Single-dose compound sodium hyaluronate eye drops and preparation method thereof

Abstract

The invention discloses a single-dose compound sodium hyaluronate eye drop and a preparation method thereof. The eye drops are prepared from the following components: sodium hyaluronate, a herba portulacae extract, a herba taraxaci extract, ginsenoside RO, ginsenoside Rb1, aminocaproic acid, an osmotic pressure regulator, one or more of vitamin A, vitamin E and a metal ion chelating agent, and the balance of water for injection. According to the invention, medicinal and edible active components are systematically screened, and the traditional Chinese medicine extract is compounded with sodium hyaluronate, so that multi-target collaborative treatment is realized. The preparation not only can prolong the drug action time, but also can remarkably improve the ocular surface microenvironment, promote corneal epithelial cell repair and maintain the tear film stability. Single-dose sterile packaging is adopted, so that addition of preservatives is avoided, and ocular surface stimulation is reduced.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceuticals, and in particular to a single-dose compound sodium hyaluronate eye drop and a preparation method thereof. Background Art

[0002] With the widespread use of electronic devices and the accelerated aging of the population, dry eye has become an important public health issue. Epidemiological studies have shown that the global incidence of dry eye is as high as 34%, and it is increasing year by year. As a chronic progressive disease, dry eye has no complete cure at present. Treatment is mainly to relieve symptoms, among which artificial tears are the most commonly used symptomatic treatment.

[0003] As a representative preparation of artificial tears, sodium hyaluronate eye drops promote epithelial cell connection and extension by binding to fibronectin and have excellent water retention, and have become the first-line drug for the treatment of dry eye. However, existing sodium hyaluronate eye drops have limitations such as short duration and lack of anti-inflammatory effect, and require frequent drops, which seriously affects patient compliance and treatment effect.

[0004] At present, ophthalmic anti-inflammatory eye drops are mainly composed of Western medicine ingredients, while the active ingredients in Chinese herbal medicines that have anti-inflammatory and eye repair effects have not been fully developed. Studies have shown that natural medicines such as bear bile, houttuynia cordata, artemisinin, mulberry leaves, chrysanthemum, and polydatin have good application prospects in the field of ophthalmology.

[0005] Patent CN201310016112.1 proposes an ophthalmic preparation with ginsenoside as the main ingredient. Ginsenosides can be divided into protopanaxadiol type (PPD type) and protopanaxatriol type (PPT type) according to their chemical structure. Among them, the PPD type includes Rb1 with neuroprotective effect, Rb2 with hypoglycemic effect, Rc with cardiovascular protection effect, Rd with neuroprotective and anti-inflammatory effect, and Rg3 with anti-tumor and immunomodulatory effect. The PPT type includes Re with antioxidant and hypoglycemic effect, Rf with anti-fatigue and immunomodulatory effect, Rg1 with cognitive improvement and anti-aging effect, and Rg2 with neuroprotective effect. This patent uses total ginsenosides instead of monomer components, and its therapeutic effect may be derived from the synergistic effect between multiple monomers.

[0006] Patent CN201711485565.3 developed an eye drop containing pranoprofen and purslane extract, which enhances the therapeutic effect on eye congestion and edema through the synergistic effect of the two. This provides a new idea for the application of Chinese and Western medicine compound preparations in the field of ophthalmology.

[0007] Based on the deficiencies in the existing technology, a compound eye drop combining sodium hyaluronate and active ingredients of traditional Chinese medicine is developed, and single-dose packaging is used to avoid microbial contamination, which has important clinical application value. Summary of the invention

[0008] The purpose of the present invention is to solve the following technical problems of the existing sodium hyaluronate eye drops: 1. short duration; 2. unstable efficacy; 3. multi-dose products are easily contaminated and cause bacterial growth.

[0009] The first aspect of the present invention provides a single-dose compound sodium hyaluronate eye drop and a preparation method thereof, wherein the single-dose compound sodium hyaluronate eye drop creatively uses sodium hyaluronate as the main active ingredient, significantly improves the stability of the tear film on the ocular surface and promotes corneal epithelial cell repair through its unique moisturizing and lubricating properties, and innovatively introduces active ingredients such as purslane extract, dandelion extract, ginsenoside monomer (ginsenoside RO, ginsenoside Rb1), vitamin A, vitamin E, etc., and various ingredients work synergistically to give full play to its performance characteristics such as promoting cell repair, anti-inflammatory, and anti-oxidation, effectively promoting corneal damage repair, and long-term relief of dry eye. At the same time, disodium edetate is used as a stabilizer, in combination with the anti-fibrinolytic properties of aminocaproic acid, and by accurately regulating the osmotic pressure and pH value, it is isotonic with tears and has the same pH, forming a stable and uniform preparation system in the injection water medium. Moreover, single-dose packaging can better avoid the problem that compound eye drops packaged in multiple doses are easily contaminated and grown with bacteria.

[0010] The solution of the present invention to solve the above technical problems is as follows:

[0011] Single-dose compound sodium hyaluronate eye drops, including the following drug components:

[0012] Sodium hyaluronate 0.08wt%-0.15wt% or 0.28wt%-0.35wt%;

[0013] Portulaca oleracea extract 0.01wt%-0.20wt%;

[0014] Dandelion extract 0.01wt%-0.20wt%;

[0015] Ginsenoside RO 0.01wt%-0.20wt%;

[0016] Ginsenoside Rb1 0.001wt%-0.01wt%;

[0017] Aminocaproic acid 0.15wt%-0.25wt%;

[0018] Osmotic pressure regulator 0.5wt%-2.48wt%;

[0019] The remaining amount of water for injection;

[0020] It also includes one or a mixture of any of vitamins, metal ion chelating agents, and pH adjusters.

