A buccal nano preparation and its preparation method and application

Abstract

The present invention relates to a buccal tablet nanoformulation and its preparation method and application. The buccal tablet nanoformulation comprises: a porous manganese-substituted Prussian blue analogue loaded with anti-inflammatory active ingredients and a tablet; the chemical formula of the porous manganese-substituted Prussian blue analogue is K 4‑2x Mn x (Fe(CN)6), where 1≤x≤2.

Description

Technical Field

[0001] The invention relates to a buccal tablet nano preparation and a preparation method and application thereof, belonging to the technical field of biomaterials. Background Art

[0002] Oral mucositis is a common, highly symptomatic complication of cancer treatment, affecting patients' oral function, quality of life, and ability to tolerate treatment. Severe oral mucositis can cause extreme pain and prevent patients from taking oral medication, thereby interfering with their ability to tolerate optimal treatment options, increasing the risk of local and systemic infections, and significantly increasing medical resources. In some cancer patients, oral mucositis is associated with increased mortality. The principles of oral care for cancer patients should be followed: preventing infection, controlling pain, maintaining oral function, improving quality of life, and managing accompanying oral complications.

[0003] Currently, oral mucositis medications primarily utilize antibacterial, anti-inflammatory, and analgesic mechanisms of action, gradually promoting ulcer healing. Marketed oral mucositis treatments primarily include: 1. Powders, such as Xigua Shuang and Bingpeng Powder; 2. Patches containing dexamethasone or cortisone; 3. Mouthwashes containing chlorhexidine; and 4. Polymer gel preparations. These medications suffer from limitations such as ineffective healing, the addition of hormones that compromise efficacy, the need for frequent dosing, a short oral retention time, slow drug release, or poor metabolism of the released drug.

[0004] Salivary amylase is a hydrolase secreted by the salivary glands. It belongs to the α-amylase family and can hydrolyze α-1,4-glucosidic bonds. α-Amylase can degrade natural polysaccharide carriers such as hydroxyethyl starch, dextrin, and dextran, making it suitable as an endogenous stimulus for enzyme-responsive nanoparticles. Therefore, the preparation of highly active oral mucosal materials with biomimetic structures, components, and functions is an ideal choice for constructing anti-inflammatory and analgesic materials that promote ulcer healing and maintain oral function. Summary of the Invention

[0005] In order to solve the above problems, the present invention provides a type of buccal nanoformulation for treating cancer treatment-related oral mucositis, as well as a preparation method and application thereof.

[0006] In one aspect, the present invention provides a buccal nanometer preparation, comprising: a porous manganese-substituted Prussian blue analogue loaded with an anti-inflammatory active ingredient and a tablet; the chemical formula of the porous manganese-substituted Prussian blue analogue is K 4-2x Mn x (Fe(CN)6), where 1≤x≤2.

[0007] Preferably, the porous manganese-substituted Prussian blue analogue has a particle size of 0.2 to 0.5 μm, a pore size of 13 to 18 nm, and a specific surface area of ​​8 to 25 m 2 / g.

[0008] Preferably, the anti-inflammatory active ingredient is a phosphodiesterase-4 (PDE-4) inhibitor, preferably apremilast; and the mass ratio of the anti-inflammatory active ingredient to the porous manganese-substituted Prussian blue analog is (0.03-0.30):1. This allows for optimal apremilast loading, facilitating subsequent drug release.

[0009] Preferably, the tablet is selected from at least one of dextrin, wheat starch, lactose, compressible starch (i.e., pregelatinized starch) and sucrose, preferably a mixture of wheat starch and dextrin; more preferably, the mass ratio of wheat starch to dextrin in the mixture of wheat starch and dextrin is 10:(5-1), preferably 10:3;

[0010] The content of the tablet in the buccal nano preparation is 50-60 wt %, preferably 55-57 wt %.

