Olopatadine hydrochloride-containing oral medicine composition and preparation method thereof

Abstract

The invention discloses an oral medicine composition containing olopatadine hydrochloride and a preparation method of the oral medicine composition, and relates to the technical field of pharmaceutical preparations, and the oral medicine composition is prepared from the following components in percentage by weight: 0.5-1.5% of modified olopatadine hydrochloride nanocrystals, 0.05-0.1% of xanthan gum, 0.03-0.05% of an antioxidant, 0.5-1.5% of a flavoring agent, 0.1-0.3% of olopatadine hydrochloride-containing lipidosome and 5-10% of other auxiliary materials, and the balance of purified water. The oral medicine composition is obvious in medicine effect, low in toxic and side effects, good in taste, good in controlled release and stability and high in bioavailability.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to an oral pharmaceutical composition containing olopatadine hydrochloride and a preparation method thereof. Background Art

[0002] Olopatadine hydrochloride is a second-generation selective histamine H1 receptor antagonist and is widely used in the treatment of diseases such as allergic rhinitis and urticaria. Compared with the first-generation antihistamines, it has advantages such as less central nervous system side effects and longer action time. However, existing oral preparations (such as tablets and capsules) have problems of difficult swallowing (especially in children and elderly patients), while commercially available oral liquid preparations generally have defects of poor stability, unpleasant taste (obvious bitterness), and large fluctuations in bioavailability.

[0003] Existing preparation methods of oral pharmaceutical compositions containing olopatadine hydrochloride mostly adopt the direct dissolution method, without considering the influence of the addition sequence of excipients on the solubility and stability of the drug, which easily leads to drug precipitation or uneven suspension. In addition, the sterilization process (such as high-temperature sterilization) may accelerate drug degradation, while the filtration sterilization method has a high cost, which limits industrial production.

[0004] In order to solve the above problems, the Chinese invention patent with the authorization announcement number CN118557530B discloses a pediatric pharmaceutical composition containing olopatadine hydrochloride and a preparation method thereof, which is prepared from the following components in parts by weight: 5-10 parts of olopatadine hydrochloride nanocrystals, 1-2 parts of edible micro-nano active ingredients, 0.1-0.2 parts of antioxidants, 3-5 parts of sweeteners, 0.1-0.3 parts of bird's nest peptides, 0.1-0.3 parts of dark chocolate powder, and 0.1-0.3 parts of brown rice flour. This pharmaceutical composition has obvious efficacy, low toxicity and side effects, good taste, good medication compliance and drug formation property, and a long shelf life. However, its controlled release and stability still need to be further improved.

[0005] It can be seen that developing an oral pharmaceutical composition containing olopatadine hydrochloride and a preparation method thereof, which has obvious efficacy, low toxicity and side effects, good taste, good controlled release and stability, and high bioavailability, meets the market demand, has broad market value and application prospects, and is of great significance for promoting the development of the field of olopatadine hydrochloride oral medications. Summary of the Invention

[0006] The purpose of the present invention is to provide an oral pharmaceutical composition containing olopatadine hydrochloride and a preparation method thereof, which has obvious efficacy, low toxicity and side effects, good taste, good controlled release and stability, and high bioavailability, in order to overcome the deficiencies of the prior art.

[0007] To achieve the above object, the technical solution adopted by the present invention is: an oral pharmaceutical composition containing olopatadine hydrochloride, which is prepared from the following components by weight percentage: modified olopatadine hydrochloride nanocrystals 0.5 - 1.5%, xanthan gum 0.05 - 0.1%, antioxidant 0.03 - 0.05%, flavoring agent 0.5 - 1.5%, olopatadine hydrochloride liposomes 0.1 - 0.3%, other excipients 5 - 10%, and the balance is purified water.

[0008] Preferably, the preparation method of the modified olopatadine hydrochloride nanocrystals comprises the following steps: adding olopatadine hydrochloride and β-cyclodextrin to an ethanol-water mixed solution, magnetically stirring at 45 - 55°C for 5 - 7 h; cooling the reaction solution to 4°C, standing for 10 - 13 h, filtering by suction, and then freeze-drying to obtain an inclusion complex powder; adding the inclusion complex powder to acetone to obtain an inclusion complex powder dispersion liquid, quickly injecting it into purified water containing 0.5% hydroxypropyl methylcellulose E5, and stirring to form a nano-suspension; homogenizing at 15000 psi for 6 - 8 times to control the particle size at 130 - 180 nm; adding an ethanol solution of Eudragit E100, and stirring at 55 - 65°C for 2 - 4 h to form a pH-sensitive coating layer; after centrifugation, washing with deionized water 2 - 4 times, and freeze-drying to obtain the modified olopatadine hydrochloride nanocrystals.