[0021] Furthermore, the single-dose compound sodium hyaluronate eye drops comprises the following drug components:

[0022] Sodium hyaluronate 0.09wt%-0.12wt% or 0.29wt%-0.32wt%;

[0023] Portulaca oleracea extract 0.05wt%-0.18wt%;

[0024] Dandelion extract 0.06wt%-0.15wt%;

[0025] Ginsenoside RO 0.10wt%-0.15wt%;

[0026] Ginsenoside Rb1 0.005wt%-0.008wt%;

[0027] Aminocaproic acid 0.18wt%-0.22wt%;

[0028] Osmotic pressure regulator 0.8wt%-2.23wt%;

[0029] The remaining amount of water for injection;

[0030] It also includes one or a mixture of any of vitamins, metal ion chelating agents, and pH adjusters.

[0031] The sodium hyaluronate content of the present invention is 0.08wt%-0.15wt% or 0.28wt%-0.35wt%; when the sodium hyaluronate content is 0.08wt%-0.15wt%, it is a daily maintenance dose (0.08wt%-0.15wt%), which is suitable for daily care of patients with mild dry eye, and can be used as a basic dose for preventive use, meeting the basic moisturizing needs of the ocular surface, suitable for long-term continuous use, and has good tolerance. When the sodium hyaluronate content is 0.28wt%-0.35wt%, it is a therapeutic enhancement dose (0.28wt%-0.35wt%), which is suitable for the treatment of moderate to severe dry eye, for rapid relief of acute symptoms, provides stronger ocular surface protection, accelerates corneal epithelial repair, and significantly improves ocular discomfort symptoms.

[0032] Dandelion extract is rich in flavonoids (content about 1.35%), phenolic acids, terpenes, pigments, phytosterols, sesquiterpene lactones, volatile oils and coumarins and other biologically active ingredients, and has significant anti-inflammatory, antioxidant, anti-tumor, antibacterial and antiviral activities.

[0033] Purslane (Portulaca oleracea L.) extract is derived from its fresh or dried aerial parts. In vitro studies have confirmed that it has a clear inhibitory effect on a variety of microorganisms such as Shigella dysenteriae, Salmonella typhi, Escherichia coli, Staphylococcus aureus and herpes zoster virus.

[0034] Ginsenosides are the main active ingredients in the root extract of ginseng (Panax ginseng CAMeyer). Currently, more than 40 saponin components have been identified, which can be divided into three types: PPD type (protopanaxadiol type), PPT type (protopanaxtriol type) and OA type (oleanolic acid type). Among them, ginsenoside Ro (G-Ro) belongs to the OA type ginsenoside, which is abundant in ginseng and has definite anti-aging, antioxidant and other pharmacological activities.

[0035] The purslane extract and the dandelion extract in the present invention enhance the heat-clearing and detoxifying effects through synergistic effects, while ginsenoside Ro exerts its antioxidant and tissue-protective effects, effectively protecting eye tissues from oxidative damage.

[0036] The above raw materials are all derived from commercially available standard products and meet pharmaceutical grade requirements, ensuring the quality controllability and safety of the preparations.

[0037] Furthermore, the vitamin is vitamin A, and the amount used is 0.05wt%-0.10wt%, preferably 0.06wt%-0.08wt%; and vitamin E, and the amount used is 0.05wt%-0.20wt%, preferably 0.1wt%-0.15wt%.

[0038] Further, the metal ion chelating agent is one of disodium edetate and hydroxyethylethylenediaminetriacetic acid or a mixture of the two, and the dosage of the chelating agent is 0.008wt%-0.02wt%, preferably 0.009wt%-0.015wt%. The purslane extract, dandelion extract, ginsenoside RO and ginsenoside Rb1 in the present invention are all macromolecules extracted from traditional Chinese medicine, and sodium hyaluronate is a mucopolysaccharide substance, which is easily interfered by metal ions (such as Ca2+, Mg2+, Fe2+, etc.). The metal ion chelating agent prevents the drug components from interacting with free metal ions, avoids drug degradation or failure, and prolongs the shelf life of the drug.

[0039] Furthermore, the osmotic pressure regulator includes one or a mixture of any of sodium chloride, potassium chloride, glycerol, mannitol, glucose, sorbitol, phosphate and citrate, and the amount of the osmotic pressure regulator is 0.5wt%-2.48wt%, preferably 0.8wt%-2.23wt%.

[0040] Further, the pH adjuster includes one or a mixture of any of the following: sodium hydroxide, hydrochloric acid, boric acid, borax, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, citric acid, sodium citrate, potassium citrate, acetic acid, sodium acetate, citric acid, sodium citrate, tartaric acid, sodium tartrate, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate, and the pH value of a single dose of compound sodium hyaluronate eye drops is adjusted to 6.0-7.0, preferably 6.3-6.8.

[0041] Furthermore, the average molecular weight of the sodium hyaluronate is 500,000-1.2 million. Sodium hyaluronate of this molecular weight can form a stable tear film on the ocular surface, has moderate viscoelasticity, will not affect blinking and vision, and can stay on the ocular surface for a long time to play a role. This molecular weight range is similar to the hyaluronic acid in the human body's natural tears, has excellent biocompatibility, does not cause eye irritation, and is more easily accepted by the ocular surface tissue. At the same time, it can bind a large number of water molecules to form a uniform hydration layer to protect the cornea and effectively relieve dry eye symptoms. In addition, sodium hyaluronate in this molecular weight range will not penetrate into the intraocular tissue, can be naturally metabolized with tears, and will not accumulate in the eye, ensuring the safety of long-term use.

