CN109481434B

CN109481434B - Eye drops, preparation method and application thereof

Info

Publication number: CN109481434B
Application number: CN201811550047.XA
Authority: CN
Inventors: 付欢; 王超; 尹传忠; 万利鹏; 延静
Original assignee: Hubei Grand Everyday Bright Eyes Pharmaceutical Co ltd
Current assignee: Hubei Grand Everyday Bright Eyes Pharmaceutical Co ltd
Priority date: 2018-12-18
Filing date: 2018-12-18
Publication date: 2020-11-10
Anticipated expiration: 2038-12-18
Also published as: CN109481434A

Abstract

The invention relates to the field of ophthalmic preparations, in particular to an eye drop, and a preparation method and application thereof. Each 1000ml of eye drops comprises 0.05-0.1g of bendazac lysine, 3-7g of taurine, 0.05-0.1g of pH regulator, 1.0-3.0g of osmotic pressure regulator, 0.05-0.15g of solubilizer and 0.1-0.3g of tackifier. The combination of taurine and bendazac lysine improves the treatment effect of the composition on cataract through synergistic interaction, and meanwhile, the combination of taurine and bendazac lysine can obviously reduce the side effect of eye drops, reduce eye secretion after medicine application, obviously reduce the occurrence probability of red swelling, edema and other phenomena, and improve the experience of medicine application of patients.

Description

Eye drops, preparation method and application thereof

Technical Field

The invention relates to the field of ophthalmic preparations, in particular to an eye drop, and a preparation method and application thereof.

Background

The bendazac lysine eye drops are aldose reductase inhibitors, and aldose reductase can promote glucose and galactose of human crystalline lens to be reduced into alcohol which is difficult to permeate into cell membranes, absorb water outside the cell membranes to enter the crystalline lens, so that crystalline lens protein fibers are expanded, the structure is disordered, and the light transmittance is changed, thereby forming cataract. The bendazac lysine eye drops can enter eye tissues and aqueous humor through local eye drops, and are aggregated in a crystalline lens, so that the activity of aldose reductase in eyes is effectively inhibited, the development process of cataract is delayed, and the aim of preventing or treating the cataract is fulfilled. But the bendazac lysine has larger irritation to eyes, is easy to cause red swelling and secretion increase in eyes of patients, increases the incidence rate of adverse reactions, and causes poor compliance of the patients.

Disclosure of Invention

The invention aims to provide an eye drop which has good treatment effect on cataract, can reduce the stimulation of the eye drop to eyes, reduce the medication pain of a patient, improve the compliance medication experience of the patient and improve the drug effect of a drug.

The invention also aims to provide a preparation method of the eye drops, which has simple process and controllable quality and can quickly prepare the eye drops.

Another object of the present invention is to provide an application of eye drops, which can expand the application range of eye drops.

The technical problem to be solved by the invention is realized by adopting the following technical scheme:

the invention provides an eye drop, wherein each 1000ml of the eye drop comprises 0.05-0.1g of bendazac lysine, 3-7g of taurine, 0.05-0.1gpH regulator, 1.0-3.0g of osmotic pressure regulator, 0.05-0.15g of solubilizer and 0.1-0.3g of tackifier.

The invention provides a preparation method of eye drops, which comprises the following steps: bendazac lysine, taurine, a pH adjusting agent, an osmotic pressure adjusting agent, a solubilizing agent, and a viscosity increasing agent are mixed to form the eye drop.

The invention provides an application of eye drops in preparing a medicament for treating cataract and a medicament for reducing irritation for eyes.

The eye drop, the preparation method and the application thereof have the beneficial effects that: the combination of the taurine and the bendazac lysine in the eye drops can obviously reduce the side effect of the eye drops, reduce eye secretion after the medicine is applied, obviously reduce the occurrence probability of red swelling, edema and other phenomena, and improve the experience of the medicine application of patients.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

In the description of the present invention, it should be noted that the terms "first", "second", and the like are used only for distinguishing the description, and are not intended to indicate or imply relative importance.

