CN112791050B

CN112791050B - Azithromycin eye drops

Info

Publication number: CN112791050B
Application number: CN201911108264.8A
Authority: CN
Inventors: 王超; 付欢; 刘晨曦; 万利鹏; 延静; 尹传忠
Original assignee: Hubei Grand Everyday Bright Eyes Pharmaceutical Co ltd
Current assignee: Hubei Grand Everyday Bright Eyes Pharmaceutical Co ltd
Priority date: 2019-11-13
Filing date: 2019-11-13
Publication date: 2022-11-18
Anticipated expiration: 2039-11-13
Also published as: CN112791050A

Abstract

The invention provides azithromycin eye drops, which comprise: azithromycin and a chitosan derivative, wherein the chitosan derivative has a viscosity of 1500-2000 mPa.s under the following conditions: concentration of chitosan derivative was 5 wt%, test temperature: 25 ℃, test procedure: a viscometer with a small sample holder, rotor No. 4, was used for the test at a speed of 30r/min. The azithromycin eye drops not only have proper viscosity, but also have low pipeline loss in the preparation process; and the azithromycin sustained-release tablet has excellent bacteriostatic effect, low preservative dosage and high safety, and can promote the dissolution of azithromycin, enhance the absorption effect and improve the bioavailability.

Description

Azithromycin eye drops

Technical Field

The invention relates to the field of pharmaceutical preparations, in particular to azithromycin eye drops.

Background

With the acceleration of life rhythm, the abnormity of climate and the increase of computer popularity, the incidence of various diseases of eyes is higher and higher. Currently, there are three main types of eye drops for clinically treating eye diseases: one is to dissolve antibiotics or antiviral drugs directly in distilled water to prepare a certain concentration for clinically treating eye diseases. After the preparation is dripped into eyes, the retention time of active ingredients of the medicine is short, the bioavailability of the medicine is low, and the treatment effect is not good enough; the other is to prepare the active pharmaceutical ingredient into a paste, which prolongs the retention time of the active pharmaceutical ingredient in the eye, but it blocks the view and is inconvenient to use.

Therefore, eye drops which are easy to use and excellent in therapeutic effect are still in need of further research.

Disclosure of Invention

The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, the invention provides a new azithromycin eye drop which has proper viscosity and low pipeline loss in the preparation process; and the azithromycin sustained-release tablet has excellent antibacterial effect, low preservative dosage and high safety, and can promote the dissolution of azithromycin, enhance the absorption effect and improve the bioavailability.

Therefore, in the first aspect of the invention, the invention provides azithromycin eye drops. According to the embodiment of the invention, the azithromycin eye drops comprise: azithromycin and a chitosan derivative having a viscosity of 1500 to 2000mpa.s, such as 1600, 1700, 1800, 1900 or 2000mpa.s, under the following conditions; the viscosity test conditions were as follows: concentration of chitosan derivative was 5 wt%, test temperature: 25 ℃, test procedure: the viscosity was measured using a viscometer with a small sample holder (Brookfield rotational viscometer, USA), spindle 4, at a speed of 30r/min. It should be noted that the concentration of the chitosan derivative is 5 wt%, which means that the liquid to be measured is an aqueous solution of the chitosan derivative, and the concentration of the chitosan derivative is 5 wt%. The inventor finds that the bacteriostatic effect of the azithromycin eye drops is remarkably reduced if the viscosity of the chitosan derivative is too high or too low under the test conditions. Therefore, the azithromycin eye drops containing the chitosan derivative with the viscosity of 1500-2000 mPa.s under the test conditions, provided by the embodiment of the invention, have proper viscosity and low pipeline loss in the preparation process; and the azithromycin sustained-release tablet has excellent antibacterial effect, low preservative dosage and high safety, and can promote the dissolution of azithromycin, enhance the absorption effect and improve the bioavailability.

