Eye drops containing aryl propionic acid compound

Abstract

The invention provides an eye drop containing an aryl propionic acid compound. According to the invention, the active metabolite converted from loxoprofen sodium in vivo, namely the compound as shown in the formula I and the salt thereof, is taken as effective components, and is prepared into the eye drops through a preparation means for direct eye drop administration, so that the problem that when a prodrug is directly administered, only part of the prodrug can be converted into the active metabolite, and the bioavailability is low is effectively solved. Compared with the compound shown in the formula I, the salt of the compound has high solubility and good stability, and the eye drops prepared by taking the compound as an active component have obviously improved stability and can be stored for a long time. The eye drops are small in side effect, safe, reliable in curative effect and suitable for treating inflammation of external eyes and front eyes, xerophthalmia and eye pain after operation; the raw materials are easy to obtain, the cost is low, industrial large-scale production can be realized, and remarkable economic benefits are achieved.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to an eye drop containing an arylpropionic acid compound. Background Art

[0002] Nonsteroidal anti-inflammatory drugs (NSAIDs) have anti-inflammatory, anti-allergic, and analgesic effects. Topical application can prevent and treat ocular inflammatory diseases caused by various reasons, with fewer adverse reactions and safer clinical application than glucocorticoids. Currently available nonsteroidal anti-inflammatory eye drops include NSAIDs including 0.1% pranoprofen eye drops, 0.1% diclofenac sodium eye drops, 0.5% and 0.4% ketorolac tromethamine eye drops, 0.03% flurbiprofen sodium eye drops, 0.1% nepafenac, bromfenac sodium, indomethacin and other eye drops.

[0003] However, these commonly used NSAIDs eye drops have a variety of adverse reactions, and these corneal toxicity and ocular side effects may be closely related to the active ingredients in the topical eye drops. In addition, NSAIDs eye drops should be used with caution in conditions such as diabetes, autoimmune diseases, ocular surface diseases, or early corneal lesions after eye surgery. Therefore, new varieties of ophthalmic topical nonsteroidal anti-inflammatory drugs that are safe, effective, have strong intraocular penetration, and are stable in nature are in great clinical need.

[0004] Loxoprofen Sodium is the first propionic acid precursor nonsteroidal anti-inflammatory drug, first developed by Daiichi Sankyo Co., Ltd. of Japan and first marketed in Japan in 1986. The drug is a prodrug and has no activity itself. After oral administration, loxoprofen is absorbed in the form of free acid and can be bioconverted into hydroxy metabolites with three chiral centers in the body, theoretically generating 8 stereoisomers, of which the trans-hydroxy form (such as compound of formula I) has pharmacological activity.

[0005]

[0006] Its characteristics are mainly reflected in the peak plasma concentration within 30 minutes of oral administration, small toxic and side effects, and good clinical effects. At the same time, its indications are also very wide, and it has a good analgesic and anti-inflammatory effect on chronic rheumatoid arthritis, deformed arthritis, low back pain, frozen shoulder, cervical shoulder inflammation, postoperative and trauma. At present, the dosage forms of marketed drugs are tablets, capsules, granules, patches, and gels. Guangzhou Aobo Pharmaceutical Technology Co., Ltd. has applied for a Class 2.2 new drug, loxoprofen sodium eye drops, and applied for a new drug clinical trial application in February 2020 (acceptance number CXHL2000030). It has obtained clinical implicit permission and is currently undergoing a phase II clinical trial. Its patent application CN106880590A discloses a precursor non-steroidal anti-inflammatory drug eye drops and a preparation method thereof, namely loxoprofen sodium eye drops. Loxoprofen sodium needs to enter the systemic circulation through capillaries, and after being metabolized to generate active metabolites, it returns to the target site with the blood to exert its effect. The systemic exposure in the body is low, the elimination is slow, and the bioavailability is low. Summary of the invention

[0007] Currently, the problem faced by eye drops is the low bioavailability of the active substance (<5%). At the same time, when administered in the form of the prodrug loxoprofen, the prodrug is only partially converted into active metabolites in the eye to exert its efficacy, further reducing the bioavailability.

