Traditional Chinese medicine suspension eye drops and preparation method thereof

Abstract

The invention discloses traditional Chinese medicine suspension eye drops and a preparation method thereof, and the traditional Chinese medicine suspension eye drops are prepared from the following raw materials in parts by weight: 1-3 parts of a traditional Chinese medicine composition, 4-7 parts of hydroxypropyl-beta-cyclodextrin, 0.5-2 parts of microcrystalline cellulose-sodium carboxymethyl cellulose and auxiliary materials. The traditional Chinese medicine suspension eye drops provided by the invention abandon a traditional eye ointment form, are directly dropped for use, are convenient to use, have good stability and dispersity, and are excellent in use curative effect and medication experience; on the basis of keeping the clinical efficacy of the Marcher eight-treasure ancient prescription, secondary development and research are scientifically carried out, so that the Marcher eight-treasure ancient prescription plays a greater clinical treatment role, and has a wider market development prospect.

Description

Technical Field

[0001] This invention belongs to the field of ophthalmic product technology, specifically relating to a traditional Chinese medicine suspension eye drops and its preparation method. Background Technology

[0002] Traditional Chinese medicine believes that the eyes are the upper orifices, exposed to the body surface, and are easily invaded by the six pathogenic factors, which can cause diseases. Wind and heat are the first to be affected, mainly manifested as stagnation, heat, dryness, and corneal opacity. The treatment of eye diseases by the six pathogenic factors is mostly due to blood heat stagnation, liver and kidney yin deficiency, and wind and fire disturbing the upper body.

[0003] The Eight Treasures Formula includes eight precious Chinese medicinal herbs: musk, bezoar, amber, pearl, borneol, calamine, borax, and sal ammoniac. This formula is exquisite and meticulously formulated, and has unique efficacy in treating eye diseases such as redness, swelling, pain, itching, tearing, and eyelid redness caused by wind-heat. The Eight Treasures Formula originated in Dingzhou, Hebei Province in 1582 (the tenth year of the Wanli reign of the Ming Dynasty). It has remained popular for over four hundred years. The formula uses bezoar, which is bitter, sweet, and cool in nature, clearing the liver, detoxifying, resolving blood stasis, and opening the orifices. It is suitable for eye diseases caused by liver fire disturbing the eye orifices and serves as the principal ingredient. Musk, pungent and aromatic, opens the orifices, dispels foulness, detoxifies, and disperses blood stasis to clear eye opacities, serving as the assistant ingredient. Calamine, pearl, amber, and borax astringe moisture, heal sores, reduce redness, and remove eye opacities; sal ammoniac dissipates accumulations, softens hardened masses, breaks up blood stasis, disperses nodules, and removes malignant sores and eye opacities, serving as the adjuvant ingredients. Borneol opens the orifices, disperses stagnant heat, removes eye opacities, and brightens the eyes, thus serving as the guiding ingredient. The combined effects of these ingredients are to clear heat, reduce redness, relieve itching, and remove eye opacities.

[0004] In the prior art, patent documents with publication numbers CN1209119C and CN1201750C disclose an eye powder and an eye ointment based on the aforementioned Babao ancient formula, respectively. The eye ointment, named "Ma Yinglong Babao Eye Ointment," has been developed and marketed for many years. Its formula consists of calcined calamine 32.7g, amber 0.15g, artificial musk 0.38g, artificial bezoar 0.38g, pearl 0.38g, borneol 14.8g, borax 1.2g, and sal ammoniac 0.05g. The product is a light yellow to light yellowish-brown ointment with the effects of clearing heat and reducing redness, relieving itching, and removing corneal opacity. Due to its advantages such as long-lasting efficacy, effective prevention of cross-infection, protection of the tear film, and no toxic side effects during long-term use, it has been favored by many patients for many years. However, because eye ointments need to be squeezed out and applied into the eyelid, the process is inconvenient. Furthermore, due to their oily base, the ointment doesn't spread immediately after application, causing temporary adhesion between the eyelid and the eyeball, which temporarily affects vision. Therefore, eye ointments are mostly used during rest periods, resulting in a less than ideal patient experience and limiting their further development and sales.

