High-stability eye drops and preparation method thereof

Abstract

The embodiment of the invention provides high-stability eye drops and a preparation method thereof.The method comprises the steps that traditional Chinese medicinal materials are cleaned, dried in the sun and extracted to obtain corresponding extracts; the preparation method comprises the following steps: carrying out ultrasonic breaking on a water-phase dispersion liquid of nanofibers to form nanofibers smaller than 40 nanometers, adding disodium hydrogen phosphate to adjust the pH value, standing at the temperature of lower than 0 DEG C for 1-5 hours, taking out, carrying out ultrasonic stirring at room temperature, and repeating the steps for many times to obtain a fiber liquid; adding the extract into the fiber liquid, uniformly stirring, freezing and thawing at-5 to-15 DEG C, putting at room temperature, adding a mixed alcohol solution, stirring, adding into a sterile buffer solution, and sterilizing to obtain the eye drops. The eye drops provided by the invention have excellent stability and can exert the efficacy for a long time.

Description

Technical Field

[0001] The present application relates to the technical field of preparation of eye drops, and in particular to a highly stable eye drop and a preparation method thereof. Background Art

[0002] At present, the traditional way of administering drugs for intraocular diseases is to administer drugs through the ocular surface, for example, by dripping eye drops into the eyes. In recent years, preparations based on eye drops have become a hot topic of research. However, due to the complex structure of the human eye and the presence of many barriers in the structure of the eye, the therapeutic effects of many eye drop formulations are poor. For example, due to the rapid loss of drugs on the ocular surface and the aqueous humor barrier, it is difficult for drugs in conventional eye drops to reach effective drug concentrations in the retinal tissue, and only about 10% of the drugs can enter the intraocular tissue, resulting in low bioavailability of the drugs, and repeated administration is required to maintain drug concentrations. Moreover, some drugs have poor water solubility, and the resulting oil eye drops are highly irritating to the eyes, which is not conducive to patient compliance.

[0003] Existing eye drops can effectively treat some ophthalmic diseases by extracting Chinese medicinal materials as one of the eye drop ingredients. For example, a patent discloses that eye drops are prepared by extracting honeysuckle, scutellaria and forsythia, which can effectively treat viral dendritic keratitis. However, the above patent does not effectively solve the stability problem of eye drops made of Chinese medicine preparations. After the eye drops are administered through the ocular surface, the drug concentration cannot be maintained for a long time. Summary of the invention

[0004] The embodiments of the present application provide a highly stable eye drop and a preparation method thereof, so as to solve the technical problems existing in the prior art that the eye drops cannot maintain the drug concentration for a long time and have poor drug stability.

[0005] In a first aspect, the present invention provides a method for preparing a highly stable eye drop, comprising:

[0006] S101, washing, drying and extracting the Chinese medicinal materials to obtain corresponding extracts;

[0007] S102, ultrasonically breaking the aqueous dispersion of nanofibers to form nanofibers smaller than 40 nanometers, adding disodium hydrogen phosphate to adjust the pH value, placing the dispersion at a temperature below 0° C. for 1 to 5 hours, taking the dispersion out and ultrasonically stirring the dispersion at room temperature, and repeating the process several times to obtain a fiber solution;

[0008] S103, adding the extract to the fiber liquid, stirring evenly, placing at -5 to -15°C for freeze-thawing, placing at room temperature, adding the mixed alcohol solution, stirring and adding to the sterile buffer solution, sterilizing, and obtaining the eye drops.

[0009] In an optional embodiment, the Chinese medicinal materials include at least any two of honeysuckle, forsythia and scutellaria;

[0010] And / or, the Chinese medicinal materials are tested before extraction to detect that the content of methyl parathion in the medicinal materials is not more than 5 μg / kg, and / or the content of oxydemeton-methyl is 8 μg / kg.

[0011] In an optional embodiment, the nanofiber is selected from any one of methyl cellulose, hydroxypropyl cellulose or silk fibroin nanofiber.

[0012] In an optional implementation manner, in the aqueous dispersion of the nanofibers, the mass fraction of the nanofibers dispersed in water is 0.02-1.2%.

[0013] In an optional implementation manner, during the ultrasonic fiber breaking process, the ultrasonic power is 300-400 W, and the ultrasonic time is 10-20 min.

[0014] In an optional embodiment, the mass volume of the extract and the fiber liquid is (1-2) g: (15-25) mL.

[0015] In an optional embodiment, the pH value is adjusted to 8-11, preferably 9-10.

[0016] In an optional embodiment, the mixed alcohol solution includes at least two of ethanol, n-butanol or tert-butanol.