The eye drops, the method for producing the same, and the use thereof according to the embodiments of the present invention will be specifically described below.

The eye drop provided by the embodiment of the invention comprises 0.05-0.1g of bendazac lysine, 3-7g of taurine, 0.05-0.1g of pH regulator, 1.0-3.0g of osmotic pressure regulator, 0.05-0.15g of solubilizer and 0.1-0.3g of tackifier in every 1000ml of eye drop. Or 0.07-0.09g of the bendazac lysine, 5-6g of the taurine, 0.06-0.08g of the pH regulator, 1.5-2g of the osmotic pressure regulator, 0.08-0.12g of the solubilizer and 0.2-0.25g of the tackifier are contained in each 1000ml of the eye drops.

In the prior art, the bendazac lysine eye drops can relieve or treat cataract, but the treatment effect is general in practical application, the bendazac lysine eye drops have large irritation to eyes, are easy to cause red swelling in eyes of patients after being dripped, increase secretions such as tear water and the like, the tear water is easy to wash the bendazac lysine eye drops containing active ingredients out of the eyes, and then the treatment effect of the bendazac lysine eye drops is further reduced. In the embodiment, the treatment effect of the eye drops is improved by adding taurine and the synergistic effect of the taurine and the bendazac lysine, and the combination of the taurine and the bendazac lysine can reduce the stimulation of the eye drops to the eyes of a patient, reduce the pain of the patient in medication, reduce secretions, avoid the dilution and the washing of the active ingredients by the secretions, further improve the absorption of the eyes to the active ingredients and improve the drug effect.

In addition, by controlling the proportion of the taurine and the bendazac lysine, the taurine and the bendazac lysine can further ensure that the taurine and the bendazac lysine have good synergistic effect, and simultaneously, the side effect of the eye drop can be further reduced. The taurine and the bendazac lysine can also play a good bacteriostatic role without adding other bacteriostatic agents.

And the types of auxiliary materials such as a pH regulator, an osmotic pressure regulator, a solubilizer, a tackifier and the like are further controlled, so that the stability and the drug effect of the eye drop can be ensured, the influence of the auxiliary materials on the drug effect of the eye drop is prevented, and the absorption of active ingredients in the eye drop by a human body is ensured. The dosage of the auxiliary materials in the eye drops is further controlled, so that the drug effect of the eye drops can be further ensured, and the side effect of the eye drops is reduced.

Further, the pH regulator is phosphate; preferably, sodium dihydrogen phosphate and/or disodium hydrogen phosphate. The use of the above-mentioned substance as a pH regulator ensures the stability of the eye drops and prevents the deterioration of the eye drops, and the pH regulator, in combination with an osmotic pressure regulator and a solubilizer, promotes the low absorption of the active ingredient by the human body.

Further, the osmotic pressure regulator is chloride, preferably sodium chloride. It can promote the absorption of taurine and bendazac lysine by human body, and further reduce the stimulation of eye drops to human body.

Further, the thickener is a cellulose-based substance, preferably hydroxypropylmethylcellulose. The use of the above-mentioned substance can ensure the stability of the eye drop, prevent the active ingredient from settling, and further protect the drug effect of the eye drop alone.

Further, the solubilizer is a surfactant, preferably a nonionic surfactant, and more preferably tween 80. The solubilizer can further improve the solubility of the medicine and the stability of the eye drops, improve the curative effect of the eye drops and reduce the side effect of the eye drops.

Furthermore, the 1000mL eye drop also comprises 0.01-0.03g of preservative, and the preservative is additionally added, so that the antibacterial effect of the eye drop can be further improved, and the quality guarantee period of the eye drop is prolonged. And the preservative is benzalkonium chloride, and the reagent can be used as the preservative to well sterilize.

Further, the balance of 1000mL of eye drops is water for injection.