[0005] Therefore, a new type of eye drop based on the ancient Babao formula is needed for convenient use and better patient compliance. However, since the calcined calamine, amber, artificial musk, artificial bezoar, pearl, and borneol in the Babao formula are all insoluble in water, it needs to be prepared as a suspension eye drop. Existing non-water-soluble ophthalmic herbal preparations, such as Musk Pearl Brightening Eye Drops, Zhangyi Powder, and Boyun Pill Eye Drops, generally require the herbal powder to be poured into a solvent bottle, shaken to form a suspension, and then instilled into the eyelid before use. This is because the suspension has poor long-term stability and needs to be prepared and used immediately, which is extremely inconvenient.

[0006] In view of this, the present invention is proposed. Summary of the Invention

[0007] To address the aforementioned technical problems, the present invention aims to provide a traditional Chinese medicine suspension eye drop and its preparation method. The eye drop can be directly instilled into the eyelid, making it easy to use. It solves the discomfort caused by the oily matrix in traditional eye ointments and significantly improves patient compliance.

[0008] To achieve the above objectives, the present invention adopts the following technical solution: In a first aspect, the present invention provides a traditional Chinese medicine suspension eye drop, which is prepared by weight from the following raw materials: 1-3 parts of traditional Chinese medicine composition, 4-7 parts of hydroxypropyl-β-cyclodextrin, 0.5-2 parts of microcrystalline cellulose-sodium carboxymethyl cellulose and excipients.

[0009] As a preferred embodiment of the technical solution of the present invention, the traditional Chinese medicine composition comprises the following components by weight: 600-700 parts calcined calamine, 2-4 parts amber, 7-9 parts artificial bezoar, 270-320 parts borneol, 7-9 parts artificial musk, 22-28 parts borax, 7-9 parts pearl, and 1-1.5 parts sal ammoniac.

[0010] As a preferred embodiment of the present invention, the excipients include one or more of the following: solubilizer, osmotic pressure regulator, pH regulator, preservative, and water for injection.

[0011] As a preferred embodiment of the present invention, the solubilizer is selected from one or more of ethanol, propylene glycol, glycerol, polysorbate 80, and poloxamer. Preferably, the solubilizer is polysorbate 80 or poloxamer.

[0012] As a preferred embodiment of the present invention, the osmotic pressure regulator is selected from one or more of sodium chloride, potassium chloride, glucose, and mannitol. Preferably, the osmotic pressure regulator is sodium chloride.

[0013] As a preferred embodiment of the present invention, the pH adjuster is selected from one or more of boric acid, phosphoric acid, acetic acid, hydrochloric acid, citric acid, tartaric acid, phosphate buffer, and borate buffer. Preferably, the pH adjuster is acetic acid, boric acid, citric acid, or tartaric acid.

[0014] As a preferred embodiment of the present invention, the preservative is selected from one or more of ethylparaben, ethylparaben, phenoxyethanol, benzalkonium bromide, benzalkonium chloride, sodium benzoate, phenyl esters, sorbic acid, and chlorobutanol. Preferably, the preservative is ethylparaben, benzalkonium bromide, or benzalkonium chloride.

[0015] As a preferred embodiment of the technical solution of the present invention, the pH of the traditional Chinese medicine suspension eye drops is 6.5~7.5 and the osmotic pressure is 280~320 mOsmol / kg.

[0016] Secondly, the present invention also provides a method for preparing the above-mentioned traditional Chinese medicine suspension eye drops, comprising the following steps: (1) Raw material pretreatment: Amber, artificial bezoar, artificial musk, pearl, calcined calamine, and microcrystalline cellulose-sodium carboxymethyl cellulose were respectively subjected to air jet milling until the particle size was less than 90 μm; (2) Preparation of borneol solution: Crush borneol, add hydroxypropyl-β-cyclodextrin and water for injection, seal and stir to dissolve, then add borax, sal ammonia and osmotic pressure regulator, stir to dissolve again, filter to remove bacteria, and obtain borneol solution for later use; (3) Preparation of suspension: Add the pulverized microcrystalline cellulose-carboxymethyl cellulose sodium to water for injection, stir to disperse evenly, and then homogenize in a water bath to obtain a suspension for later use. (4) Preparation of poorly soluble drug suspension: Weigh the solubilizer, stir evenly, add the crushed amber, stir and disperse evenly, then add water for injection, stir evenly, then add the crushed pearl and crushed calcined calamine in sequence, stir and disperse evenly, then sterilize and cool to room temperature. While stirring, add a pH adjuster to adjust the pH of the system to 6.5~7.0, then add pulverized artificial musk and pulverized artificial bezoar, stir and disperse evenly, and then homogenize to obtain a poorly soluble drug suspension. (5) Mixing and dispensing: Under stirring, add the borneol solution obtained in step (2) and the poorly soluble drug suspension obtained in step (4) to the suspension obtained in step (3), add pH adjuster again to adjust the pH value of the system to 6.5~7.0, add water for injection, then homogenize and disperse, filter, and finally dispense.