[0017] In an optional embodiment, the sterile buffer solution includes any one of a phosphate buffer and a borate buffer;

[0018] and / or, the pH value of the sterile buffer solution is 7.2 to 8;

[0019] And / or, the volume ratio of the fiber liquid, the mixed alcohol solution and the sterile buffer solution is (0.1-5):(1-10):100.

[0020] In a second aspect, the embodiments of the present application provide a highly stable eye drop, which is prepared by a preparation method according to any one of the embodiments of the first aspect of the present application.

[0021] The highly stable eye drops and preparation method thereof provided in the embodiments of the present application also have the following beneficial effects:

[0022] 1. In this application, the eye drops prepared by mixing the Chinese medicine extract and the nanofiber solution and then freezing and thawing at low temperature can have long-lasting medicinal properties and continuously sterilize and reduce inflammation in the eyes. First, the nanofibers are dissolved at low temperature, mixed with the extract, and the fiber crystal growth is controlled under low-temperature freeze-thaw conditions, so that the obtained fiber crystals contain the components in the extract. During use, as the fiber crystals exert their medicinal effects in the tears, they are more effective and can also improve the stability of the eye drops, making it less likely for the eye drops to precipitate.

[0023] 2. In this application, before the extract is prepared, the pesticide residue content in traditional Chinese medicine is effectively reduced, making the eye drops safer. In addition, the fiber molecular structure of nanofibers contains abundant functional groups, which are easy to combine with the bactericidal and anti-inflammatory substances in the extract, further improving the bactericidal and anti-inflammatory effects of the eye drops. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the present application and, together with the description, serve to explain the principles of the present application.

[0025] Figure 1 This is a process flow chart of the preparation method of the highly stable eye drops provided in the embodiments of the present application.

[0026] The above drawings have shown clear embodiments of the present application, which will be described in more detail later. These drawings and text descriptions are not intended to limit the scope of the present application in any way, but to illustrate the concept of the present application to those skilled in the art by referring to specific embodiments. DETAILED DESCRIPTION

[0027] Exemplary embodiments will be described in detail herein, examples of which are shown in the accompanying drawings. When the following description refers to the drawings, the same numbers in different drawings represent the same or similar elements unless otherwise indicated. The implementations described in the following exemplary embodiments do not represent all implementations consistent with the present application. Instead, they are merely examples of devices and methods consistent with some aspects of the present application as detailed in the appended claims.

[0028] The technical solution of the present application and how the technical solution of the present application solves the above-mentioned technical problems are described in detail below with specific embodiments. The following specific embodiments can be combined with each other, and the same or similar concepts or processes may not be repeated in some embodiments. The embodiments of the present application will be described below in conjunction with the accompanying drawings.

[0029] In the present application, the extracts of the corresponding Chinese medicinal materials are extracted by the method recorded in the Chinese Pharmacopoeia, such as the method of recording Shuanghuanglian eye drops. The present application adopts the method described in the first aspect above to extract the extracts of honeysuckle, scutellaria and forsythia, and the above medicinal materials are soaked in water for half an hour to one hour according to a certain proportion, and then decocted. After decocting for about one hour, the filtrate is collected, and the water is added and decocted again for about one hour. The filtrates collected from the two decoctions are mixed and concentrated into a clear paste, and when cooled to room temperature, an ethanol solution is added, stirred and allowed to stand for 12 to 20 hours, the supernatant is filtered, and the ethanol is recovered until there is no alcohol taste. After adding water and standing for 12 hours, the supernatant is filtered and concentrated again into a clear paste with a relative density of 1.11 to 1.16, ethanol is added to make the ethanol content reach 85%, and the mixture is allowed to stand for 10 to 20 hours, and the supernatant is filtered and recovered until there is no alcohol taste to obtain an extract.

[0030] In the present application, the medicinal materials mentioned in the first aspect of the present application may also be extracted separately, and the method used is still carried out according to the record in the Chinese Pharmacopoeia. For example, first extract the Forsythia suspensa to obtain the Forsythia suspensa extract. Then extract the honeysuckle to obtain the honeysuckle extract, extract the scutellaria baicalensis to obtain the scutellaria baicalensis extract, and then mix the Forsythia suspensa extract, the honeysuckle extract and the scutellaria baicalensis extract to obtain the extract.

[0031] The above extraction method is not limited thereto, and those skilled in the art can also make modifications based on the above method to effectively extract the effective components of the corresponding medicinal materials. And since there are patents that disclose the residues of methamidophos and omethoate in the above medicinal materials, therefore, during the extraction process, detection is also adopted to detect methamidophos and omethoate in the medicinal materials to ensure that their contents are within the range mentioned in the first aspect above.