[0008] The present invention uses the trans-hydroxy active metabolite of loxoprofen (the compound of formula I and its salt) as an effective ingredient directly as eye drops, and prolongs the retention time of the drug in the cornea through effective preparation means, reduces the frequency of administration, and improves the permeability of the cornea, so that more effective ingredients can enter the eye and directly exert anti-inflammatory and analgesic effects, thereby achieving good therapeutic effects.

[0009] The solution to achieve the above invention object is:

[0010] The present invention provides an eye drop containing an arylpropionic acid compound, and specifically relates to an anti-inflammatory and analgesic eye drop containing a compound of formula I and a salt thereof as an effective ingredient.

[0011] The present invention provides an eye drop containing an arylpropionic acid compound, comprising:

[0012] (a) Compounds of formula I and their salts

[0013]

[0014] (b) an excipient for ophthalmic preparations; wherein the content of the compound represented by formula I is 0.05 to 1.0 wt %;

[0015] The salt is selected from the following forms:

[0016] The sodium salt of the compound of formula I shown in formula II;

[0017] The diethylamine salt of the compound of formula I shown in formula III;

[0018] The tromethamine salt of the compound of formula I shown in formula IV;

[0019] The ethanolamine salt of the compound of formula I shown in formula V;

[0020] The L-lysine salt of the compound of formula I shown in formula VI;

[0021] The L-arginine salt of the compound of formula I shown in formula VII;

[0022] The triethanolamine salt of the compound of formula I shown in formula VIII;

[0023] The N-methylglucosamine salt of the compound of formula I shown in formula IX;

[0024] 1-(2-hydroxyethyl)-pyrrolidine salt of the compound of formula I represented by formula X; magnesium salt of the compound of formula I represented by formula XI;

[0025] The calcium salt of the compound of formula I shown in formula XII;

[0026] The tert-butylamine salt of the compound of formula I shown in formula XIII;

[0027] The piperazine salt of the compound of formula I shown in formula XIV:

[0028]

[0029] According to an embodiment of the present invention, the salt is preferably in the following forms:

[0030] The diethylamine salt of the compound of formula I shown in formula III;

[0031] The tromethamine salt of the compound of formula I shown in formula IV;

[0032] The ethanolamine salt of the compound of formula I shown in formula V;

[0033] The L-lysine salt of the compound of formula I shown in formula VI;

[0034] The L-arginine salt of the compound of formula I shown in formula VII;

[0035] The triethanolamine salt of the compound of formula I shown in formula VIII;

[0036] Formula IX is the N-methylglucamine salt of the compound of formula I.

[0037] According to an embodiment of the present invention, the excipients of the ophthalmic preparation include a metal ion complexing agent, a thickener, an antibacterial agent, an osmotic pressure regulator, and a pH regulator.

[0038] According to an embodiment of the present invention, the metal ion complexing agent is selected from at least one of disodium edetate, calcium sodium edetate, dihydroxyethylglycine, ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid and penta(carboxymethyl)diethylenetriamine, aminotriacetic acid, sodium gluconate, sodium citrate, and tartaric acid; the content of the metal ion complexing agent is 0.01 to 0.1 wt%.

[0039] According to an embodiment of the present invention, the thickener is selected from at least one of sodium hyaluronate, hydroxypropyl methylcellulose, polysorbate 20, carbomer, xanthan gum, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium polyacrylate, microcrystalline cellulose, povidone, glycerol, sodium alginate, poloxamer, dextran, and polycarbophil; the content of the thickener is 0.01 to 0.1 wt%.