[0011] In the present invention, a nanoformulation represented by a porous manganese-substituted Prussian blue analogue can be used as a carrier to load clinically used anti-inflammatory agents (such as apremilast, an inhibitor of phosphodiesterase-4 (PDE-4)). The nanomaterial also has certain anti-oxidative stress properties. Preferably, a wheat starch-dextrin mixture is used as a tablet to release the drug in response to α-amylase degradation. Studies have shown that the buccal tablet preparation has good drug release properties and can meet the needs of rapid treatment of oral mucositis. Among them, wheat starch is used as a filler and is preferably mixed with dextrin with good compressibility and adhesion. The mass ratio of wheat starch to dextrin is 10: (5-1), preferably 10:3. This buccal tablet has simple ingredients and is safe. The buccal tablet prepared has good compressibility, excellent disintegration performance, and high bioavailability.

[0012] In another aspect, the present invention provides a method for preparing a buccal nanoformulation, comprising:

[0013] (1) stirring, centrifuging, and washing a porous manganese-substituted Prussian blue analog, an anti-inflammatory active ingredient, and a solvent to obtain a porous manganese-substituted Prussian blue analog loaded with the anti-inflammatory active ingredient;

[0014] (2) The porous manganese-substituted Prussian blue analogue loaded with anti-inflammatory active ingredients is mixed with ultrapure water to obtain a stock solution, and then the solution is stirred and mixed to form tablets, and finally tablets are pressed to obtain the buccal nano preparation.

[0015] Among them, thanks to the rich porosity and large pore size of PMPB NC, it is easy to encapsulate apremilast on PMPB NC; at the same time, apremilast is also bound to the surface of PMPB NC through electrostatic adsorption.

[0016] Preferably, the mass ratio of the anti-inflammatory active ingredient to the porous manganese-substituted Prussian blue analog is (0.1-1.0):1; the solvent is at least one of dimethyl sulfoxide, anhydrous ethanol, N,N-dimethylformamide (DMF), ultrapure water, and phosphate buffer. In this patent, the apremilast raw material is a white to off-white crystalline powder with a melting point of 153.0°C-156.0°C. It is almost non-hygroscopic and readily soluble in acetonitrile, N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO). It is very slightly soluble in methanol and almost insoluble in water, ethanol, isopropanol, and methyl tert-butyl ether, making it a typical poorly soluble drug. In terms of the loading method of apremilast, DMSO, anhydrous ethanol, N,N-dimethylformamide (DMF), ultrapure water and phosphate buffer were used as dispersing solvents to improve the solubility of apremilast (compared with ultrapure water). At the same time, the loading rate of apremilast in Apr@PMPB NC obtained with the same ratio of raw materials (apremilast and porous manganese-substituted Prussian blue analogues) was also increased.

[0017] Preferably, the concentration of the stock solution is 0.02-0.10 mg / μL; the ratio of the stock solution to the tablet is (8-12) μL: (13-15) mg; and the tableting pressure is 100-200 MPa.

[0018] Preferably, the preparation method of the porous manganese-substituted Prussian blue analogue comprises:

[0019] 1) under stirring, adding a mixed solution B containing bovine serum albumin and M4[Fe(CN)6] dropwise to a mixed solution A containing bovine serum albumin and a manganese source to obtain a mixed solution C;

[0020] 2) The mixed solution C is centrifuged and washed to obtain a porous manganese-substituted Prussian blue analogue.

[0021] Among them, bovine serum albumin (BSA) is mainly used as a 2+ and [Fe(CN)6] 4- It is a chelating agent for ions, promoting the co-precipitation of Mn and Fe to form PMPB NC, and can also serve as a porogen.

[0022] Furthermore, preferably, the stirring is magnetic stirring, the rotation speed of the magnetic stirring is 800-1000 rpm, the temperature is 55-65° C., and the time is 30-60 minutes.

[0023] In another aspect, the present invention provides a use of a buccal nanoformulation in the preparation of a medicament for treating chemotherapy-related oral mucositis.

