CN112791050A - Azithromycin eye drops - Google Patents
Azithromycin eye drops Download PDFInfo
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- CN112791050A CN112791050A CN201911108264.8A CN201911108264A CN112791050A CN 112791050 A CN112791050 A CN 112791050A CN 201911108264 A CN201911108264 A CN 201911108264A CN 112791050 A CN112791050 A CN 112791050A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention provides azithromycin eye drops, which comprise: azithromycin and a chitosan derivative, said chitosan derivative having a viscosity of 1500-2000 mpa.s under the following conditions, the test conditions being: 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 30 r/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 antibacterial effect, low preservative dosage and high safety, and can promote the dissolution of azithromycin, enhance the absorption effect and improve the bioavailability.
Description
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 ingredients into paste, which prolongs the retention time of the active ingredients in eyes, but it blocks the sight 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 30 r/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 are suitable in viscosity and low in 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 the viscosity of 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 30 r/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 the recovery time is prolonged. Therefore, the azithromycin eye drops with the viscosity of 800-1200 mPa.s under the test conditions have a better bacteriostatic effect, and the solubility of azithromycin is effectively improved.
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 disclosed 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 wt% 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 bacterial inhibition of the azithromycin are further promoted.
According to the embodiment of the invention, the azithromycin eye drops contain: 1-5 wt% of chitosan derivative, 1-5 wt% of azithromycin, 0.05-0.5 wt% of metal ion complexing agent, 0.5-4 wt% of osmotic pressure regulator, 0.1-1 wt% of pH regulator, 0.05-0.5 wt% of solubilizer and 0.001-0.005 wt% 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 to 0.5% by weight of the sodium citrate (e.0.11, 0.15, 0.2, 0.25, 0.26, 0.3, 0.35, 0.4 or 0.45% by weight), 0.5% by weight of the mannitol (e.1, 0.1, 0.5% by weight of the poloxamer (e.1, 0.5%, 0.9, 0.1, 0.5% by weight) of the alcohol (e.1, 0.1.5%, 1.5%, 1.9, 0.9% by weight) to 1.5%, 1., 0.001-0.005 wt% of benzalkonium chloride (such as 0.002, 0.003, 0.004 or 0.005 wt%), and the balance of water, wherein the pH of the azithromycin eye drops is 6.0-6.6. 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: 1.5-2.5 wt% of azithromycin, 2.0-2.5 wt% of chitosan derivative, 0.2-0.3 wt% of edetate disodium, 0.5-0.6 wt% of sodium chloride, 0.1-0.3 wt% of citric acid, 0.1-0.3 wt% of sodium citrate, 1.3-1.4 wt% of mannitol, 0.2-0.4 wt% of poloxamer, 0.002-0.004 wt% of benzalkonium chloride and the balance of water, wherein the pH of the azithromycin eye drop is 6.0-6.6 (such as 6.2, 6.3 and 6.4). 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.
In a second aspect of the present invention, the present invention provides use of a chitosan derivative for the preparation of azithromycin eye drops, which have a viscosity of 800 to 1200mpa.s under the following conditions, and which are 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 30 r/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 are suitable in viscosity and low in 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 the embodiment of the invention, the aqueous solution of the chitosan derivative is further subjected to dry heat sterilization at 120-125 ℃ for 10-20 min. Therefore, the azithromycin eye drops have good sterilization effect, and the prepared azithromycin eye drops have 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 30 r/min.
The inventor finds that the azithromycin eye drops prepared from the chitosan derivative with the viscosity of 1500-2000 mPa.s under the test conditions have proper viscosity, and the pipeline loss is low when the system provided by the embodiment of the invention is used for preparing the azithromycin eye drops.
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 present invention, referring 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; and finally, introducing the sodium hydroxide aqueous solution in the sodium hydroxide aqueous solution storage device 103 into a dosing device 104 through a second filtering and sterilizing device 107, and stirring to adjust the pH value to 6.0-6.6 so as to obtain the azithromycin eye drops.
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 and the azithromycin are mixed 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 comprises 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 water 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 medicine | Azithromycin | 1.0-5.0 |
| Tackifier (Chitosan derivative) | 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, rotor No. 4, was used at a speed of 30 r/min.
2. Preparation method of azithromycin eye drops
2.1 the required amount of 40% (40kg) 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 dosing tank under the stirring state (20HZ, 2891rpm/50HZ), continuously stirring for 60 minutes, then adjusting the speed to 35Hz for 9-11 minutes to completely disperse the N, O-carboxymethyl chitosan, transferring to a 200L dosing tank, flushing the 100L dosing tank and a pipeline with the injection water with the prescription amount of about 5% (5kg), transferring to the 200L dosing tank, starting stirring, cooling to the temperature of 121 ℃ for 15 minutes, and cooling to the temperature of 30 ℃ or below to be used as the liquid medicine 1 for later use.