[0040] According to an embodiment of the present invention, the antibacterial agent is selected from one or more of benzalkonium chloride, methylparaben, ethylparaben, propylparaben, butylparaben, benzalkonium bromide, sorbic acid, chlorobutanol, and boric acid; the content of the antibacterial agent is 0.01 to 0.02 wt%.

[0041] According to an embodiment of the present invention, the osmotic pressure regulator is selected from at least one of sodium chloride, potassium chloride, boric acid, borax, glycerol, propylene glycol, mannitol, sodium sulfate, potassium sulfate, sodium nitrate, potassium nitrate, glucose, sorbitol, and sodium cromoglycate; the content of the osmotic pressure regulator is 0.5-2.0wt%.

[0042] According to an embodiment of the present invention, the pH adjuster is selected from at least one of disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, boric acid, borax, hydrochloric acid, phosphoric acid, acetic acid, sodium acetate, citric acid, sodium citrate, citric acid, sodium citrate, tartaric acid, and sodium tartrate; the pH adjuster is used to adjust the pH of the eye drops to 6.0-8.0.

[0043] The present invention also provides an application of the eye drops in preparing drugs for preventing or treating ophthalmic diseases, and specifically relates to an application of the eye drops in preparing drugs for treating inflammation of the outer eye and anterior eye, dry eye, and postoperative eye pain.

[0044] Among them, inflammation of the external eye and the anterior eye includes at least one of conjunctivitis, keratitis, scleritis, blepharitis, superficial scleritis, iridocyclitis, and postoperative inflammation.

[0045] Beneficial effects of the present invention:

[0046] Compared with the prior art, the present invention uses the active metabolite of loxoprofen sodium converted in vivo, i.e., the compound of formula I and its salt as the effective ingredient, and prepares it into eye drops by means of preparation for direct eye drop administration, which effectively solves the problem that only part of the prodrug can be converted into active metabolites and has low bioavailability when it is directly administered. Compared with the compound of formula I, its salt has high solubility and good stability, and the eye drops prepared with it as the active ingredient have significantly improved stability and can be stored for a long time. In addition, the eye drops have few side effects, are safe and have reliable efficacy, and are suitable for treating inflammation of the external eye and the anterior eye, dry eye, and postoperative eye pain; the raw materials are easy to obtain, the cost is low, and industrial large-scale production can be achieved, with significant economic benefits. DETAILED DESCRIPTION

[0047] In order to make the above-mentioned purposes, features and advantages of the present disclosure more obvious and easy to understand, the specific implementation methods of the present disclosure are described in detail below in conjunction with specific embodiments. In the following description, many specific details are set forth to facilitate a full understanding of the present disclosure, but the present disclosure can also be implemented in other ways different from those described herein, and those skilled in the art can make similar generalizations without violating the connotation of the present disclosure, so the present disclosure is not limited by the specific embodiments disclosed below.

[0048] Example 1 Preparation of Compounds of Formula I

[0049] The preparation method of the compound of formula I of the present invention refers to patent: ZL201610435178.8 A method for preparing the active metabolite of loxoprofen.

[0050] Example 2 Solubility in Water of Salts of Formula I

[0051] Weigh 20 mg each of the free acid of the compound of formula I, the sodium salt of the compound of formula I, the diethylamine salt, the tromethamine salt, the ethanolamine salt, the L-lysine salt, the L-arginine salt, the triethanolamine salt, the N-methylglucamine salt, the 1-(2-hydroxyethyl)-pyrrolidine salt, the magnesium salt, the calcium salt, and the tert-butylamine salt, and use the solubility test method in the general rules of the 2015 edition of the Chinese Pharmacopoeia to add the samples into an appropriate amount of 25°C water, shake vigorously for 30 seconds every 5 minutes, and observe the dissolution within 30 minutes; when there are no visible solute particles, it is regarded as completely dissolved. Very soluble means that 1g (ml) of solute can be dissolved in less than 1ml of solvent; easily soluble means that 1g (ml) of solute can be dissolved in 1 to less than 10ml of solvent; soluble means that 1g (ml) of solute can be dissolved in 10 to less than 30ml of solvent; slightly soluble means that 1g (ml) of solute can be dissolved in 30 to less than 100ml of solvent; slightly soluble means that 1g (ml) of solute can be dissolved in 100 to less than 1000ml of solvent; very slightly soluble means that 1g (ml) of solute can be dissolved in 1000 to less than 10000ml of solvent; almost insoluble or insoluble means that 1g (ml) of solute cannot be completely dissolved in 10000ml of solvent. The results are shown in Table 1:

[0052] Table 1 Solubility test

[0053] name Solubility (based on free acid) Pharmacopoeia Solubility Free acid About 1.00mg / mL Slightly soluble Sodium salt Greater than 92.78 mg / mL Soluble Diethylamine salt Greater than 78.02 mg / mL Soluble Tromethamine salt Greater than 67.88 mg / mL Soluble Ethanolamine salt Greater than 81.06 mg / mL Soluble L-Lysine salt Greater than 63.57 mg / mL Soluble L-Arginine salt Greater than 59.53 mg / mL Soluble Triethanolamine salt Greater than 63.09 mg / mL Soluble N-Methylglucosamine salt Greater than 56.55 mg / mL Soluble 1-(2-Hydroxyethyl)-pyrrolidinoyl salt Greater than 69.00 mg / mL Soluble Magnesium salt Greater than 96.72 mg / mL Soluble Calcium salt Greater than 93.82 mg / mL Soluble Tert-butylamine salt Greater than 78.02 mg / mL Soluble

[0054] As can be seen from the above, after the active metabolite of loxoprofen (i.e., free acid) is prepared into a new salt form, the solubility is increased by about 60 to 100 times. The improvement of the physicochemical properties is helpful for the preparation of solution-type preparations.

[0055] Example 3 Stability Study of Salts of Formula I Compounds

[0056] The salt of the compound of formula I and the free acid of the compound of formula I were subjected to an influencing factor test and an accelerated stability test, and the method is as shown in the Chinese Pharmacopoeia 2015 edition.

[0057] First, the influencing factors test:

[0058] 1) High temperature test: Take the salt of the compound of formula I and the free acid of the compound of formula I, place them at 60°C for 10 days, take samples on the 10th day, measure various indicators and compare them with the samples at time 0. The results are shown in the table below.

[0059] 2) High humidity test: The salt of the compound of formula I and the free acid of the compound of formula I were placed at RH75% for 10 days. Samples were taken on the 10th day and various indicators were measured and compared with those of the sample on day 0. The results are shown in the table below.

[0060] 3) Strong light irradiation test: Take the salt of the compound of formula I and the free acid of the compound of formula I, place them under the condition of illumination of (4500±500) Lux for 10 days, take samples on the 10th day, measure various indicators and compare them with the samples at 0, the results are shown in Table 2:

[0061] Table 2 Stability of compounds

[0062]

[0063]

[0064]

[0065] The results show that compared with the free acid of the compound of formula I, the various salt solids of the compound of formula I, including crystalline and amorphous forms, have good stability under the experimental conditions of influencing factors.

[0066] Second, accelerated stability test

[0067] The salt of the compound of formula I and the free acid of the compound of formula I were subjected to a 6-month accelerated stability test in a constant temperature and humidity chamber. The conditions were: 40°C / 75% relative humidity (RH), and samples were taken at 1, 2, 3, and 6 months, respectively, and the purity and impurity tests and PXRD characterization after accelerated stability were performed by high performance liquid chromatography. The results are shown in Table 3:

[0068] Table 3 Accelerated stability of compounds

[0069]

[0070]

[0071] The results show that compared with strong base salts such as the sodium salt of the compound of formula I, the solids of diethylamine salt, tromethamine salt, ethanolamine salt, L-lysine salt, L-arginine salt, triethanolamine salt, and N-methylglucamine salt of the compound of formula I have better stability under accelerated experimental conditions, while the free acid of the compound of formula I is unstable.