[0024] Beneficial effects:

[0025] (1) The oral mucositis buccal tablet prepared by the present invention has good wet adhesion and can control the release of drugs. The buccal tablet responds to amylase degradation in the oral environment and quickly releases drugs, thereby achieving the purpose of treating oral ulcers;

[0026] (2) The present invention also discloses a use of the oral mucositis buccal tablet in the preparation of a medicament for treating chemotherapy-related oral mucositis. The prepared oral mucositis buccal tablet will have good clinical transformation application prospects as a biomedical material. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 Schematic diagram of transmission electron microscopy of PMPB NC, the product synthesized in Example 1;

[0028] Figure 2 The UV-visible absorption spectra of the synthesized product Apr@PMPB NC, apremilast, and PMPB NC in Example 2 are shown;

[0029] Figure 3 This is a diagram showing the wet adhesion effect of the buccal tablet nanoformulation with the active ingredient Apr@PMPB NC prepared in Example 3;

[0030] Figure 4 Schematic diagram of the cumulative drug release of apremilast and nanocarrier PMPBNC over time in PBS with or without α-amylase from the drug-loaded buccal tablet in Example 3. DETAILED DESCRIPTION

[0031] The present invention is further described below through the following embodiments. It should be understood that the following embodiments are only used to illustrate the present invention, rather than to limit the present invention.

[0032] The present disclosure aims to prepare a buccal tablet for oral mucositis with high biocompatibility, fast drug release and onset, and good anti-inflammatory and pro-repair capabilities. Specifically, a wheat starch-dextrin mixture can be used as a tablet, porous manganese can be introduced to replace Prussian blue analogs as a nanocarrier, and the anti-inflammatory active ingredient is apremilast, an inhibitor of phosphodiesterase-4 (PDE-4). Studies have shown that the buccal tablet nanoformulation has high biosafety, excellent drug release performance, good immunomodulatory ability, and the ability to promote cell migration and repair, and has broad application prospects in the field of oral biomedicine technology.

[0033] The following is an exemplary description of a method for preparing a buccal nanoformulation for treating cancer-related oral mucositis.

[0034] A manganese source and bovine serum albumin (BSA) are dissolved in ultrapure water, and the system is mixed evenly and placed in a magnetic stirring oil bath to obtain a mixed solution A (hereinafter referred to as solution A). Wherein, the manganese source is selected from at least one of manganese chloride, manganese carbonate, manganese nitrate, and manganese dihydrogen phosphate. Preferably, the parameter setting package of the magnetic stirring oil bath is: temperature of 55 to 65 ° C, time of 30 to 60 minutes, and speed of 800 to 1000 rpm. As an example, 6.25 mg MnCl2 and 50 mg bovine serum albumin (BSA) are dissolved in 10 mL of ultrapure water, and the system is mixed evenly and placed in a magnetic stirring oil bath, and stirred at a constant temperature of 60 ° C and 800 rpm for 30 minutes to obtain solution A.

[0035] K4[Fe(CN)6] and bovine serum albumin (BSA) are dissolved in ultrapure water, mixed thoroughly, and placed in a magnetic stirring oil bath to obtain a mixed solution B (hereinafter referred to as solution B). Preferably, the parameters of the magnetic stirring oil bath are set as follows: temperature of 55-65°C, time of 30-60 minutes, and speed of 800-1000 rpm. As an example, 16.88 mg of K4[Fe(CN)6] and 50 mg of bovine serum albumin (BSA) are dissolved in 10 mL of ultrapure water, mixed thoroughly, and placed in a magnetic stirring oil bath. Stirring is constant at 60°C and 800 rpm for 30 minutes to obtain solution B.

[0036] While maintaining solution A in a stirring state, solution B is added dropwise to solution A, and stirring is continued at a constant temperature in a magnetic stirring oil bath. The reaction is completed to obtain a mixed solution C (hereinafter referred to as solution C). Preferably, the parameters of the magnetic stirring oil bath are set to include: a temperature of 55-65° C., a stirring time of 30-60 minutes, and a rotation speed of 800-1000 rpm (for example, stirring at a constant temperature of 60° C. and 800 rpm for 60 minutes).

[0037] Solution C is taken out and placed at room temperature for cooling for 12 to 24 hours (e.g., 24 hours) for aging treatment, the purpose of which is to perform biomineralization, using protein as a stabilizer and structure-directing agent, and finally preparing a porous manganese-substituted nano-Prussian blue analogue.