[0009] Preferably, the molar ratio of olopatadine hydrochloride to β-cyclodextrin is 1:1; the ethanol-water mixed solution is a mixture of ethanol and water in a volume ratio of 1:1.

[0010] Preferably, the mass ratio of olopatadine hydrochloride to the ethanol-water mixed solution is 1:(3 - 5).

[0011] Preferably, the amount ratio of the inclusion complex powder to acetone is 5 g:100 mL.

[0012] Preferably, the volume ratio of the inclusion complex powder dispersion liquid to the purified water containing 0.5% hydroxypropyl methylcellulose E5 is 1:15.

[0013] Preferably, the mass percentage concentration of the Eudragit E100 ethanol solution is 5 - 10%.

[0014] Preferably, the dry weight ratio of Eudragit E100 to the nano-suspension is (10 - 20):100.

[0015] Preferably, the antioxidant is rosemary extract.

[0016] Preferably, the flavoring agent is a mixture of sucralose and honey powder in a mass ratio of 1:(1 - 2).

[0017] Preferably, the preparation method of the olopatadine hydrochloride liposome comprises the following steps: adding soybean phospholipid, cholesterol, and lactoferrin into ethanol, heating and stirring in a water bath at 50-55°C for 1-2 h, rotary evaporating to remove ethanol to obtain a lipid film; adding an olopatadine hydrochloride ethanol solution, hydrating, and then subjecting to high-pressure homogenization to obtain the olopatadine hydrochloride liposome.

[0018] Preferably, the mass ratio of the soybean phospholipid, cholesterol, lactoferrin, and ethanol is 3:1:0.5:(10-15).

[0019] Preferably, the concentration of the olopatadine hydrochloride ethanol solution is 1-3 mg / mL.

[0020] Preferably, the mass ratio of the olopatadine hydrochloride to the lipid film is (1-3):10.

[0021] Preferably, the temperature of hydration is 35-45°C and the time is 30-60 min.

[0022] Preferably, the pressure of high-pressure homogenization is 800-1200 bar and the number of cyclic homogenization times is 3-5 times.

[0023] Preferably, the other excipients are a mixture of glycerol, polysorbate 80, and propylene glycol in a mass ratio of (3-5):1:(0.8-1.2).

[0024] Another object of the present invention is to provide a preparation method of the olopatadine hydrochloride oral pharmaceutical composition, comprising the following steps: mixing each raw material evenly according to the mass percentage, filtering through a 0.35-μm microporous membrane to remove impurities and larger particles, and then filling into a sterile container and storing in a sealed and light-proof manner.

[0025] Due to the application of the above technical solutions, the present invention has the following beneficial effects:

[0026] (1) The olopatadine hydrochloride oral pharmaceutical composition disclosed by the present invention is prepared from the following components by weight percentage: modified olopatadine hydrochloride nanocrystals 0.5-1.5%, xanthan gum 0.05-0.1%, antioxidant 0.03-0.05%, flavoring agent 0.5-1.5%, olopatadine hydrochloride liposome 0.1-0.3%, other excipients 5-10%, and the balance being purified water. Through the mutual cooperation and common action of each component, the prepared composition product has obvious drug efficacy, low toxicity and side effects, good taste, excellent controlled release and stability, and high bioavailability.

[0027] (2) The oral pharmaceutical composition containing olopatadine hydrochloride disclosed by the present invention, in which the modified olopatadine hydrochloride nanocrystals are included by β-cyclodextrin, can effectively mask the bitterness of the drug and inhibit oxidative degradation; the inclusion complex further forms organic nanocrystals by the anti-solvent precipitation method, and the surface is modified with a pH-sensitive polymer to achieve the dual functions of taste masking and controlled release; by adding the modified olopatadine hydrochloride nanocrystals, the solubility and bioavailability of the drug can be increased, the release can be delayed and the irritation can be reduced. The olopatadine hydrochloride liposome can improve the concentration of the drug in the target tissue through passive targeting or active targeting, reduce the side effects caused by systemic distribution, and thus improve the bioavailability. In addition, the liposome membrane material can also isolate the direct contact between olopatadine hydrochloride and gastrointestinal enzymes, acidic / alkaline environment, avoid drug degradation, and ensure the complete absorption of the active ingredient.