[0072] Example 4

[0073] Table 4 Raw materials and proportions of eye drops

[0074]

[0075]

[0076] Preparation process:

[0077] (1) Weigh the prescribed amount of the main drug, metal ion complexing agent, thickener, antibacterial agent, osmotic pressure regulator and pH regulator, add them to an appropriate amount of water for injection, and stir until completely dissolved;

[0078] (2) Adjust the pH value of the solution in (1) to 6-8, adjust the osmotic pressure molar concentration to 260-320 mOsmol / kg, and make up to 500 ml with water for injection;

[0079] (3) The eye drops in (2) are filtered through a 0.22 μm filter in a Class A clean area, and then filled and sealed in a "blow-fill-seal" integrated machine, with a filling volume of 0.4 to 0.8 ml;

[0080] (4) Cool to 4°C and keep for 1 to 3 hours.

[0081] Example 5 Sample stability:

[0082] Take the above prescription 1 to 8 eye drops, place them in a sealed container, and place them away from light at a temperature of 40℃±2℃ and RH75%±5% for 6 months. Take samples for inspection at the 1st, 3rd and 6th month respectively, and compare the results with the 0-day sample. The results are shown in Table 5:

[0083] Table 5 Stability test results of eye drops of prescriptions 1 to 8

[0084]

[0085]

[0086] The results show that the eye drops containing the salt of the compound of formula I prepared by prescription 2-8, when placed at 40℃±2℃, RH75%±5% for 6 months, have no significant change in the content of the eye drops, and the total impurities of the eye drops are also low, meeting the limit requirements, and have good stability. However, the eye drops containing the sodium salt of the compound of formula I prepared by prescription 1, when placed at 40℃±2℃, RH75%±5% for 6 months, have a significant decrease in the content of the eye drops, and a significant increase in the total impurities of the eye drops, indicating that it has poor stability under long-term placement.

[0087] Example 6 Eye irritation test:

[0088] Healthy New Zealand white rabbits were observed for eyelids, cornea, conjunctiva and other tissues under slit lamp 24 hours before the test. The test was started only after confirming that there was no ocular lesion. The left and right eyes of the rabbits were used as self-controls, and the right eye was given the test compound (prescription 2-8).

[0089] A multiple-dose irritation experiment was conducted, with the specific method being: 50 μl was administered each time, 3 times a day, for 7 consecutive days, and the left eye was administered with the same frequency and the same amount of normal saline as a control.

[0090] After each application of the drug, the rabbits were observed for eye irritation symptoms such as frequent blinking, photophobia, and tearing. Eye irritation scores were performed according to the Draize eye irritation scoring principle. The results are shown in Table 6:

[0091] Scoring criteria:

[0092]

[0093] Eye irritation response score standard:

[0094] Points 0-1 2-3 4-6 7-9 evaluate No stimulation Mild irritation Moderate stimulation Intensity stimulation

[0095] Table 6 Irritation scores of prescriptions 2 to 8 on rabbit eyes

[0096]

[0097]

[0098] According to the experimental results, in the prescription 2 and prescription 8 administration groups, some rabbits had mild congestion symptoms, but the average score of eye irritation reaction did not exceed 1 point. In the other prescription administration groups, there were no obvious irritation symptoms, indicating that the eye drops prepared by the present invention have no irritation to rabbit eyes after multiple administration and have good biocompatibility.

