dextimolol maleate of the present invention, wherein:

[0028] The polymer material is Carbomer 980, and the amount used is 1.5-15 parts by weight, preferably 2-12 parts by weight, and more preferably 2-10 parts by weight; or, the polymer material is Carbomer 940, and the amount used is 1.5-15 parts by weight, preferably 2-8 parts by weight, and more preferably 2-6 parts by weight; and / or

[0029] The polymer material is hydroxypropyl methylcellulose K4M, and the amount used is 2-18 parts by weight, preferably 3-15 parts by weight, and more preferably 3-13 parts by weight; or, the polymer material is hydroxypropyl methylcellulose E4M, and the amount used is 2-18 parts by weight, preferably 3-15 parts by weight, and more preferably 3-13 parts by weight; and / or

[0030] The polymer material is selected from poloxamer 407, and the amount used is 100-350 parts by weight, preferably 110-300 parts by weight, and more preferably 150-280 parts by weight; and / or, the polymer material is poloxamer 188, and the amount used is 10-120 parts by weight, preferably 15-100 parts by weight, and more preferably 15-90 parts by weight; and / or

[0031] The polymer material is selected from polycarbophil, and the amount used is 3-30 parts by weight, preferably 4-22 parts by weight, and more preferably 4-18 parts by weight; and / or

[0032] The polymer material is selected from gellan gum, and the amount used is 0.5-9 parts by weight, preferably 1-8 parts by weight, and more preferably 1.5-6 parts by weight.

[0033] According to the pharmaceutical composition comprising dextimolol maleate of the present invention, wherein:

[0034] The osmotic pressure regulator is glycerol, and the amount used is 10-35 parts by weight, preferably 12-30 parts by weight, and more preferably 18-26 parts by weight; and / or

[0035] The osmotic pressure regulator is mannitol, and the amount used is 20-60 parts by weight, preferably 25-50 parts by weight, and more preferably 30-45 parts by weight; and / or

[0036] The osmotic pressure regulator is sodium chloride, and the amount used is 1-8 parts by weight, preferably 1.5-7 parts by weight, and more preferably 1.5-6 parts by weight.

[0037] According to the pharmaceutical composition comprising dextimolol maleate of the present invention, wherein:

[0038] The antibacterial agent is benzalkonium chloride or benzalkonium bromide, and the amount used is 0-0.5 parts by weight, preferably 0-0.25 parts by weight, and more preferably 0-0.12 parts by weight; or

[0039] The antibacterial agent is sodium benzoate, and the dosage is 0-4 parts by weight, preferably 0-3 parts by weight, and more preferably 0-2.5 parts by weight.

[0040] According to the pharmaceutical composition comprising dextimolol maleate of the present invention, wherein:

[0041] The stabilizer is EDTA and / or EDTA-2Na, and the amount used is 0.1-0.5 parts by weight, preferably 0.15-0.4 parts by weight, and more preferably 0.2-0.3 parts by weight.

[0042] According to the pharmaceutical composition comprising dextimolol maleate of the present invention, wherein:

[0043] The pH regulator is sodium hydroxide and / or triethanolamine, and a proper amount of the pH regulator is added to make the pH of the pharmaceutical composition 5.5-7.8, preferably, 6.0-7.8, and more preferably, 6.5-7.5.

[0044] Another object of the present invention is to provide a method for preparing the above-mentioned pharmaceutical composition comprising dexamolol maleate, the method comprising the following steps:

[0045] (1) Take an appropriate amount of water for injection, evenly disperse the prescribed amount of polymer material on the liquid surface, let it stand until it becomes clear and transparent, and then stir it evenly to obtain a gel matrix for later use;

[0046] (2) adding a prescribed amount of dextimolol maleate to an appropriate amount of water for injection, stirring until completely dissolved, then adding a prescribed amount of an osmotic pressure regulator, an antibacterial agent (optional) and a stabilizer, stirring until completely dissolved, to obtain a mixed solution comprising dextimolol maleate, an osmotic pressure regulator, an antibacterial agent (optional) and a stabilizer, adding the mixed solution to the gel matrix obtained in step (1), and adding a pH regulator to adjust the pH to 5.5-7.8 under stirring;

[0047] (3) Add water for injection to the full amount, stir evenly, and filter to obtain a pharmaceutical composition containing dextrotimolol maleate.

[0048] According to the method of the present invention, the pharmaceutical composition comprising dextimolol maleate is in the form of a gel preparation, preferably in the form of an ophthalmic gel preparation.

[0049] Another object of the present invention is to provide use of the above-mentioned pharmaceutical composition containing dexamolol maleate in the preparation of a medicament for treating glaucoma or ocular hypertension.

