An oral pharmaceutical composition containing olopatadine hydrochloride and its preparation method

Abstract

The present invention discloses an oral pharmaceutical composition containing olopatadine hydrochloride and a preparation method thereof, relating to the technical field of pharmaceutical preparations. The composition comprises the following components, calculated by weight: 0.5-1.5% modified olopatadine hydrochloride nanocrystals, 0.05-0.1% xanthan gum, 0.03-0.05% antioxidant, 0.5-1.5% flavoring agent, 0.1-0.3% olopatadine hydrochloride liposomes, 5-10% other excipients, and the balance being purified water. The oral pharmaceutical composition has significant efficacy, low toxic and side effects, good taste, excellent controlled release and stability, and high bioavailability.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular 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 widely used to treat conditions such as allergic rhinitis and urticaria. Compared with first-generation antihistamines, it offers advantages such as fewer central nervous system side effects and a longer duration of action. However, existing oral formulations (such as tablets and capsules) can cause difficulty swallowing (especially in children and the elderly), while commercially available oral liquid preparations generally suffer from poor stability, unpleasant taste (distinct bitterness), and large bioavailability fluctuations.

[0003] Existing methods for preparing oral compositions containing olopatadine hydrochloride often use direct dissolution methods, which fail to consider the impact of the order of excipient addition on drug solubility and stability. This can easily lead to drug precipitation or uneven suspension. Furthermore, sterilization processes (such as high-temperature sterilization) can accelerate drug degradation, while filtration sterilization methods are costly, limiting industrial production.

[0004] To address these issues, Chinese invention patent CN118557530B discloses a pharmaceutical composition for children containing olopatadine hydrochloride and its preparation method. The composition comprises the following components, by weight: 5-10 parts olopatadine hydrochloride nanocrystals, 1-2 parts edible micro-nano active ingredient, 0.1-0.2 parts antioxidant, 3-5 parts sweetener, 0.1-0.3 parts bird's nest peptide, 0.1-0.3 parts dark chocolate powder, and 0.1-0.3 parts brown rice flour. This pharmaceutical composition exhibits significant efficacy, minimal toxicity and side effects, a pleasant taste, excellent compliance and drugability, and a long shelf life. However, its controlled release and stability still require further improvement.

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

[0006] The present invention aims to overcome the deficiencies of the prior art and to provide an oral pharmaceutical composition containing olopatadine hydrochloride having significant efficacy, low toxicity and side effects, good taste, excellent controlled release and stability, and high bioavailability, and a preparation method thereof.

[0007] To achieve the above object, the present invention adopts a technical solution: an oral pharmaceutical composition containing olopatadine hydrochloride, comprising the following components in percentage by weight: 0.5-1.5% modified olopatadine hydrochloride nanocrystals, 0.05-0.1% xanthan gum, 0.03-0.05% antioxidant, 0.5-1.5% flavoring agent, 0.1-0.3% olopatadine hydrochloride liposomes, 5-10% other excipients, and the balance being 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 mixture, magnetically stirring at 45-55° C. for 5-7 hours; cooling the reaction solution to 4° C. and standing for 10-13 hours, filtering and freeze-drying to obtain an inclusion compound powder; adding the inclusion compound powder to acetone to obtain an inclusion compound powder dispersion, rapidly injecting the dispersion into purified water containing 0.5% hydroxypropyl methylcellulose E5, and stirring to form a nanosuspension; homogenizing at 15,000 psi for 6-8 times to control the particle size to 130-180 nm; adding an ethanol solution of Eudragit E100, stirring at 55-65° C. for 2-4 hours 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; and the ethanol-water mixture 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 mixture is 1:(3-5).

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

[0012] Preferably, the volume ratio of the inclusion complex powder dispersion and 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 nanosuspension 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 method for preparing the olopatadine hydrochloride-containing liposomes comprises the following steps: adding soybean lecithin, cholesterol, and lactoferrin to ethanol, heating in a water bath at 50-55° C. with stirring for 1-2 hours, and removing the ethanol by rotary evaporation to obtain a lipid film; adding an olopatadine hydrochloride ethanol solution, hydrating, and then homogenizing under high pressure to obtain the olopatadine hydrochloride-containing liposomes.

