A kind of lifalast and tea polyphenols eye drop composition

Abstract

The invention discloses a lifalast and tea polyphenol eye drop composition; the composition comprises the following components in weight percentage: 4.5% to 5.5% lifalast, 0.09% to 0.11% buffer, 0.65% to 0.85% osmotic pressure regulator, 0.3% to 0.9% tea polyphenol, an appropriate amount of pH regulator, and the remainder of water for injection. The quality of the lifalast eye drop composition of the invention is not lower than that of the reference preparation Xiidra, and the stability is equivalent to that of the reference preparation Xiidra, and the non-clinical mouse model shows a better therapeutic effect than that of lifalast and tea polyphenol alone.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations and relates to a composition of lifalast eye drops, in particular to a composition of lifalast and tea polyphenol eye drops. Background Art

[0002] Dry eye disease (DED) is an inflammatory disease of the ocular surface that can lead to severe disability, especially in the elderly population. The mainstays of treatment include artificial tears, tear duct plugs, topical anti-inflammatory drugs, and corticosteroids. In the past few years, only cyclosporine-A emulsion has been added to the existing treatments, but most patients stop using it because it causes a burning sensation in the eyes. Therefore, new research for better treatment options led to the discovery of the lymphocyte function-associated antigen 1 (LFA-1) antagonist, lifalast. It blocks T cell activation and the release of inflammatory mediators, thereby inhibiting the inflammatory pathway in DED. It was approved by the US Food and Drug Administration for the treatment of DED in July 2016. It is the first new drug in the field of dry eye treatment in the past 13 years and the first new drug in the lymphocyte function-associated antigen 1 (LFA-1) antagonist class approved by the FDA for the treatment of dry eye disease.

[0003] Novartis withdrew its application on June 18 after the EMA said the effectiveness of Xiidra (5% lifitegrast ophthalmic solution) had not been proven in different symptoms of dry eye disease. The EMA said: "While some effect was seen in reducing dry eye, the improvement was not clinically significant." The EMA also pointed out that although dry eye is a chronic disease, there is no data on the long-term treatment effects of Xiidra.

[0004] Lifamide is easily oxidized, and the relatively stable pH range is 7.0-8.0, and the more optimal pH range is 7.2-7.5. Because the product is easily oxidized, antioxidants and nitrogen filling protection need to be added. According to the prescription composition of the present invention, no additional antioxidants need to be added, and a preparation product with stability not lower than the reference preparation (trade name: Xiidra) can be prepared, and the animal model shows better efficacy than Lifamide and tea polyphenols alone. Summary of the invention

[0005] The object of the present invention is to provide a lifalast and tea polyphenol eye drop composition which overcomes the above problems or at least partially solves the above problems.

[0006] The objective of the present invention is achieved through the following technical solutions:

[0007] The present invention relates to a lifalast and tea polyphenol composition, which comprises the following components in percentage by weight:

[0008]

[0009]

[0010] As a preferred embodiment, the composition of lifalast and tea polyphenols comprises the following components in percentage by weight:

[0011]

[0012] As an embodiment of the present invention, the buffer is selected from at least one of anhydrous disodium hydrogen phosphate, anhydrous sodium dihydrogen phosphate, anhydrous dipotassium hydrogen phosphate, and anhydrous potassium dihydrogen phosphate.

[0013] As an embodiment of the present invention, the osmotic pressure regulator is selected from sodium chloride, glucose, phosphate or citrate.

[0014] As an embodiment of the present invention, the pH adjuster is selected from at least one of dilute hydrochloric acid and sodium hydroxide.

[0015] As an embodiment of the present invention, the pH adjuster adjusts the pH value of the composition to 7.0-8.0.

[0016] The present invention also relates to a method for preparing a composition of lifalast and tea polyphenols, the method comprising the following steps:

[0017] S1. Take the buffer, osmotic pressure regulator, tea polyphenols and water for injection, and stir to dissolve;

[0018] S2, adding the lifalast, stirring and dissolving, and then adding a pH adjuster to adjust the pH value to 7.0-8.0;

[0019] S3, filtering and filling to obtain the composition of ritalistat and tea polyphenols.

[0020] As an embodiment of the present invention, in step S1, the temperature is raised to 30-60°C and then stirred for dissolution.

[0021] As an embodiment of the present invention, in step S3, the filtration uses a 0.22 μm PES filter membrane.

[0022] The present invention also relates to the use of a lifalast and tea polyphenol composition in preparing medicines for treating ophthalmic diseases, in particular to the use of a lifalast and tea polyphenol composition in preparing medicines for treating dry eyes.