[0028] (3) The oral pharmaceutical composition containing olopatadine hydrochloride disclosed by the present invention, xanthan gum can adhere to the surface of the gastrointestinal mucosa, extend the residence time of the preparation in the gastrointestinal tract, cooperate with the sustained-release characteristics of the nanocrystals and liposomes, and further improve the drug absorption efficiency. In addition, it can also improve the fluidity of the preparation, prevent the sedimentation of nanocrystal / liposome particles, and maintain the uniformity of the system.

[0029] (4) The oral pharmaceutical composition containing olopatadine hydrochloride disclosed by the present invention, through the combination of nanocrystals and liposomes and the collaborative design of functional excipients, breaks through the limitations of traditional oral preparations, has significant advantages in terms of drug efficacy, safety, patient compliance, etc., provides a more optimized solution for the clinical application of olopatadine hydrochloride, and has high scientific research and commercial transformation value. Detailed implementation mode

[0030] The following description is used to disclose the present invention so that those skilled in the art can implement the present invention. The preferred embodiments in the following description are only examples, and those skilled in the art can think of other obvious variants.

[0031] Example 1, an oral pharmaceutical composition containing olopatadine hydrochloride, is prepared from the following components by weight percentage: 0.5% of modified olopatadine hydrochloride nanocrystals, 0.05% of xanthan gum, 0.03% of antioxidant, 0.5% of flavoring agent, 0.1% of olopatadine hydrochloride liposome, 5% of other excipients, and the balance is purified water.

[0032] The preparation method of the modified olopatadine hydrochloride nanocrystals comprises the following steps: adding olopatadine hydrochloride and β-cyclodextrin into an ethanol-water mixed solution, magnetically stirring at 45°C for 5 h; cooling the reaction solution to 4°C, standing for 10 h, filtering by suction, and then freeze-drying to obtain an inclusion complex powder; adding the inclusion complex powder into acetone to obtain a dispersion liquid of the inclusion complex powder, quickly injecting it into purified water containing 0.5% hydroxypropyl methylcellulose E5, and stirring to form a nano-suspension; homogenizing at 15000 psi for 6 times to control the particle size at 130 nm; adding an ethanol solution of Eudragit E100, and stirring at 55°C for 2 h to form a pH-sensitive coating layer; after centrifugation, washing twice with deionized water, and freeze-drying to obtain the modified olopatadine hydrochloride nanocrystals; the molar ratio of olopatadine hydrochloride to β-cyclodextrin is 1:1; the ethanol-water mixed solution is prepared by mixing ethanol and water in a volume ratio of 1:1.

[0033] The mass ratio of olopatadine hydrochloride to the ethanol-water mixed solution is 1:3; the amount ratio of the inclusion complex powder to acetone is 5 g:100 mL; the volume ratio of the dispersion liquid of the inclusion complex powder to the purified water containing 0.5% hydroxypropyl methylcellulose E5 is 1:15; the mass percentage concentration of the Eudragit E100 ethanol solution is 5%; the dry weight ratio of Eudragit E100 to the nano-suspension is 10:100; the antioxidant is rosemary extract; the flavoring agent is a mixture of sucralose and honey powder in a mass ratio of 1:1.

[0034] The preparation method of the liposome containing olopatadine hydrochloride comprises the following steps: adding soybean phospholipid, cholesterol, and lactoferrin into ethanol, heating and stirring in a water bath at 50°C for 1 h, and rotary evaporating to remove ethanol to obtain a lipid film; adding an ethanol solution of olopatadine hydrochloride, and hydrating and then subjecting to high-pressure homogenization to obtain the liposome containing olopatadine hydrochloride; the mass ratio of soybean phospholipid, cholesterol, lactoferrin, and ethanol is 3:1:0.5:10; the concentration of the ethanol solution of olopatadine hydrochloride is 1 mg / mL; the mass ratio of olopatadine hydrochloride to the lipid film is 1:10; the temperature of hydration is 35°C and the time is 30 min; the pressure of high-pressure homogenization is 800 bar, and the number of cycles of homogenization is 3 times; the other auxiliary materials are a mixture of glycerol, polysorbate 80, and propylene glycol in a mass ratio of 3:1:0.8.

[0035] A preparation method of the oral pharmaceutical composition containing olopatadine hydrochloride comprises the following steps: mixing each raw material evenly according to the mass percentage, filtering through a 0.35-μm microporous filter membrane to remove impurities and larger particles, and then filling into a sterile container and storing it sealed in the dark.