[0038] Solution C is centrifuged and washed to obtain a nanocarrier porous manganese-substituted Prussian blue analogue PMPB NC. The centrifugation speed is 10,000 to 11,000 rpm for 10 to 15 minutes. The number of washes is at least two. As an example, Solution C is centrifuged at 10,000 rpm for 15 minutes, and the precipitate is collected. The precipitate is redispersed in deionized water, washed, and centrifuged three times to obtain a product, namely, a nanocarrier porous manganese-substituted Prussian blue analogue PMPBNC. The product is stored at 4°C until use.

[0039] A porous manganese-substituted Prussian blue analog, an anti-inflammatory active ingredient, and a solvent were stirred, centrifuged, and washed to obtain a porous manganese-substituted Prussian blue analog loaded with an anti-inflammatory active ingredient. As an example, 10 mg of PMPB NC and 5 mg of apremilast were redispersed in 10 mL of dimethyl sulfoxide (DMSO) and stirred at room temperature for 24 hours to obtain solution D. The solution was centrifuged at 10,000 rpm for 15 minutes, and the precipitate was collected. The precipitate was redispersed in deionized water, washed, and centrifuged three times to obtain the product, apremilast-loaded PMPB NC, designated Apr@PMPB NC. The product was stored at 4°C until use.

[0040] Apr@PMPB NC was prepared into a stock solution with a concentration of 20 to 100 mg / mL (eg, 50 mg / mL) using ultrapure water for later use.

[0041] The stock solution and tablets were mixed and then compressed to form a buccal nanoformulation. As an example, 13 mg of tablets (wheat starch:dextrin = 10:3) were weighed, 10 μL of 50 mg / mL Apr@PMPB NC stock solution was added dropwise to the tablets, stirred to bind them, and then compressed in a tablet press to form a buccal nanoformulation containing Apr@PMPB NC as the active ingredient.

[0042] The following examples are further given to illustrate the present invention in detail. It should also be understood that the following examples are only used to further illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above content of the present invention all fall within the scope of protection of the present invention. The specific process parameters and the like in the following examples are only examples within a suitable range, that is, those skilled in the art can make selections within a suitable range through the description herein, and are not limited to the specific numerical values ​​exemplified below.

[0043] Example 1

[0044] In this embodiment 1, a method for synthesizing the nanocarrier PMPB NC is provided, and the synthesis steps are as follows:

[0045] 6.25 mg of MnCl₂ and 50 mg of bovine serum albumin (BSA) were dissolved in 10 mL of ultrapure water. The mixture was then placed in a magnetically stirred oil bath and stirred at 60°C for 30 minutes to obtain Solution A. Separately, 16.88 mg of K₄[Fe(CN)₆] and 50 mg of bovine serum albumin (BSA) were dissolved in 10 mL of ultrapure water. The mixture was then placed in a magnetically stirred oil bath and stirred at 60°C for 30 minutes to obtain Solution B. While Solution A was stirring, Solution B was added dropwise to Solution A. The mixture was stirred at 60°C in the magnetically stirred oil bath for 60 minutes. The reaction was completed to obtain Solution C. Solution C was removed and allowed to cool at room temperature for 24 hours to age. Solution C was centrifuged at 10,000 rpm for 15 minutes, and the precipitate was collected. The precipitate was redispersed in deionized water, washed, and centrifuged three times to obtain the product, the nanocarrier porous manganese-substituted Prussian blue analogue PMPBNC.

[0046] Figure 1 The transmission electron microscopy diagram of the PMPB NC synthesized in Example 1 is a spherical nanoparticle with a particle size of about 200 nm, indicating the successful preparation of the nanocarrier with a pore size of 13-18 nm and a specific surface area of ​​8-25 m 2 / g.

[0047] Example 2

[0048] In this Example 2, a method for synthesizing the buccal tablet component Apr@PMPB NC is provided, and the synthesis steps are as follows:

[0049] 10 mg of PMPB NC and 5 mg of apremilast were dispersed in 10 mL of dimethyl sulfoxide (DMSO) and stirred at room temperature for 24 h to obtain solution D. The solution was centrifuged at 10,000 r / min for 15 min, and the precipitate was collected. The precipitate was redispersed in deionized water, washed, and centrifuged three times to obtain the product, Apr@PMPB NC.