[0017] As a preferred embodiment of the technical solution of the present invention, in step (3), the homogeneous dispersion speed is 8000~15000 rpm; In step (5), the filter mesh size is 300~500 mesh.

[0018] Compared with the prior art, the present invention has the following beneficial effects: (1) The present invention provides a traditional Chinese medicine suspension eye drops, which abandons the traditional eye ointment dosage form, can be directly dripped, is convenient to use, and has good stability and dispersibility, and has excellent therapeutic effect and medication experience.

[0019] (2) The traditional Chinese medicine suspension eye drops provided by this invention use a large amount of calcined calamine in the raw materials of the Mayinglong Babao ancient formula. However, calcined calamine has poor water solubility and lipid solubility, making it extremely difficult to develop into a stable suspension eye drops. Based on this situation, the applicant creatively introduced a specific suspending agent, microcrystalline cellulose-sodium carboxymethyl cellulose complex, to maintain the uniform dispersion of insoluble mineral drug solid particles in the liquid and prevent them from settling and clumping. In addition, a solubilizer is added to improve the apparent solubility of the poorly soluble drug amber in the solvent. The two types of excipients complement each other and improve the physical stability of the product.

[0020] (3) The present invention provides a method for preparing a traditional Chinese medicine suspension eye drops. Borneol is encapsulated with hydroxypropyl-β-cyclodextrin to prepare a suspension eye drops, which greatly improves the water solubility and stability of borneol and significantly reduces its eye irritation. In addition, the surface properties of the encapsulated particles are more uniform, which helps to improve the physical stability of the suspension system and ensure accurate dosage.

[0021] (4) The present invention provides a method for preparing a traditional Chinese medicine suspension eye drops, which further utilizes micronization dispersion technology to disperse and suspend poorly soluble medicinal materials such as amber, pearl, calcined calamine, artificial musk, and artificial bezoar. This solves the problems of aggregation (particle size <90μm), sedimentation, and stratification of mineral medicinal materials in eye drops. The suspension eye drops prepared by the above technology have good stability, small particle size, and can maintain a uniform morphology for a long time. This meets all the requirements of the Chinese Pharmacopoeia for "suspension eye drops" and improves the bioavailability of the product.

[0022] In summary, the modified formulation of this invention provides a suspension eye drop that can be directly applied to the eye. This not only makes it convenient to use but also effectively solves the discomfort caused by the oily matrix in eye ointments, greatly improving the patient's medication experience. In addition, its significant therapeutic effect makes it easier to gain the acceptance of patients.

[0023] Furthermore, this invention, combining the dosage form characteristics of eye drops with modern pharmacological research methods, innovates upon the traditional product while maintaining the clinical efficacy of the Ma Yinglong Babao formula. It scientifically conducts secondary development research to enhance its clinical therapeutic effects and broaden its market prospects. The development of this product serves as a good example and guide for the secondary development of renowned traditional Chinese medicines in my country. Attached Figure Description

[0024] Figure 1 The particle size distribution of the product obtained in Example 1 is shown.

[0025] Figure 2 The particle size distribution of the product obtained in Example 2 is shown.

[0026] Figure 3 The particle size distribution of the product obtained in Comparative Example 1 is shown.

[0027] Figure 4 The particle size distribution of the product obtained in Comparative Example 2 is shown.

[0028] Figure 5 The particle size distribution of the product obtained in Comparative Example 3 is shown.

[0029] Figure 6 The particle size distribution of the product obtained in Comparative Example 4 is shown.

[0030] Figure 7 The particle size distribution of the product obtained in Comparative Example 5 is shown.

[0031] Figure 8 This is a comparison diagram of the products of Comparative Example 6 and Example 1. Detailed Implementation

[0032] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0033] Unless otherwise specified, all raw materials used in this invention can be purchased from the market and their specifications meet the testing and usage standards.

[0034] The microcrystalline cellulose-carboxymethyl cellulose sodium used in the examples is model 611P.

[0035] The poloxamer used in this example is poloxamer 188.

[0036] It should be particularly emphasized that, unless otherwise specified, all parts mentioned in this invention are by weight, and the weight examples are not strictly specific amounts. Those skilled in the art can flexibly scale up or down the quantities according to actual needs for production.