[0036] Example 2. An oral pharmaceutical composition containing olopatadine hydrochloride, which is prepared from the following components by weight percentage: modified olopatadine hydrochloride nanocrystals 0.7%, xanthan gum 0.07%, antioxidant 0.035%, flavoring agent 0.8%, olopatadine hydrochloride liposomes 0.15%, other excipients 6%, and the balance is purified water.

[0037] The preparation method of the modified olopatadine hydrochloride nanocrystals includes the following steps: adding olopatadine hydrochloride and β-cyclodextrin to an ethanol-water mixed solution, and magnetically stirring at 47°C for 5.5 h; cooling the reaction solution to 4°C, standing for 11 h, filtering by suction, and then freeze-drying to obtain an inclusion complex powder; adding the inclusion complex powder to acetone to obtain an inclusion complex powder dispersion liquid, and quickly injecting it into purified water containing 0.5% hydroxypropyl methylcellulose E5, and stirring to form a nano-suspension; homogenizing at 15000 psi for 7 times to control the particle size at 140 nm; adding an ethanol solution of Eudragit E100, and stirring at 57°C for 2.5 h to form a pH-sensitive coating layer; after centrifugation, washing 3 times with deionized water, and freeze-drying to obtain modified olopatadine hydrochloride nanocrystals; the molar ratio of olopatadine hydrochloride to β-cyclodextrin is 1:1; the ethanol-water mixed solution is a mixture of ethanol and water in a volume ratio of 1:1; the mass ratio of olopatadine hydrochloride to the ethanol-water mixed solution is 1:3.5; the amount ratio of the inclusion complex powder to acetone is 5 g:100 mL; the volume ratio of the inclusion complex powder dispersion liquid to purified water containing 0.5% hydroxypropyl methylcellulose E5 is 1:15; the mass percentage concentration of the Eudragit E100 ethanol solution is 6%; the dry weight ratio of Eudragit E100 to the nano-suspension is 13:100.

[0038] The antioxidant is rosemary extract; the flavoring agent is a mixture of sucralose and honey powder in a mass ratio of 1:1.3.

[0039] The preparation method of the olopatadine hydrochloride liposomes includes the following steps: adding soybean phospholipid, cholesterol, and lactoferrin to ethanol, heating and stirring in a water bath at 52°C for 1.2 h, and rotary evaporating to remove ethanol to obtain a lipid film; adding an olopatadine hydrochloride ethanol solution, and hydrating and then subjecting to high-pressure homogenization to obtain olopatadine hydrochloride liposomes; the mass ratio of soybean phospholipid, cholesterol, lactoferrin, and ethanol is 3:1:0.5:12; the concentration of the olopatadine hydrochloride ethanol solution is 1.5 mg / mL; the mass ratio of olopatadine hydrochloride to the lipid film is 1.5:10; the temperature of hydration is 38°C and the time is 40 min; the pressure of high-pressure homogenization is 900 bar, and the number of cycles of homogenization is 4 times; the other excipients are a mixture of glycerol, polysorbate 80, and propylene glycol in a mass ratio of 3.5:1:0.9.

[0040] A preparation method of the olopatadine hydrochloride-containing oral pharmaceutical composition, comprising the following steps: After mixing each raw material evenly by mass percentage, filter through a 0.35 μm microporous filter membrane to remove impurities and large particles, and then fill into a sterile container and store sealed in the dark.

[0041] Example 3, an olopatadine hydrochloride-containing oral pharmaceutical composition, comprising the following components by weight percentage: modified olopatadine hydrochloride nanocrystals 1%, xanthan gum 0.08%, antioxidant 0.04%, flavoring agent 1%, olopatadine hydrochloride-containing liposomes 0.2%, other excipients 7.5%, and the balance being purified water.