[0032] Example 1

[0033] A method for preparing highly stable eye drops, comprising:

[0034] The Chinese medicinal materials Fructus Forsythiae, Radix Scutellariae and Flos Lonicerae are washed, dried in the sun and extracted to obtain corresponding extracts.

[0035] The aqueous dispersion of silk fibroin nanofibers is ultrasonically broken into fibers to form nanofibers smaller than 40 nanometers. Disodium hydrogen phosphate is added to adjust the pH value to 9. The fibers are placed at a temperature below 0°C for 1 to 5 hours, taken out and ultrasonically stirred at room temperature. This process is repeated several times to obtain a fiber liquid.

[0036] The extract was added to the fiber solution, stirred evenly, and then placed at -15°C for freeze-thawing. The solution was placed at room temperature, and a 1:1 mixed alcohol solution of n-butanol and ethanol was added. The solution was stirred and added to a sterile borate buffer solution for sterilization to obtain eye drops.

[0037] The volume ratio of the fiber liquid, the mixed alcohol solution and the sterile buffer solution is 2:10:100; the mass volume of the extract and the fiber liquid is 2g:20mL.

[0038] Example 2

[0039] A method for preparing highly stable eye drops, comprising:

[0040] The Chinese medicinal materials Forsythia suspensa and honeysuckle are washed, dried in the sun and extracted to obtain corresponding extracts.

[0041] The aqueous dispersion of hydroxypropyl cellulose nanofibers is ultrasonically broken into fibers to form nanofibers smaller than 40 nanometers. Disodium hydrogen phosphate is added to adjust the pH value to 8. The fibers are placed at a temperature below 0°C for 1 to 5 hours, taken out and ultrasonically stirred at room temperature. This process is repeated several times to obtain a fiber liquid.

[0042] The extract was added to the fiber solution, stirred evenly, and then placed at -10°C for freeze-thawing. The solution was placed at room temperature, and a 1:1 mixed alcohol solution of n-butanol and ethanol was added. The solution was stirred and added to a sterile borate buffer solution for sterilization to obtain eye drops.

[0043] The volume ratio of the fiber liquid, the mixed alcohol solution and the sterile buffer solution is 1:5:100; the mass volume of the extract and the fiber liquid is 1 g:20 mL.

[0044] Example 3

[0045] A method for preparing highly stable eye drops, comprising:

[0046] The Chinese medicinal materials Fructus Forsythiae, Radix Scutellariae and Flos Lonicerae are washed, dried in the sun and extracted to obtain corresponding extracts.

[0047] The aqueous dispersion of methylcellulose nanofibers is ultrasonically broken into fibers to form nanofibers smaller than 40 nanometers. Disodium hydrogen phosphate is added to adjust the pH value to 8.5. The fibers are placed at a temperature below 0°C for 1 to 5 hours, taken out and ultrasonically stirred at room temperature. This process is repeated several times to obtain a fiber liquid.

[0048] The extract was added to the fiber solution, stirred evenly, and then placed at -8°C for freeze-thawing. The solution was placed at room temperature, and a 1:1 mixed alcohol solution of n-butanol and ethanol was added. The solution was stirred and added to a sterile borate buffer solution for sterilization to obtain eye drops.

[0049] The volume ratio of the fiber liquid, the mixed alcohol solution and the sterile buffer solution is 4:9:100; the mass volume of the extract and the fiber liquid is 2g:25mL.

[0050] Comparative Example 1

[0051] A method for preparing eye drops, comprising:

[0052] The Chinese medicinal materials Fructus Forsythiae, Radix Scutellariae and Flos Lonicerae are washed, dried in the sun and extracted to obtain corresponding extracts.

[0053] The aqueous dispersion of silk fibroin nanofibers is ultrasonically broken into fibers to form nanofibers smaller than 40 nanometers. Disodium hydrogen phosphate is added to adjust the pH value to 9. The fibers are placed at a temperature below 0°C for 1 to 5 hours, taken out and ultrasonically stirred at room temperature. This process is repeated several times to obtain a fiber liquid.

[0054] The extract is added to the fiber liquid, and after being stirred evenly, a 1:1 mixed alcohol solution of n-butanol and ethanol is added, and the mixture is added to a sterile borate buffer solution with stirring, and sterilized to obtain eye drops.

[0055] The volume ratio of the fiber liquid, the mixed alcohol solution and the sterile buffer solution is 2:10:100; the mass volume of the extract and the fiber liquid is 2g:20mL.

