Double-layered buccal tablet for preventing and treating oral ulcer and preparation method and application thereof

Abstract

The present application relates to a kind of double-layered lozenge for preventing and treating oral ulcer and its preparation method, the double-layered lozenge is prepared from immediate-release layer containing isoquercitrin and sustained-release layer containing selenium polysaccharide;Wherein, the weight ratio of the dosing amount of isoquercitrin and selenium polysaccharide is (7.5-20):(17.5-5), and the total weight of dosing amount is 25.The present application controls the dosage of isoquercitrin and selenium polysaccharide and the release sequence of sustained-release adhesion, forms an adhesion layer on the wound surface pretreated by isoquercitrin, can realize the advantages of improving the efficacy on oral ulcer, and adjusting oral flora balance, preventing the recurrence of oral ulcer.

Description

Technical Field

[0001] This invention belongs to the field of medicine, specifically relating to a double-layered lozenge for the prevention and treatment of oral ulcers, its preparation method, and its application. Background Technology

[0002] Oral ulcers are a common disease of the oral mucosa, characterized by significant local burning pain during flare-ups and recurring symptoms, causing considerable inconvenience to daily life. Although the exact cause is not fully understood, research shows that its occurrence is closely related to local inflammatory storms, oxidative stress, and immune imbalance. Traditional treatments such as antibiotics and hormones can relieve symptoms, but they suffer from significant side effects, high recurrence rates, and an inability to address multiple pathological aspects simultaneously.

[0003] Isoquercetin, a derivative of quercetin, is a flavonol compound with significant anti-inflammatory and antioxidant capabilities. It can rapidly neutralize free radicals and inhibit inflammatory pathways, but its poor water solubility and short retention time in the oral cavity make it difficult to maintain a sustained effect when used alone. Selenium polysaccharide is an organoselenium compound formed by the combination of selenium and polysaccharides. It can promote mucosal repair and regulate immunity, but its onset of action is slow, and in the acute phase of ulcers, exudate and protein in untreated wounds may hinder the adhesion of selenium polysaccharide, resulting in low bioavailability. Both are limited in their use alone for the treatment of oral ulcers.

[0004] Although current compound preparations for oral ulcers attempt to combine multiple active ingredients, they are all released in a disordered and synchronous manner. Existing technologies have not recognized the pathological stage of "first clearing inflammation / oxidative damage, and then initiating repair," and thus cannot maximize the potential of the ingredients.

[0005] Bilayer tablets are an advanced dosage form combining immediate-release (IR) and sustained-release (SR) properties, achieving rapid onset of action or localized treatment through the oral mucosa. Bilayer tablets typically consist of two layers: an immediate-release layer (IR layer) that rapidly disintegrates or dissolves to quickly release the drug; and a sustained-release layer (SR layer) that slowly releases the drug through a hydrophilic gel, hydrophobic matrix, or membrane-controlled technology to maintain a long-lasting effect. They are commonly manufactured using a tableting process, employing a bilayer tablet press (such as GEA Courtoy or Korsch XM) to achieve high-precision layer compression, ensuring interlayer bonding and integrity.

[0006] Although bilayer tablet technology has been used for taste masking or gastrointestinal dispensing, it has never been applied to time-sequential drug release design targeting specific pathological mechanisms in the treatment of oral ulcers. Furthermore, there are no known bilayer lozenges for the treatment of oral ulcers that combine isoquercitrin and selenium polysaccharide. Summary of the Invention

[0007] Based on this, the purpose of this invention is to provide isoquercetin-selenium polysaccharide bilayer oral tablets with time-release function, their preparation method and application, wherein the bilayer oral tablets can be used for the treatment of oral ulcers and regulate the balance of oral flora, improving the oral microenvironment.

[0008] The first aspect of the present invention is to provide a double-layer oral lozenge for preventing and treating oral ulcers, which is prepared from an immediate-release layer containing isoquercetin as an active ingredient and a sustained-release layer containing selenium polysaccharide as an active ingredient.

[0009] The mass ratio of isoquercetin to selenium-containing polysaccharides was (7.5-20):(17.5-5).

[0010] In some embodiments, the isoquercitrin accounts for 3 / 76 to 2 / 19 of the mass of the immediate-release layer.