According to the embodiment of the invention, the azithromycin eye drops can further comprise at least one of the following additional technical characteristics:

according to the embodiment of the invention, the azithromycin eye drops have the viscosity of 800-1200 mPa.s under the following conditions, such as 900, 1000, 1100 or 1200 mPa.s; the viscosity test conditions were as follows: and (3) testing temperature: 25 ℃, test procedure: the viscosity of azithromycin eye drops was measured using a viscometer (Brookfield rotary viscometer, usa) with a small sample holder, spindle No. 4, at a rotation speed of 30r/min. It should be noted that when the viscosity of the azithromycin eye drops is tested, the tested liquid is the azithromycin eye drops. The inventor finds that the azithromycin eye drops with proper viscosity are beneficial to the absorption of eyelids and have better treatment effect, and if the viscosity of the azithromycin eye drops is too high, the active ingredients are slowly released and are not beneficial to the absorption; if the viscosity of the azithromycin eye drops is too low, the azithromycin eye drops are easy to run off from eyelids after administration, so that the azithromycin eye drops are less absorbed by diseased parts and prolong the recovery time. Therefore, the azithromycin eye drops with the viscosity of 800-1200 mPa.s under the test conditions have better bacteriostatic effect and effectively improve the solubility of azithromycin.

According to the embodiment of the invention, the azithromycin eye drops contain 1-5 wt% of chitosan derivative, such as 1.5, 2, 2.5, 3, 3.5, 4 or 4.5 wt%. The inventor finds that if the mass fraction of the chitosan derivative in the azithromycin eye drops is too large or too small, the viscosity of the azithromycin eye drops under the aforementioned test conditions is too large or too small, resulting in a significant decrease in the bacteriostatic effect of the azithromycin eye drops. Therefore, when the mass fraction of the chitosan derivative is 1-5 wt%, the azithromycin eye drops provided by the embodiment of the invention have a better antibacterial effect, effectively improve the solubility of azithromycin, enhance the absorption effect and improve the bioavailability.

According to the embodiment of the invention, the azithromycin eye drops contain 2.0-2.5 weight percent of chitosan derivative. Therefore, the azithromycin eye drops provided by the embodiment of the invention have a better bacteriostatic effect, the solubility of azithromycin is improved, the absorption effect is enhanced, and the bioavailability is improved.

According to an embodiment of the present invention, the chitosan derivative includes at least one selected from the group consisting of carboxymethyl chitosan, carboxyethyl chitosan, carboxypropyl chitosan, carboxybutyl chitosan, and succinic acid chitosan. In some embodiments, the chitosan derivative is N, O-carboxymethyl chitosan.

According to the embodiment of the invention, the azithromycin eye drops further comprise: metal ion complexing agent, osmotic pressure regulator, pH regulator, solubilizer and preservative. According to a preferred embodiment of the present invention, the metal ion complexing agent includes at least one selected from the group consisting of disodium edetate, tartaric acid, and calcium sodium edetate. According to an embodiment of the invention, the solubilizer comprises at least one selected from the group consisting of poloxamer, tween-80, hydroxypropyl- β -cyclodextrin and polyethylene glycol-12-hydroxystearate. According to an embodiment of the invention, the preservative comprises at least one selected from benzalkonium chloride, benzalkonium bromide, sorbic acid, methylparaben, ethylparaben, benzoic acid and benzyl alcohol. According to an embodiment of the present invention, the osmotic pressure regulator includes at least one selected from the group consisting of sodium chloride, mannitol, potassium chloride, glycerol, sorbitol, glucose and propylene glycol. According to an embodiment of the invention, the pH adjusting agent comprises at least one selected from citric acid, sodium citrate, sodium hydroxide, boric acid, borax. According to an embodiment of the invention, the poloxamer is poloxamer 407. According to a more preferred embodiment of the present invention, the metal ion complexing agent is edetate disodium, the osmotic pressure regulator is sodium chloride and mannitol, the pH regulator is citric acid, sodium citrate and sodium hydroxide, the solubilizer is poloxamer, and the preservative is benzalkonium chloride. The azithromycin eye drops provided by the embodiment of the invention contain the components, so that the absorption of azithromycin can be further promoted, the bioavailability is improved, and the using effect is further improved. And the dissolution and the bacteriostatic activity of the azithromycin are further promoted.

According to the embodiment of the invention, the azithromycin eye drops contain: 1 to 5 weight percent of chitosan derivative, 1 to 5 weight percent of azithromycin, 0.05 to 0.5 weight percent of metal ion complexing agent, 0.5 to 4 weight percent of osmotic pressure regulator, 0.1 to 1 weight percent of pH regulator, 0.05 to 0.5 weight percent of solubilizer and 0.001 to 0.005 weight percent of preservative. Therefore, the azithromycin eye drops disclosed by the embodiment of the invention have a better antibacterial effect, higher solubility, enhanced absorption effect and improved bioavailability.