[0037] Example 1 A traditional Chinese medicine suspension eye drop, prepared by weight from the following raw materials: Table 1 Raw material composition of Example 1 Serial Number raw materials Dosage 1 amber 52.5mg 2 Artificial bezoar 135.0mg 3 Artificial Musk 135.0mg 4 pearl 135.0mg 5 Calamine 11.5g 5 Propylene glycol 2.0g 6 Twain 80 0.4g Water for Injection 150mL 7 Borneol 5.15g 8 Hydroxypropyl-β-cyclodextrin 54.3g Water for Injection 100mL 9 Borax 0.45g 10 Realgar 17.5mg 11 Sodium chloride 2.0g 12 Microcrystalline cellulose - sodium carboxymethyl cellulose 10.0g Water for Injection 650mL 13 5% acetic acid solution Appropriate amount 14 Water for Injection Add water to 1000mL In this embodiment, a method for preparing the above-mentioned traditional Chinese medicine suspension eye drops is provided, comprising the following steps: (1) Raw material pretreatment: Amber, artificial bezoar, artificial musk, pearl, calcined calamine, and microcrystalline cellulose-sodium carboxymethyl cellulose were respectively subjected to air jet milling until the particle size was less than 90 μm; (2) Preparation of borneol solution: Crush borneol, add hydroxypropyl-β-cyclodextrin and 100mL of water for injection, seal and stir to dissolve at 40℃, then add borax, sal ammonia, and sodium chloride as osmotic pressure regulator, stir to dissolve again, filter with a 0.22-micron microporous membrane to remove bacteria, and obtain borneol solution for later use; (3) Preparation of suspension: Add the pulverized microcrystalline cellulose-carboxymethyl cellulose sodium to 650 mL of water for injection, stir to disperse evenly, and then homogenize after water bath (60℃, 30 min) (3 times, 5 minutes each time, 12000 rpm) to obtain a suspension for later use. (4) Preparation of poorly soluble drug suspension: Weigh the solubilizer (propylene glycol, Tween 80), stir evenly, add the crushed amber, stir and disperse evenly, then add 150 mL of water for injection, stir evenly, then add the crushed pearl and crushed calcined calamine in sequence, stir and disperse evenly, sterilize at 121℃ for 30 min, and cool to room temperature. While stirring, add 5% acetic acid solution to adjust the pH of the system to 7.05, then add crushed artificial musk and crushed artificial bezoar, stir and disperse evenly, then homogenize (3 times, 5 minutes each time, 12000 rpm) to obtain a poorly soluble drug suspension. (5) Mixing and dispensing: Under stirring, add the borneol solution obtained in step (2) and the poorly soluble drug suspension obtained in step (4) to the suspension obtained in step (3), add 5% acetic acid solution to adjust the pH value of the system to 7.05, add water for injection to 1000mL, then homogenize and disperse, filter through 400 mesh, and finally dispense 5mL into each bottle.