[0011] In some embodiments, the selenium polysaccharide accounts for 1 / 38 to 7 / 76 of the mass of the sustained-release layer.

[0012] In some embodiments, the weight ratio of isoquercitrin to selenium-containing polysaccharide is (10-17.5):(15-7.5), more preferably (10-15):(15-10).

[0013] In some embodiments, the excipients of the immediate-release layer include sodium carboxymethyl starch and mannitol, wherein the ratio of sodium carboxymethyl starch to mannitol is (12.5-20):(87.5-80), and the total weight of both is 100.

[0014] In some preferred embodiments, the ratio of sodium carboxymethyl starch to mannitol is (12.5-15):(87.5-85).

[0015] In a more preferred embodiment, the weight ratio of isoquercetin to selenium-containing polysaccharide is (10-15):(15-10), and the ratio of sodium carboxymethyl starch to mannitol is (12.5-15):(87.5-85). The isoquercetin-selenium polysaccharide bilayer lozenges obtained from this formulation not only have excellent immediate and sustained-release properties but also superior drug activity.

[0016] In some embodiments, the excipients of the sustained-release layer include carbomer, HPMC, penetration enhancers, and fillers;

[0017] The filler may be microcrystalline cellulose;

[0018] The carbomer can be Carbomer 971P, and / or Carbomer 974P.

[0019] The HPMC is HPMC K4M and / or HPMC K15M.

[0020] A second aspect of the present invention is to provide a method for preparing any of the above-mentioned double-layer oral lozenges for preventing and treating oral ulcers.

[0021] A method for preparing a double-layered lozenge for preventing and treating oral ulcers includes the following steps:

[0022] S1: Mix selenium polysaccharide with carbomer, HPMC, chitosan and microcrystalline cellulose evenly to obtain powder; add binder to powder, make soft material, granulate, add lubricant, mix to obtain sustained-release layer particles.

[0023] S2: Mix isoquercetin, sodium carboxymethyl starch, mannitol and microcrystalline cellulose evenly, add binder to granulate, dry and add lubricant to granulate to obtain immediate release layer particles;

[0024] S3: The sustained-release layer particles are lightly compressed and pre-formed, then the immediate-release layer particles are added to cover the sustained-release layer particles, and the tablets are compressed into tablets.

[0025] In some embodiments, the ratio of the sustained-release layer to the immediate-release layer is 1:1.

[0026] In some implementations, the pressure in step S3 is 10kN-15kN.

[0027] In some embodiments, the adhesive is a variety of adhesives commonly used in the pharmaceutical field, preferably a 5% PVPK30 ethanol solution and a 3% HPMC ethanol solution.

[0028] In some embodiments, the lubricant is a variety of lubricants commonly used in the pharmaceutical industry, with magnesium stearate, sodium stearate fumarate, and polyethylene glycol being preferred lubricants.

[0029] A third aspect of the invention is to provide the use of the double-layered lozenge in the preparation of a medicament for the prevention or treatment of oral ulcers.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] We discovered that controlling the appropriate ratio and release order of isoquercetin and selenium polysaccharide is crucial for achieving good immediate and sustained-release properties, resulting in a time-release isoquercetin-selenium polysaccharide bilayer lozenge. This invention addresses the issues of low synergistic efficiency and poor compatibility between these two drugs by controlling the release order of immediate isoquercetin and sustained-release selenium polysaccharide, allowing selenium polysaccharide to form an adhesive layer on the isoquercetin-pretreated wound surface. This improves the efficacy for oral ulcers, regulates oral flora balance, and prevents recurrence of oral ulcers. Attached Figure Description

[0032] Figure 1This is a schematic diagram of the isoquercitrin dissolution test results.

[0033] Figure 2 This is a schematic diagram of the selenium polysaccharide dissolution test results. Detailed Implementation

[0034] To facilitate understanding of the present invention, a more complete description will be provided below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a thorough and complete understanding of the disclosure of the present invention.

[0035] Unless otherwise specified, experimental methods in the following examples were performed under standard conditions, such as those described in the fourth edition of *Molecular Cloning: A Laboratory Manual*, edited by Green and Sambrook, published in 2013, or according to the manufacturer's recommendations. All commonly used chemical reagents used in the examples are commercially available products.