[0042] Meanwhile, in the preparation process, 0.08wt%-0.15wt% or 0.28wt%-0.35wt% of the sodium hyaluronate of the molecular weight is separately mixed and dissolved with 0.001wt%-0.01wt% of ginsenoside Rb1. Ginsenoside Rb1 has a unique self-assembly property in aqueous solution and can form a micelle structure with a particle size of less than 8nm. This property can not only improve the water solubility of sodium hyaluronate, but more importantly, it can be used as a new type of ocular drug delivery system. Encapsulating sodium hyaluronate in Rb1 micelles can give full play to the synergistic advantages of the two: Rb1 micelles provide a stable nanocarrier system, while sodium hyaluronate (500,000-1.2 million molecular weight) has excellent biocompatibility and moisturizing effect. This combination can not only improve the ocular bioavailability of the drug, but also prolong the residence time of the drug on the ocular surface through sustained release, thereby enhancing the therapeutic effect. At the same time, since both components have good biosafety, their composite preparations may reduce ocular irritation and improve patient compliance.

[0043] Further, the preferred single-dose compound sodium hyaluronate eye drops include the following drug components:

[0044]

[0045] Add water for injection to the balance.

[0046] Furthermore, the preferred single-dose compound sodium hyaluronate eye drops include the following pharmaceutical components:

[0047]

[0048] Disodium edetate 0.009wt%-0.015wt%;

[0049] Aminocaproic acid 0.18wt%-0.22wt%;

[0050] Osmotic fluid regulator 0.8wt%-2.23wt%;

[0051] pH regulator to adjust pH to 6.3-6.8;

[0052] Add water for injection to the balance.

[0053] The second aspect of the present invention provides a method for preparing the single-dose compound sodium hyaluronate eye drops, comprising the following steps:

[0054] 1) Take 20% to 35wt% of the total amount of the preparation solution of water for injection, the temperature of the water for injection is below 60°C, and under stirring, add 0.8wt%-2.23wt% of osmotic pressure regulator, 0.05wt%-0.18wt% of purslane extract, 0.06wt%-0.15wt% of dandelion extract, 0.10wt%-0.15wt% of ginsenoside RO, and 0.18wt%-0.22wt% of aminocaproic acid in sequence, and stir each material until it is dissolved before adding the next material, and observe until it is completely dissolved to obtain a mixed solution;

[0055] 2) Continue to add one or any combination of 0.008wt%-0.02wt% of metal ion chelating agent, 0.05wt%-0.10wt% of vitamin A, and 0.05wt%-0.20wt% of vitamin E to the mixed solution, stirring and dissolving each material before adding the next material, and visually observe until it is completely dissolved to obtain solution 1;

[0056] 3) Take 40% to 60wt% of the total amount of the preparation water for injection, the temperature of the water for injection is below 60°C, add 0.08wt%-0.15wt% or 0.28wt%-0.35wt% of sodium hyaluronate under slow stirring; fully swell, add 0.001wt%-0.01wt% of ginsenoside Rb1, and observe until it is completely dissolved to obtain solution 2;

[0057] 4) Add the above solution 1 and solution 2 into the dilution tank, continue stirring for 2-6 hours, add pH adjuster to adjust the pH value to 6.0-7.0, and add water for injection to the total amount of solution;

[0058] 5) The liquid medicine is filtered through a 0.45μm membrane cartridge filter that has passed the bubble point test for 10 to 40 minutes, and the intermediate is tested for sodium hyaluronate content, pH value, osmotic pressure, and visible foreign matter;

[0059] 6) The liquid medicine is filtered and sterilized twice through a 0.22μm sterilizing filter that has passed the bubble point test, and then enters the filling room after filtration and sterilization;

[0060] 7) Blowing, filling and sealing.

[0061] Furthermore, in the preparation method, the stirring rate in step 1) and step 2) is 200-500 r / min; the stirring rate in step 3) is 400-1200 r / min; and the stirring rate in step 4) is 30-60 Hz.

[0062] Furthermore, in the preparation method, the vitamin is vitamin A, and the amount used is 0.05wt%-0.10wt%, preferably 0.06wt%-0.08wt%; and vitamin E, and the amount used is 0.05wt%-0.20wt%, preferably 0.1wt%-0.15wt%.

[0063] Furthermore, in the preparation method, the metal ion chelating agent is one of disodium edetate and hydroxyethylethylenediaminetriacetic acid or a mixture of the two, and the amount of the chelating agent is 0.008wt%-0.02wt%, preferably 0.009wt%-0.015wt%.

[0064] The present invention has the following advantages over the prior art:

[0065] The present invention aims at the clinical application limitations of the existing sodium hyaluronate eye drops in the treatment of dry eye, such as short duration of efficacy and high frequency of administration, and develops a compound preparation. Through systematic screening of active ingredients of medicinal and edible origin, multiple active components such as purslane extract, dandelion extract, ginsenoside monomers (ginsenoside RO, ginsenoside Rb1), vitamin A, vitamin E and sodium hyaluronate are rationally matched to establish a compound sodium hyaluronate eye drop preparation. The preparation synergizes through multiple pharmacological mechanisms such as inhibiting the release of inflammatory mediators and the expression of chemokines, removing active oxygen free radicals in the eye, improving optic nerve microcirculation and oxygen supply status, enhancing the hypoxia tolerance of retinal blood vessels and optic nerves, and promoting the repair and regeneration of corneal epithelial cells. Clinical pharmacodynamic studies have shown that it has significant therapeutic advantages, can not only effectively prolong the drug action time, but also significantly improve the ocular surface microenvironment, promote corneal epithelial cell repair, maintain tear film stability, and provide retinal protection. Through the above technical scheme, the present invention successfully solves the key problems of existing sodium hyaluronate eye drops in clinical applications, provides a new drug delivery system for the standardized treatment of dry eye, and has significant clinical application value.