According to the embodiment of the invention, the azithromycin eye drops contain: 1 to 5% by weight of a chitosan derivative (e.g. 2, 3 or 4% by weight), 1 to 5% by weight of the azithromycin (e.g. 2, 3 or 4% by weight), 0.05 to 0.5% by weight of the edetate disodium (e.g. 0.1, 0.2, 0.3 or 0.4% by weight), 0.2 to 1% by weight of the sodium chloride (e.g. 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 or 0.9% by weight), 0.1 to 0.5% by weight of the citric acid (e.g. 0.2, 0.25, 0.3, 0.35, 0.4 or 0.45% by weight), 0.1-0.5 wt% of the sodium citrate (such as 0.11, 0.15, 0.2, 0.25, 0.26, 0.3, 0.35, 0.4 or 0.45 wt%), 0.5-2 wt% of the mannitol (0.6, 0.7, 0.8, 0.9, 0.95, 1, 1.2, 1.4, 1.6, 1.76, 1.8 or 1.9 wt%), 0.05-0.5 wt% of the poloxamer (such as 0.1, 0.15, 0.2, 0.25, 0.29, 0.3, 0.35, 0.4 or 0.45 wt%), 0.001-0.005 wt% of the benzalkonium chloride (such as 0.002, 0.003, 0.004 or 0.005 wt%), and the balance water, and the pH of the eye drops is 6.0-6.0. Therefore, the azithromycin eye drops provided by the embodiment of the invention have the advantages of better bacteriostatic effect, higher solubility of azithromycin, enhanced absorption effect and improved bioavailability.

According to the embodiment of the invention, the azithromycin eye drops contain: 1.5-2.5 wt% of the azithromycin, 2.0-2.5 wt% of chitosan derivative, 0.2-0.3 wt% of the edetate disodium, 0.5-0.6 wt% of the sodium chloride, 0.1-0.3 wt% of the citric acid, 0.1-0.3 wt% of the sodium citrate, 1.3-1.4 wt% of the mannitol, 0.2-0.4 wt% of the poloxamer, 0.002-0.004 wt% of the benzalkonium chloride and the balance of water, and the pH value of the azithromycin eye drops is 6.0-6.6 (such as 6.2, 6.3 and 6.4). Therefore, the azithromycin eye drops provided by the embodiment of the invention have the advantages of better bacteriostatic effect, higher solubility of azithromycin, enhanced absorption effect and improved bioavailability.

In a second aspect of the present invention, the present invention proposes the use of a chitosan derivative for the preparation of azithromycin eye drops, which has a viscosity of 800 to 1200mpa.s under the following conditions, and which is provided in the form of an aqueous solution having a concentration of 1 to 5% by weight; wherein, the viscosity test conditions of the azithromycin eye drops are as follows: and (3) testing temperature: 25 ℃, test procedure: the viscosity of the azithromycin eye drops is tested by a viscometer with a small sample holder and a No. 4 rotor under the condition of the rotating speed of 30r/min. The inventor finds that the bacteriostatic effect of the azithromycin eye drops is remarkably reduced if the viscosity of the azithromycin eye drops is too high or too low under the test conditions. Therefore, the azithromycin eye drops with the viscosity of 800-1200 mPa.s under the test conditions, provided by the embodiment of the invention, have proper viscosity and low pipeline loss in the preparation process; and the azithromycin sustained-release tablet has excellent antibacterial effect, low preservative dosage and high safety, and can promote the dissolution of azithromycin, enhance the absorption effect and improve the bioavailability.

According to an embodiment of the present invention, the above-mentioned use may further include at least one of the following additional technical features:

according to an embodiment of the present invention, the aqueous solution of the chitosan derivative further comprises an osmotic pressure regulator and a metal ion complexing agent. In some embodiments, the aqueous solution of the chitosan derivative further comprises sodium chloride and edetate disodium.

According to an embodiment of the present invention, the aqueous solution of the chitosan derivative is further subjected to dry heat sterilization at a temperature of 120 to 125 ℃ for 10 to 20min. Therefore, the azithromycin eye drops have good sterilization effect, higher safety and better bacteriostatic effect.

In a third aspect of the present invention, a system 100 for preparing azithromycin ophthalmic solution is presented. According to an embodiment of the invention, with reference to fig. 1, the system comprises:

a chitosan derivative aqueous solution storage device 101 containing a chitosan derivative at a concentration of 1 to 5% by weight, the chitosan derivative having a viscosity of 1500 to 2000mpa.s under the following conditions: the test conditions were as follows: concentration of chitosan derivative was 5 wt%, test temperature: 25 ℃; the testing steps are as follows: a viscometer with a small sample holder, rotor No. 4, was used at a speed of 30r/min.