Further, the embodiment of the invention also provides a preparation method of the eye drops, which comprises the following steps:

firstly, the dosage of each substance is calculated according to the formula, and then the pH regulator raw material is mixed with water for injection to obtain the pH regulator liquid.

The bendazac lysine and the solubilizer are mixed with a proper amount of injection water to obtain a first mixed solution, and the bendazac lysine and the solubilizer are mixed and dissolved firstly, so that the dissolution degree of the raw materials can be improved, and the content of active ingredients in the eye drops can be improved.

Mixing and dissolving taurine and a proper amount of injection water, ensuring that all materials can be uniformly mixed, ensuring that the taurine can be fully mixed with the bendazac lysine and ensuring the synergistic effect of the taurine and the bendazac lysine.

Adding a proper amount of injection water into the reactor, heating to 90-100 ℃, heating the injection water, improving the solubility of each substance, and facilitating the uniform mixing of each substance. And then mixing the solution with a tackifier, a pH regulator, an osmotic pressure regulator, a first mixed solution and taurine in sequence to obtain a liquid medicine.

Then the liquid medicine is cooled after being continuously stirred for 25 to 40 minutes at the temperature of between 90 and 100 ℃, and the continuous stirring at the temperature is more beneficial to uniformly mixing all the raw materials in the eye drop. After cooling, filtering and fixing the volume to ensure that each raw material meets the specification.

The features and properties of the present invention are described in further detail below with reference to examples.

Example 1

This example provides an eye drop (1000mL) comprising 0.05g bendazac lysine, 3g taurine, 0.05g pH adjusting agent, 1.0g sodium chloride, 0.05g tween 80, 0.1g hydroxypropylmethylcellulose, and the balance water. Wherein the pH regulator is a mixture of sodium dihydrogen phosphate and disodium hydrogen phosphate.

The present embodiment also provides a method for preparing an eye drop:

dissolving sodium dihydrogen phosphate and disodium hydrogen phosphate in injection water to obtain pH regulator solution;

dissolving tween 80 and bendazac lysine in injection water to obtain a first mixed solution;

dissolving taurine in the injection water to obtain a taurine solution;

adding a proper amount of injection water into a reactor, heating to 90 ℃, then sequentially mixing with hydroxypropyl methyl cellulose, a pH regulator solution, an osmotic pressure regulator, a first mixed solution and a taurine solution, keeping the temperature at 90 ℃, stirring for 40 minutes, cooling, and adding the injection water to a constant volume.

Examples 2 to 6

Examples 2 to 6 provide eye drops which are the same as the eye drop raw material provided in example 1 except for the specific amount; examples 2 to 6 provide eye drops which are substantially the same as those provided in example 1 except for the difference in the operating conditions.

Example 2

The eye drop (1000mL) comprises 0.1g of bendazac lysine, 7g of taurine, 0.1g of pH regulator, 3.0g of sodium chloride, 0.15g of Tween 80, 0.3g of hydroxypropyl methylcellulose and the balance of water. Wherein the pH regulator is sodium dihydrogen phosphate. The heating temperature was 100 ℃ and the stirring was continued for 40 minutes.

Example 3

The eye drop (1000mL) comprises 0.07g of bendazac lysine, 6g of taurine, 0.08g of pH regulator, 1.5g of sodium chloride, 0.12g of Tween 80, 0.2g of hydroxypropyl methylcellulose and the balance of water. Wherein the pH regulator is disodium hydrogen phosphate. The heating temperature was 95 ℃ and the stirring was continued for 30 minutes.

Example 4

The eye drop (1000mL) comprises 0.09g of bendazac lysine, 5g of taurine, 0.06g of pH regulator, 2g of sodium chloride, 0.08g of Tween 80, 0.25g of hydroxypropyl methylcellulose and the balance of water. Wherein the pH regulator is a mixture of disodium hydrogen phosphate and sodium dihydrogen phosphate. The heating temperature was 97 ℃ and the stirring time was 35 minutes.