[0066] 1. Multi-target synergistic treatment mechanism: Sodium hyaluronate (molecular weight of 500,000-1.2 million) is the main active ingredient. The molecular weight range is similar to that of hyaluronic acid in human natural tears and has excellent biocompatibility. Through the synergistic effect of natural active ingredients of medicinal and edible origin (purslane extract, dandelion extract, ginsenoside RO, Rb1) and sodium hyaluronate, the expression of inflammatory factors is significantly inhibited, the hypoxia tolerance of retinal blood vessels and optic nerves is enhanced, active oxygen free radicals in the eye are removed, optic nerve microcirculation is improved, nutritional support for corneal epithelial cells is provided, and damage repair is promoted.

[0067] 2. Unique drug delivery system. Ginsenoside Rb1 has hydrophobic triterpenes or steroid aglycones and hydrophilic sugar side chains in structure. The self-assembly characteristics of ginsenoside Rb1 are used to form micelle structures with a particle size of <8nm. Sodium hyaluronate is encapsulated in Rb1 micelles to provide a stable nanocarrier system, which can not only improve the water solubility of sodium hyaluronate, but also prolong the drug's residence time on the ocular surface through sustained release, effectively maintain the moisture of the ocular surface, and improve bioavailability. It can significantly prolong the duration of therapeutic action, improve patient compliance, and promote the repair of corneal epithelial cells.

[0068] 3. Unique formula optimization, ginsenoside RO exerts an immunomodulatory effect, promotes tissue repair through macrophage activation, and vitamins A and E provide antioxidant protection.

[0069] 4. Optimized formulation stability. Disodium edetate is used as a metal ion chelator to prevent the degradation of drug ingredients. The anti-fibrinolytic properties of aminocaproic acid are combined to improve the stability of the formulation. The osmotic pressure and pH value (6.0-7.0) are precisely controlled to ensure isotonicity and pH with tears.

[0070] 5. Improved safety of use, using single-dose sterile packaging, avoiding the addition of preservatives, reducing ocular surface irritation, ready for use, preventing secondary contamination, and easy to carry and store. DETAILED DESCRIPTION

[0071] The preferred embodiments of the present invention will be described in detail below in conjunction with the examples. It should be understood that the following examples are provided only for the purpose of illustration and are not intended to limit the scope of the present invention. Those skilled in the art may make various modifications and substitutions to the present invention without departing from the purpose and spirit of the present invention.

[0072] Example 1

[0073] The components of single-dose compound sodium hyaluronate eye drops are as follows:

[0074] Components Weight percentage (%) Components Weight percentage (%) Sodium hyaluronate 0.10wt%; Vitamin A 0.10wt%; Edetate Disodium 0.01wt%; Vitamin E 0.10wt%; Aminocaproic acid 0.20wt%; Sodium chloride 0.8wt%; Purslane Extract 0.05wt% Dandelion Extract 0.10wt% Ginsenoside RO 0.10wt%; Sodium hydroxide Adjust pH to 6.5; Ginsenoside Rb1 0.005wt%; Water for injection Add to balance

[0075] The preparation method of the above-mentioned compound sodium hyaluronate eye drops comprises the steps:

[0076] 1. Take 30wt% of the total amount of injection water, the temperature is below 60°C, add it into a stainless steel barrel as water for pre-dissolving the auxiliary materials, and add the above-mentioned prescription amount of osmotic pressure regulator, purslane extract, dandelion extract, ginsenoside RO, and aminocaproic acid in sequence under stirring. After each material is stirred and dissolved, add the next material and observe until it is completely dissolved to obtain a mixed solution;

[0077] 2. Continue to add the above-prescribed amount of metal ion chelating agent, vitamin A, and vitamin E to the mixed solution in sequence. After each material is stirred and dissolved, add the next material and observe until it is completely dissolved to obtain solution 1;

[0078] 3. Take 60 wt% of the total amount of water for injection, add it to a stainless steel barrel at a temperature below 60°C, and add an accurately weighed amount of sodium hyaluronate under slow stirring; fully swell, add the prescribed amount of ginsenoside Rb1, and visually observe until it is completely dissolved to obtain solution 2;

[0079] 4. Add the above solution 1 and solution 2 into the dilution tank, start stirring, continue stirring for 2 hours, add pH adjuster to adjust the pH to 6.5, and add water for injection to the full amount;

[0080] 5. The liquid medicine is filtered through a 0.45μm membrane cartridge filter that has passed the bubble point test for 20 minutes, and the intermediate is tested for sodium hyaluronate content, pH, osmotic pressure, visible foreign matter, etc.;

[0081] 6. The liquid medicine is filtered and sterilized twice through a 0.22μm sterilizing filter that has passed the bubble point test, and then enters the filling room after filtration and sterilization;

[0082] 7. Blowing, filling and sealing.

[0083] Example 2

[0084] The components of single-dose compound sodium hyaluronate eye drops are as follows:

[0085] Components Weight percentage (%) Components Weight percentage (%) Sodium hyaluronate 0.12wt%; Vitamin A 0.05wt%; Edetate Disodium 0.02wt%; Vitamin E 0.15wt%; Aminocaproic acid 0.20wt%; Citrate 0.8wt%; Purslane Extract 0.10wt% Dandelion Extract 0.20wt% Ginsenoside RO 0.05wt%; Sodium Citrate Adjust pH to 6.8; Ginsenoside Rb1 0.008wt%; Water for injection Add to balance

[0086] The preparation method of the above-mentioned compound sodium hyaluronate eye drops comprises the steps:

[0087] 1. Take 35wt% of the total amount of injection water, the temperature is below 60°C, add it into a stainless steel barrel as water for pre-dissolving the auxiliary materials, and add the above-mentioned prescription amount of osmotic pressure regulator, purslane extract, dandelion extract, ginsenoside RO, and aminocaproic acid in sequence under stirring. After each material is stirred and dissolved, add the next material and observe until it is completely dissolved to obtain a mixed solution;