[0023] As an embodiment of the present invention, the dosage form of the drug includes eye drops, films, and gels.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] The quality of the lifalast eye drop composition of the present invention is not lower than that of the reference preparation Xiidra, and its stability is equivalent to that of the reference preparation Xiidra. In addition, the non-clinical mouse model shows a better therapeutic effect than that of lifalast and tea polyphenols alone. DETAILED DESCRIPTION

[0026] The present invention is described in detail below in conjunction with embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that, for those of ordinary skill in the art, some adjustments and improvements can also be made without departing from the concept of the present invention. These all belong to the protection scope of the present invention.

[0027] Examples 1-3

[0028] Preparation method: Weigh the prescribed amount of anhydrous disodium hydrogen phosphate, sodium chloride, tea polyphenols and water for injection (Table 1), heat to 40°C, stir to dissolve, add the prescribed amount of lifalast raw material, stir to dissolve, adjust the pH value to 7.0-8.0 with appropriate amount of hydrochloric acid or sodium hydroxide, filter through 0.22μm PES filter membrane, and fill to obtain lifalast-tea polyphenols eye drops.

[0029] Table 1

[0030]

[0031] Comparative Example 1 (prepared with reference to the reference preparation formula)

[0032] Preparation method: Weigh the prescribed amount of anhydrous disodium hydrogen phosphate, sodium chloride, sodium thiosulfate pentahydrate and water for injection (Table 2), heat to 40°C, stir to dissolve, add the prescribed amount of lifalast raw material, stir to dissolve, adjust the pH value to 7.0-8.0 with appropriate amount of hydrochloric acid or sodium hydroxide, filter through 0.22μm PES filter membrane, and fill to obtain lifalast eye drops.

[0033] Table 2

[0034]

[0035] Comparative Example 2

[0036] Preparation method: Weigh the prescribed amount of disodium hydrogen phosphate anhydrous, sodium chloride, sodium thiosulfate pentahydrate, and 4% water for injection, heat to 40°C, stir to dissolve, add the prescribed amount of lifalast raw material, stir to dissolve, adjust the pH value to 7.0-8.0 with appropriate amount of hydrochloric acid or sodium hydroxide, filter through 0.22μm PES filter membrane, and fill to obtain lifalast eye drops.

[0037] Table 3

[0038]

[0039] Comparative Example 3: Tea Polyphenols Eye Drops

[0040] Preparation method: Weigh the prescription amount (Table 4) of anhydrous disodium hydrogen phosphate, sodium chloride, tea polyphenols, and 95% water for injection, stir to dissolve, use appropriate amount of hydrochloric acid or sodium hydroxide to adjust the pH value to 7.0-8.0, filter through a 0.22μm PES filter membrane, and fill to obtain eye drops.

[0041] Table 4

[0042]

[0043] Example 4: Quality and stability studies

[0044] The samples and reference preparations prepared according to Examples 1-3 and Comparative Example 1 were tested for properties, pH value, osmotic pressure, related substances, and content. The specific results are shown in Table 5:

[0045] Table 5

[0046]

[0047] Stability studies

[0048] The samples prepared according to Examples 2-3 and Comparative Example 1 and the reference preparation were placed at a temperature of 40-42°C and a humidity of RH 25%-45%. Samples were taken in January, February and March to test properties, pH value, osmotic pressure, related substances and content. The specific results are shown in Tables 6 and 7:

[0049] Table 6 Summary of stability data of Example 2-3

[0050]

[0051] Table 7. Comparative Example 1 and Reference Preparation Stability Data Summary

[0052]

[0053]

[0054] Example 5. Evaluation of therapeutic efficacy in non-clinical mouse models

[0055] The tear osmotic pressure of patients with dry eye disease is significantly increased, and its osmotic pressure is 326422.1mOsmol / L, while the tear osmotic pressure of normal people is 30249.7mOsmol / L. Therefore, using osmotic pressure as a diagnostic indicator for dry eye disease has better sensitivity and specificity than any other diagnostic indicator for dry eye disease.

[0056] Experimental methods:

[0057] Preparation of high saline eye drops: Prepare sodium chloride solution with an osmotic pressure of 500mOsmol / L.

[0058] 100 female BALB / c mice aged 6-8 weeks were selected and randomly divided into a high saline eye drops group (control group), lifalast eye drops (trade name: Xiidra) + a sodium chloride solution with an osmotic pressure of 500mOsmol / L (reference preparation group), homemade lifalast eye drops (formulation composition of Example 2) + a sodium chloride solution with an osmotic pressure of 500mOsmol / L (preparation group of the present invention), lifalast eye drops (formulation composition of comparative example 2) + a sodium chloride solution with an osmotic pressure of 500mOsmol / L (preparation group of comparative example 2), and tea polyphenol eye drops (formulation composition of comparative example 3) + a sodium chloride solution with an osmotic pressure of 500mOsmol / L (preparation group of comparative example 3);

[0059] Control group: 500mOsmol / L sodium chloride solution was used for eye drops, 5 times a day, for 28 days.