The inventors found that azithromycin eye drops prepared from a chitosan derivative having a viscosity of 1500 to 2000mpa.s under the above-mentioned test conditions have a suitable viscosity and have low pipe loss when the azithromycin eye drops are prepared using the system according to an embodiment of the present invention.

According to an embodiment of the present invention, the system may further include at least one of the following additional features:

according to an embodiment of the invention, with reference to fig. 1, the system further comprises:

an azithromycin aqueous solution storage device 102, which contains azithromycin;

a sodium hydroxide aqueous solution storage device 103 containing sodium hydroxide; and

and the dosing device 104 is connected with the chitosan derivative aqueous solution storage device 101, the azithromycin aqueous solution storage device 102 and the sodium hydroxide aqueous solution storage device 103 respectively.

According to an embodiment of the present invention, referring to fig. 2, the system further comprises:

a dry heat sterilization device 105, wherein the dry heat sterilization device 105 is connected with the dosing device 104;

a first filtering and sterilizing device 106, wherein the dosing device 104 is connected with the azithromycin water solution storage device 102 through the first filtering and sterilizing device 106;

a second filtration and sterilization device 107, wherein the dosing device 104 is connected with the sodium hydroxide aqueous solution storage device 103 through the second filtration and sterilization device 107.

It should be noted that, referring to fig. 2, the operation flow of preparing azithromycin eye drops by using the system 100 according to the embodiment of the present invention is as follows: firstly, introducing the chitosan derivative aqueous solution in the chitosan derivative aqueous solution storage device 101 into a batching device 104 through a conduit, and performing dry heat sterilization on the chitosan derivative aqueous solution introduced into the batching device 104 through a dry heat sterilization device 105; secondly, introducing the azithromycin aqueous solution in the azithromycin aqueous solution storage device 102 into a batching device 104 through a first filtering and sterilizing device 106, and stirring until all materials are uniformly mixed; finally, the aqueous sodium hydroxide solution in the aqueous sodium hydroxide solution storage device 103 is introduced into the compounding device 104 through the second filtration and sterilization device 107, and stirred so as to adjust the pH to 6.0 to 6.6, thereby obtaining the azithromycin ophthalmic solution.

The inventors have found that when the aqueous chitosan derivative solution is introduced from the aqueous chitosan derivative solution storage device to the compounding device through the conduit, the viscosity of the aqueous chitosan derivative solution is suitable, and the pipe loss is low. In addition, compared with filtration sterilization, when the chitosan derivative aqueous solution is sterilized by a dry heat sterilization device, the sterilization effect is better, the safety is higher, and the prepared azithromycin eye drops have better antibacterial effect; meanwhile, the inventor also finds that the chitosan derivative is mixed with the azithromycin in the aqueous solution, so that the solubility of the azithromycin in the aqueous solution is enhanced.

According to an embodiment of the present invention, the storage device for an aqueous solution of a chitosan derivative further comprises an osmotic pressure regulator and a metal ion complexing agent. In some embodiments, the chitosan derivative aqueous solution storage device further comprises sodium chloride and edetate disodium. The dispersion of the chitosan derivative, sodium chloride and edetate disodium in water may be carried out in a storage device for an aqueous solution of the chitosan derivative.

According to the embodiment of the invention, the azithromycin aqueous solution storage device further contains a pH regulator, a solubilizer, an osmotic pressure regulator and a preservative. In some embodiments, the azithromycin aqueous solution storage device further contains citric acid, sodium citrate, poloxamer, mannitol and benzalkonium chloride. It is noted that the dispersion of azithromycin, citric acid, sodium citrate, poloxamer, mannitol and benzalkonium chloride in water can be carried out in an azithromycin aqueous solution storage device.

Drawings

FIG. 1 is a schematic diagram of the system architecture for preparing azithromycin eye drops, according to an embodiment of the invention;

figure 2 is a schematic diagram of the system structure for preparing azithromycin eye drops according to an embodiment of the invention.

Reference numerals:

101: chitosan derivative aqueous solution storage device

102: azithromycin aqueous solution storage device

103: sodium hydroxide aqueous solution storage device

104: batching device

105: dry heat sterilization device

106: first filtering and sterilizing device

107: second filtering and sterilizing device

Detailed Description

The following detailed description of embodiments of the invention is intended to be illustrative, and not to be construed as limiting the invention.