[0088] 2. Continue to add the above-prescribed amount of metal ion chelating agent, vitamin A, and vitamin E to the mixed solution in sequence. After each material is stirred and dissolved, add the next material and observe until it is completely dissolved to obtain solution 1;

[0089] 3. Take 50 wt% of the total amount of water for injection, add it to a stainless steel barrel at a temperature below 60°C, and add an accurately weighed amount of sodium hyaluronate while slowly stirring; fully swell, add the prescribed amount of ginsenoside Rb1, and visually observe until it is completely dissolved to obtain solution 2;

[0090] 4. Add the above solution 1 and solution 2 into the dilution tank, start stirring, continue stirring for 2 hours, add pH adjuster to adjust the pH to 6.5, and add water for injection to the total amount of solution;

[0091] 5. The liquid medicine is filtered through a 0.45μm membrane cartridge filter that has passed the bubble point test for 20 minutes, and the intermediate is tested for sodium hyaluronate content, pH, osmotic pressure, visible foreign matter, etc.;

[0092] 6. The liquid medicine is filtered and sterilized twice through a 0.22μm sterilizing filter that has passed the bubble point test, and then enters the filling room after filtration and sterilization;

[0093] 7. Blowing, filling and sealing.

[0094] Example 3

[0095] The components of single-dose compound sodium hyaluronate eye drops are as follows:

[0096] Components Weight percentage (%) Components Weight percentage (%) Sodium hyaluronate 0.08wt%; Vitamin A 0.10wt%; Edetate Disodium 0.01wt%; Vitamin E 0.20wt%; Aminocaproic acid 0.20wt%; Potassium chloride 2.0wt%; Purslane Extract 0.20wt% Dandelion Extract 0.10wt% Ginsenoside RO 0.20wt%; Sodium tartrate Adjust pH to 6.2; Ginsenoside Rb1 0.01wt%; Water for injection Add to balance

[0097] The preparation method of the above-mentioned compound sodium hyaluronate eye drops comprises the steps:

[0098] 1. Take 25wt% of the total amount of injection water, the temperature is below 60°C, add it into a stainless steel barrel as water for pre-dissolving the auxiliary materials, and add the above-mentioned prescription amount of osmotic pressure regulator, purslane extract, dandelion extract, ginsenoside RO, and aminocaproic acid in sequence under stirring. After each material is stirred and dissolved, add the next material and observe until it is completely dissolved to obtain a mixed solution;

[0099] 2. Continue to add the above-prescribed amount of metal ion chelating agent, vitamin A, and vitamin E to the mixed solution in sequence. After each material is stirred and dissolved, add the next material and observe until it is completely dissolved to obtain solution 1;

[0100] 3. Take 40 wt% of the total amount of water for injection, add it to a stainless steel barrel at a temperature below 60°C, slowly add an accurately weighed amount of sodium hyaluronate while stirring; fully swell, add the prescribed amount of ginsenoside Rb1, and visually observe until it is completely dissolved to obtain solution 2;

[0101] 4. Add the above solution 1 and solution 2 into the dilution tank, start stirring, continue stirring for 2 hours, add pH adjuster to adjust the pH to 6.5, and add water for injection to the total amount of solution;

[0102] 5. The liquid medicine is filtered through a 0.45μm membrane cartridge filter that has passed the bubble point test for 20 minutes, and the intermediate is tested for sodium hyaluronate content, pH, osmotic pressure, visible foreign matter, etc.;

[0103] 6. The liquid medicine is filtered and sterilized twice through a 0.22μm sterilizing filter that has passed the bubble point test, and then enters the filling room after filtration and sterilization;

[0104] 7. Blowing, filling and sealing.

[0105] Example 4

[0106] The components of single-dose compound sodium hyaluronate eye drops are as follows:

[0107]

[0108]

[0109] The preparation method of the above-mentioned compound sodium hyaluronate eye drops is the same as the steps in Example 1.

[0110] Example 5

[0111] The components of single-dose compound sodium hyaluronate eye drops are as follows:

[0112] Components Weight percentage (%) Components Weight percentage (%) Sodium hyaluronate 0.32wt%; Vitamin A 0.05wt%; Edetate Disodium 0.01wt%; Vitamin E 0.20wt%; Aminocaproic acid 0.15wt%; Potassium chloride 0.8wt%; Purslane Extract 0.05wt% Dandelion Extract 0.15wt% Ginsenoside RO 0.10wt%; Potassium Citrate Adjust pH to 6.8; Ginsenoside Rb1 0.01wt%; Water for injection Add to balance

[0113] The preparation method of the above-mentioned compound sodium hyaluronate eye drops is the same as the steps in Example 2.

[0114] Example 6

[0115] The components of single-dose compound sodium hyaluronate eye drops are as follows:

[0116] Components Weight percentage (%) Components Weight percentage (%) Sodium hyaluronate 0.28wt%; Vitamin A 0.10wt%; Edetate Disodium 0.02wt%; Vitamin E 0.18wt%; Aminocaproic acid 0.25wt%; Mannitol 1.5wt%; Purslane Extract 0.15t％ Dandelion Extract 0.20wt% Ginsenoside RO 0.18wt%; Disodium hydrogen phosphate Adjust pH to 6.2; Ginsenoside Rb1 0.01wt%; Water for injection Add to balance

[0117] The preparation method of the above-mentioned compound sodium hyaluronate eye drops is the same as the steps in Example 3.