[0038] Example 2 A traditional Chinese medicine suspension eye drop, prepared by weight from the following raw materials: Table 2 Raw material composition of Example 2 Serial Number raw materials Dosage 1 amber 45mg 2 Artificial bezoar 116.0mg 3 Artificial Musk 116.0mg 4 pearl 116.0mg 5 Calamine 9.6g 5 Propylene glycol 1.8g 6 Polosham 0.4g Water for Injection 150mL 7 Borneol 4.32g 8 Hydroxypropyl-β-cyclodextrin 48.5g Water for Injection 100mL 9 Borax 0.38g 10 Realgar 15mg 11 Sodium chloride 2.0g 12 Microcrystalline cellulose - sodium carboxymethyl cellulose 12g Water for Injection 650mL 13 5% acetic acid solution Appropriate amount 14 Water for Injection Add water to 1000mL In this embodiment, a method for preparing the above-mentioned traditional Chinese medicine suspension eye drops is provided, comprising the following steps: (1) Raw material pretreatment: Amber, artificial bezoar, artificial musk, pearl, calcined calamine, and microcrystalline cellulose-sodium carboxymethyl cellulose were respectively subjected to air jet milling until the particle size was less than 90 μm; (2) Preparation of borneol solution: Crush borneol, add hydroxypropyl-β-cyclodextrin and 100mL of water for injection, seal and stir to dissolve at 40℃, then add borax, sal ammonia, and sodium chloride as osmotic pressure regulator, stir to dissolve again, filter with a 0.22-micron microporous membrane to remove bacteria, and obtain borneol solution for later use; (3) Preparation of suspension: Add the pulverized microcrystalline cellulose-carboxymethyl cellulose sodium to 650 mL of water for injection, stir to disperse evenly, and then homogenize after water bath (60℃, 30 min) (3 times, 5 minutes each time, 12000 rpm) to obtain a suspension for later use. (4) Preparation of poorly soluble drug suspension: Weigh the solubilizer (propylene glycol, poloxamer), stir evenly, add the crushed amber, stir and disperse evenly, then add 150 mL of water for injection, stir evenly, then add the crushed pearl and crushed calcined calamine in sequence, stir and disperse evenly, sterilize at 121℃ for 30 min, and cool to room temperature. While stirring, add 5% acetic acid solution to adjust the pH of the system to 6.9, then add crushed artificial musk and crushed artificial bezoar, stir and disperse evenly, then homogenize (3 times, 5 minutes each time, 12000 rpm) to obtain a poorly soluble drug suspension. (5) Mixing and dispensing: Under stirring, add the borneol solution obtained in step (2) and the poorly soluble drug suspension obtained in step (4) to the suspension obtained in step (3), add 5% acetic acid solution again to adjust the pH value of the system to 6.9, add water for injection to 1000mL, then homogenize and disperse, filter through 400 mesh, and finally dispense 5mL into each bottle.

[0039] Example 3 A traditional Chinese medicine suspension eye drop, prepared by weight from the following raw materials: Table 3 Raw material composition of Example 3 Serial Number raw materials Dosage 1 amber 60.0mg 2 Artificial bezoar 152.0mg 3 Artificial Musk 152.0mg 4 pearl 152.0mg 5 Calamine 13.1g 5 Propylene glycol 2.2g 6 Twain 80 0.4g Water for Injection 150mL 7 Borneol 5.92g 8 Hydroxypropyl-β-cyclodextrin 62.12g Water for Injection 100mL 9 Borax 0.51g 10 Realgar 20.0mg 11 Sodium chloride 2.0g 12 Microcrystalline cellulose - sodium carboxymethyl cellulose 8g Water for Injection 650mL 13 5% acetic acid solution Appropriate amount 14 Water for Injection Add water to 1000mL In this embodiment, a method for preparing the above-mentioned traditional Chinese medicine suspension eye drops is provided, comprising the following steps: (1) Raw material pretreatment: Amber, artificial bezoar, artificial musk, pearl, calcined calamine, and microcrystalline cellulose-sodium carboxymethyl cellulose were respectively subjected to air jet milling until the particle size was less than 90 μm; (2) Preparation of borneol solution: Crush borneol, add hydroxypropyl-β-cyclodextrin and 100mL of water for injection, seal and stir to dissolve at 40℃, then add borax, sal ammonia, and sodium chloride as osmotic pressure regulator, stir to dissolve again, filter with a 0.22-micron microporous membrane to remove bacteria, and obtain borneol solution for later use; (3) Preparation of suspension: Add the pulverized microcrystalline cellulose-carboxymethyl cellulose sodium to 650 mL of water for injection, stir to disperse evenly, and then homogenize after water bath (60℃, 30 min) (3 times, 5 minutes each time, 12000 rpm) to obtain a suspension for later use. (4) Preparation of poorly soluble drug suspension: Weigh the solubilizer (propylene glycol, Tween 80), stir evenly, add the crushed amber, stir and disperse evenly, then add 150 mL of water for injection, stir evenly, then add the crushed pearl and crushed calcined calamine in sequence, stir and disperse evenly, sterilize at 121℃ for 30 min, and cool to room temperature. While stirring, add 5% acetic acid solution to adjust the pH of the system to 6.7, then add crushed artificial musk and crushed artificial bezoar, stir and disperse evenly, then homogenize (3 times, 5 minutes each time, 12000 rpm) to obtain a poorly soluble drug suspension. (5) Mixing and dispensing: Under stirring, add the borneol solution obtained in step (2) and the poorly soluble drug suspension obtained in step (4) to the suspension obtained in step (3), add 5% acetic acid solution again to adjust the pH value of the system to 6.7, add water for injection to 1000mL, then homogenize and disperse, filter through 400 mesh, and finally dispense 5mL into each bottle.