[0050] Figure 2 Figure 3 shows the UV-visible absorption spectra of the synthesized product Apr@PMPB NC, apremilast, and PMPB NC. The absorption spectrum of Apr@PMPB NC shows apremilast's characteristic absorption peak, indicating successful loading of apremilast onto PMPB NC. The mass ratio of apremilast, the anti-inflammatory active ingredient, to the porous manganese-substituted Prussian blue analog in the resulting Apr@PMPB NC is 0.226:1.

[0051] Example 3

[0052] In this embodiment 3, a method for synthesizing a buccal tablet is provided, and the synthesis steps are as follows:

[0053] Apr@PMPB NC was prepared into a 50 mg / mL stock solution using ultrapure water. A tablet formulation (wheat starch:dextrin = 10:3) was weighed out (13 mg). 10 μL of the 50 mg / mL Apr@PMPB NC stock solution was added dropwise to the dextrin and stirred to form a buccal nanoformulation containing Apr@PMPB NC as the active ingredient. The tablet formulation contained 55% of the active ingredient.

[0054] Figure 3 This is a diagram showing the wet adhesion effect of the prepared buccal tablet nanoformulation with the active ingredient Apr@PMPB NC. The buccal tablet can adhere to a single inorganic interface and different inorganic interfaces, and also has good adhesion to mouse kidney tissue, indicating its strong adhesion and can achieve adhesion in the wet environment of the oral cavity.

[0055] Example 4

[0056] In this Example 4, a method for an in vitro drug release experiment of the drug-loaded buccal tablet prepared in Example 3 is provided. The testing method is as follows: 15 portions of the buccal tablet nanoformulation prepared in Example 3, wherein the active ingredient is Apr@PMPB NC, are placed in a dialysis bag. 6 mL of a PBS solution containing α-amylase is added to the dialysis bag. The dialysis bag is clamped and immersed in 30 mL of a PBS solution containing α-amylase. The bag is then placed on a shaker at 37° C. and shaken. At fixed time points (0 min, 30 min, 1 h, 2 h, 3 h, 4 h, 7 h, 10 h, and 24 h), 1 mL of the PBS solution outside the dialysis bag is removed and immediately supplemented with 1 mL of the same PBS solution. The absorbance of the removed PBS solution is measured by UV-Vis in the range of 200-800 nm. The absorbance at 232 nm is calculated, and the actual concentration of the release is calculated according to the standard release curve to obtain a schematic curve of the cumulative apremilast release amount-time in response to α-amylase. The same method was applied to the example in which 6 mL of ordinary PBS solution was added to the dialysis bag to obtain a schematic curve of the cumulative release amount of Apremilast in PBS versus time.

[0057] In vitro nanocarrier PMPB NC release experiment:

[0058] Thirty portions of the buccal nanoformulation prepared in Example 3, containing Apr@PMPB NC as the active ingredient, were placed in a dialysis apparatus (the apparatus allows the passage of particles with a diameter of ∼800 nm). 1.5 mL of a PBS solution containing α-amylase was added to the dialysis apparatus. The dialysis apparatus was then placed in 150 mL of a PBS solution containing α-amylase. The Mn concentration in the sample solution was determined by ICP analysis at various time points (0 h, 0.5 h, 1 h, 4 h, 8 h, 12 h, and 24 h), and the Mn concentration in the sample solution in the dialysis apparatus at the endpoint was statistically analyzed to produce a cumulative release-time curve of the nanocarrier PMPB NC in the PBS solution containing α-amylase. The same method was applied to an example in which a plain PBS solution was added to the dialysis apparatus to produce a cumulative release-time curve of the nanocarrier PMPB NC in PBS.

[0059] Figure 4 Figure 3 is a schematic diagram of the cumulative drug release of apremilast and nanocarrier PMPB NC from drug-loaded buccal tablets in PBS with and without α-amylase. The results showed that apremilast was rapidly released in PBS containing α-amylase, reaching a peak release within 4 hours. At the same time, the release rate and total amount of nanocarrier PMPB NC in PBS containing α-amylase were higher than those in ordinary PBS, indicating that the buccal tablet nanoformulation has good α-amylase-responsive rapid drug release capabilities.