[0018] Preferably, the mass ratio of soybean lecithin, 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 olopatadine hydrochloride to lipid film is (1-3):10.

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

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

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

[0024] Another object of the present invention is to provide a method for preparing the oral pharmaceutical composition containing olopatadine hydrochloride, comprising the steps of: uniformly mixing the raw materials according to 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 sealing it to protect from light.

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

[0026] (1) The oral pharmaceutical composition containing olopatadine hydrochloride disclosed in the present invention comprises the following components in percentage by weight: 0.5-1.5% modified olopatadine hydrochloride nanocrystals, 0.05-0.1% xanthan gum, 0.03-0.05% antioxidant, 0.5-1.5% flavoring agent, 0.1-0.3% olopatadine hydrochloride liposomes, 5-10% other excipients, and the balance being purified water. Through the interaction and synergy between the components, the prepared composition product has significant 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 in the present invention comprises modified olopatadine hydrochloride nanocrystals encapsulated by β-cyclodextrin, which can effectively mask the bitter taste of the drug and inhibit oxidative degradation; the inclusion complex is further formed into organic nanocrystals by an 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; the addition of modified olopatadine hydrochloride nanocrystals can increase the solubility and bioavailability of the drug, delay release, and reduce irritation. The oliposomes containing olopatadine hydrochloride increase the concentration of the drug in the target tissue through passive or active targeting, reduce the side effects caused by systemic distribution, and thus improve bioavailability. In addition, the liposome membrane material can also isolate olopatadine hydrochloride from direct contact with gastrointestinal enzymes and acidic / alkaline environments, avoiding drug degradation and ensuring the complete absorption of the active ingredient.

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

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

[0030] The following description is intended to disclose the present invention so that those skilled in the art can implement the present invention. The preferred embodiments described below are merely examples, and those skilled in the art may conceive of other obvious variations.

[0031] Example 1. An oral pharmaceutical composition containing olopatadine hydrochloride, comprising the following components by weight: 0.5% modified olopatadine hydrochloride nanocrystals, 0.05% xanthan gum, 0.03% antioxidant, 0.5% flavoring agent, 0.1% olopatadine hydrochloride liposomes, 5% other excipients, and the balance being purified water.

[0032] The modified olopatadine hydrochloride nanocrystal preparation method comprises the following steps: adding olopatadine hydrochloride and β-cyclodextrin to an ethanol-water mixture, and magnetically stirring at 45°C for 5 hours; cooling the reaction solution to 4°C, standing for 10 hours, filtering, and freeze-drying to obtain an inclusion compound powder; adding the inclusion compound powder to acetone to obtain an inclusion compound powder dispersion, rapidly injecting the dispersion into purified water containing 0.5% hydroxypropyl methylcellulose E5, and stirring to form a nanosuspension; homogenizing at 15,000 psi for 6 times to control the particle size to 130 nm; adding an ethanol solution of Eudragit E100, and stirring at 55°C for 2 hours 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; and the ethanol-water mixture is a mixture of ethanol and water in a volume ratio of 1:1.

[0033] The mass ratio of olopatadine hydrochloride to the ethanol-water mixture is 1:3; the molar ratio of the inclusion compound powder to acetone is 5 g:100 mL; the volume ratio of the inclusion compound powder dispersion to 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 nanosuspension is 10:100; the antioxidant is rosemary extract; and the flavoring agent is a mixture of sucralose and honey powder in a mass ratio of 1:1.

[0034] The preparation method of olopatadine hydrochloride-containing liposomes comprises the following steps: adding soybean lecithin, cholesterol, and lactoferrin to ethanol, heating in a water bath at 50° C. with stirring for 1 hour, and removing the ethanol by rotary evaporation to obtain a lipid film; adding an olopatadine hydrochloride ethanol solution, hydrating, and then subjecting to high-pressure homogenization to obtain olopatadine hydrochloride-containing liposomes; the mass ratio of the soybean lecithin, cholesterol, lactoferrin, and ethanol is 3:1:0.5:10; the concentration of the olopatadine hydrochloride ethanol solution is 1 mg / mL; the mass ratio of the olopatadine hydrochloride to the lipid film is 1:10; the hydration temperature is 35° C., and the time is 30 minutes; the high-pressure homogenization pressure is 800 bar, and the number of homogenization cycles is 3; and the other excipients are glycerol, polysorbate 80, and propylene glycol mixed in a mass ratio of 3:1:0.8.