[0036] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit the invention. The term "and / or" as used in this invention includes any and all combinations of one or more of the associated listed items.

[0037] To facilitate understanding of this technology, some terms and phrases are defined below.

[0038] Isoquercitrin, also known as isoquercitrin, is a natural flavonoid glycoside compound with the chemical name 3,3′,4′,5,7-pentahydroxyflavone-3-β-glucoside.

[0039]

[0040] In this article, the term "prevention and treatment" refers to prevention and / or treatment in conventional medicine. The double-layer oral lozenge of this invention can be used for the prevention and / or treatment of oral ulcers.

[0041] The present invention will be further described in detail below with reference to specific embodiments.

[0042] The sources of the materials involved in the following embodiments:

[0043] Selenium polysaccharide, with organic selenium accounting for 96% of the total selenium mass, Guangdong Fengjing Element Technology Co., Ltd.

[0044] Isoquercetin: Guangdong Jinjunkang Biotechnology Co., Ltd.

[0045] Sodium carboxymethyl starch: Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd.

[0046] Mannitol: Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd.

[0047] HPMC K4M: Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd.

[0048] HPMC K15M: Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd.

[0049] Carbomer 971P: Shandong Huling New Materials Co., Ltd.

[0050] Carbomer 974P: Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd.

[0051] Chitosan: Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd.

[0052] Magnesium stearate: Huzhou Linghu Xinwang Chemical Co., Ltd.

[0053] Microcrystalline cellulose: Huzhou Linghu Xinwang Chemical Co., Ltd.

[0054] PVP K30: Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd.

[0055] Example 1

[0056] The bilayer sheet preparation method described in this embodiment includes the following steps:

[0057] 1. Preparation of the sustained-release layer, including the following steps:

[0058] ① Selenium polysaccharide, carbomer, HPMC, chitosan and microcrystalline cellulose were passed through a 100-mesh sieve, weighed according to the prescription in Table 1, and then mixed evenly in a mixer for 15 min.

[0059] ② Add 10mg of 3% HPMC K4M ethanol solution to the mixed powder as a binder, make a soft material (it can be formed into a ball by hand and dispersed by light pressure), and granulate it through a 24-mesh sieve;

[0060] ③ The wet granules were dried in a 40℃ forced-air drying oven for 2 hours;

[0061] ④ The dried granules are sized through a 20-mesh sieve, and 3 mg of magnesium stearate is added and mixed for 5 min to obtain sustained-release granules.

[0062] 2. Preparation of the immediate-release layer includes the following steps:

[0063] ① Pass isoquercetin, sodium carboxymethyl starch, mannitol and microcrystalline cellulose through a 100-mesh sieve, and mix them according to the prescription in Table 1 for 10 min;

[0064] ② Granulation: Add 10mg of 5% PVP K30 ethanol solution as a binder and granulate through a 24-mesh sieve;

[0065] ③ The wet granules were dried in a 40℃ forced-air drying oven for 1.5 hours;

[0066] ④ Sieve the granules through a 20-mesh sieve, add 3mg of magnesium stearate and mix for 5 minutes to obtain immediate-release granules.

[0067] 3. Tableting

[0068] ① Weigh out 190mg of sustained-release granules and fill them into the mold, then gently press to pre-form (pressure 2kN).

[0069] ② Add immediate-release granules (190mg) to cover the sustained-release layer;

[0070] ③ Press the tablets according to the pressure set in Table 1.

[0071] Table 1: Prescriptions for each group

[0072]

[0073]

[0074]

[0075] Note: The total amount of immediate-release layer / sustained-release layer must meet the requirement of 190mg of immediate-release layer + 190mg of sustained-release layer = 380mg. This includes the binders and lubricants added during preparation. The amount of filler (microcrystalline cellulose) is a balance value and may vary according to specific circumstances and conventional methods.

[0076] Example 2: Release Characteristic Determination

[0077] Take 6 test tablets from each of the various embodiments and put them into a settling basket.