2.2 injecting 30 percent (30kg) 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 (670rpm/50Hz) 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 formula 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 amount of about 10 percent (5kg +5kg) of the prescription is added into a 50L batching tank, and the mixture is directly filtered to a 200L batching tank through 2 filters with the diameter of 0.22 mu m, and is continuously stirred (40Hz) for 18-22 minutes until the mixture is uniformly mixed.
2.4 passing 2mol/L sodium hydroxide solution (30 ℃ and below) 4.3 kg-5.4 kg through 10L batching tank, filtering to 200L batching tank through 2 filters with 0.22 mu m, adding water for injection (5 kg-6 kg, 30 ℃ and below) with the amount of about 5% -6% of the prescription to wash the 10L batching tank and pipeline, passing through 2 filters with 0.22 mu m (PES filter element), directly filtering to 200L batching tank, adjusting the pH to 6.3 +/-0.3 (6.0-6.6), adding water for injection (30 ℃ and below, passing through 2 filters with 0.22 mu m) to full amount, continuing stirring (40Hz) for more than 30 minutes until the solution is a uniform milky 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 and a No. 4 rotor, and testing 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 | 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 1508 mPa.s; the viscosity of the azithromycin eye drops is 816 mPa.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 | 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 1964 mPa.s; the viscosity of the azithromycin eye drops is 1192 mPa.s.
Example 3
The formulation composition of azithromycin eye drops is shown in the following table 4, and 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 1610 mPa.s; the viscosity of the azithromycin eye drops is 892 mPa.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 as the tackifier.
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 viscosity increasing agent.
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 1125 mPa.s.
Comparison of bacteriostatic Activity
The azithromycin eye drops of examples 1 to 3 and comparative examples 1 to 4 were subjected to a bacteriostatic activity test.
80 New Zealand rabbits are inoculated with staphylococcus aureus and pseudomonas aeruginosa liquid in the left and right eyes separately, and after infection for 24 hr, the rabbit eyes are graded and counted in mathematical theory to make the animal model in each group have no obvious difference in infection degree.
The test treatment effect is graded and graded according to the following standard: 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; level 1: blood vessels were congested, bright red, slightly edematous, secretion coverage <6 mm; and 2, stage: blood vessels are congested and purple red, the blood vessels are difficult to distinguish and obviously suffer from edema, and secretion coverage is full of 6 mm; and 3, level: diffuse hyperemia, purple color, edema to near-occlusive secretion coverage of the eyelids >6 mm.
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 each, and 160 experimental eyes were used, which were experimental examples 1, 2, and 3 and comparative examples 1 and 2, respectively, and a blank control group, which was administered continuously for 3 days, 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 cotton balls with sterile saline, lightly smearing the cotton balls on the upper eyelid and the lower eyelid, putting the cotton balls into a sterile test tube filled with 5mL of physiological saline, uniformly mixing, taking 0.5mL of the cotton balls in a sterile environment, pouring the cotton balls into a prepared common agar culture medium plate, uniformly spreading the cotton balls, putting the mixture into a culture medium at 37 ℃ for culturing for 18h, and judging the culture results of the two bacteria as shown in tables 5-7 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:
the results in tables 5 to 7 show 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 the azithromycin eye drops with appropriate viscosity are beneficial to the absorption of eyelids and have a good treatment effect, when the viscosity of the medicine is high, the active ingredients are slowly released and are not beneficial to the absorption, and when the viscosity of the medicine is low, the azithromycin eye drops are easy to run off from the eyelids after administration, so that the absorption of diseased parts is low, 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 is 0.5 percent ammonium dihydrogen phosphate solution-acetonitrile (73: 27); the flow rate is 1.0 mL/min; the detection wavelength was 210 nm. 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 expressly stated or limited, the terms "mounted," "connected," "secured," and the like are to be construed broadly and can, for example, be fixedly connected, detachably connected, or integrally formed; 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 herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean 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 is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, 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 (10)
1. An azithromycin eye drop, which is characterized by comprising: azithromycin and a chitosan derivative having a viscosity of 1500 to 2000mpa.s under the following conditions, said viscosity test conditions being 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: a viscometer with a small sample holder, rotor No. 4, was used for the test at a speed of 30 r/min.
2. The azithromycin eye drop according to claim 1, which has a viscosity of 800 to 1200mpa.s under the following conditions for a viscosity test:
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 a viscometer with a small sample holder and a No. 4 rotor under the condition of the rotating speed of 30 r/min.
3. The azithromycin eye drop according to claim 1, which contains 1 to 5% by weight of a chitosan derivative.
4. The azithromycin eye drop according to claim 1, which contains 2.0 to 2.5% by weight of a chitosan derivative.
5. Azithromycin ophthalmic solution according to claim 1, wherein said chitosan derivative comprises at least one selected from the group consisting of carboxymethyl chitosan, carboxyethyl chitosan, carboxypropyl chitosan, carboxybutyl chitosan and succinic chitosan;
preferably, the chitosan derivative is N, O-carboxymethyl chitosan.