[0035] A method for preparing the oral pharmaceutical composition containing olopatadine hydrochloride comprises the following steps: uniformly mixing the raw materials according to 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 sealing it to avoid light.

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

[0037] The preparation method of the modified olopatadine hydrochloride nanocrystals comprises the following steps: adding olopatadine hydrochloride and β-cyclodextrin to an ethanol-water mixture, and magnetically stirring at 47°C for 5.5 hours; cooling the reaction solution to 4°C and standing for 11 hours, filtering and freeze-drying to obtain inclusion compound powder; adding the inclusion compound powder to acetone to obtain an inclusion compound powder dispersion, and rapidly injecting the dispersion into purified water containing 0.5% hydroxypropyl methylcellulose E5, and stirring to form a nanosuspension; homogenizing at 15,000 psi for 7 times to control the particle size to 140 nm; and adding Eudragit The invention relates to an ethanol solution of Eudragit E100, stirred at 57° C. for 2.5 hours to form a pH-sensitive coating layer; after centrifugation, the mixture is washed three times with deionized water and freeze-dried to obtain modified olopatadine hydrochloride nanocrystals; the molar ratio of olopatadine hydrochloride to β-cyclodextrin is 1:1; the ethanol-water mixture is a mixture of ethanol and water in a volume ratio of 1:1; the mass ratio of olopatadine hydrochloride to the ethanol-water mixture is 1:3.5; the molar ratio of the inclusion complex powder to acetone is 5 g:100 mL; the volume ratio of the inclusion complex powder dispersion to purified water containing 0.5% hydroxypropyl methylcellulose E5 is 1:15; the mass percentage concentration of the Eudragit E100 ethanol solution is 6%; and the dry weight ratio of Eudragit E100 to the nanosuspension 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-containing liposomes comprises the following steps: adding soybean lecithin, cholesterol, and lactoferrin to ethanol, heating in a water bath at 52° C. with stirring for 1.2 hours, and removing the ethanol by rotary evaporation to obtain a lipid film; adding an olopatadine hydrochloride ethanol solution, hydrating, and then subjecting to high-pressure homogenization to obtain the olopatadine hydrochloride-containing liposomes; the mass ratio of the soybean lecithin, 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 the olopatadine hydrochloride to the lipid film is 1.5:10; the hydration temperature is 38° C. and the time is 40 minutes; the high-pressure homogenization pressure is 900 bar, and the number of homogenization cycles is 4; and the other excipients are glycerol, polysorbate 80, and propylene glycol mixed in a mass ratio of 3.5:1:0.9.

[0040] A method for preparing the oral pharmaceutical composition containing olopatadine hydrochloride comprises the following steps: uniformly mixing the raw materials according to 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 sealing it to avoid light.

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

[0042] The preparation method of the modified olopatadine hydrochloride nanocrystals comprises the following steps: adding olopatadine hydrochloride and β-cyclodextrin to an ethanol-water mixture, and magnetically stirring at 50°C for 6 hours; cooling the reaction solution to 4°C and standing for 11.5 hours, filtering, and freeze-drying to obtain an inclusion compound powder; adding the inclusion compound powder to acetone to obtain an inclusion compound powder dispersion, and rapidly injecting the dispersion into purified water containing 0.5% hydroxypropyl methylcellulose E5, and stirring to form a nanosuspension; homogenizing at 15,000 psi for 7 times to control the particle size to 150 nm; and adding Eudragit The invention relates to an ethanol solution of Eudragit E100, stirred at 60° C. for 3 hours to form a pH-sensitive coating layer; after centrifugation, the mixture is washed three times with deionized water and freeze-dried to obtain modified olopatadine hydrochloride nanocrystals; the molar ratio of olopatadine hydrochloride to β-cyclodextrin is 1:1; the ethanol-water mixture is a mixture of ethanol and water in a volume ratio of 1:1; the mass ratio of olopatadine hydrochloride to the ethanol-water mixture is 1:4; the molar ratio of the inclusion complex powder to acetone is 5 g:100 mL; the volume ratio of the inclusion complex powder dispersion 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%; and the dry weight ratio of Eudragit E100 to the nanosuspension 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-containing liposomes comprises the following steps: adding soybean lecithin, cholesterol, and lactoferrin to ethanol, heating in a water bath at 53° C. with stirring for 1.5 hours, and removing the ethanol by rotary evaporation to obtain a lipid film; adding an olopatadine hydrochloride ethanol solution, hydrating, and then subjecting to high-pressure homogenization to obtain the olopatadine hydrochloride-containing liposomes; the mass ratio of the soybean lecithin, 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., the time is 45 minutes, the high-pressure homogenization pressure is 1000 bar, and the number of homogenization cycles is 4.