[0050] Another object of the present invention is to provide an ophthalmic gel preparation comprising dextimolol maleate, and the technical scheme thereof is as follows:

[0051] An ophthalmic gel preparation comprising dextimolol maleate, wherein the components and dosages of the ophthalmic gel preparation are as follows:

[0052]

[0053] According to the ophthalmic gel preparation containing dextimolol maleate of the present invention, the components and dosages of the ophthalmic gel preparation are as follows:

[0054]

[0055]

[0056] According to the ophthalmic gel preparation containing dextimolol maleate of the present invention, the components and dosages of the ophthalmic gel preparation are as follows:

[0057]

[0058] According to the ophthalmic gel preparation containing dextimolol maleate of the present invention, wherein:

[0059] The polymer material is selected from one or more of carbomer, poloxamer, polycarbophil, cellulose derivatives, poly-N-isopropylacrylamide, chitosan, hyaluronic acid, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol, sodium alginate, xanthan gum, and gellan gum;

[0060] The osmotic pressure regulator is selected from one or more of glycerol, mannitol, sodium chloride, sorbitol, glucose and propylene glycol;

[0061] The antibacterial agent is selected from one or more of sodium benzoate, benzalkonium chloride, benzalkonium bromide, phenylethyl alcohol, benzyl alcohol, methylparaben, phenoxyethanol, and methylparaben;

[0062] The stabilizer is selected from EDTA and / or EDTA-2Na;

[0063] The pH regulator is selected from one or more of sodium hydroxide, potassium hydroxide, triethanolamine, ethanolamine, borax, boric acid, hydrochloric acid, acetic acid, sulfuric acid, phosphate, citric acid, and sodium citrate.

[0064] According to the ophthalmic gel preparation containing dextimolol maleate of the present invention, wherein:

[0065] The polymer material is selected from carbomer, and the carbomer is selected from one or more of carbomer 934, carbomer 940, carbomer 941, carbomer 971, carbomer 973, carbomer 980 and carbomer 981, preferably carbomer 940 and / or carbomer 980; and / or

[0066] The polymer material is selected from cellulose derivatives, including but not limited to one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, carboxymethyl cellulose, sodium methylcellulose, sodium carboxymethyl cellulose, preferably hydroxypropyl methylcellulose; preferably, the hydroxypropyl methylcellulose is selected from one or more of hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose E4M and hydroxypropyl methylcellulose E10M, preferably hydroxypropyl methylcellulose K4M and / or hydroxypropyl methylcellulose E4M; and / or

[0067] The polymer material is selected from poloxamer, and the poloxamer is one or more of poloxamer 407, poloxamer 188 and poloxamer 338, preferably poloxamer 407 and poloxamer 188; and / or

[0068] The polymer material is selected from polycarbophil; and / or

[0069] The polymer material is selected from gellan gum.

[0070] According to the ophthalmic gel preparation containing dextimolol maleate of the present invention, wherein:

[0071] The polymer material is Carbomer 980, and the amount used is 1.5-15 parts by weight, preferably 2-12 parts by weight, and more preferably 2-10 parts by weight; or, the polymer material is Carbomer 940, and the amount used is 1.5-15 parts by weight, preferably 2-8 parts by weight, and more preferably 2-6 parts by weight; and / or

[0072] The polymer material is hydroxypropyl methylcellulose K4M, and the amount used is 2-18 parts by weight, preferably 3-15 parts by weight, and more preferably 3-13 parts by weight; or, the polymer material is hydroxypropyl methylcellulose E4M, and the amount used is 2-18 parts by weight, preferably 3-15 parts by weight, and more preferably 3-13 parts by weight; and / or

[0073] The polymer material is selected from poloxamer 407, and the amount used is 100-350 parts by weight, preferably 110-300 parts by weight, and more preferably 150-280 parts by weight; and / or, the polymer material is poloxamer 188, and the amount used is 10-120 parts by weight, preferably 15-100 parts by weight, and more preferably 15-90 parts by weight; and / or

[0074] The polymer material is selected from polycarbophil, and the amount used is 3-30 parts by weight, preferably 4-22 parts by weight, and more preferably 4-18 parts by weight; and / or

[0075] The polymer material is selected from gellan gum, and the amount used is 0.5-9 parts by weight, preferably 1-8 parts by weight, and more preferably 1.5-6 parts by weight.

[0076] According to the ophthalmic gel preparation containing dextimolol maleate of the present invention, wherein:

[0077] The osmotic pressure regulator is glycerol, and the amount used is 10-35 parts by weight, preferably 12-30 parts by weight, and more preferably 18-26 parts by weight; and / or

[0078] The osmotic pressure regulator is mannitol, and the amount used is 20-60 parts by weight, preferably 25-50 parts by weight, and more preferably 30-45 parts by weight; and / or

[0079] The osmotic pressure regulator is sodium chloride, and the amount used is 1-8 parts by weight, preferably 1.5-7 parts by weight, and more preferably 1.5-6 parts by weight.

[0080] According to the ophthalmic gel preparation containing dextimolol maleate of the present invention, wherein:

[0081] The antibacterial agent is benzalkonium chloride or benzalkonium bromide, and the amount used is 0-0.5 parts by weight, preferably 0-0.25 parts by weight, and more preferably 0-0.12 parts by weight; or

[0082] The antibacterial agent is sodium benzoate, and the dosage is 0-4 parts by weight, preferably 0-3 parts by weight, and more preferably 0-2.5 parts by weight.

[0083] According to the ophthalmic gel preparation containing dextimolol maleate of the present invention, wherein:

[0084] The stabilizer is EDTA and / or EDTA-2Na, and the amount used is 0.1-0.5 parts by weight, preferably 0.15-0.4 parts by weight, and more preferably 0.2-0.3 parts by weight.