[0118] Comparative Example 1

[0119] The components of single-dose compound sodium hyaluronate eye drops are as follows:

[0120] Components Weight percentage (%) Components Weight percentage (%) Sodium hyaluronate 0.10wt%; Vitamin A 0.10wt%; Edetate Disodium 0.01wt%; Vitamin E 0.10wt%; Aminocaproic acid 0.20wt%; Sodium chloride 0.8wt%; Sodium hydroxide Adjust pH to 6.5; Water for injection Add to balance

[0121] The preparation method of the above-mentioned compound sodium hyaluronate eye drops comprises the steps:

[0122] 1. Take 30wt% of the total amount of water for injection, the temperature is below 60°C, add it into a stainless steel barrel as water for pre-dissolving the auxiliary materials, and add the above-prescribed amount of osmotic pressure regulator and aminocaproic acid in sequence under stirring. After each material is stirred and dissolved, add the next material and observe until it is completely dissolved to obtain a mixed solution;

[0123] 2. Continue to add the above-prescribed amount of metal ion chelating agent, vitamin A, and vitamin E to the mixed solution in sequence. After each material is stirred and dissolved, add the next material and observe until it is completely dissolved to obtain solution 1;

[0124] 3. Take 60 wt% of the total amount of water for injection, add it to a stainless steel barrel at a temperature below 60°C, add an accurately weighed amount of sodium hyaluronate while slowly stirring; fully swell and visually observe until it is completely dissolved to obtain Solution 2;

[0125] 4. Add the above solution 1 and solution 2 into the dilution tank, start stirring, continue stirring for 2 hours, add pH adjuster to adjust the pH to 6.5, and add water for injection to the total amount of solution;

[0126] 5. The liquid medicine is filtered through a 0.45μm membrane cartridge filter that has passed the bubble point test for 20 minutes, and the intermediate is tested for sodium hyaluronate content, pH, osmotic pressure, visible foreign matter, etc.;

[0127] 6. The liquid medicine is filtered and sterilized twice through a 0.22μm sterilizing filter that has passed the bubble point test, and then enters the filling room after filtration and sterilization;

[0128] 7. Blowing, filling and sealing.

[0129] Comparative Example 2

[0130] The components of single-dose compound sodium hyaluronate eye drops are as follows:

[0131] Components Weight percentage (%) Components Weight percentage (%) Sodium hyaluronate 0.30wt%; Vitamin A 0.05wt%; Edetate Disodium 0.02wt%%; Vitamin E 0.15wt%; Aminocaproic acid 0.20wt%%; Sodium chloride 0.8wt%; Sodium hydroxide Adjust pH to 6.5; Water for injection Add to balance

[0132] The preparation method of the above-mentioned compound sodium hyaluronate eye drops comprises the steps:

[0133] 1. Take 30wt% of the total amount of water for injection, the temperature is below 60°C, add it into a stainless steel barrel as water for pre-dissolving the auxiliary materials, and add the above-prescribed amount of osmotic pressure regulator and aminocaproic acid in sequence under stirring. After each material is stirred and dissolved, add the next material and observe until it is completely dissolved to obtain a mixed solution;

[0134] 2. Continue to add the above-prescribed amount of metal ion chelating agent, vitamin A, and vitamin E to the mixed solution in sequence. After each material is stirred and dissolved, add the next material and observe until it is completely dissolved to obtain solution 1;

[0135] 3. Take 60 wt% of the total amount of water for injection, add it to a stainless steel barrel at a temperature below 60°C, add an accurately weighed amount of sodium hyaluronate while slowly stirring; fully swell and visually observe until it is completely dissolved to obtain Solution 2;

[0136] 4. Add the above solution 1 and solution 2 into the dilution tank, start stirring, continue stirring for 2 hours, add pH adjuster to adjust the pH to 6.5, and add water for injection to the total amount of solution;

[0137] 5. The liquid medicine is filtered through a 0.45μm membrane cartridge filter that has passed the bubble point test for 20 minutes, and the intermediate is tested for sodium hyaluronate content, pH, osmotic pressure, visible foreign matter, etc.;

[0138] 6. The liquid medicine is filtered and sterilized twice through a 0.22μm sterilizing filter that has passed the bubble point test, and then enters the filling room after filtration and sterilization;

[0139] 7. Blowing, filling and sealing.

[0140] Test Example 1

[0141] Quality attribute investigation

[0142] In accordance with the quality requirements of ophthalmic preparations in Part IV of the 2020 edition of the Chinese Pharmacopoeia, the properties, pH, osmotic pressure molar concentration, clarity and color of each ophthalmic composition of Examples 1-6 and Comparative Examples 1-2 were investigated, and the results are shown in Table 1.

[0143] Table 1 Quality attributes of different ophthalmic compositions

[0144]

[0145] Test Example 2

[0146] Stability test

[0147] Since the main active ingredient sodium hyaluronate in the compound sodium hyaluronate eye drops is a mucopolysaccharide substance, various Chinese medicine ingredients are mostly macromolecular compounds or organic substances, which are easily affected by various physical and chemical factors and greatly affected by environmental factors, such as high temperature, high humidity, strong light, etc., degradation or water loss may occur. Therefore, the stability test of Example 1 and Example 4 in this occurrence was carried out to ensure that the eye drops are within the quality control range.

[0148] The packaging of the commercially available samples of the compound sodium hyaluronate eye drops prepared in Example 1 and Example 4 was taken and stability was investigated for three months in a constant temperature and humidity chamber under accelerated conditions (temperature 40°C ± 2°C, relative humidity RH 25% ± 5%) (inspection items: appearance, pH, HA-Na content (mg / m1), osmotic pressure ratio).

[0149] Table 2 Results of sample stability test under accelerated conditions

[0150]

[0151] Conclusion: The samples produced in Example 1 and Example 4 of the present invention were placed at 40°C ± 2°C and relative humidity RH 25% ± 5% for 3 months, and there was no significant change in the content, appearance, pH, osmotic pressure molar concentration, etc. of sodium hyaluronate (HA-Na).