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

[0046] A method for preparing the oral pharmaceutical composition containing olopatadine hydrochloride comprises the following steps: uniformly mixing the raw materials according to 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 sealing it to avoid light.

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

[0048] The preparation method of the modified olopatadine hydrochloride nanocrystals comprises the following steps: adding olopatadine hydrochloride and β-cyclodextrin to an ethanol-water mixture, and magnetically stirring at 53° C. for 6.5 hours; cooling the reaction solution to 4° C. and standing for 12.5 hours, filtering and freeze-drying to obtain inclusion compound powder; adding the inclusion compound powder to acetone to obtain an inclusion compound powder dispersion, and rapidly injecting the dispersion into purified water containing 0.5% hydroxypropyl methylcellulose E5, and stirring to form a nanosuspension; homogenizing at 15,000 psi for 8 times to control the particle size to 170 nm; and adding Eudragit The invention relates to an ethanol solution of Eudragit E100, stirred at 63° C. for 3.5 hours to form a pH-sensitive coating layer; after centrifugation, the mixture is washed four times with deionized water and freeze-dried to obtain modified olopatadine hydrochloride nanocrystals; the molar ratio of olopatadine hydrochloride to β-cyclodextrin is 1:1; the ethanol-water mixture is a mixture of ethanol and water in a volume ratio of 1:1; the mass ratio of olopatadine hydrochloride to the ethanol-water mixture is 1:4.5; the molar ratio of the inclusion compound powder to acetone is 5 g:100 mL; the volume ratio of the inclusion compound powder dispersion to purified water containing 0.5% hydroxypropyl methylcellulose E5 is 1:15; the mass percentage concentration of the Eudragit E100 ethanol solution is 9%; and the dry weight ratio of Eudragit E100 to the nanosuspension is 18:100.

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

[0050] The preparation method of the olopatadine hydrochloride-containing liposomes comprises the following steps: adding soybean lecithin, cholesterol, and lactoferrin to ethanol, heating in a water bath at 54° C. with stirring for 1.8 hours, and removing the ethanol by rotary evaporation to obtain a lipid film; adding an olopatadine hydrochloride ethanol solution, hydrating, and then subjecting the mixture to high-pressure homogenization to obtain the olopatadine hydrochloride-containing liposomes; the mass ratio of the soybean lecithin, cholesterol, lactoferrin, and ethanol is 3:1:0.5:14; the concentration of the olopatadine hydrochloride ethanol solution is 2.5 mg / mL; the mass ratio of the olopatadine hydrochloride to the lipid film is 2.5:10; the hydration temperature is 43° C., the time is 55 minutes, the high-pressure homogenization pressure is 1100 bar, and the number of homogenization cycles is 5.

[0051] The other auxiliary materials are glycerol, polysorbate 80, and propylene glycol mixed in a mass ratio of 4.5:1:1.1.

[0052] A method for preparing the oral pharmaceutical composition containing olopatadine hydrochloride comprises the following steps: uniformly mixing the raw materials according to 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 sealing it to avoid light.