[0085] According to the ophthalmic gel preparation containing dextimolol maleate of the present invention, wherein:

[0086] The pH regulator is sodium hydroxide and / or triethanolamine, and a proper amount of the pH regulator is added to make the pH of the ophthalmic gel preparation 5.5-7.8, preferably 6.0-7.8, and more preferably 6.5-7.5.

[0087] According to the ophthalmic gel preparation containing dextimolol maleate of the present invention, the ophthalmic gel preparation is divided into a multi-dose package and a single-dose package, wherein the single-dose package does not contain an antibacterial agent.

[0088] Another object of the present invention is to provide a method for preparing the above-mentioned ophthalmic gel preparation containing dexamolol maleate, the method comprising the following steps:

[0089] (1) Take an appropriate amount of water for injection, evenly disperse the prescribed amount of polymer material on the liquid surface, let it stand until it becomes clear and transparent, and then stir it evenly to obtain a gel matrix for later use;

[0090] (2) adding a prescribed amount of dextimolol maleate to an appropriate amount of water for injection, stirring until completely dissolved, then adding a prescribed amount of an osmotic pressure regulator, an antibacterial agent (optional) and a stabilizer, stirring until completely dissolved, to obtain a mixed solution comprising dextimolol maleate, an osmotic pressure regulator, an antibacterial agent (optional) and a stabilizer, adding the mixed solution to the gel matrix obtained in step (1), and adding a pH regulator to adjust the pH to 5.5-7.8 under stirring;

[0091] (3) Add water for injection to the full amount, stir evenly, filter, and package to obtain an ophthalmic gel preparation containing dextrotimolol maleate.

[0092] Another object of the present invention is to provide use of the above-mentioned ophthalmic gel preparation containing dexamolol maleate for treating glaucoma or ocular hypertension.

[0093] Technical Effects

[0094] The present invention has found a pharmaceutical composition / ophthalmic gel preparation containing right timolol maleate with excellent quality indicators by investigating the properties, related substances, content determination, pH value, stability, administration compliance, eye irritation and eye retention time of the pharmaceutical composition / ophthalmic gel preparation containing right timolol maleate. Specifically, the pharmaceutical composition / ophthalmic gel preparation of the present invention has a comparable glaucoma treatment effect with timolol maleate (levorotatory), but has less cardiovascular side effects and higher safety for long-term administration, and the pharmaceutical composition containing right timolol maleate of the present invention as an ophthalmic gel preparation has no irritation to the eye, a longer retention time and better drug efficacy. DETAILED DESCRIPTION

[0095] The present invention is further described below in conjunction with embodiments, but the present invention is not limited to the embodiments listed.

[0096] Unless otherwise specified, the materials used in the following examples were purchased from conventional commercial sources.

[0097] Example 1

[0098]

[0099]

[0100] 1. Take 450g of water for injection, and evenly disperse the prescribed amount of poloxamer 188 and poloxamer 407 on the liquid surface, and stir evenly after leaving it until it becomes clear and transparent to obtain a gel matrix for later use;

[0101] 2. Add the prescribed amount of dextimolol maleate to 100 g of water for injection, stir until completely dissolved, then add the prescribed amount of sodium chloride, sodium benzoate and EDTA, stir until completely dissolved, add to the gel matrix, add triethanolamine solution under stirring to adjust the pH to 5.5-7.8;

[0102] 3. Add water for injection to 1000 g, stir evenly, filter, and package to obtain dextimolol maleate ophthalmic gel preparation.

[0103] Example 2

[0104]

[0105] 1. Take 500g of water for injection, and evenly disperse the prescribed amount of Carbomer 980 and Polycarbophil on the liquid surface, and stir evenly after leaving until it becomes clear and transparent to obtain a gel matrix for later use;

[0106] 2. Add the prescribed amount of dextimolol maleate to 200 g of water for injection, stir until completely dissolved, then add the prescribed amount of sodium chloride, benzalkonium chloride and EDTA, stir until completely dissolved, add to the gel matrix, add triethanolamine solution under stirring to adjust the pH to 5.5-7.8;

[0107] 3. Add water for injection to 1000 g, stir evenly, filter, and package to obtain dextimolol maleate ophthalmic gel preparation.

[0108] Example 3

[0109]

[0110]

[0111] 1. Take 400g of water for injection, disperse the prescribed amount of polycarbophil and poloxamer 407 evenly on the liquid surface, let it stand until it becomes clear and transparent, then stir evenly to obtain a gel matrix for later use;

[0112] 2. Add the prescribed amount of dextimolol maleate to 200 g of water for injection, stir until completely dissolved, then add the prescribed amount of mannitol, benzalkonium chloride and EDTA-2Na, stir until completely dissolved, add to the gel matrix, and add sodium hydroxide solution under stirring to adjust the pH to 5.5-7.8;

[0113] 3. Add water for injection to 1000 g, stir evenly, filter, and package to obtain dextimolol maleate ophthalmic gel preparation.

[0114] Example 4

[0115]

[0116] 1. Take 400g of water for injection, and evenly disperse the prescribed amount of poloxamer 407 and poloxamer 188 on the liquid surface, and stir evenly after leaving it until it becomes clear and transparent to obtain a gel matrix for later use;

[0117] 2. Add the prescribed amount of dextimolol maleate to 150 g of water for injection, stir until completely dissolved, then add the prescribed amount of glycerol, sodium chloride, sodium benzoate and EDTA, stir until completely dissolved, add to the gel matrix, add triethanolamine solution under stirring to adjust the pH to 5.5-7.8;

[0118] 3. Add water for injection to 1000 g, stir evenly, filter, and package to obtain dextimolol maleate ophthalmic gel preparation.