[0152] Test Example 3

[0153] Eye irritation test

[0154] The compound sodium hyaluronate eye drops produced in Example 4 of the present invention are used for eye irritation test, and healthy adult New Zealand rabbits are used as test animals. Within 24 hours before the test, check that both eyes of each rabbit are normal. After pre-selection, mark and weigh the animals. During the test, fix the rabbit, gently pull the lower eyelid of the left eye away from the eyeball to form a small socket, inject about 200uL of the test solution of Example 4, and close the eyelid for 30 seconds; the right eye is the control side, and about 200uL of blank control solution (0.9% sodium chloride solution) is injected in the same way, and the eyelid is closed for 30 seconds. Observe and record the results of 4, 24, and 48 hours and the general state of the animals, and score according to the eye injury scoring system. Check both eyes of each animal 4h, 24h, and 48h after instillation.

[0155] Table 3 Observation results of rabbit eye irritation and injury reaction

[0156]

[0157]

[0158] The results show that the eye irritation test reaction of the test side of all test animals in the test observation period of the compound sodium hyaluronate eye drops of Example 4 of the present invention is negative, and the test eye reaction is no greater than that of the control eye. The observation of anterior eye irritation symptoms, the observation of flicker in the anterior chamber, the determination of the number of blinks, the observation of the lens, and the fundus examination did not show eye irritation and eye damage. The above results show that the compound sodium hyaluronate eye drops of the present invention are non-irritating to the eyes and have high safety.

[0159] Test Example 4

[0160] Abnormal toxicity test of single-dose medicinal eye drop bottle

[0161] Take a single-dose low-density polyethylene medicinal eye drop bottle with an inner surface area of ​​120 cm2 in Example 1 of the present invention, cut it into small pieces of suitable length and width of 0.3 cm, rinse it twice with injection water, 50 ml each time, and dry it at low temperature. Move it into a glass container, add 20 ml of 0.9% sodium chloride injection, place it in a high-pressure steam sterilizer at 110°C for 30 minutes, then take it out and cool it for use.

[0162] Ten SPF KM mice weighing 18-22 g were selected, of which 5 mice were marked and weighed using 2% gentian violet staining, and each was intravenously administered 0.5 mL of the test solution, and the other 5 mice were intravenously administered 0.5 mL of the blank control solution (0.9% sodium chloride injection), and the injection was completed evenly within 4-5 seconds.

[0163] During the test, the mice had no abnormal reactions and no deaths. Under the conditions of this test, the single-dose medicinal eye drop bottle had no toxic reactions and the abnormal toxicity test was qualified.

[0164] Test Example 5

[0165] Effect of compound sodium hyaluronate eye drops on dry eye syndrome

[0166] In order to further demonstrate the actual effect of the compound sodium hyaluronate eye drops of the present invention, healthy adult C57 / BL6 mice were selected as the corneal epithelial injury model, and 5u1 of a solution containing 0.20% benzalkonium chloride was topically instilled into both eyes of the mice twice a day for 14 consecutive days, while the mice in the control group received a topical instillation of 5u1 of 0.9% sodium chloride solution. After modeling, the compound sodium hyaluronate eye drops in Example 1, Example 4, Comparative Example 1, and Comparative Example 2 of the present invention and commercially available sodium hyaluronate eye drops were selected to treat the model mice, twice a day, 5u1 each time, for 8 consecutive days, and on the 2nd, 4th, 6th and 8th days after treatment, a tear secretion test (Schirmer I test) was performed 2h after administration, and the tear secretion amount was determined by measuring the length (mm) of the soaked test paper.

[0167] Table 1 Tear secretion test

[0168]

[0169]

[0170] Compared with the model group, in the six treatment groups of Example 1, Example 4, Comparative Example 1, Comparative Example 2 and commercially available sodium hyaluronate eye drops of the present invention, the length of the test paper soaked became longer, and the tear secretion function of the mice induced by dry eye was restored to varying degrees; and the therapeutic effects of Example 1 and Example 4 were better than those of Comparative Example 1, Comparative Example 2 and commercially available sodium hyaluronate eye drops, indicating that the compound sodium hyaluronate eye drops can show better therapeutic effects when the Chinese medicine composition is added.

[0171] Corneal fluorescein staining was used to examine corneal surface defects and score was performed to evaluate the treatment effect.

[0172] Table 2 Corneal fluorescein staining scores

[0173]

[0174] On the 2nd, 4th, 6th and 8th days after treatment, the six treatment groups of the present invention were found to have different degrees of reduction in fluorescein staining scores compared with the model group, indicating that the ocular surface damage induced by dry eye in mice was restored. From the data, it can be seen that the treatment effects of Example 1 and Example 4 of the present invention are better than those of Comparative Example 1, Comparative Example 2 and commercially available sodium hyaluronate eye drops. Through experiments, the compound sodium hyaluronate eye drops can more effectively promote the repair of mouse corneal cells when the Chinese medicine composition is added.

[0175] In summary, the present invention uses a Chinese medicine composition as an active ingredient, which works synergistically with sodium hyaluronate, not only effectively relieves the symptoms of dry eye, but also inhibits the inflammatory response from a mechanism, promotes the repair of damaged corneal cells in patients with dry eye, and maintains the moisture of the eye, thereby achieving the therapeutic effect. Compared with existing treatment methods for dry eye, this is a more targeted and effective treatment strategy. In addition, by controlling the concentration of various Chinese medicine ingredients and combining appropriate pharmaceutical excipients, the safety of treatment and patient compliance can be further improved.