[0040] Comparative Example 1 The microcrystalline cellulose-carboxymethyl cellulose sodium in Example 1 was replaced with polyvinyl alcohol, and the preparation process was adjusted accordingly.

[0041] Comparative Example 2 The microcrystalline cellulose-carboxymethyl cellulose sodium in Example 1 was replaced with carbomer, and the preparation process was adjusted accordingly.

[0042] Comparative Example 3 The microcrystalline cellulose-carboxymethyl cellulose sodium in Example 1 was replaced with 5g of microcrystalline cellulose-carboxymethyl cellulose sodium and 5g of polyvinyl alcohol, and the preparation process was adjusted accordingly.

[0043] Comparative Example 4 The use of propylene glycol and Tween 80 in Example 1 is omitted, and the preparation process is adjusted accordingly.

[0044] Comparative Example 5 The use of hydroxypropyl-β-cyclodextrin in step (2) of Example 1 is omitted, and the preparation process is adjusted accordingly.

[0045] Comparative Example 6 The use of sodium carboxymethyl cellulose in Example 1 is omitted, and the preparation process is adjusted accordingly.

[0046] Experimental Example 1 This test examined the changes in particle size and sedimentation volume ratio of the product in the examples and the product in the comparative examples, and used this to evaluate the stability. The sediment of the suspension eye drops should not clump or aggregate, and should be easily redispersible after shaking. Specific test results are shown in Table 4 and... Figures 1-8 As shown, where, Figure 1 The particle size distribution is shown in Example 1. The particle size range is 20-30 μm, and no particles larger than 50 μm were detected, which meets the requirements. Figure 2 The particle size distribution of Example 2 shows that no particles larger than 50 μm were detected, which meets the requirements. Figure 3 The particle size distribution is shown in Comparative Example 1. The figure shows particle aggregation, which does not meet the requirements. Figure 4 The particle size distribution is shown in Comparative Example 2. The figure shows particle aggregation and the detection of particles larger than 90 μm, which does not meet the requirements. Figure 5 The particle size distribution diagram for Comparative Example 3 shows particle aggregation, which does not meet the requirements. Figure 6 The particle size distribution is shown in Comparative Example 4. Since propylene glycol and Tween 80 were not added, the amber could not be wetted and dispersed, resulting in a large number of aggregates in the figure and the detection of particles larger than 90 μm, which does not meet the requirements. Figure 7 The particle size distribution is shown in Comparative Example 5. Due to the absence of hydroxypropyl-β-cyclodextrin, borneol was precipitated, and particles larger than 90 μm were detected, which does not meet the requirements. Figure 8 The image shows a comparison of the products of Comparative Example 6 and Example 1 (Example 1 is on the left, and Comparative Example 6 is on the right). Since no suspending agent was added, the product of Comparative Example 6 clumped at the bottom and was not easily dispersed even after shaking, which does not meet the requirements.

[0047] Sedimentation volume ratio test method: Measure 50 mL of the test sample using a stoppered graduated cylinder, stopper tightly, shake vigorously for 1 min, and record the initial height Ho of the suspension. Let stand for 3 hours, and record the final height H of the suspension. Calculate the sedimentation volume ratio using the following formula: Sedimentation volume ratio = H / Ho. The sedimentation volume ratio of the eye drops suspension should not be less than 0.90.

[0048] Particle size test: Take the test sample and shake it vigorously. Immediately measure an appropriate amount and place it on a glass slide. Prepare three slides in total. Perform the particle size and particle size distribution determination according to the method (Chinese Pharmacopoeia General Chapter 0982, Method I, Microscopic Method). Examine the number of particles larger than 50 μm and larger than 90 μm in the entire field of view of the coverslip under a microscope. If no particles larger than 90 μm are detected, and the number of particles larger than 50 μm is no more than two, it is considered to meet the requirements.

[0049] Table 4 Results of particle size variation and sedimentation volume ratio variation Test case granularity Settlement volume ratio Example 1 Compliant with regulations, no particles larger than 50 μm were detected. 1.0 Example 2 Compliant with regulations, no particles larger than 50 μm were detected. 1.0 Example 3 Compliant with regulations, no particles larger than 50 μm were detected. 1.0 Comparative Example 1 It does not comply with regulations and there is a gathering. 0.73 Comparative Example 2 It does not comply with regulations and there is a gathering. 0.56 Comparative Example 3 It does not comply with regulations and there is a gathering. 0.50 Comparative Example 4 It does not comply with regulations and there is a gathering. 0.41 Comparative Example 5 It does not meet the requirements; borneol is present. 0.85 Comparative Example 6 It does not meet the requirements and has lumps at the bottom. 0.15 The results showed that the particle size of the suspended traditional Chinese medicine eye drops prepared in Example 1 met the requirements and the sedimentation volume ratio was 1, indicating that the suspended traditional Chinese medicine eye drops prepared by the present invention had good stability and were not easy to settle; while the comparative sample was easy to aggregate or clump, indicating that its stability was poor and it was easy to settle.