[0119] Example 5

[0120]

[0121] 1. Take 500g of water for injection, disperse the prescribed amount of polycarbophil evenly on the liquid surface, let it stand until it becomes clear and transparent, then stir evenly to obtain a gel matrix for later use;

[0122] 2. Add the prescribed amount of dextimolol maleate to 200 g of water for injection, stir until completely dissolved, then add the prescribed amount of mannitol, benzalkonium bromide and EDTA-2Na, stir until completely dissolved, add to the gel matrix, add triethanolamine solution under stirring to adjust the pH to 5.5-7.8;

[0123] 3. Add water for injection to 1000 g, stir evenly, filter, and package to obtain dextimolol maleate ophthalmic gel preparation.

[0124] Example 6

[0125]

[0126]

[0127] 1. Take 400g of water for injection, and evenly disperse the prescribed amount of poloxamer 407 and poloxamer 188 on the liquid surface, and stir evenly after leaving it until it becomes clear and transparent to obtain a gel matrix for later use;

[0128] 2. Add the prescribed amount of dextimolol maleate to 150 g of water for injection, stir until completely dissolved, then add the prescribed amount of glycerol, benzalkonium chloride and EDTA, stir until completely dissolved, add to the gel matrix, add triethanolamine solution under stirring to adjust the pH to 5.5-7.8;

[0129] 3. Add water for injection to 1000 g, stir evenly, filter, and package to obtain dextimolol maleate ophthalmic gel preparation.

[0130] Example 7 Preparation of Dextimolol Maleate Ophthalmic Gel (without Antibacterial Agent)

[0131]

[0132] 1. Take 400g of water for injection, and evenly disperse the prescribed amount of poloxamer 407 and poloxamer 188 on the liquid surface, and stir evenly after leaving it until it becomes clear and transparent to obtain a gel matrix for later use;

[0133] 2. Add the prescribed amount of dextimolol maleate to 150 g of water for injection, stir until completely dissolved, then add the prescribed amount of glycerol and EDTA, stir until completely dissolved, add to the gel matrix, and add sodium hydroxide solution under stirring to adjust the pH to 5.5-7.8;

[0134] 3. Add water for injection to 1000 g, stir evenly, filter, and package to obtain dextimolol maleate ophthalmic gel preparation.

[0135] Example 8

[0136]

[0137]

[0138] 1. Take 400g of water for injection, disperse the prescribed amount of poloxamer 407, poloxamer 188 and polycarbophil evenly on the liquid surface, let it stand until it becomes clear and transparent, then stir evenly to obtain a gel matrix for later use;

[0139] 2. Add the prescribed amount of dextimolol maleate to 150 g of water for injection, stir until completely dissolved, then add the prescribed amount of glycerol, sodium chloride, benzalkonium chloride and EDTA, stir until completely dissolved, add to the gel matrix, add triethanolamine solution under stirring to adjust the pH to 5.5-7.8;

[0140] 3. Add water for injection to 1000 g, stir evenly, filter, and package to obtain dextimolol maleate ophthalmic gel preparation.

[0141] Example 9

[0142]

[0143] 1. Take 400g of water for injection, and evenly disperse the prescribed amount of Carbomer 940 and Hydroxypropyl Methylcellulose E4M on the liquid surface, and stir evenly after leaving until it becomes clear and transparent to obtain a gel matrix for later use;

[0144] 2. Add the prescribed amount of dextimolol maleate to 150 g of water for injection, stir until completely dissolved, then add the prescribed amount of glycerol, benzalkonium bromide and EDTA, stir until completely dissolved, add to the gel matrix, and add sodium hydroxide solution under stirring to adjust the pH to 5.5-7.8;

[0145] 3. Add water for injection to 1000 g, stir evenly, filter, and package to obtain dextimolol maleate ophthalmic gel preparation.

[0146] Example 10

[0147]

[0148] 1. Take 500g of water for injection, and evenly disperse the prescribed amount of Carbomer 940 and Hydroxypropyl Methylcellulose K4M on the liquid surface, and stir evenly after leaving until it becomes clear and transparent to obtain a gel matrix for later use;

[0149] 2. Add the prescribed amount of dextimolol maleate to 200 g of water for injection, stir until completely dissolved, then add the prescribed amount of glycerol, benzalkonium chloride and EDTA-2Na, stir until completely dissolved, add to the gel matrix, and add sodium hydroxide solution under stirring to adjust the pH to 5.5-7.8;

[0150] 3. Add water for injection to 1000 g, stir evenly, filter, and package to obtain dextimolol maleate ophthalmic gel preparation.

[0151] Embodiment 11

[0152]

[0153]

[0154] 1. Take 500g of water for injection, and evenly disperse the prescribed amount of hydroxypropyl methylcellulose E4M and gellan gum on the liquid surface, and stir evenly after leaving it until it becomes clear and transparent to obtain a gel matrix for later use;

[0155] 2. Add the prescribed amount of dextimolol maleate to 200 g of water for injection, stir until completely dissolved, then add the prescribed amount of mannitol, benzalkonium chloride and EDTA, stir until completely dissolved, add to the gel matrix, add triethanolamine solution under stirring to adjust the pH to 5.5-7.8;

[0156] 3. Add water for injection to 1000 g, stir evenly, filter, and package to obtain dextimolol maleate ophthalmic gel preparation.