[0060] Example 5

[0061] The preparation process for the buccal tablet component, Apr@PMPB NC, in Example 5 was similar to that of Example 2, except that 10 mg of PMPB NC and 1 mg of apremilast were dispersed in 10 mL of dimethyl sulfoxide (DMSO) and stirred at room temperature for 24 hours to obtain Solution D. The solution was then centrifuged at 10,000 rpm for 15 minutes, and the precipitate was collected. The precipitate was redispersed in deionized water, washed, and centrifuged three times to obtain the product, Apr@PMPB NC. The mass ratio of apremilast, the anti-inflammatory active ingredient, to the porous manganese-substituted Prussian blue analog in the resulting Apr@PMPB NC was 0.031:1.

[0062] Example 6

[0063] The preparation process for the buccal tablet component Apr@PMPB NC in Example 6 was similar to that of Example 2, except that 10 mg of PMPB NC and 2 mg of apremilast were dispersed in 10 mL of dimethyl sulfoxide (DMSO) and stirred at room temperature for 24 hours to obtain Solution D. The solution was then centrifuged at 10,000 rpm for 15 minutes, and the precipitate was collected. The precipitate was redispersed in deionized water, washed, and centrifuged three times to obtain the product, Apr@PMPB NC. The mass ratio of apremilast, the anti-inflammatory active ingredient, to the porous manganese-substituted Prussian blue analog in the resulting Apr@PMPB NC was 0.065:1.

[0064] Example 7

[0065] The preparation process for the buccal tablet component, Apr@PMPB NC, in Example 7 was similar to that of Example 2, except that 10 mg of PMPB NC and 10 mg of apremilast were dispersed in 10 mL of dimethyl sulfoxide (DMSO) and stirred at room temperature for 24 hours to obtain Solution D. The solution was then centrifuged at 10,000 rpm for 15 minutes, and the precipitate was collected. The precipitate was redispersed in deionized water, washed, and centrifuged three times to obtain the product, Apr@PMPB NC. The mass ratio of apremilast, the anti-inflammatory active ingredient, to the porous manganese-substituted Prussian blue analog in the resulting Apr@PMPB NC was 0.230:1.

[0066] Example 8

[0067] The preparation process for the drug-loaded buccal tablets in Example 8 was similar to that of Example 3, with the following differences: 13 mg of the drug was weighed into tablets (starch:dextrin = 9:1), 10 μL of a 50 mg / mL Apr@PMPB NC stock solution was added dropwise to the dextrin, and the mixture was stirred to form a buccal nanoformulation containing the active ingredient Apr@PMPB NC. The resulting tablets contained 55 wt% of the active ingredient.

[0068] Example 9

[0069] The preparation process for the drug-loaded buccal tablets in Example 9 was similar to that of Example 3, except that 13 mg of the drug was weighed into tablets (starch:dextrin = 1:0), 10 μL of a 50 mg / mL Apr@PMPB NC stock solution was added dropwise to the dextrin, and the mixture was stirred and bonded to form a buccal nanoformulation containing Apr@PMPB NC as the active ingredient. The resulting tablets contained 55 wt% of the active ingredient.

[0070] Example 10

[0071] The preparation process for the drug-loaded buccal tablets in Example 10 was similar to that of Example 3, except that 13 mg of the drug was weighed into tablets (starch:dextrin = 0:1). 10 μL of a 50 mg / mL Apr@PMPB NC stock solution was added dropwise to the dextrin, stirred, and bonded to form a buccal nanoformulation containing Apr@PMPB NC as the active ingredient. The resulting tablets contained 55 wt% of the active ingredient.

[0072] Example 11

[0073] The preparation process of the drug-loaded buccal tablets in Example 11 was similar to that of Example 3, except that: PMPBNC was prepared into a 50 mg / mL stock solution using ultrapure water for later use; 13 mg was weighed and formed into tablets (starch:dextrin = 10:3), and 10 μL of the 50 mg / mL PMPB NC stock solution was dropped into the dextrin and stirred to form a buccal nanoformulation containing PMPB NC as the active ingredient.

[0074] Example 12

[0075] The preparation process for the drug-loaded buccal tablets in Example 12 was similar to that of Example 3, except that 15 mg of the drug was weighed into tablets (starch:dextrin = 10:3). 10 μL of a 50 mg / mL Apr@PMPB NC stock solution was added dropwise to the dextrin and stirred to form a buccal nanoformulation containing the active ingredient Apr@PMPB NC. The resulting tablets contained 58.8 wt% of the active ingredient.