[0053] Example 5, an oral pharmaceutical composition containing olopatadine hydrochloride, comprising the following components by weight: 1.5% modified olopatadine hydrochloride nanocrystals, 0.1% xanthan gum, 0.05% antioxidant, 1.5% flavoring agent, 0.3% olopatadine hydrochloride liposomes, 10% other excipients, 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 to an ethanol-water mixture, and magnetically stirring at 55°C for 7 hours; cooling the reaction solution to 4°C and standing for 13 hours, filtering and freeze-drying to obtain an inclusion compound powder; adding the inclusion compound powder to acetone to obtain an inclusion compound powder dispersion, and rapidly injecting the dispersion into purified water containing 0.5% hydroxypropyl methylcellulose E5, and stirring to form a nanosuspension; homogenizing at 15,000 psi for 8 times to control the particle size to 180 nm; and adding Eudragit The invention relates to an ethanol solution of Eudragit E100, stirred at 65° C. for 4 hours to form a pH-sensitive coating layer; after centrifugation, the mixture is washed four times with deionized water and freeze-dried to obtain modified olopatadine hydrochloride nanocrystals; the molar ratio of olopatadine hydrochloride to β-cyclodextrin is 1:1; the ethanol-water mixture is a mixture of ethanol and water in a volume ratio of 1:1; the mass ratio of olopatadine hydrochloride to the ethanol-water mixture is 1:5; the molar ratio of the inclusion complex powder to acetone is 5 g:100 mL; the volume ratio of the inclusion complex powder dispersion to purified water containing 0.5% hydroxypropyl methylcellulose E5 is 1:15; the mass percentage concentration of the Eudragit E100 ethanol solution is 10%; and the dry weight ratio of Eudragit E100 to the nanosuspension 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-containing liposomes comprises the following steps: adding soybean lecithin, cholesterol, and lactoferrin to ethanol, heating in a water bath at 55° C. with stirring for 2 hours, and removing the ethanol by rotary evaporation to obtain a lipid film; adding an olopatadine hydrochloride ethanol solution, hydrating, and then subjecting the mixture to high-pressure homogenization to obtain the olopatadine hydrochloride-containing liposomes; the mass ratio of the soybean lecithin, 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 the olopatadine hydrochloride to the lipid film is 3:10; the hydration temperature is 45° C., the time is 60 minutes, the high-pressure homogenization pressure is 1200 bar, and the number of homogenization cycles is 5.

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

[0058] A method for preparing the oral pharmaceutical composition containing olopatadine hydrochloride comprises the following steps: uniformly mixing the raw materials according to 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 sealing it to avoid light.

[0059] Comparative Example 1 provides an oral pharmaceutical composition containing olopatadine hydrochloride and a preparation method thereof, which is basically the same as Example 1, except that an equal amount of olopatadine hydrochloride liposomes is used instead of the modified olopatadine hydrochloride nanocrystals.

[0060] Comparative Example 2 provides an oral pharmaceutical composition containing olopatadine hydrochloride and a preparation method thereof, which is substantially the same as Example 1, except that an equal amount of olopatadine hydrochloride nanocrystals prepared in Example 1 of the authorized invention patent CN118557530B is used instead of the modified olopatadine hydrochloride nanocrystals.

[0061] In order to further illustrate the beneficial technical effects of the oral pharmaceutical compositions containing olopatadine hydrochloride involved in each embodiment of the present invention, relevant performance tests were conducted on the oral pharmaceutical compositions containing olopatadine hydrochloride involved in each example. The test results are shown in Table 1. The test methods are as follows:

[0062] (1) Bioavailability experiment: Referring to the bioavailability and bioequivalence guidelines of Part IV of the 2020 edition of the Chinese Pharmacopoeia, 70 healthy adult male SD rats were selected and randomly divided into 7 groups, with 10 rats in each group. The oral liquid pharmaceutical compositions containing olopatadine hydrochloride prepared in Examples 1-5 and Comparative Examples 1-2 were administered, respectively, at a dose of 5 mg / kg. Blood was collected from the retroorbital 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 the plasma was determined by high performance liquid chromatography (HPLC), and the pharmacokinetic parameters (peak time T max , area under the concentration-time curve (AUC), was used to compare bioavailability.

[0063] (2) Stability test: Each product was placed under the conditions of a temperature of 30±2°C, a relative humidity of 65%±5%, and an illumination of 4500±500LX for 30 days. The total impurity content of the samples before and after the test was measured, and the rate of increase of the total impurity content was calculated. The rate of increase = (total impurity content after 30 days - total impurity content on day 0) / total impurity content on day 0. The total impurity content was determined by high performance liquid chromatography (referring to the high performance liquid chromatography method in the General Chapter 0512 of the Fourth Part of the 2015 edition of the Chinese Pharmacopoeia).