[0157] Example 12

[0158]

[0159] 1. Take 500g of water for injection, and evenly disperse the prescribed amount of Carbomer 940 and Polycarbophil on the liquid surface, and stir evenly after leaving until it becomes clear and transparent to obtain a gel matrix for later use;

[0160] 2. Add the prescribed amount of dextimolol maleate to 200 g of water for injection, stir until completely dissolved, then add the prescribed amount of glycerol, benzalkonium bromide and EDTA, stir until completely dissolved, add to the gel matrix, add triethanolamine solution under stirring to adjust the pH to 5.5-7.8;

[0161] 3. Add water for injection to 1000 g, stir evenly, filter, and package to obtain dextimolol maleate ophthalmic gel preparation.

[0162] Example 13

[0163]

[0164]

[0165] 1. Take 500g of water for injection, and evenly disperse the prescribed amount of Carbomer 980 and Hydroxypropyl Methylcellulose K4M on the liquid surface, and stir evenly after leaving until it becomes clear and transparent to obtain a gel matrix for later use;

[0166] 2. Add the prescribed amount of dextimolol maleate to 200 g of water for injection, stir until completely dissolved, then add the prescribed amount of glycerol, benzalkonium bromide and EDTA-2Na, stir until completely dissolved, add to the gel matrix, add triethanolamine solution under stirring to adjust the pH to 5.5-7.8;

[0167] 3. Add water for injection to 1000 g, stir evenly, filter, and package to obtain dextimolol maleate ophthalmic gel preparation.

[0168] Embodiment 14

[0169]

[0170] 1. Take 500g of water for injection, and evenly disperse the prescribed amount of hydroxypropyl methylcellulose K4M and gellan gum on the liquid surface, and stir evenly after leaving it until it becomes clear and transparent to obtain a gel matrix for later use;

[0171] 2. Add the prescribed amount of dextimolol maleate to 200 g of water for injection, stir until completely dissolved, then add the prescribed amount of mannitol, benzalkonium chloride and EDTA, stir until completely dissolved, add to the gel matrix, add triethanolamine solution under stirring to adjust the pH to 5.5-7.8;

[0172] 3. Add water for injection to 1000 g, stir evenly, filter, and package to obtain dextimolol maleate ophthalmic gel preparation.

[0173] Embodiment 15

[0174]

[0175] 1. Take 400g of water for injection, evenly disperse the prescribed amount of hydroxypropyl methylcellulose K4M on the liquid surface, let it stand until it becomes clear and transparent, then stir evenly to obtain a gel matrix for later use;

[0176] 2. Add the prescribed amount of dextimolol maleate to 200 g of water for injection, stir until completely dissolved, then add the prescribed amount of mannitol, glycerol, sodium benzoate and EDTA-2Na, stir until completely dissolved, add to the gel matrix, add triethanolamine solution under stirring to adjust the pH to 5.5-7.8;

[0177] 3. Add water for injection to 1000 g, stir evenly, filter, and package to obtain dextimolol maleate ophthalmic gel preparation.

[0178] Example 16

[0179]

[0180]

[0181] 1. Take 500g of water for injection, and evenly disperse the prescribed amount of hydroxypropyl methylcellulose E4M and carbomer 980 on the liquid surface, and stir evenly after leaving until it becomes clear and transparent to obtain a gel matrix for later use;

[0182] 2. Add the prescribed amount of dextimolol maleate to 200 g of water for injection, stir until completely dissolved, then add the prescribed amount of mannitol, benzalkonium chloride and EDTA-2Na, stir until completely dissolved, add to the gel matrix, add triethanolamine solution under stirring to adjust the pH to 5.5-7.8;

[0183] 3. Add water for injection to 1000 g, stir evenly, filter, and package to obtain dextimolol maleate ophthalmic gel preparation.

[0184] Comparative Example

[0185] Comparative Examples 1-3

[0186] In this example, 200 tubes of each of three comparative samples were prepared with reference to the raw materials and gel preparation method of Example 10, which are Comparative Examples 1 to 3. The only difference between Comparative Examples 1 to 3 and Example 10 is the type and amount of polymer materials.

[0187]

[0188] Comparative Example 4 Preparation of Dextimolol Maleate Eye Ointment

[0189]

[0190]

[0191] 1. Heat lanolin, liquid paraffin and vaseline at 80°C to melt, stir and mix evenly to obtain ointment base A, and set aside.

[0192] 2. Add polyethylene glycol 400 to a beaker and heat at 80°C until melted. Add the prescribed amount of dextimolol maleate to the melted polyethylene glycol 400 and stir evenly. Then add benzalkonium chloride and stir to mix evenly to obtain a mixture B.

[0193] 3. Add mixture B to ointment base A, stir and mix evenly at 80°C, continue stirring until the eye ointment cools and sets, and package to obtain dextrotimolol maleate eye ointment.