[0076] Table 1 shows the composition and parameters of some of the buccal nanoformulations of the present invention:

[0077]

[0078] Wherein, encapsulation efficiency = encapsulated drug amount in the preparation / total encapsulated and unencapsulated drug amount in the preparation × 100%.

[0079] Table 2 shows the composition and parameters of some of the buccal nanoformulations of the present invention:

[0080]

[0081] Among them, the definition of excellent in Table 2 is: the tablet surface is firm, the formability is good, not loose, and not sticking; the definition of good is: the tablet surface is relatively firm, the formability is good, not loose, and not sticking;

[0082] The definition is: the tablet surface is slightly loose, the formability is slightly poor, and there is no adhesion.

Claims

1. A buccal nano preparation, characterized in that: include: Porous manganese substituted Prussian blue analogue loaded with anti-inflammatory active ingredients and formed into tablets; the chemical formula of the porous manganese substituted Prussian blue analogue is K 4-2x Mn x (Fe(CN)6), wherein 1≤x≤2; the anti-inflammatory active ingredient is apremilast; the mass ratio of the anti-inflammatory active ingredient to the porous manganese-substituted Prussian blue analog is (0.065-0.226):1; the tablet is a mixture of wheat starch and dextrin; the mass ratio of wheat starch to dextrin in the mixture of wheat starch and dextrin is 10:(5-1); The preparation method of the buccal nano preparation comprises: (1) A porous manganese-substituted Prussian blue analogue, an anti-inflammatory active ingredient, and a solvent are stirred, centrifuged, and washed to obtain a porous manganese-substituted Prussian blue analogue loaded with the anti-inflammatory active ingredient; (2) The porous manganese-substituted Prussian blue analogue loaded with anti-inflammatory active ingredients is mixed with ultrapure water to obtain a stock solution, and then mixed and formed into tablets, and finally tableted to obtain the buccal nanoformulation.

2. The buccal nano preparation according to claim 1, wherein The porous manganese-substituted Prussian blue analogue has a particle size of 200 to 500 nm, a pore size of 13 to 18 nm, and a specific surface area of ​​8 to 25 m 2 / g.

3. The buccal nano preparation according to claim 1, characterized in that The content of the tablet in the buccal nano preparation is 50-60 wt %.

4. The buccal nano preparation according to claim 3, wherein The content of the tablet in the buccal nano preparation is 55-57 wt %.

5. The buccal nano preparation according to claim 3, characterized in that The mass ratio of wheat starch to dextrin in the mixture of wheat starch and dextrin is 10:

3.

6. The buccal nano preparation according to claim 1, characterized in that The mass ratio of the anti-inflammatory active ingredient to the porous manganese-substituted Prussian blue analogue is (0.1-1.0):1; the solvent is at least one of dimethyl sulfoxide, anhydrous ethanol, N,N-dimethylformamide (DMF), ultrapure water and phosphate buffer.

7. The buccal nanoformulation according to claim 1, wherein The concentration of the stock solution is 0.02-0.10 mg / μL; the ratio of the stock solution to the tablet is (8-12) μL: (13-15) mg; and the tableting pressure is 100-200 MPa.

8. The buccal nano preparation according to claim 1, characterized in that The preparation method of the porous manganese-substituted Prussian blue analogue comprises: 1) Under stirring, a mixed solution B containing bovine serum albumin and M4[Fe(CN)6] is added dropwise to a mixed solution A containing bovine serum albumin and a manganese source to obtain a mixed solution C; 2) The mixed solution C is centrifuged and washed to obtain a porous manganese-substituted Prussian blue analogue.

9. The buccal nano preparation according to claim 1, characterized in that The stirring is magnetic stirring, the rotation speed of the magnetic stirring is 800-1000 rpm, the temperature is 55-65° C., and the time is 30-60 minutes.

10. Use of the buccal nanoformulation according to any one of claims 1 to 9 in preparing a medicament for treating chemotherapy-related oral mucositis.

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