1. Formula composition of azithromycin eye drops

The formulation composition of azithromycin eye drops is shown in the following table 1.

Table 1: formula of azithromycin eye drops

Function of	Name of material	Content (wt%)
			Main drug	Azithromycin	1.0-5.0
Tackifier (Chitosan derivative)Thing)	Such as N, O-carboxymethyl chitosan	1.0-5.0
			Metal ion complexing agent	Such as edetate disodium	0.05-0.5
Osmotic pressure regulator	Such as sodium chloride	0.2-1
			pH regulator	Such as citric acid	0.1-0.5
pH regulator	Such as sodium citrate	0.1-0.5
			Osmotic pressure regulator	Such as mannitol	0.5-2.0
Solubilizer	Such as poloxamer 407	0.05-0.5
			Preservative	Such as benzalkonium chloride	0.001-0.005
--	Water for injection	The balance being water

Wherein:

the viscosity of the tackifier is 1500-2000 mPa.s;

and the viscosity test conditions of the tackifier are as follows:

the tackifier concentration was 5 wt%, test temperature: 25 ℃, test procedure: a viscometer with a small sample holder, a No. 4 rotor, was used at a speed of 30r/min.

2. Preparation method of azithromycin eye drops

2.1 the required amount of 40% (40 kg) of water for injection (above 70 ℃) is poured into a 100L batching tank, the prescribed amount of sodium chloride and edetate disodium are added, stirred to be completely dissolved, and cooled to below 40 ℃. Adding the N, O-carboxymethyl chitosan with the prescription amount into the 100L proportioning tank under the stirring state (20HZ, 2891rpm/50 HZ), continuously stirring for 60 minutes, then regulating the speed to 35Hz, 9-11 minutes to completely disperse the N, O-carboxymethyl chitosan, transferring to a 200L proportioning tank, flushing the 100L proportioning tank and a pipeline with injection water with the prescription amount of about 5 percent (5 kg), transferring to the 200L proportioning tank, starting stirring, stirring at 121 ℃ for 15 minutes, and cooling to 30 ℃ or below to be used as liquid medicine 1 for later use.

2.2 injecting 30 percent (30 kg) of injection water into a 50L dosing tank, cooling to 30 ℃ or below, adding the prescription amount of citric acid, stirring to completely dissolve, then adding the prescription amount of azithromycin under stirring, and stirring for more than 90 minutes at 45Hz (670 rpm/50 Hz) until the azithromycin is completely dissolved. Adding poloxamer 407, sodium citrate, mannitol and benzalkonium chloride (dissolved by a small amount of hot water) in the prescription amount, and continuously stirring (25-35 Hz) for more than 30 minutes until all the materials are completely dissolved to serve as liquid medicine 2 for later use.

2.3 open the bottom valve, and add the liquid medicine 2 to the 200L dosage tank through 2 filters with 0.22 μm (PES filter element) under the condition of continuously stirring the liquid medicine 1. The injection water (30 ℃ and below) with the prescription amount of about 10 percent (5 kg +5 kg) is added into a 50L batching tank, and is directly filtered to a 200L batching tank through 2 filters with the diameter of 0.22 mu m, and the mixture is continuously stirred (40 Hz) for 18 to 22 minutes until the mixture is uniformly mixed.

2.4 through 10L batching tank, through 2 pieces 0.22 um filter to 200L batching tank, add prescription amount about 5% -6% injection water (5 kg-6 kg,30 ℃ and below) wash 10L batching tank and pipeline, through 2 pieces 0.22 um (PES filter core) filter, filter to 200L batching tank directly, adjust pH to 6.3 + -0.3 (6.0-6.6), supplement injection water (30 ℃ and below, through 2 pieces 0.22 um filter) to full dose, continue stirring (40 Hz) for more than 30 minutes, until it is uniform slightly opalescent or colorless viscous liquid.

3. Viscosity of azithromycin eye drops

The prepared azithromycin eye drops have the following viscosity measuring conditions: and (3) testing temperature: 25 ℃, test procedure: adopting a viscometer with a small sample holder, a No. 4 rotor, and measuring the viscosity of the azithromycin eye drops at the rotating speed of 30 r/min;

the viscosity of the azithromycin eye drops is 800-1200 mPa.s.

Example 1

The formulation composition of the azithromycin eye drops is shown in the following table 2, and the azithromycin eye drops are prepared according to the method.