[0194] Comparative Example 5 Preparation of Dextimolol Maleate Eye Drops

[0195]

[0196] 1. Take 500 mL of water for injection, add the prescribed amount of dextimolol maleate, sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium chloride, EDTA and benzalkonium chloride, and stir to dissolve.

[0197] 2. Add water for injection to 1000 mL, stir evenly, filter, and divide into packages to obtain dextimolol maleate eye drops.

[0198] Experimental Section

[0199] Experimental Example 1: Gel pH Determination

[0200] The properties of the dextimolol maleate ophthalmic preparations prepared in Examples 1-16 and Comparative Examples 1-5 were recorded, and the pH value was determined at the same time. The determination method referred to the General Rules of the 2020 Edition of the Chinese Pharmacopoeia (0631). The results are shown in Table 1 below.

[0201] Table 1

[0202] sample pH Characteristics sample pH Characteristics Example 1 6.13 Clear, medium viscosity Example 12 6.84 Clear, medium viscosity Example 2 7.08 Clear, medium viscosity Example 13 7.78 Clear, medium viscosity Example 3 7.13 Clear, medium viscosity Embodiment 14 7.23 Clear, medium viscosity Example 4 6.81 Clear, medium viscosity Embodiment 15 7.19 Clear, medium viscosity Example 5 5.53 Clear, medium viscosity Example 16 6.68 Clear, medium viscosity Example 6 6.96 Clear, medium viscosity Comparative Example 1 6.95 Clear, high viscosity Example 7 7.07 Clear, medium viscosity Comparative Example 2 6.87 Clear, low viscosity Example 8 5.68 Clear, medium viscosity Comparative Example 3 7.26 Turbid, high viscosity Example 9 6.42 Clear, medium viscosity Comparative Example 4 7.13 Turbid, high viscosity Example 10 6.92 Clear, medium viscosity Comparative Example 5 7.03 Clear, liquid Embodiment 11 7.02 Clear, medium viscosity

[0203] The gel preparations prepared in Examples 1-16 of the present invention have good properties, the samples are clear and have moderate viscosity. The pH value of ophthalmic preparations is generally controlled within the range of 5.5 to 7.8. Too high or too low pH will cause irritation to the eyes. The pH value is preferably 6.5-7.5. According to this experimental example, the pH value range of all ophthalmic gel preparations of the present invention is 5.53-7.78, which meets the quality requirements of ophthalmic preparations.

[0204] Experimental Example 2: Stability Experiment

[0205] The gel preparation samples prepared in Examples 1, 2, 3, 6, 7, 9, 10, 11 and Comparative Examples 1-5 were subjected to accelerated stability study (30°C ± 2°C, relative humidity 65% ​​± 5%), the properties of the preparations were observed at 0 and 3 months, and the related substances and contents of the samples were determined. The accelerated stability results are shown in Table 2 below.

[0206] Table 2

[0207]

[0208]

[0209] The properties, related substances, contents and pH of the gel preparation samples prepared in Examples 1, 2, 3, 6, 7, 9, 10 and 11 did not change significantly within 3 months of accelerated testing, and the stability was good.

[0210] In Comparative Example 3, when the amount of Carbomer 940 was too large (greater than 15 parts by weight), the gel had too high a viscosity and became turbid, and after 3 months of stability test, it was slightly stratified; in Comparative Example 1, when the amount of Hydroxypropyl Methylcellulose K4M was too large (greater than 18 parts by weight), although the color was still transparent, the viscosity-increasing effect was too strong and the viscosity was too large.

[0211] Experimental Example 3: Evaluation of ocular drug administration compliance

[0212] The gels prepared in Examples 2, 3, 6, 10 and 11 and the ophthalmic preparations prepared in Comparative Examples 2, 4 and 5 were put into the eyes of 4 healthy volunteers to evaluate their compliance. The volunteers washed their eyes with a cleansing eyewash for 20 seconds before and after use, with an interval of 20 minutes between each test.

[0213] Good compliance (easy to enter the eyes, not easy to flow out after entering the eyes, no sticky feeling) is 3 points; poor compliance (not easy to squeeze out, a lot of sticky eyes after entering the eyes or a lot of flow out after entering the eyes) is 0 points. Based on the actual experience of use, the score ranges from 0 to 3 points.

[0214] Table 3 Comparison of average compliance scores of samples in each group

[0215] Example 2 Example 3 Example 6 Example 10 Embodiment 11 Comparative Example 2 Comparative Example 4 Comparative Example 5 2.61 2.59 2.82 2.73 2.29 1.46 0.75 1.29

[0216] The eye gels prepared in Examples 2, 3, 6, 10 and 11 have moderate viscosity, are easily dropped into the eyes, and are not easy to flow out with tears after entering the eyes; after entering the eyes, due to the low amount of Carbomer 940 (less than 1.5 parts by weight), the viscosity of Comparative Example 2 is low after entering the eyes, and it is still easy to flow out with tears; Comparative Example 4 is an eye ointment texture, which is easy to cover the eyes after use, affecting daily life and work; Comparative Example 5 is a solution, which flows out in large quantities with tears after entering the eyes.