[0042] The preparation method of the modified olopatadine hydrochloride nanocrystals comprises the following steps: Add olopatadine hydrochloride and β-cyclodextrin to an ethanol-water mixed solution, and stir magnetically at 50 °C for 6 h; Cool the reaction solution to 4 °C, let it stand for 11.5 h, filter by suction and then freeze-dry to obtain an inclusion complex powder; Add the inclusion complex powder to acetone to obtain an inclusion complex powder dispersion liquid, and quickly inject it into purified water containing 0.5% hydroxypropyl methylcellulose E5, and stir to form a nano-suspension; Homogenize at 15000 psi for 7 times to control the particle size at 150 nm; Add an ethanol solution of Eudragit E100, and stir at 60 °C for 3 h to form a pH-sensitive coating layer; After centrifugation, wash 3 times with deionized water, and obtain modified olopatadine hydrochloride nanocrystals after freeze-drying; The molar ratio of olopatadine hydrochloride to β-cyclodextrin is 1:1; The ethanol-water mixed solution is a mixture of ethanol and water in a volume ratio of 1:1; The mass ratio of olopatadine hydrochloride to the ethanol-water mixed solution is 1:4; The amount ratio of the inclusion complex powder to acetone is 5 g:100 mL; The volume ratio of the inclusion complex powder dispersion liquid to purified water containing 0.5% hydroxypropyl methylcellulose E5 is 1:15; The mass percentage concentration of the Eudragit E100 ethanol solution is 7.5%; The dry weight ratio of Eudragit E100 to the nano-suspension is 15:100.

[0043] The antioxidant is rosemary extract; The flavoring agent is a mixture of sucralose and honey powder in a mass ratio of 1:1.5.

[0044] The preparation method of the olopatadine hydrochloride liposome comprises the following steps: adding soybean phospholipid, cholesterol, and lactoferrin into ethanol, heating and stirring in a water bath at 53 °C for 1.5 h, rotary evaporating to remove ethanol to obtain a lipid film; adding an olopatadine hydrochloride ethanol solution, hydrating, and then subjecting to high-pressure homogenization to obtain the olopatadine hydrochloride liposome; the mass ratio of the soybean phospholipid, cholesterol, lactoferrin, and ethanol is 3:1:0.5:13; the concentration of the olopatadine hydrochloride ethanol solution is 2 mg / mL; the mass ratio of the olopatadine hydrochloride to the lipid film is 2:10; the hydration temperature is 40 °C and the time is 45 min; the pressure of the high-pressure homogenization is 1000 bar and the number of cyclic homogenization times is 4 times.

[0045] The other excipients are a mixture of glycerol, polysorbate 80, and propylene glycol in a mass ratio of 4:1:1.

[0046] A preparation method of the olopatadine hydrochloride oral pharmaceutical composition comprises the following steps: mixing each raw material evenly according to the mass percentage, filtering through a 0.35 μm microporous filter membrane to remove impurities and larger particles, and then filling into a sterile container and storing it sealed and protected from light.

[0047] Example 4, an olopatadine hydrochloride oral pharmaceutical composition, is prepared from the following components by weight percentage: modified olopatadine hydrochloride nanocrystals 1.3%, xanthan gum 0.09%, antioxidant 0.045%, flavoring agent 1.3%, olopatadine hydrochloride liposome 0.25%, other excipients 9%, and the balance is purified water.

[0048] The preparation method of the modified olopatadine hydrochloride nanocrystals comprises the following steps: adding olopatadine hydrochloride and β-cyclodextrin into an ethanol-water mixture, magnetically stirring at 53 °C for 6.5 h; cooling the reaction solution to 4 °C, standing for 12.5 h, filtering by suction and then freeze-drying to obtain an inclusion complex powder; adding the inclusion complex powder into acetone to obtain a dispersion of the inclusion complex powder, quickly injecting it into purified water containing 0.5% hydroxypropyl methylcellulose E5, and stirring to form a nano-suspension; homogenizing at 15000 psi for 8 times to control the particle size at 170 nm; adding an ethanol solution of Eudragit E100, stirring at 63 °C for 3.5 h to form a pH-sensitive coating layer; after centrifugation, washing 4 times with deionized water, and freeze-drying to obtain the modified olopatadine hydrochloride nanocrystals; the molar ratio of olopatadine hydrochloride to β-cyclodextrin is 1:1; the ethanol-water mixture is composed of ethanol and water mixed at a volume ratio of 1:1; the mass ratio of olopatadine hydrochloride to the ethanol-water mixture is 1:4.5; the amount ratio of the inclusion complex powder to acetone is 5 g:100 mL; the volume ratio of the dispersion of the inclusion complex powder to the purified water containing 0.5% hydroxypropyl methylcellulose E5 is 1:15; the mass percentage concentration of the Eudragit E100 ethanol solution is 9%; the dry weight ratio of Eudragit E100 to the nano-suspension is 18:100.

[0049] The antioxidant is rosemary extract; the flavoring agent is composed of sucralose and honey powder mixed at a mass ratio of 1:1.8.