Example 5

The eye drop (1000mL) comprises 0.08g of bendazac lysine, 5.5g of taurine, 0.07g of pH regulator, 1.8g of sodium chloride, 0.09g of Tween 80, 0.22g of hydroxypropyl methylcellulose, 0.01g of benzalkonium chloride, and the balance of water. Wherein the pH regulator is disodium hydrogen phosphate. The heating temperature was 92 ℃ and the stirring duration was 37 minutes.

Example 6

The eye drop (1000mL) comprises 0.06g of bendazac lysine, 4.5g of taurine, 0.09g of pH regulator, 1.5g of sodium chloride, 0.07g of Tween 80, 0.15g of hydroxypropyl methylcellulose, 0.03g of benzalkonium chloride, and the balance of water. Wherein the pH regulator is a mixture of disodium hydrogen phosphate and sodium dihydrogen phosphate. The heating temperature was 94 ℃ and the stirring duration was 32 minutes.

Comparative example 1: eye drops were prepared according to the preparation method provided in example 1, except that the content of taurine was 3g, bendazac lysine was not contained, and the contents of the remaining components were unchanged.

Comparative example 2: eye drops were prepared according to the preparation method provided in example 1, except that the content of bendazac lysine was 0.05g, taurine was not contained, and the contents of the remaining components were unchanged.

Animal experiments:

wistar rats were selected and then injected subcutaneously with a small dose (4mg/Kg) of sodium selenite once every other day for 3 consecutive times. Then, 50 successfully molded rats were selected, weighed 80 to 120g and half of males and females, and randomly grouped into 10 rats each, one of which was a control group, to which injection water was added, and the remaining 4 rats were an experimental group to which eye drops of example 1, example 5, comparative example 1 and comparative example 2 were added in sequence. The experimental group was dropped at 0.5mg/Kg, while the control group was dropped with the same amount of water for injection. The administration is performed 2 times daily for 15 days. After 15 days of mydriasis with 1% atropine in each group of animals, lenticular opacity was detected and recorded by slit lamp microscopy, and the evaluation criteria were found in sons' thought, high autumn. 40-42. Wherein "-" indicates that the lens is clear; "+" indicates that the lens nucleus is turbid, but the cortex remains clear; "" indicates opacity of both the lens nucleus and cortex. See table 1 for specific results.

TABLE 1 test results

	Crystalline lens	-	+	*
					Control group	20	0	1	19
Example 1	20	19	1	0
					Example 5	20	18	2	0
Comparative example 1	20	0	5	15
					Comparative example 2	20	11	8	1

As can be seen from Table 1, the eye drop of the invention has good effect of restoring the clarity of crystalline lens by the synergistic effect of taurine and bendazac lysine, and has good treatment effect on cataract.

Taking 25 rats (without cornea turbidity, conjunctiva congestion, edema and secretion) with no damage in eye detection, dividing the rats into 5 groups randomly, wherein each group comprises 5 rats, one group is a control group, and dripping injection water, and the rest 4 groups are experimental groups and dripping the eye drops of example 1, example 5, comparative example 1 and comparative example 2 in sequence; the dripping amount is 50ul (1-2 drops), and the dripping is continuously carried out for 15 days, 3 times per day.

After the first liquid medicine is dripped on the first day, the seventh day and the 15 th day, eye secretion of mice is collected, the maximum secretion amount of each group of animals is recorded, the average secretion amount of each group is calculated, the maximum secretion amount of each group and the content of bendazac lysine and taurine in the total secretion are detected by high performance liquid chromatography, and the detection results are shown in tables 2-4.

TABLE 2 test results on day one

TABLE 3 test results on the seventh day

TABLE 4 test results on the fifteenth day

As can be seen from tables 2 to 4, the ophthalmic solution containing bendazac lysine containing taurine is effective in alleviating irritation of bendazac lysine to eyes and preventing the bendazac lysine from overflowing, thereby increasing the absorption of the drug on the ocular surface.