[0050] Experimental Example 2 The stability of this experiment was investigated using the following methods.

[0051] 2.1 Detection Method 2.1.1 Method for determining borneol content (1) Chromatographic conditions and system suitability test: The chromatographic column is a capillary column with 5% phenyl-95% dimethyl polysiloxane (or similar polarity) as the stationary phase; the initial temperature is 75℃, maintained for 2 minutes, and then increased to 115℃ at a rate of 5℃ per minute; the injection port temperature is 200℃; the detector temperature is 250℃. The theoretical plate number, calculated based on the borneol peak, should not be less than 2000.

[0052] (2) Preparation of reference solution: Take an appropriate amount of borneol reference standard, weigh it accurately, and add ethyl acetate to prepare a solution containing 5 mg per 1 mL.

[0053] (3) Preparation of test solution: Accurately measure 15 mL of eye drops, place it in a 50 mL volumetric flask, accurately add 10 mL of ethyl acetate, shake well, weigh, sonicate for 5 minutes, replenish the lost weight with ethyl acetate, shake well, centrifuge (10000 rpm, 5 minutes), and take the ethyl acetate layer to obtain the test solution.

[0054] (4) Determination method: Accurately pipette 1 μL of the reference solution and the test solution into the gas chromatograph and determine the result.

[0055] 2.2 Influencing Factors Experiment The suspension eye drops prepared in Example 1 were packaged in eye drop bottles and placed under light (4500 lx ± 500 lx) and high temperature (50°C) conditions for 10 days. Samples were taken on the 5th and 10th days to test various stability indicators. The results are shown in Table 5.

[0056] Table 5. Results of the experiment on factors affecting suspension eye drops. As can be seen from Table 5, the suspension eye drops prepared in this invention met the quality requirements after being placed under high temperature (50℃) and light conditions for 10 days, and there were no significant changes in various quality indicators, indicating that the samples prepared in the examples had good stability.

[0057] 2.3 Accelerated Testing The suspension eye drops prepared in Example 1 were packaged in an eye drop bottle and placed at a temperature of 40℃±2℃ and a relative humidity of 25%±5% for 6 months. Samples were taken at the end of the 1st, 2nd, 3rd and 6th months to test various stability indicators. The results are shown in Table 6.

[0058] Table 6 Results of Accelerated Tests on Suspension Eye Drops Month of inspection Properties granularity redistribution Settlement volume ratio Osmolar concentration (mOsmol / kg) Borneol content Visible foreign objects 0 brown suspension Compliant Compliant 1.0 299 95% Compliant 1 brown suspension Compliant Compliant 1.0 299 95% Compliant 2 brown suspension Compliant Compliant 1.0 302 94% Compliant 3 brown suspension Compliant Compliant 1.0 308 96% Compliant 6 brown suspension Compliant Compliant 1.0 310 98% Compliant As can be seen from Table 6, the suspension eye drops prepared by the process of the present invention showed no significant changes in various quality indicators compared with day 0 after being placed at 40℃±2℃ and 25%±5%RH for 6 months, indicating good stability.

[0059] 2.3 Long-term test The suspension eye drops prepared in Example 1 were packaged in an eye drop bottle and placed at a temperature of 25±2℃ and a relative humidity of 40%±5% for 6 months. Samples were taken at the 3rd, 6th and 9th months to test various stability indicators. The results are shown in Table 7.

[0060] Table 7 Results of long-term test of suspension eye drops Month of inspection Properties pH value granularity redistribution Settlement volume ratio Osmolar concentration (mOsmol / kg) Borneol content Visible foreign objects 0 brown suspension 7.05 Compliant Compliant 1.0 299 95% Compliant 3 brown suspension 7.05 Compliant Compliant 1.0 299 94% Compliant 6 brown suspension 7.04 Compliant Compliant 1.0 301 95% Compliant 9 brown suspension 7.04 Compliant Compliant 1.0 302 96% Compliant As can be seen from Table 7, the suspension eye drops prepared by the process of the present invention showed no significant changes in various quality indicators compared with day 0 after being placed at 25℃±2℃ and 40%±5%RH for 9 months, indicating good stability.