[0050] The preparation method of the liposome containing olopatadine hydrochloride comprises the following steps: adding soybean phospholipid, cholesterol, and lactoferrin into ethanol, heating and stirring in a water bath at 54 °C for 1.8 h, rotary evaporating to remove ethanol to obtain a lipid film; adding an ethanol solution of olopatadine hydrochloride, hydrating and then performing high-pressure homogenization to obtain the liposome containing olopatadine hydrochloride; the mass ratio of soybean phospholipid, cholesterol, lactoferrin, and ethanol is 3:1:0.5:14; the concentration of the ethanol solution of olopatadine hydrochloride is 2.5 mg / mL; the mass ratio of olopatadine hydrochloride to the lipid film is 2.5:10; the temperature of hydration is 43 °C and the time is 55 min; the pressure of high-pressure homogenization is 1100 bar and the number of cycles of homogenization is 5 times.

[0051] The other excipients are composed of glycerol, polysorbate 80, and propylene glycol mixed at a mass ratio of 4.5:1:1.1.

[0052] A preparation method of the oral pharmaceutical composition containing olopatadine hydrochloride comprises the following steps: mixing the raw materials according to the mass percentage, filtering through a 0.35 μm microporous filter membrane to remove impurities and larger particles, and then filling into a sterile container and storing in a sealed and light-proof manner.

[0053] Example 5. An oral pharmaceutical composition containing olopatadine hydrochloride, which is prepared from the following components by weight percentage: modified olopatadine hydrochloride nanocrystals 1.5%, xanthan gum 0.1%, antioxidant 0.05%, flavoring agent 1.5%, olopatadine hydrochloride liposomes 0.3%, other excipients 10%, and the balance being purified water.

[0054] The preparation method of the modified olopatadine hydrochloride nanocrystals comprises the following steps: adding olopatadine hydrochloride and β-cyclodextrin into an ethanol-water mixed solution, and magnetically stirring at 55°C for 7 h; cooling the reaction solution to 4°C, standing for 13 h, filtering by suction, and then freeze-drying to obtain an inclusion complex powder; adding the inclusion complex powder into acetone to obtain an inclusion complex powder dispersion liquid, quickly injecting it into purified water containing 0.5% hydroxypropyl methylcellulose E5, and stirring to form a nano-suspension; homogenizing at 15000 psi for 8 times to control the particle size at 180 nm; adding an ethanol solution of Eudragit E100, and stirring at 65°C for 4 h to form a pH-sensitive coating layer; after centrifugation, washing 4 times with deionized water, and freeze-drying to obtain the modified olopatadine hydrochloride nanocrystals; the molar ratio of olopatadine hydrochloride to β-cyclodextrin is 1:1; the ethanol-water mixed solution is prepared by mixing ethanol and water in a volume ratio of 1:1; the mass ratio of olopatadine hydrochloride to the ethanol-water mixed solution is 1:5; the amount ratio of the inclusion complex powder to acetone is 5 g:100 mL; the volume ratio of the inclusion complex powder dispersion liquid to the purified water containing 0.5% hydroxypropyl methylcellulose E5 is 1:15; the mass percentage concentration of the Eudragit E100 ethanol solution is 10%; the dry weight ratio of Eudragit E100 to the nano-suspension is 20:100.

[0055] The antioxidant is rosemary extract; the flavoring agent is a mixture of sucralose and honey powder in a mass ratio of 1:2.

[0056] The preparation method of the olopatadine hydrochloride liposomes comprises the following steps: adding soybean phospholipid, cholesterol, and lactoferrin into ethanol, heating and stirring in a water bath at 55°C for 2 h, and rotary evaporating to remove ethanol to obtain a lipid film; adding an olopatadine hydrochloride ethanol solution, and hydrating and then subjecting to high-pressure homogenization to obtain the olopatadine hydrochloride liposomes; the mass ratio of soybean phospholipid, cholesterol, lactoferrin, and ethanol is 3:1:0.5:15; the concentration of the olopatadine hydrochloride ethanol solution is 3 mg / mL; the mass ratio of olopatadine hydrochloride to the lipid film is 3:10; the temperature of hydration is 45°C and the time is 60 min; the pressure of high-pressure homogenization is 1200 bar and the number of cycles of homogenization is 5 times.

[0057] The other excipients are a mixture of glycerol, polysorbate 80, and propylene glycol in a mass ratio of 5:1:1.2.