6. The azithromycin eye drop according to claim 1, further comprising: metal ion complexing agent, osmotic pressure regulator, pH regulator, solubilizer and preservative;
preferably, the first and second electrodes are formed of a metal,
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 selected from citric acid, sodium citrate, sodium hydroxide, boric acid and borax;
more preferably still, the first and second liquid crystal compositions are,
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.
7. The azithromycin eye drop of claim 6, which contains: 1-5 wt% of chitosan derivative, 1-5 wt% of azithromycin, 0.05-0.5 wt% of metal ion complexing agent, 0.5-4 wt% of osmotic pressure regulator, 0.1-1 wt% of pH regulator, 0.05-0.5 wt% of solubilizer and 0.001-0.005 wt% of preservative;
preferably, the azithromycin eye drops contain: 1-5 wt% of chitosan derivative, 1-5 wt% of azithromycin, 0.05-0.5 wt% of edetate disodium, 0.2-1 wt% of sodium chloride, 0.1-0.5 wt% of citric acid, 0.1-0.5 wt% of sodium citrate, 0.5-2 wt% of mannitol, 0.05-0.5 wt% of poloxamer, 0.001-0.005 wt% of benzalkonium chloride and the balance of water, wherein the pH value of the azithromycin eye drops is 6.0-6.6.
8. The method of claim 7, wherein the azithromycin eye drops contains: 1.5-2.5 wt% of azithromycin, 2.0-2.5 wt% of chitosan derivative, 0.2-0.3 wt% of edetate disodium, 0.5-0.6 wt% of sodium chloride, 0.1-0.3 wt% of citric acid, 0.1-0.3 wt% of sodium citrate, 1.3-1.4 wt% of mannitol, 0.2-0.4 wt% of poloxamer, 0.002-0.004 wt% of benzalkonium chloride and the balance of water, wherein the pH of the azithromycin eye drop is 6.0-6.6.
9. Use of a chitosan derivative for the preparation of azithromycin eye drops having 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,
the viscosity test conditions of the azithromycin eye drops are as follows:
and (3) testing temperature: at a temperature of 25 c,
the testing steps are as follows: adopting a viscometer with a small sample holder and a No. 4 rotor to test the viscosity of the azithromycin eye drops under the condition of the rotating speed of 30 r/min;
optionally, the aqueous solution of the chitosan derivative is further subjected to dry heat sterilization at 120-125 ℃ for 10-20 min.
10. A system for preparing azithromycin eye drops, which is characterized by comprising:
a chitosan derivative aqueous solution storage device, wherein the chitosan derivative aqueous solution storage device contains a chitosan derivative with the concentration of 1-5 wt%,
the chitosan derivative has a viscosity of 1500-2000 mPa.s under the following conditions, and the viscosity test conditions are as follows:
the concentration of the chitosan derivative was 5 wt%;
and (3) testing temperature: at a temperature of 25 c,
the testing steps are as follows: a viscometer with a small sample holder, rotor No. 4, was used for the test at a speed of 30 r/min.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030143259A1 (en) * | 1999-03-31 | 2003-07-31 | Samir Roy | Topical treatment or prevention of ocular infections |
| CN1814299A (en) * | 2005-12-22 | 2006-08-09 | 涂家生 | Macrolide antibiotics sodium hyaluronate eye transfer system |
| CN101444477A (en) * | 2009-01-06 | 2009-06-03 | 中国药科大学 | Azithromycin ophthalmic instant molding gel and preparation method thereof |
| CN102824305A (en) * | 2012-08-02 | 2012-12-19 | 南京恒道医药科技有限公司 | Azithromycin eye drops and preparation method thereof |
| US20170007635A1 (en) * | 2009-03-06 | 2017-01-12 | Insite Vision Corporation | Ocular treatment with reduced intraocular pressure |
| CN107854424A (en) * | 2017-10-30 | 2018-03-30 | 沈小玲 | A kind of azithromycin ocular in-situ gel and preparation method thereof |
-
2019
- 2019-11-13 CN CN201911108264.8A patent/CN112791050B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030143259A1 (en) * | 1999-03-31 | 2003-07-31 | Samir Roy | Topical treatment or prevention of ocular infections |
| CN1814299A (en) * | 2005-12-22 | 2006-08-09 | 涂家生 | Macrolide antibiotics sodium hyaluronate eye transfer system |
| CN101444477A (en) * | 2009-01-06 | 2009-06-03 | 中国药科大学 | Azithromycin ophthalmic instant molding gel and preparation method thereof |
| US20170007635A1 (en) * | 2009-03-06 | 2017-01-12 | Insite Vision Corporation | Ocular treatment with reduced intraocular pressure |
| CN102824305A (en) * | 2012-08-02 | 2012-12-19 | 南京恒道医药科技有限公司 | Azithromycin eye drops and preparation method thereof |
| CN107854424A (en) * | 2017-10-30 | 2018-03-30 | 沈小玲 | A kind of azithromycin ocular in-situ gel and preparation method thereof |
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