[0217] Experimental Example 4: Eye Irritation Test

[0218] (1) One eye irritation test

[0219] Take 10 healthy rabbits (Experimental Animal Center of Guangzhou University of Chinese Medicine) and divide them into 5 groups, 2 rabbits in each group, one male and one female. 80 μL of the gel preparations prepared in Example 2, Example 3, Example 6, Example 10 and Example 11 were applied to the left eye of the rabbit, and the right eye was not administered as a blank control. After administration, the eye was passively closed for 10 seconds, and the irritation of the eye after 6h, 12h, 24h, and 48h after administration was recorded, and scored according to the eye irritation scoring standard table. The total score of each group was divided by the number of animals, which was the final eye irritation score, and the degree of irritation was judged according to the eye irritation evaluation standard table.

[0220] (2) Multiple eye irritation tests

[0221] Take 10 healthy rabbits (Experimental Animal Center of Guangzhou University of Chinese Medicine) and divide them into 5 groups, 2 rabbits in each group, one male and one female. 80 μL of the gel preparations prepared in Example 2, Example 3, Example 6, Example 10 and Example 11 were applied to the left eye of the rabbit, and the right eye was not given as a blank control. After administration, the eye was passively closed for 10 seconds. Administer once every 24 hours for 1 week, record the irritation of the eye before administration every day and 1, 2 and 3 days after the last administration, and score according to the eye irritation scoring standard table, divide the total score of each group by the number of animals, that is, the final eye irritation score, and judge the degree of irritation according to the eye irritation evaluation standard table.

[0222] The eye irritation scoring standard table is shown in Table 4 below.

[0223] Table 4

[0224]

[0225] The eye irritation evaluation standard table is shown in Table 5 below.

[0226] Table 5

[0227]

[0228] The eye irritation scoring results after single and multiple administrations are shown in Tables 6 and 7 below, respectively.

[0229] Table 6 Single administration irritation results

[0230]

[0231] Table 7 Multiple administration irritation results

[0232]

[0233] After single and multiple administrations, the eyes of the rabbits on the administration side were observed at various time points, and no congestion, edema, or secretions were observed. The average score of each group was 0, indicating that the gel preparation of the present invention is relatively safe and non-irritating to the eyes.

[0234] Experimental Example 5: Determination of the concentration of right timolol in rabbit tears after administration

[0235] Take 6 healthy rabbits (Experimental Animal Center of Guangzhou University of Chinese Medicine) and divide them into 3 groups, 2 in each group, one male and one female. 50 μl of the gel preparations prepared in Example 2, Example 6 and Example 10 were respectively dripped into the conjunctival sac under the left eye of the rabbit as the test group, and 50 μl of the solution prepared in Comparative Example 5 of the same specification was dripped into the conjunctival sac under the right eye of a random group of rabbits as the control group, and passively closed for 30 seconds after administration. At 15, 30, 60 and 120 minutes after administration, filter paper (precision weighing) was placed in the upper eyelid of the rabbit, passively closed for 30 seconds to absorb tears, and then taken out, accurately weighed, eluted with mobile phase, and the supernatant was taken after centrifugation to determine the concentration of right timolol in tears by HPLC, and the results are shown in Table 8 below.

[0236] Table 8 Concentration results of right timolol in tears after administration of different dosage forms

[0237]

[0238] Note: ND: Dex-timolol not detected

[0239] After the dextimolol maleate gel preparations prepared in Examples 2, 6 and 10 were dropped into rabbit eyes, the concentration of dextimolol in tears was significantly higher than that of the eye drop preparations at the same time. This is because, compared with the solution, the gel preparation has a higher viscosity after entering the eye, which reduces the elimination of the drug by tears, thereby significantly prolonging the retention time in the eye.

Claims

1. A pharmaceutical composition comprising dexamolol maleate, wherein: The components and dosage of the pharmaceutical composition are as follows: Dextrotimolol maleate, calculated as dextrotimolol, 1-25 parts by weight 1.5-470 parts by weight of polymer material Osmotic pressure regulator 1-60 parts by weight Antibacterial agent 0-4 parts by weight Stabilizer 0.1-0.5 parts by weight pH adjuster appropriate amount Water for injection is added to 1000 parts by weight.

2. The pharmaceutical composition comprising dexamolol maleate according to claim 1, wherein: The polymer material is selected from one or more of carbomer, poloxamer, polycarbophil, cellulose derivatives, poly-N-isopropylacrylamide, chitosan, hyaluronic acid, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol, sodium alginate, xanthan gum, and gellan gum; The osmotic pressure regulator is selected from one or more of glycerol, mannitol, sodium chloride, sorbitol, glucose and propylene glycol; The antibacterial agent is selected from one or more of sodium benzoate, benzalkonium chloride, benzalkonium bromide, phenylethyl alcohol, benzyl alcohol, methylparaben, phenoxyethanol, and methylparaben; The stabilizer is selected from EDTA and / or EDTA-2Na; The pH regulator is selected from one or more of sodium hydroxide, potassium hydroxide, triethanolamine, ethanolamine, borax, boric acid, hydrochloric acid, acetic acid, sulfuric acid, phosphate, citric acid, and sodium citrate.