[0058] A preparation method of the olopatadine hydrochloride-containing oral pharmaceutical composition comprises the following steps: after mixing each raw material evenly by mass percentage, filtering through a 0.35 μm microporous filter membrane to remove impurities and large particles, and then filling into a sterile container and storing it sealed away from light.

[0059] Comparative Example 1. In this example, an olopatadine hydrochloride-containing oral pharmaceutical composition and its preparation method are provided, which are basically the same as those in Example 1, except that an equal amount of olopatadine hydrochloride liposome is used to replace the modified olopatadine hydrochloride nanocrystal.

[0060] Comparative Example 2. In this example, an olopatadine hydrochloride-containing oral pharmaceutical composition and its preparation method are provided, which are basically the same as those in Example 1, except that an equal amount of olopatadine hydrochloride nanocrystal prepared in Example 1 of the authorized invention patent CN118557530B is used to replace the modified olopatadine hydrochloride nanocrystal.

[0061] To further illustrate the beneficial technical effects of the olopatadine hydrochloride-containing oral pharmaceutical compositions involved in the embodiments of the present invention, relevant performance tests are carried out on the olopatadine hydrochloride-containing oral pharmaceutical compositions involved in each example. The test results are shown in Table 1, and the test methods are as follows:

[0062] (1) Bioavailability experiment: Referring to the General Principles of Bioavailability and Bioequivalence 9012 in Part IV of the Chinese Pharmacopoeia 2020 Edition, 70 healthy adult male SD rats are randomly divided into 7 groups, with 10 rats in each group. The olopatadine hydrochloride-containing liquid oral pharmaceutical compositions prepared in Examples 1-5 and Comparative Examples 1-2 are respectively administered, and the dose is 5 mg / kg. Blood is taken from the posterior orbital venous plexus of the rats at 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, and 8 h after administration, and the concentration of olopatadine hydrochloride in plasma is determined by high performance liquid chromatography (HPLC), and the pharmacokinetic parameters (peak time T max , area under the concentration-time curve AUC) are calculated to compare the bioavailability.

[0063] (2) Stability experiment: The products of each example are placed for 30 days under the conditions of temperature 30±2°C, relative humidity 65%±5%, and illuminance 4500±500 LX for investigation. The total impurity content of the samples before and after the test is determined, and the increase rate of the total impurity content is calculated. The increase rate = (total impurity content after 30 days - total impurity content at 0 day) / total impurity content at 0 day. Among them, the determination method of the total impurity content is high performance liquid chromatography (refer to General Principles of High Performance Liquid Chromatography 0512 in Part IV of the Chinese Pharmacopoeia 2015 Edition).

[0064] (3)Taste evaluation experiment: 60 volunteers (aged 18 - 65 years old, with an equal number of males and females) were selected to taste the olopatadine hydrochloride liquid oral preparation compositions prepared in each example. A 5 - point scoring standard was adopted (1 point: extremely poor taste, unacceptable; 2 points: relatively poor taste; 3 points: average taste; 4 points: relatively good taste; 5 points: good taste) for taste scoring, and the average score was calculated.

[0065] (4)Pharmacodynamic experiment: 350 child volunteer subjects suffering from allergic eczema were invited and randomly divided into 7 groups, corresponding to the products of Examples 1 - 5 and Comparative Examples 1 - 2 respectively, with 50 people in each group. The corresponding olopatadine hydrochloride liquid oral preparation compositions were used for a 2 - week efficacy and safety test, taken 2 times a day, 3 mg each time, taken directly. After the test, the volunteer subjects in each group were comprehensively scored from the perspectives of efficacy, safety and compliance. The scoring range was 1 - 10 points, and the higher the score, the better the effect. The average of the scores of each volunteer at each inspection point in each group was taken as the score of this inspection point for this group.

[0066] Table 1

[0067]

[0068] As can be seen from the above table, the olopatadine hydrochloride oral drug compositions involved in each example of the present invention have more excellent bioavailability, stability, taste and pharmacodynamic effects than the products of the comparative examples. The combined use of olopatadine hydrochloride liposomes and modified olopatadine hydrochloride nanocrystals is beneficial to improving the above - mentioned properties.

[0069] The above - mentioned examples are only for explaining the technical concept and characteristics of the present invention, and the purpose is to enable those who are familiar with this technology to understand the content of the present invention and implement it accordingly. It cannot be used to limit the protection scope of the present invention. All equivalent changes or modifications made according to the spirit and essence of the present invention should be covered within the protection scope of the present invention.