Table 2: formula of azithromycin eye drops

Name of material	Function of	Weight (%)
			Azithromycin	Main medicine	1.5
N, O-carboxymethyl chitosan	Tackifier	1.0
			Edetate disodium salt	Metal ion complexing agent	0.05
Sodium chloride	Osmotic pressure regulator	0.2
			Citric acid	pH regulator	0.10
Citric acid sodium salt	PH regulator	0.11
			Mannitol	Osmotic pressure regulator	0.50
Poloxamer 407	Solubilizer	0.05
			Benzalkonium chloride	Preservative	0.001
Water for injection is added to	--	The balance being water

The viscosity test conditions for the tackifier and those for the azithromycin ophthalmic solution are as described above. The concrete result is as follows: the viscosity of the N, O-carboxymethyl chitosan is 1508mPa.s; the viscosity of the azithromycin eye drops is 816mPa.s.

Example 2

The formulation composition of the azithromycin eye drops is shown in the following table 3, and the azithromycin eye drops are prepared according to the method.

Table 3: formula of azithromycin eye drops

Name of material	Function of	Weight (%)
			Azithromycin	Main medicine	5.0
N, O-carboxymethyl chitosan	Tackifier	5.0
			Edetate disodium	Metal ion complexing agent	0.5
Sodium chloride	Osmotic pressure regulator	3.6
			Citric acid	PH regulator	0.5
Citric acid sodium salt	pH regulator	0.5
			Mannitol	Osmotic pressure regulator	2.0
Poloxamer 407	Solubilizer	0.5
			Benzalkonium chloride	Preservative agent	0.005
Water for injection is added to	--	The balance being water

The viscosity test conditions for the tackifier and those for the azithromycin ophthalmic solution are as described above. The concrete result is as follows: the viscosity of the N, O-carboxymethyl chitosan is 1964mPa.s; the viscosity of the azithromycin eye drops is 1192mPa.s.

Example 3

The formulation composition of the azithromycin eye drops is shown in the following table 4, and the azithromycin eye drops are prepared according to the method.

Table 4: formula of azithromycin eye drops

Name of material	Function of	Weight (%)
			Azithromycin	Main medicine	2.0
N, O-carboxymethyl chitosan	Tackifier	2.3
			Edetate disodium	Metal ion complexing agent	0.24
Sodium chloride	Osmotic pressure regulator	0.53
			Citric acid	pH regulator	0.21
Citric acid sodium salt	PH regulator	0.24
			Mannitol	Osmotic pressure regulator	1.36
Poloxamer 407	Solubilizer	0.29
			Benzalkonium chloride	Preservative	0.003
Water for injection is added to	--	The balance being water

The viscosity test conditions for the tackifier and those for the azithromycin ophthalmic solution are as described above. The concrete result is as follows: the viscosity of the N, O-carboxymethyl chitosan is 1610mPa.s; the viscosity of the azithromycin eye drops is 892mPa.s.

Comparative example 1

The formulation and preparation are essentially the same as in example 1, except that: the viscosity of the N, O-carboxymethyl chitosan is 2046mPa.s, and the viscosity of the azithromycin eye drops is 1268mPa.s under the same test conditions and method by adopting the N, O-carboxymethyl chitosan with the concentration of 5.2 weight percent.

Comparative example 2

The formulation and preparation are essentially the same as in example 1, except that: the viscosity of the N, O-carboxymethyl chitosan is 1424mPa.s, and the viscosity of the azithromycin eye drops is 705mPa.s under the same test conditions and method by adopting the N, O-carboxymethyl chitosan with the concentration of 0.8 weight percent as the tackifier.

Comparative example 3

The formulation and preparation are essentially the same as in example 1, except that: the viscosity of the azithromycin eye drops is 65mPa.s under the same test conditions and method without adding N, O-carboxymethyl chitosan.

Comparative example 4

The viscosity measurement result of the original imported product (Azasite) of the azithromycin eye drops under the same test conditions and method is 1125mPa.

Comparison of bacteriostatic Activity

The azithromycin eye drops of examples 1 to 3 and comparative examples 1 to 4 were subjected to bacteriostatic activity test.

80 New Zealand rabbits are inoculated with staphylococcus aureus and pseudomonas aeruginosa liquid in the left and right eyes separately, after infection for 24 hr, the eyes of each rabbit are graded and counted in mathematical mode to make the infection degree of each animal model have no obvious difference.