3. The pharmaceutical composition comprising dexamolol maleate according to claim 1 or 2, wherein: The polymer material is selected from carbomer, and the carbomer is selected from one or more of carbomer 934, carbomer 940, carbomer 941, carbomer 971, carbomer 973, carbomer 980 and carbomer 981, preferably carbomer 940 and / or carbomer 980; and / or The polymer material is selected from cellulose derivatives, including one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, carboxymethyl cellulose, sodium methylcellulose, sodium carboxymethyl cellulose, preferably hydroxypropyl methylcellulose; preferably, the hydroxypropyl methylcellulose is selected from one or more of hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose E4M and hydroxypropyl methylcellulose E10M, preferably hydroxypropyl methylcellulose K4M and / or hydroxypropyl methylcellulose E4M; and / or The polymer material is selected from poloxamer, and the poloxamer is one or more of poloxamer 407, poloxamer 188 and poloxamer 338, preferably poloxamer 407 and / or poloxamer 188; and / or The polymer material is selected from polycarbophil; and / or The polymer material is selected from gellan gum.

4. The pharmaceutical composition comprising dexamolol maleate according to claim 1 or 2, wherein: The polymer material is Carbomer 980, and the amount used is 1.5-15 parts by weight, preferably 2-12 parts by weight, and more preferably 2-10 parts by weight; or, the polymer material is Carbomer 940, and the amount used is 1.5-15 parts by weight, preferably 2-8 parts by weight, and more preferably 2-6 parts by weight; and / or The polymer material is hydroxypropyl methylcellulose K4M, and the amount used is 2-18 parts by weight, preferably 3-15 parts by weight, and more preferably 3-13 parts by weight; or, the polymer material is hydroxypropyl methylcellulose E4M, and the amount used is 2-18 parts by weight, preferably 3-15 parts by weight, and more preferably 3-13 parts by weight; and / or The polymer material is selected from poloxamer 407, and the amount used is 100-350 parts by weight, preferably 110-300 parts by weight, and more preferably 150-280 parts by weight; and / or, the polymer material is poloxamer 188, and the amount used is 10-120 parts by weight, preferably 15-100 parts by weight, and more preferably 15-90 parts by weight; and / or The polymer material is selected from polycarbophil, and the amount used is 3-30 parts by weight, preferably 4-22 parts by weight, and more preferably 4-18 parts by weight; and / or The polymer material is selected from gellan gum, and the amount used is 0.5-9 parts by weight, preferably 1-8 parts by weight, and more preferably 1.5-6 parts by weight.

5. The pharmaceutical composition comprising dexamolol maleate according to claim 1 or 2, wherein: The osmotic pressure regulator is glycerol, and the amount used is 10-35 parts by weight, preferably 12-30 parts by weight, and more preferably 18-26 parts by weight; and / or The osmotic pressure regulator is mannitol, and the amount used is 20-60 parts by weight, preferably 25-50 parts by weight, and more preferably 30-45 parts by weight; and / or The osmotic pressure regulator is sodium chloride, and the amount used is 1-8 parts by weight, preferably 1.5-7 parts by weight, and more preferably 1.5-6 parts by weight.

6. The pharmaceutical composition comprising dexamolol maleate according to claim 1 or 2, wherein: The antibacterial agent is benzalkonium chloride or benzalkonium bromide, and the amount used is 0-0.5 parts by weight, preferably 0-0.25 parts by weight, and more preferably 0-0.12 parts by weight; or The antibacterial agent is sodium benzoate, and the dosage is 0-4 parts by weight, preferably 0-3 parts by weight, and more preferably 0-2.5 parts by weight.

7. The pharmaceutical composition comprising dexamolol maleate according to claim 1 or 2, wherein: The stabilizer is EDTA and / or EDTA-2Na, and the amount used is 0.1-0.5 parts by weight, preferably 0.15-0.4 parts by weight, and more preferably 0.2-0.3 parts by weight.

8. The pharmaceutical composition comprising dexamolol maleate according to claim 1 or 2, wherein: The pH regulator is sodium hydroxide and / or triethanolamine, and a proper amount of the pH regulator is added to make the pH of the pharmaceutical composition 5.5-7.8, preferably, 6.0-7.8, and more preferably, 6.5-7.

5.

9. A method for preparing a pharmaceutical composition comprising dexamolol maleate as claimed in any one of claims 1 to 8, the method comprising the following steps: (1) Take an appropriate amount of water for injection, evenly disperse the prescribed amount of polymer material on the liquid surface, let it stand until it becomes clear and transparent, and then stir it evenly to obtain a gel matrix for later use; (2) adding a prescribed amount of dextimolol maleate to an appropriate amount of water for injection, stirring until completely dissolved, then adding a prescribed amount of an osmotic pressure regulator, an antibacterial agent and a stabilizer, stirring until completely dissolved, to obtain a mixed solution comprising dextimolol maleate, an osmotic pressure regulator, an antibacterial agent and a stabilizer, adding the mixed solution to the gel matrix obtained in step (1), and adding a pH regulator to adjust the pH to 5.5-7.8 under stirring; (3) Add water for injection to the full amount, stir evenly, and filter to obtain a pharmaceutical composition containing dextrotimolol maleate.

10. An ophthalmic gel preparation comprising dextimolol maleate, comprising the pharmaceutical composition comprising dextimolol maleate according to any one of claims 1 to 8.

11. Use of the pharmaceutical composition comprising dextimolol maleate according to any one of claims 1 to 8 or the ophthalmic gel preparation comprising dextimolol maleate according to claim 10 for treating glaucoma or ocular hypertension.

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