Claims

1. An eye drop comprising an aryl propionic acid compound, characterized in that: It contains: (a) Compounds of formula I and their salts (b) an excipient for ophthalmic preparations; wherein the content of the compound represented by formula I is 0.05 to 1.0 wt %; and the salt is selected from the following forms: The sodium salt of the compound of formula I shown in formula II; The diethylamine salt of the compound of formula I shown in formula III; The tromethamine salt of the compound of formula I shown in formula IV; The ethanolamine salt of the compound of formula I shown in formula V; The L-lysine salt of the compound of formula I shown in formula VI; The L-arginine salt of the compound of formula I shown in formula VII; The triethanolamine salt of the compound of formula I shown in formula VIII; The N-methylglucosamine salt of the compound of formula I shown in formula IX; 1-(2-hydroxyethyl)-pyrrolidine salt of the compound of formula I represented by formula X; A magnesium salt of a compound of formula I represented by formula XI; The calcium salt of the compound of formula I shown in formula XII; The tert-butylamine salt of the compound of formula I shown in formula XIII; The piperazine salt of the compound of formula I shown in formula XIV:

2. The eye drops according to claim 1, characterized in that The salt is selected from the following forms: The diethylamine salt of the compound of formula I shown in formula III; The tromethamine salt of the compound of formula I shown in formula IV; The ethanolamine salt of the compound of formula I shown in formula V; The L-lysine salt of the compound of formula I shown in formula VI; The L-arginine salt of the compound of formula I shown in formula VII; The triethanolamine salt of the compound of formula I shown in formula VIII; Formula IX is the N-methylglucamine salt of the compound of formula I.

3. The eye drops according to claim 2, characterized in that The ophthalmic preparation excipients include metal ion complexing agents, thickeners, antibacterial agents, osmotic pressure regulators, and pH regulators.

4. The ophthalmic preparation according to claim 2, characterized in that The metal ion complexing agent is selected from at least one of disodium edetate, calcium sodium edetate, dihydroxyethylglycine, ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid and penta(carboxymethyl)diethylenetriamine, aminotriacetic acid, sodium gluconate, sodium citrate, and tartaric acid; the content of the metal ion complexing agent is 0.01-0.1wt%.

5. The ophthalmic preparation according to claim 2, characterized in that The thickener is selected from at least one of sodium hyaluronate, hydroxypropyl methylcellulose, polysorbate 20, carbomer, xanthan gum, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium polyacrylate, microcrystalline cellulose, povidone, glycerol, sodium alginate, poloxamer, dextran, and polycarbophil; the content of the thickener is 0.01-0.1wt%.

6. The eye drops containing aryl propionic acid compounds according to claim 2, characterized in that: The antibacterial agent is selected from one or more of benzalkonium chloride, methylparaben, ethylparaben, propylparaben, butylparaben, benzalkonium bromide, sorbic acid, chlorobutanol and boric acid; the content of the antibacterial agent is 0.01-0.02wt%.

7. The eye drops according to claim 2, characterized in that The osmotic pressure regulator is selected from at least one of sodium chloride, potassium chloride, boric acid, borax, glycerol, propylene glycol, mannitol, sodium sulfate, potassium sulfate, sodium nitrate, potassium nitrate, glucose, sorbitol, and sodium cromoglycate; the content of the osmotic pressure regulator is 0.5-2.0wt%.

8. The eye drops according to claim 2, characterized in that The pH adjuster is selected from at least one of disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, boric acid, borax, hydrochloric acid, phosphoric acid, acetic acid, sodium acetate, citric acid, sodium citrate, citric acid, sodium citrate, tartaric acid, and sodium tartrate; the pH adjuster is used to adjust the pH of the eye drops to 6.0-8.

0.

9. Use of the eye drops according to any one of claims 1 to 8 in the preparation of drugs for preventing or treating ophthalmic diseases.

10. Use of the eye drops according to any one of claims 1 to 8 in the preparation of drugs for treating inflammation of the external eye and the anterior eye, dry eye, and postoperative eye pain; the inflammation of the external eye and the anterior eye includes at least one of conjunctivitis, keratitis, scleritis, blepharitis, superficial scleritis, iridocyclitis, and postoperative inflammation.

Images