The test treatment effect was graded according to the following criteria: level 0: blood vessels are normal, eyes are bright and no secretion exists; level 0.5: blood vessels were slightly engorged, no secretion coverage, and eyes were slightly inflamed; stage 1: blood vessels were congested, bright red, slightly edematous, secretion coverage <6mm; and 2, stage: blood vessels are congested, are purple red, are difficult to distinguish and are obviously edematous, and secretion covers and is full of 6mm; and 3, level: diffuse hyperemia, purple color, edema to eyelid near-closure secretion coverage >6mm.

The test method comprises the following steps:

the model of the success of the bacterial infection of staphylococcus aureus and pseudomonas aeruginosa was randomly divided into 8 groups of 10 rabbits, 160 experimental eyes were counted, and the experimental groups 1, 2, and 3 and the comparative groups 1 and 2 and the blank control group were administered for 3 days continuously, 1 time in the morning and evening each day, and the blank control group was administered with physiological saline at the same time each day.

The identification time of bacteria at the cornea of each group of rabbit eyes is 24 hours, 48 hours and 72 hours before and after treatment, and the specific operation is as follows: and (3) wetting a cotton ball with sterile saline, lightly smearing an upper eyelid and a lower eyelid, putting the cotton ball into a sterile test tube filled with 5mL of physiological saline, uniformly mixing, taking 0.5mL of the cotton ball under a sterile environment, pouring the cotton ball onto a prepared common agar culture medium plate, uniformly paving the cotton ball, putting the plate into a culture medium at 37 ℃ for culturing for 18h, and judging the culture results of the two bacteria as shown in tables 5 to 7 below.

Table 5: therapeutic Effect of Staphylococcus aureus keratitis in different test groups

Table 6: therapeutic efficacy of Pseudomonas aeruginosa keratitis in different test groups

Table 7: bacterial culture results of rabbit ocular secretion before and after treatment of rabbit keratitis

Remarking: in table 7 above, staphylococcus aureus; aerugo refers to pseudomonas aeruginosa

Analysis and conclusion:

from the results of tables 5 to 7, it can be seen that compared with comparative examples 1 to 4, the azithromycin eye drops prepared in examples 1 to 3 have a significantly superior negative turning effect on the rabbit suffering from keratitis after administration, and the data in tables 5 to 6 of comparative examples 1 to 4 have a statistical significance (P < 0.05) in comparison with example 1, which is derived from the fact that azithromycin eye drops with suitable viscosity are easy to be absorbed by the eyelid to achieve a better therapeutic effect, and when the viscosity of the drug is higher, the active ingredient is slowly released to be not easy to be absorbed, and when the viscosity of the drug is lower, the azithromycin eye drops are easy to run off from the eyelid after administration, so that the absorption of the affected part is less, and the recovery time is prolonged.

Comparison of solubility of Azithromycin

The concentration of azithromycin added to the azithromycin eye drops in the embodiment 1 is the same as that of the azithromycin added in the comparative example 1, and the actual content of the azithromycin in the two groups of the eye drops is determined by adopting a high performance liquid chromatography, and the specific operation is as follows:

the chromatographic column is Irregular-HC18 column; the mobile phase was 0.5% ammonium dihydrogen phosphate solution-acetonitrile (73; the flow rate is 1.0mL/min; the detection wavelength was 210nm. Precisely measuring 10 mu L of the product, measuring the content of the azithromycin by an external standard method according to the chromatographic conditions, and measuring six times in parallel.

The results show that: the actual content of azithromycin in the eye drops of example 1 was 100.95% ± 1.26%, whereas the actual content of azithromycin in the eye drops of comparative example 1 was only 91.25% ± 1.58%, which was significantly less than that of example 1, and was significantly different from that of example 1 (P < 0.01), it was concluded that azithromycin added in comparative example 1 might not be completely dissolved, resulting in a lower actual value. Thus, it is shown that the addition of an appropriate amount of N, O-carboxymethyl chitosan helps to improve the solubility of azithromycin in the system.

Furthermore, the terms "first", "second" and "first" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one such feature. In the description of the present invention, "a plurality" means at least two, e.g., two, three, etc., unless specifically limited otherwise.

In the present invention, unless otherwise explicitly stated or limited, the terms "mounted," "connected," "fixed," and the like are to be construed broadly, e.g., as being permanently connected, detachably connected, or integral; may be mechanically coupled, may be electrically coupled or may be in communication with each other; they may be directly connected or indirectly connected through intervening media, or they may be connected internally or in any other suitable relationship, unless expressly stated otherwise. The specific meanings of the above terms in the present invention can be understood by those skilled in the art according to specific situations.