[0064] (3) Taste evaluation experiment: 60 volunteers (aged 18-65 years, half male and half female) were selected to taste the olopatadine hydrochloride liquid oral preparation composition prepared in each example. The taste was scored using a 5-point scoring system (1 point: extremely bad taste, difficult to accept; 2 points: poor taste; 3 points: average taste; 4 points: good taste; 5 points: good taste) and the average score was calculated.

[0065] (4) Pharmacodynamics test: 350 children with atopic eczema were randomly divided into 7 groups, each group consisting of 50 volunteers, each group receiving the corresponding olopatadine hydrochloride liquid oral preparation composition for a 2-week efficacy and safety test. The patients were taken 2 times a day, 3 mg each time, directly. After the test, each group of volunteers was given a comprehensive score based on efficacy, safety, and compliance. The score range was 1-10, with the higher the score, the better the effect. The average score of each test point of each group of volunteers was taken as the score of that test point of the group.

[0066] Table 1

[0067]

[0068] As can be seen from the above table, the oral pharmaceutical compositions containing olopatadine hydrochloride according to the embodiments of the present invention have better bioavailability, stability, taste, and efficacy than the comparative example products. The combined use of olopatadine hydrochloride liposomes and modified olopatadine hydrochloride nanocrystals is beneficial for improving the above-mentioned properties.

[0069] The above embodiments are only for illustrating the technical concept and features of the present invention. Their purpose is to enable people familiar with this technology to understand the content of the present invention and implement it accordingly. They are not intended to limit the scope of protection of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the scope of protection of the present invention.

Claims

1. An oral pharmaceutical composition containing olopatadine hydrochloride, characterized in that: The invention comprises 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 antioxidant, 0.5-1.5% of flavoring agent, 0.1-0.3% of olopatadine hydrochloride liposomes, 5-10% of other excipients, and the balance of purified water; The preparation method of the modified olopatadine hydrochloride nanocrystals comprises the following steps: adding olopatadine hydrochloride and β-cyclodextrin to an ethanol-water mixture, magnetically stirring at 45-55° C. for 5-7 hours; cooling the reaction solution to 4° C. and standing for 10-13 hours, filtering and freeze-drying to obtain an inclusion compound powder; adding the inclusion compound powder to acetone to obtain an inclusion compound powder dispersion, rapidly injecting the dispersion into purified water containing 0.5% hydroxypropyl methylcellulose E5, and stirring to form a nanosuspension; homogenizing at 15,000 psi for 6-8 times to control the particle size to 130-180 nm; adding an ethanol solution of Eudragit E100, stirring at 55-65° C. for 2-4 hours 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. The preparation method of the olopatadine hydrochloride-containing liposomes comprises the following steps: adding soybean lecithin, cholesterol, and lactoferrin to ethanol, heating in a water bath at 50-55° C. with stirring for 1-2 hours, and removing the ethanol by rotary evaporation to obtain a lipid film; adding an olopatadine hydrochloride ethanol solution, hydrating, and then homogenizing under high pressure to obtain the olopatadine hydrochloride-containing liposomes; the mass ratio of the soybean lecithin, cholesterol, lactoferrin, and ethanol is 3:1:0.5:(10-15); and the mass ratio of the olopatadine hydrochloride to the lipid film is (1-3):

10.

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

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

15.

4. The oral pharmaceutical composition containing olopatadine hydrochloride according to claim 1, characterized in that: The mass percentage concentration of the Eudragit E100 ethanol solution is 5-10%; the dry weight ratio of the Eudragit E100 and the nanosuspension is (10-20):

100.

5. The oral pharmaceutical composition containing olopatadine hydrochloride according to claim 1, characterized in that: The antioxidant is rosemary extract; the flavoring agent is a mixture of sucralose and honey powder in a mass ratio of 1:(1-2).

6. The oral pharmaceutical composition containing olopatadine hydrochloride according to claim 1, characterized in that: The concentration of the olopatadine hydrochloride ethanol solution is 1-3 mg / mL; the hydration temperature 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 homogenization cycles is 3-5 times.

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

8. A method for preparing the oral pharmaceutical composition containing olopatadine hydrochloride according to any one of claims 1 to 7, characterized in that: The method comprises the following steps: uniformly mixing the raw materials according to mass percentage, filtering through a 0.35 μm microporous filter membrane to remove impurities and larger particles, and then filling the mixture into a sterile container and sealing the container to protect it from light.

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