[0056] Comparative Example 2

[0057] A method for preparing eye drops, comprising:

[0058] The Chinese medicinal materials Fructus Forsythiae, Radix Scutellariae and Flos Lonicerae are washed, dried in the sun and extracted to obtain corresponding extracts.

[0059] The aqueous dispersion of silk fibroin nanofibers is ultrasonically broken into fibers to form nanofibers smaller than 40 nanometers, thereby obtaining a fiber liquid.

[0060] The extract is added to the fiber liquid, and after being stirred evenly, a 1:1 mixed alcohol solution of n-butanol and ethanol is added, and the mixture is added to a sterile borate buffer solution with stirring, and sterilized to obtain eye drops.

[0061] The volume ratio of the fiber liquid, the mixed alcohol solution and the sterile buffer solution is 2:10:100; the mass volume of the extract and the fiber liquid is 2g:20mL.

[0062] Comparative Example 3

[0063] A method for preparing eye drops, comprising:

[0064] The Chinese medicinal materials Fructus Forsythiae, Radix Scutellariae and Flos Lonicerae are washed, dried in the sun and extracted to obtain corresponding extracts.

[0065] The extract is added into a sterile borate buffer solution and sterilized to obtain eye drops.

[0066] The volume ratio of the fiber liquid, the mixed alcohol solution and the sterile buffer solution is 2:10:100; the mass volume of the extract and the fiber liquid is 2g:20mL.

[0067] Comparative Example 4

[0068] Levofloxacin eye drops available on the market.

[0069] Performance Testing:

[0070] 1. Eye irritation test

[0071] Healthy rabbits were randomly divided into 4 groups, with 10 rabbits in each group. One drop of moxifloxacin hydrochloride eye drops prepared in Example 1, Comparative Example 1, Comparative Example 2 or Comparative Example 3 was instilled into the left eye of the rabbits, and one drop of normal saline was instilled into the right eye of the rabbits as a control, once a day for 10 consecutive days. The eye irritation of the moxifloxacin hydrochloride eye drops prepared in Example 1, Comparative Example 1, Comparative Example 2 or Comparative Example 3 was investigated 1 hour after the first eye drop and 1 hour after the eye drop on the 10th day by sodium fluorescein staining and slit lamp examination.

[0072] The evaluation items and evaluation scores of eye irritation degree are as follows:

[0073] Cornea: 0 points - no opacity; 1 point - scattered or diffuse opacity, the iris is clearly visible; 2 points - the translucent area is easy to distinguish, and the iris is blurred; 3 points - grayish white translucent areas appear, the details of the iris are unclear, and the size of the pupil can be barely seen; 4 points - the cornea is opaque and the iris cannot be recognized.

[0074] Iris: 0 points - normal; 1 point - obvious deepening of wrinkles, congestion, swelling, mild congestion around the cornea, pupil still responds to light; 2 points - bleeding / necrotic visible to the naked eye / no response to light (or more than one of them). Conjunctival congestion (referring to the palpebral conjunctiva and bulbar conjunctiva): 0 points - normal blood vessels; 1 point - bright red blood vessels; 2 points - dark red blood vessels, blood vessels are difficult to distinguish; 3 points - diffuse congestion and purple red.

[0075] Edema: 0 points - no edema; 1 point - mild edema (including eyelids); 2 points - obvious edema with partial ectropion of eyelids; 3 points - edema to the eyelids being half closed; 4 points - edema to the eyelids being more than half closed.

[0076] Discharge: 0 points - no discharge; 1 point - a small amount of discharge; 2 points - discharge makes the eyelids and eyelashes moist or sticky; 3 points - discharge makes the entire eye area moist or sticky.

[0077] The total score of eye irritation evaluation and its corresponding evaluation criteria are as follows:

[0078] Non-irritation: 0-3 (including 0 and excluding 3).

[0079] Mild irritation: 3-8 (including 3 and excluding 8) points.

[0080] Moderate irritation: 8-12 (including 8 and excluding 12) points.

[0081] Severe irritation: 12-16 (inclusive) points.

[0082] The higher the total score of the eye irritation evaluation, the stronger the eye irritation.

[0083] The eye irritation evaluation results of the eye drops prepared in Examples 1 to 3 and Comparative Examples 1 to 4 are shown in Table 1 below.

[0084] Table 1. Evaluation results:

[0085]

[0086] It can be seen from Table 1 that the eye drops prepared in Examples 1 to 3 of the present application are non-irritating to the eyes, have high pharmaceutical safety, and enable patients to have stronger compliance.