In the description of the specification, reference to the description of "one embodiment," "some embodiments," "an example," "a specific example," or "some examples" or the like means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are exemplary and not to be construed as limiting the present invention, and that changes, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims

1. An azithromycin eye drop, which is characterized by comprising: azithromycin and chitosan derivatives, wherein the chitosan derivatives are N, O-carboxymethyl chitosan, and the azithromycin eye drops contain 1~5 percent by weight of chitosan derivatives;

the chitosan derivative has a viscosity of 1500 to 2000mPa.s under the following conditions, and the viscosity test conditions are as follows:

the concentration of the chitosan derivative was 5% by weight,

and (3) testing temperature: at a temperature of 25 c,

the testing steps are as follows: the viscometer with a small sample holder and a No. 4 rotor are adopted to test under the condition that the rotating speed is 30r/min,

wherein the azithromycin eye drops have the viscosity of 800 to 1200mPa.s under the following conditions, and the viscosity test conditions are as follows:

and (3) testing temperature: at a temperature of 25 c,

the testing steps are as follows: the viscosity of the azithromycin eye drops is tested by adopting a viscometer with a small sample holder and a No. 4 rotor under the condition of the rotating speed of 30r/min.

2. Azithromycin eye drops according to claim 1, which contain 2.0 to 2.5 percent by weight of chitosan derivatives.

3. The azithromycin eye drop according to claim 1, further comprising: metal ion complexing agent, osmotic pressure regulator, pH regulator, solubilizer and preservative.

4. Azithromycin ophthalmic solution according to claim 3,

the metal ion complexing agent comprises at least one selected from edetate disodium, tartaric acid and edetate calcium sodium;

the solubilizer comprises at least one selected from poloxamer, tween-80, hydroxypropyl-beta-cyclodextrin and polyethylene glycol-12-hydroxystearate;

the preservative comprises at least one selected from benzalkonium chloride, benzalkonium bromide, sorbic acid, methylparaben, ethylparaben, benzoic acid and benzyl alcohol;

the osmotic pressure regulator comprises at least one selected from the group consisting of sodium chloride, mannitol, potassium chloride, glycerol, sorbitol, glucose and propylene glycol;

the pH regulator comprises at least one of citric acid, sodium citrate, sodium hydroxide, boric acid and borax.

5. The azithromycin eye drop according to claim 4, wherein the metal ion complexing agent is edetate disodium, the osmotic pressure regulator is sodium chloride and mannitol, the pH regulator is citric acid, sodium citrate and sodium hydroxide, the solubilizer is poloxamer, and the preservative is benzalkonium chloride.

6. Azithromycin ophthalmic solutions according to any one of claims 3 to 5, which contain: 1~5 wt% of chitosan derivative, 1~5 wt% of azithromycin, 0.05 to 0.5 wt% of metal ion complexing agent, 0.5 to 4 wt% of osmotic pressure regulator, 0.1 to 1 wt% of pH regulator, 0.05 to 0.5 wt% of solubilizer and 0.001 to 0.005 wt% of preservative.

7. Azithromycin ophthalmic solutions according to any one of claims 3 to 5, which contain: 1~5 wt% of chitosan derivative, 1~5 wt% of azithromycin, 0.05 to 0.5 wt% of edetate disodium, 0.2 to 1 wt% of sodium chloride, 0.1 to 0.5 wt% of citric acid, 0.1 to 0.5 wt% of sodium citrate, 0.5 to 2 wt% of mannitol, 0.05 to 0.5 wt% of poloxamer, 0.001 to 0.005 wt% of benzalkonium chloride, and the balance of water, wherein the pH of the azithromycin eye drop is 6.0 to 6.6.

8. Azithromycin ophthalmic solutions according to any one of claims 3 to 5, which contain: 1.5 to 2.5 weight percent of azithromycin, 2.0 to 2.5 weight percent of chitosan derivative, 0.2 to 0.3 weight percent of edetate disodium, 0.5 to 0.6 weight percent of sodium chloride, 0.1 to 0.3 weight percent of citric acid, 0.1 to 0.3 weight percent of sodium citrate, 1.3 to 1.4 weight percent of mannitol, 0.2 to 0.4 weight percent of poloxamer, 0.002 to 0.004 weight percent of benzalkonium chloride and the balance of water, and the pH of the azithromycin eye drop is 6.0 to 6.6.