[0060] Reference preparation group: first instill reference preparation ritalista eye drops, then instill 500mOsmol / L sodium chloride solution 30 minutes later, 5 times a day for each, and continue instilling for 28 days

[0061] The preparation group of the present invention: first drip the homemade preparation ritahlast eye drops, and then drip 500mOsmol / L sodium chloride solution 30 minutes later, each dripping 5 times a day, and continuing the eye drops for 28 days.

[0062] Comparative Example 2 Preparation Group: First drip the lifalast eye drops of Comparative Example 2, and then drip 500mOsmol / L sodium chloride solution 30 minutes later, 5 times each day, and continue to drip for 28 days.

[0063] Comparative Example 3 preparation group: first drip the tea polyphenols eye drops of Comparative Example 3, and then drip 500mOsmol / L sodium chloride solution 30 minutes later, 5 times each day, and continue to drip for 28 days.

[0064] The tear secretion volume and tear osmotic pressure were used for evaluation. The specific methods are as follows:

[0065] Determination of tear secretion: The tear secretion of BALB / c mice was determined by the Schirmer I method. Under a slit lamp microscope, phenol red cotton thread was clamped with micro forceps and placed in the outer canthus of the eye of BALB / c mice. It was removed after 60 seconds, and the length of the phenol red cotton thread wetted was measured with a millimeter ruler.

[0066] Tear osmotic pressure determination: First, a conversion table for the tear osmotic pressure measurement values ​​of BALB / c mice was established. Mouse tears were collected on the 0th and 28th days of the experiment, and the tear osmotic pressure values ​​were determined by freezing point osmotic pressure. The tear osmotic pressure was converted based on the established conversion table for the tear osmotic pressure measurement values ​​of BALB / c mice.

[0067] Test results:

[0068] Table 8. Tear secretion of BALB / c mice

[0069]

[0070] Table 9. Tear osmotic pressure of BALB / c mice mOsmol / L

[0071]

[0072] Through the two indicators of tear secretion and tear osmotic pressure of BALB / c mice, it can be concluded that the therapeutic effect of the preparation group of the present invention on BALB / c mice with dry eye model is significantly higher than that of the reference preparation group and the comparative example group. The preparation group of comparative example 3 (i.e., tea polyphenol eye drops) is slightly better than the control group, but lower than the preparation group of the present invention and the reference preparation. That is, the combination of lifalast and tea polyphenols has a significantly higher therapeutic effect than the same dose of lifalast or tea polyphenols alone.

[0073] The above describes the specific embodiments of the present invention. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art may make various modifications or variations within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. A composition of lifalast and tea polyphenols for treating dry eye, characterized in that: The composition comprises the following components in weight percentage: Lifalast 4.5%~5.5%, Buffer 0.09%~0.11%, Osmotic pressure regulator 0.65%~0.85%, Tea polyphenols 0.3%~0.9%, pH regulator adjusts the pH value to 7.0-8.0, Remaining amount of water for injection.

2. The lifalast and tea polyphenols composition according to claim 1, characterized in that: The composition comprises the following components in weight percentage: Lifastat 5.0%, Buffer 0.1%, Osmotic pressure regulator 0.75%, Tea polyphenols 0.3%~0.9%, pH regulator adjusts the pH value to 7.0-8.0, Remaining amount of water for injection.

3. The lifalast and tea polyphenols composition according to claim 1, characterized in that: The buffer is selected from at least one of anhydrous disodium hydrogen phosphate, anhydrous sodium dihydrogen phosphate, anhydrous dipotassium hydrogen phosphate, and anhydrous potassium dihydrogen phosphate.

4. The lifalast and tea polyphenols composition according to claim 1, characterized in that: The osmotic pressure regulator is selected from sodium chloride, glucose, phosphate or citrate.

5. The lifalast and tea polyphenols composition according to claim 1, characterized in that: The pH value adjuster is selected from at least one of dilute hydrochloric acid and sodium hydroxide.

6. The lifalast and tea polyphenols composition according to claim 1, characterized in that: The pH adjuster adjusts the pH value of the composition to 7.2-7.

5.

7. A method for preparing the lifalast and tea polyphenols composition according to claim 1, characterized in that: The method comprises the following steps: S1. Take the buffer, osmotic pressure regulator, tea polyphenols and water for injection, and stir to dissolve; S2, adding the lifalast, stirring and dissolving, and then adding a pH adjuster to adjust the pH value to 7.0-8.0; S3, filtering and filling to obtain the composition of ritalistat and tea polyphenols.

8. The method for preparing the composition of lifalast and tea polyphenols according to claim 7, characterized in that: In step S1, the temperature is raised to 30-60°C and then stirred to dissolve. In step S3, the filtration is performed using a 0.22 μm PES filter membrane.

9. Use of the lifalast and tea polyphenols composition according to claim 1 in preparing a drug for treating dry eye.

10. The use according to claim 9, characterized in that The dosage forms of the drug include eye drops, films and gels.

Images