[0087] 2. Stability test

[0088] According to the guidance of the preparation stability test of the "Chinese Pharmacopoeia", the eye drops prepared in Examples 1 to 3 and Comparative Examples 1 to 4, which were packaged in low-density polyethylene medicinal eye drop bottles, were placed at 60°C for 0 days, 5 days and 10 days. The properties and impurity content of the moxifloxacin hydrochloride eye drops were investigated at different investigation time points, thereby investigating the high temperature stability of the eye drops prepared in Examples 1 to 3 and Comparative Examples 1 to 4. The results are shown in Table 2.

[0089] Table 2. Stability test results

[0090]

[0091] As can be seen from Table 2, the eye drops prepared in Examples 1 to 3 of the present application have excellent stability.

[0092] It should be noted that, for the above-mentioned method embodiments, for the sake of simplicity, they are all described as a series of action combinations, but those skilled in the art should know that the present application is not limited by the described action sequence, because according to the present application, some steps can be performed in other sequences or simultaneously. Secondly, those skilled in the art should also know that the embodiments described in the specification are all optional embodiments.

[0093] In the above embodiments, the description of each embodiment has its own emphasis. For the part not described in detail in a certain embodiment, please refer to the relevant description of other embodiments. The technical features of the above embodiments can be combined arbitrarily. In order to make the description concise, all possible combinations of the technical features in the above embodiments are not described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0094] Those skilled in the art will readily appreciate other embodiments of the present application after considering the specification and practicing the invention disclosed herein. The present application is intended to cover any modification, use or adaptation of the present application, which follows the general principles of the present application and includes common knowledge or customary techniques in the art that are not disclosed in the present application. The specification and examples are intended to be exemplary only, and the true scope and spirit of the present application are indicated by the following claims.

[0095] It should be understood that the present application is not limited to the precise structures that have been described above and shown in the drawings, and that various modifications and changes may be made without departing from the scope thereof. The scope of the present application is limited only by the appended claims.

Claims

1. A method for preparing highly stable eye drops, characterized in that: include: S101, washing, drying and extracting the Chinese medicinal materials to obtain corresponding extracts; S102, ultrasonically breaking the aqueous dispersion of nanofibers to form nanofibers smaller than 40 nanometers, adding disodium hydrogen phosphate to adjust the pH value, placing the dispersion at a temperature below 0° C. for 1 to 5 hours, taking the dispersion out and ultrasonically stirring the dispersion at room temperature, and repeating the process several times to obtain a fiber solution; S103, adding the extract to the fiber liquid, stirring evenly, placing at -5 to -15°C for freeze-thawing, placing at room temperature, adding the mixed alcohol solution, stirring and adding to the sterile buffer solution, sterilizing, and obtaining the eye drops.

2. The method for preparing the highly stable eye drops according to claim 1, characterized in that: The Chinese medicinal materials include at least any two of honeysuckle, forsythia and scutellaria; And / or, the Chinese medicinal materials are tested before extraction to detect that the content of methyl parathion in the medicinal materials is not more than 5 μg / kg, and / or the content of oxydemeton-methyl is 8 μg / kg.

3. The method for preparing the highly stable eye drops according to claim 1, characterized in that: The nanofiber is selected from any one of methyl cellulose, hydroxypropyl cellulose or silk fibroin nanofiber.

4. The method for preparing the highly stable eye drops according to claim 1 or 3, characterized in that: In the aqueous phase dispersion of the nanofibers, the mass fraction of the nanofibers dispersed in water is 0.02-1.2%.

5. The method for preparing the highly stable eye drops according to claim 1, characterized in that: During the ultrasonic fiber breaking process, the ultrasonic power is 300-400W, and the ultrasonic time is 10-20min.

6. The method for preparing the highly stable eye drops according to claim 1, characterized in that: The mass volume of the extract and the fiber liquid is (1-2) g: (15-25) mL.

7. The method for preparing the highly stable eye drops according to claim 1, characterized in that: The pH value is adjusted to 8-11, preferably 9-10.

8. The method for preparing the highly stable eye drops according to claim 1, characterized in that: The mixed alcohol solution includes at least two of ethanol, n-butanol or tert-butanol.

9. The method for preparing the highly stable eye drops according to claim 1, characterized in that: The sterile buffer solution includes any one of a phosphate buffer and a borate buffer; and / or, the pH value of the sterile buffer solution is 7.2 to 8; And / or, the volume ratio of the fiber liquid, the mixed alcohol solution and the sterile buffer solution is (0.1-5):(1-10):

100.

10. A highly stable eye drop, characterized in that: The eye drops are prepared by the preparation method according to any one of claims 1 to 9.

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