Claims

1. Single-dose compound sodium hyaluronate eye drops, characterized in that: The drug contains the following ingredients: Sodium hyaluronate 0.08wt%-0.15wt% or 0.28wt%-0.35wt%; Portulaca oleracea extract 0.01wt%-0.20wt%; Dandelion extract 0.01wt%-0.20wt%; Ginsenoside RO 0.01wt%-0.20wt%; Ginsenoside Rb1 0.001wt%-0.01wt%; Aminocaproic acid 0.15wt%-0.25wt%; Osmotic pressure regulator 0.5wt%-2.48wt%; The remaining amount of water for injection; It also includes one or a mixture of any of vitamins, metal ion chelators, and pH adjusters.

2. The single-dose compound sodium hyaluronate eye drops according to claim 1, characterized in that: The drug contains the following ingredients: Sodium hyaluronate 0.09wt%-0.12wt% or 0.29wt%-0.32wt%; Portulaca oleracea extract 0.05wt%-0.18wt%; Dandelion extract 0.06wt%-0.15wt%; Ginsenoside RO 0.10wt%-0.15wt%; Ginsenoside Rb1 0.005wt%-0.008wt%; Aminocaproic acid 0.18wt%-0.22wt%; Osmotic pressure regulator 0.8wt%-2.23wt%; The remaining amount of water for injection; It also includes one or a mixture of any of vitamins, metal ion chelators, and pH adjusters.

3. The single-dose compound sodium hyaluronate eye drops according to claim 1, characterized in that: The vitamins are vitamin A, and the amount used is 0.05wt%-0.10wt%, preferably 0.06wt%-0.08wt%; and vitamin E, and the amount used is 0.05wt%-0.20wt%, preferably 0.1wt%-0.15wt%.

4. The single-dose compound sodium hyaluronate eye drops according to claim 1, characterized in that: The metal ion chelating agent is one of disodium edetate and hydroxyethylethylenediaminetriacetic acid or a mixture of the two. The amount of the chelating agent is 0.008wt%-0.02wt%, preferably 0.009wt%-0.015wt%.

5. The single-dose compound sodium hyaluronate eye drops according to claim 1, characterized in that: The osmotic pressure regulator includes one or a mixture of any of sodium chloride, potassium chloride, glycerol, mannitol, glucose, sorbitol, phosphate and citrate, and the amount of the osmotic pressure regulator is 0.5wt%-2.48wt%, preferably 0.8wt%-2.23wt%.

6. The single-dose compound sodium hyaluronate eye drops according to claim 1, characterized in that: The pH regulator includes one or a mixture of any of the following: sodium hydroxide, hydrochloric acid, boric acid, borax, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, citric acid, sodium citrate, potassium citrate, acetic acid, sodium acetate, citric acid, sodium citrate, tartaric acid, sodium tartrate, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. The pH value of the single-dose compound sodium hyaluronate eye drops is adjusted to 6.0-7.0, preferably 6.3-6.

8.

7. The single-dose compound sodium hyaluronate eye drops according to claim 1, characterized in that: The average molecular weight of the sodium hyaluronate is 500,000-1.2 million.

8. A method for preparing the single-dose compound sodium hyaluronate eye drops according to any one of claims 1 to 7, characterized in that: The steps include: 1) Take 20% to 35wt% of the total amount of the preparation solution of water for injection, the temperature of the water for injection is below 60°C, and under stirring, add 0.8wt%-2.23wt% of osmotic pressure regulator, 0.05wt%-0.18wt% of purslane extract, 0.06wt%-0.15wt% of dandelion extract, 0.10wt%-0.15wt% of ginsenoside RO, and 0.18wt%-0.22wt% of aminocaproic acid in sequence, and stir each material until it is dissolved before adding the next material, and observe until it is completely dissolved to obtain a mixed solution; 2) Continue to add one or any combination of 0.008wt%-0.02wt% of metal ion chelating agent, 0.05wt%-0.10wt% of vitamin A, and 0.05wt%-0.20wt% of vitamin E to the mixed solution, stirring and dissolving each material before adding the next material, and visually observe until it is completely dissolved to obtain solution 1; 3) Take 40% to 60wt% of the total amount of the preparation water for injection, the temperature of the water for injection is below 60°C, add 0.08wt%-0.15wt% or 0.28wt%-0.35wt% of sodium hyaluronate under slow stirring; fully swell, add 0.001wt%-0.01wt% of ginsenoside Rb1, and observe until it is completely dissolved to obtain solution 2; 4) Add the above solution 1 and solution 2 into the dilution tank, continue stirring for 2-6 hours, add pH adjuster to adjust the pH value to 6.0-7.0, and add water for injection to the total amount of solution; 5) The liquid medicine is filtered through a 0.45μm membrane cartridge filter that has passed the bubble point test for 10 to 40 minutes, and the intermediate is tested for sodium hyaluronate content, pH value, osmotic pressure, and visible foreign matter; 6) The liquid medicine is filtered and sterilized twice through a 0.22μm sterilizing filter that has passed the bubble point test, and then enters the filling room after filtration and sterilization; 7) Blowing, filling and sealing.

9. The preparation method according to claim 8, characterized in that: The stirring rate in step 1) and step 2) is 200-500 r / min; the stirring rate in step 3) is 400-1200 r / min; the stirring rate in step 4) is 30-60 Hz.

10. The preparation method according to claim 8, characterized in that: The vitamins are vitamin A, and the amount used is 0.05wt%-0.10wt%, preferably 0.06wt%-0.08wt%; and vitamin E, and the amount used is 0.05wt%-0.20wt%, preferably 0.1wt%-0.15wt%; The metal ion chelating agent is one of disodium edetate and hydroxyethylethylenediaminetriacetic acid or a mixture of the two. The amount of the chelating agent is 0.008wt%-0.02wt%, preferably 0.009wt%-0.015wt%.

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