Claims

1. An olopatadine hydrochloride oral pharmaceutical composition, characterized in that, It is prepared from the following components by weight percentage: 0.5 - 1.5% of modified olopatadine hydrochloride nanocrystals, 0.05 - 0.1% of xanthan gum, 0.03 - 0.05% of antioxidant, 0.5 - 1.5% of flavoring agent, 0.1 - 0.3% of olopatadine hydrochloride liposomes, 5 - 10% of other excipients, and the balance is purified water.

2. The oral pharmaceutical composition containing olopatadine hydrochloride according to claim 1, characterized in that, The preparation method of the modified olopatadine hydrochloride nanocrystals includes the following steps: adding olopatadine hydrochloride and β-cyclodextrin into an ethanol-water mixture, magnetically stirring at 45 - 55°C for 5 - 7 h; cooling the reaction solution to 4°C, standing for 10 - 13 h, filtering by suction and then freeze-drying to obtain an inclusion complex powder; adding the inclusion complex powder into acetone to obtain an inclusion complex powder dispersion liquid, quickly injecting it into purified water containing 0.5% hydroxypropyl methylcellulose E5, and stirring to form a nano-suspension; homogenizing at 15000 psi for 6 - 8 times to control the particle size at 130 - 180 nm; adding an ethanol solution of Eudragit E100, and stirring at 55 - 65°C for 2 - 4 h to form a pH-sensitive coating layer; after centrifugation, washing with deionized water for 2 - 4 times, and freeze-drying to obtain the modified olopatadine hydrochloride nanocrystals.

3. The oral pharmaceutical composition containing olopatadine hydrochloride according to claim 2, wherein The molar ratio of the olopatadine hydrochloride to β-cyclodextrin is 1:1; the ethanol-water mixture is composed of ethanol and water mixed at a volume ratio of 1:1; the mass ratio of the olopatadine hydrochloride to the ethanol-water mixture is 1:(3 - 5).

4. The oral pharmaceutical composition containing olopatadine hydrochloride according to claim 2, characterized in that, The mass ratio of the inclusion complex powder to acetone is 5 g:100 mL; the volume ratio of the inclusion complex powder dispersion liquid to purified water containing 0.5% hydroxypropyl methylcellulose E5 is 1:

15.

5. The oral pharmaceutical composition containing olopatadine hydrochloride according to claim 2, wherein The mass percentage concentration of the Eudragit E100 ethanol solution is 5 - 10%; the dry weight ratio of the Eudragit E100 to the nano-suspension is (10 - 20):

100.

6. The oral pharmaceutical composition containing olopatadine hydrochloride according to claim 1, wherein The antioxidant is rosemary extract; the flavoring agent is composed of sucralose and honey powder mixed at a mass ratio of 1:(1 - 2).

7. The oral pharmaceutical composition containing olopatadine hydrochloride according to claim 1, characterized in that, The preparation method of the olopatadine hydrochloride liposomes includes the following steps: adding soybean phospholipid, cholesterol, and lactoferrin into ethanol, heating and stirring in a water bath at 50 - 55°C for 1 - 2 h, and rotary evaporating to remove ethanol to obtain a lipid film; adding an olopatadine hydrochloride ethanol solution, and hydrating and then subjecting to high-pressure homogenization to obtain the olopatadine hydrochloride liposomes.

8. The oral pharmaceutical composition containing olopatadine hydrochloride according to claim 7, characterized in that, The mass ratio of the soybean phospholipid, cholesterol, lactoferrin, and ethanol is 3:1:0.5:(10 - 15); the concentration of the olopatadine hydrochloride ethanol solution is 1 - 3 mg / mL; the mass ratio of the olopatadine hydrochloride to the lipid film is (1 - 3):10; the temperature of hydration is 35 - 45°C, and the time is 30 - 60 min; the pressure of the high-pressure homogenization is 800 - 1200 bar, and the number of cycles of homogenization is 3 - 5 times.

9. The oral pharmaceutical composition containing olopatadine hydrochloride according to claim 1, characterized in that, The other excipients are composed of glycerol, polysorbate 80, and propylene glycol mixed at a mass ratio of (3 - 5):1:(0.8 - 1.2).

10. A method for preparing an oral pharmaceutical composition containing olopatadine hydrochloride according to any one of claims 1-9, characterized in that, It includes the following steps: After mixing all raw materials evenly by mass percentage, filter through a 0.35μm microporous filter membrane to remove impurities and larger particles, and then fill them into a sterile container and store them sealed away from light.

Images