Before each administration and after 5 minutes, 30 minutes and 60 minutes after administration, the cornea, iris and conjunctiva were observed with naked eyes directly or with a magnifying glass for irritation and were scored, and the scoring criteria are shown in table 5(cn102670494.b), and then the total score was calculated based on the scoring criteria and the irritation was judged based on the total score, and the average score (═ total score/5) was calculated based on the judging criteria shown in table 6, and the evaluation results were shown in table 7.

TABLE 5 evaluation criteria

TABLE 6 evaluation of irritation

Score value	0-3	4-8	9-12	13-16
					Evaluation of	Has no irritation	Mild stimulation	Moderate stimulation	Stimulation of intensity

TABLE 7 test results

As can be seen from table 7, eye drops which contain bendazac lysine for the treatment of cataract after addition of taurine have significantly reduced irritation to eyes.

In summary, the eye drops provided in embodiments 1 to 6 of the present invention improve the treatment effect of cataract by the synergistic effect of taurine and bendazac lysine, and the combination of taurine and bendazac lysine can significantly reduce the side effects of the eye drops, reduce the eye secretion after the application of the drug, and significantly reduce the occurrence probability of red swelling, edema and other phenomena, thereby improving the experience of the patient in medication.

The embodiments described above are some, but not all embodiments of the invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the invention as claimed, but is merely representative of selected embodiments of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Claims

1. An eye drop, characterized in that, per 1000ml of the eye drop comprises 0.05-0.1g of bendazac lysine, 3-7g of taurine, 0.05-0.1g of pH regulator, 1.0-3.0g of osmotic pressure regulator, 0.05-0.15g of solubilizer and 0.1-0.3g of tackifier.

2. The eye drop according to claim 1, wherein 0.07 to 0.09g of the bendazac lysine, 5 to 6g of the taurine, 0.06 to 0.08g of the pH regulator, 1.5 to 2g of the osmotic pressure regulator, 0.08 to 0.12g of the solubilizing agent, and 0.2 to 0.25g of the viscosity increasing agent are contained per 1000ml of the eye drop.

3. The eye drop according to claim 1 or 2, wherein the pH adjuster is a phosphate salt.

4. The eye drop according to claim 3, wherein the pH adjuster is sodium dihydrogen phosphate and/or disodium hydrogen phosphate.

5. The eye drop according to claim 1 or 2, wherein the osmotic pressure regulator is chloride.

6. The eye drop according to claim 5, wherein the osmotic pressure regulator is sodium chloride.

7. The eye drop according to claim 1 or 2, wherein the viscosity-increasing agent is a cellulose-based substance.

8. The eye drop according to claim 7, wherein the viscosity-increasing agent is hydroxypropylmethylcellulose.

9. The eye drop according to claim 1 or 2, wherein the solubilizing agent is a surfactant.

10. The eye drop according to claim 9, wherein the solubilizer is a nonionic surfactant.

11. The eye drop according to claim 10, wherein the solubilizer is tween 80.

12. A method for preparing eye drops according to claim 1, comprising the steps of: bendazac lysine, taurine, a pH adjusting agent, an osmotic pressure adjusting agent, a solubilizing agent, and a viscosity increasing agent are mixed to form the eye drop.

13. The method according to claim 12, wherein the eye drop is a liquid medicine obtained by heating water for injection to 90 to 100 ℃ and mixing the heated water for injection with a viscosity-increasing agent, a pH-adjusting agent, an osmotic pressure-adjusting agent, bendazac lysine, a solubilizing agent, and taurine in this order.

14. Use of the eye drop of claim 1 in the preparation of a medicament for the treatment of cataract.

15. Use of an eye drop according to claim 1 for the preparation of a medicament for reducing irritation of the eye.