[0078] The dissolution vessel was pre-filled with 100 mL of artificial saliva (Huizhiheyuan Biotechnology (Suzhou) Co., Ltd.), the temperature was (37±0.5)℃, and the rotation speed was set to 50 rpm.

[0079] Start the dissolution apparatus and take 2 mL of solution at 2 min, 5 min, 30 min and 60 min respectively, and add an equal volume of fresh medium.

[0080] The solution samples were filtered through a 0.45 μm filter membrane, and the dissolution rates of isoquercetin and selenium polysaccharide were determined by microwave digestion (HNO3-H2O2) before detection by HPLC and AFS, respectively.

[0081] Record the dissolution (release) values ​​at each time point. See Table 2 for the results. Figure 1 and Figure 2.

[0082] Table 2: Dissolution Rate

[0083]

[0084]

[0085] In vitro dissolution studies showed that, under artificial saliva medium, (37±0.5)℃, and 50 rpm dissolution conditions, the bilayer tablets prepared in Examples 1-7, 10, and 11 all exhibited good immediate-release and sustained-release characteristics: the isoquercetin in the immediate-release layer dissolved at over 95% within 5 minutes, while the sustained-release layer showed almost no release in the first 5 minutes, followed by a slow and continuous release over 1 hour. In contrast, the monolayer tablets prepared using the same raw materials and excipients as in Example 5, which were only mixed and compressed, showed that isoquercetin and selenium polysaccharide began to dissolve simultaneously, and isoquercetin failed to dissolve completely within 5 minutes. Examples 8 and 9 illustrate that when the amount of disintegrant (sodium carboxymethyl starch) in the immediate-release layer is small and the amount of sustained-release matrix agent (HPMC) in the sustained-release layer is large, the tableting pressure increases, and the dissolution of the active ingredient will be slower accordingly. The active ingredients in both the immediate-release and sustained-release layers cannot be fully dissolved within 5 minutes and 1 hour, respectively. Conversely, the dissolution of the active ingredient will be accelerated, and the sustained-release layer cannot start to release slowly and continuously for 1 hour after 2 minutes.

[0086] Example 3: Efficacy Experiment of Drugs for Oral Ulcers

[0087] Eighty-four qualified SPF-grade SD golden hamsters (half male and half female) were selected and randomly divided into a normal control group (n=6) and a model group (n=78) according to sex and weight. In the model group, animals were lightly anesthetized with ether, and 10 g / mL of areca nut extract was subcutaneously injected into the upper oral mucosa of each hamster (0.1 mL / hamster on each side) to establish an oral ulcer model. The ulcer area was measured the day after modeling. Seventy-two model hamsters were randomly divided into 12 groups (n=6 each) based on sex, ulcer area, and weight. The control group received no medication. In the dexamethasone oral patch group, the patch was applied and pressed until it dissolved (ensuring the patch covered the entire ulcer surface, 1 patch / side / time, 2 times / day). The other groups received one tablet of the test drug sublingually three times / day.

[0088] Oral ulcers in each group of animals were scored before administration and on days 1, 2, 3, 5, 7, 10, and 14 after administration. On the same day, all animals except the normal control group were photographed from the same angle using the same scale. The ulcer area of ​​each group of golden hamsters was measured using ImageJ software, and the ulcer healing rate was calculated based on the ulcer area. Ulcer healing rate (%) = (initial ulcer area - ulcer area on the day of administration) / initial ulcer area. The day after the last administration, oral flora were collected, and bacterial 16S rDNA high-throughput sequencing (Guangzhou Huateng Biomedical Technology Co., Ltd.) was performed to detect the number of Bifidobacterium and Staphylococcus aureus.

[0089] Scoring Criteria

[0090]

[0091] The results are as follows:

[0092] Table 3: Scoring

[0093]

[0094]

[0095]

[0096] Table 4: Ulcer Healing Rate

[0097]

[0098]

[0099] Table 5: Bacterial Count

[0100]

[0101] Experimental results show that the oral lozenges of the present invention can significantly reduce oral ulcer scores in rats, improve ulcer healing rates, increase the content of probiotics in the oral cavity, and inhibit the growth of harmful bacteria.