[0061] The applicant declares that the present invention is illustrated by the above embodiments, but the present invention is not limited to the above embodiments, that is, it does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of individual raw materials in the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A traditional Chinese medicine suspension eye drop, characterized in that, The Chinese medicine composition is prepared from 1-3 parts of Chinese medicine composition, 4-7 parts of hydroxypropyl-β-cyclodextrin, 0.5-2 parts of microcrystalline cellulose-sodium carboxymethyl cellulose and auxiliary materials by weight.

2. The traditional Chinese medicine suspension eye drop of claim 1, characterized in that, The Chinese medicine composition is prepared from 600-700 parts of calcined calamine, 2-4 parts of amber, 7-9 parts of artificial ox gall, 270-320 parts of borneol, 7-9 parts of artificial musk, 22-28 parts of borax, 7-9 parts of pearl and 1-1.5 parts of sal amarum by weight. 3.The traditional Chinese medicine suspension eye drop of claim 1, characterized in that, The auxiliary materials include one or more of solubilizing agent, osmotic pressure regulator, pH regulator, preservative and water for injection.

4. The traditional Chinese medicine suspension eye drop of claim 3, characterized in that, The solubilizing agent is selected from one or more of ethanol, propylene glycol, glycerol, polysorbate 80 and poloxamer.

5. The traditional Chinese medicine suspension eye drop of claim 3, characterized in that, The osmotic pressure regulator is selected from one or more of sodium chloride, potassium chloride, glucose and mannitol.

6. The traditional Chinese medicine suspension eye drop of claim 3, characterized in that, The pH regulator is selected from one or more of boric acid, phosphoric acid, acetic acid, hydrochloric acid, citric acid, citric acid, acetic acid, tartaric acid, phosphate buffer and boric acid buffer.

7. The traditional Chinese medicine suspension eye drop of claim 3, characterized in that, The preservative is selected from one or more of hydroxyethyl benzoate, ethyl parahydroxybenzoate, phenoxyethanol, benzalkonium bromide, benzalkonium chloride, sodium benzoate, hydroxybenzoate, sorbic acid and chlorobutanol.

8. The traditional Chinese medicine suspension eye drop of claim 1, characterized in that, The pH of the Chinese medicine suspension eye drops is 6.5-7.5, and the osmotic pressure is 280-320 mOsmol / kg.

9. A method for preparing the traditional Chinese medicine suspension eye drop according to any one of claims 1-8, characterized in that, The method comprises the following steps: (1) Pretreatment of raw materials: airflow crushing of amber, artificial ox gall, artificial musk, pearl, calcined calamine and microcrystalline cellulose-sodium carboxymethyl cellulose to a particle size of less than 90 μm; (2) Preparation of borneol solution: crushing of borneol, adding hydroxypropyl-β-cyclodextrin and water for injection, stirring and dissolving after sealing, then adding borax, sal amarum and osmotic pressure regulator, stirring and dissolving again, filtering and sterilizing to obtain borneol solution for standby; (3) Preparation of suspension: adding crushed microcrystalline cellulose-sodium carboxymethyl cellulose into water for injection, stirring to disperse uniformly, then homogenizing and dispersing after water bath to obtain suspension for standby; (4) Preparation of insoluble drug suspension: weighing solubilizing agent, stirring uniformly, then adding crushed amber, stirring and dispersing uniformly, then adding water for injection, stirring uniformly, then adding crushed pearl and crushed calcined calamine in sequence, stirring and dispersing uniformly, then sterilizing and cooling to room temperature; Under stirring, adding pH regulator to adjust the pH value of the system to 6.5-7.0, then adding crushed artificial musk and crushed artificial ox gall, stirring and dispersing uniformly, then homogenizing and dispersing to obtain insoluble drug suspension; (5) Mixing and dispensing: under stirring, adding borneol solution obtained in step (2) and insoluble drug suspension obtained in step (4) into suspension obtained in step (3), then adding pH regulator to adjust the pH value of the system to 6.5-7.0, supplementing water for injection, then homogenizing and dispersing, filtering and finally dispensing.

10. The method of claim 9, wherein, In step (3), the rotation speed of homogenizing and dispersing is 8000-15000 rpm; In step (5), the filter mesh is 300-500 meshes.

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