[0102] Compared with the normal control group, the scores of D1, D2, D3, D5, D7, D10, and D14 were significantly increased in the model control group after administration. Compared with the model control group, the scores of D3, D5, D7, D10, and D14 were significantly decreased in Examples 1-6 of this invention after administration (P ≤ 0.05). Compared with Examples 1, 6, dexamethasone patches, monolayer isoquercitrin tablets, monolayer selenium polysaccharide tablets, mixed monolayer tablets, and Examples 7, 10, and 11, the scores of D7, D10, and D14 were significantly decreased in Examples 2-5 after administration (P ≤ 0.05).

[0103] Compared with the model control group, the healing rates of Examples 1-6 after administration were significantly increased on days 5, 7, 10, and 14 (P ≤ 0.05); compared with Examples 1, 6, dexamethasone patches, monolayer isoquercitrin tablets, monolayer selenium polysaccharide tablets, mixed monolayer tablets, and Examples 7, 10, and 11, the healing rates of Examples 2-5 after administration were significantly increased on days 5, 7, 10, and 14 (P ≤ 0.05).

[0104] Compared with the normal control group, the model control group showed a significant increase in Staphylococcus aureus (P ≤ 0.05) and a significant decrease in Bifidobacteria (P ≤ 0.05); compared with the model control group, Examples 1-6 of this invention showed a significant decrease in Staphylococcus aureus (P ≤ 0.05) and a significant increase in Bifidobacteria (P ≤ 0.05); compared with Examples 1, 6, dexamethasone patches, monolayer isoquercitrin tablets, monolayer selenium polysaccharide tablets, mixed monolayer tablets, Examples 7, 10, and 11, Examples 2-5 showed a significant decrease in Staphylococcus aureus (P ≤ 0.05) and a significant increase in Bifidobacteria (P ≤ 0.05).

[0105] Monolayer experiments confirmed that isoquercitrin alone or in combination with selenium polysaccharide did not achieve significant therapeutic effects. Comparative studies found that reversing the release order of the two (Example 7) or changing their ratio (Examples 10, 11) resulted in less efficacy than in Example 5 with optimized ratio and order. This indicates that controlling the ratio of isoquercitrin and selenium polysaccharide, releasing isoquercitrin first for anti-inflammatory and antioxidant treatment of the ulcer surface, and then releasing selenium polysaccharide to exert its immune repair effect on the isoquercitrin-pretreated wound, can achieve unexpected therapeutic effects on oral ulcers, increase the number of beneficial bacteria in the oral cavity, reduce the number of harmful bacteria, and regulate the oral microecology.

[0106] This invention designs a bilayer structure of "isoquercetin rapid release + selenium polysaccharide sustained release adhesion" and optimizes its formulation to achieve an oral ulcer healing chain of "anti-inflammatory, antioxidant and immune repair", which can regulate oral flora and prevent oral ulcer recurrence.

[0107] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A double-layered lozenge for preventing and treating oral ulcers, characterized in that, The double-layer oral lozenge is prepared from an immediate-release layer containing isoquercetin as the active ingredient and a sustained-release layer containing selenium polysaccharide as the active ingredient. The weight ratio of isoquercetin to selenium polysaccharide is (7.5-20):(17.5-5), and the total weight of the dosage is 25. The mass percentage of isoquercetin in the immediate-release layer is 3 / 76-2 / 19, and the mass percentage of selenium polysaccharide in the sustained-release layer is 1 / 38-7 / 76. The excipients of the immediate-release layer include sodium carboxymethyl starch and mannitol, and the ratio of sodium carboxymethyl starch to mannitol is (12.5-20):(87.5-80), with a total weight of 100. The excipients of the sustained-release layer include carbomer, HPMC, a penetration enhancer, and a filler. The penetration enhancer is chitosan, and the filler is microcrystalline cellulose.

2. The double-layer oral lozenge according to claim 1, characterized in that, The weight ratio of isoquercitrin to selenium polysaccharide is (10-17.5):(15-7.5).

3. The double-layer oral lozenge according to claim 1, characterized in that, The weight ratio of isoquercitrin to selenium polysaccharide is (10-15):(15-10), and the ratio of sodium carboxymethyl starch to mannitol is (12.5-15):(87.5-85).

4. The double-layered lozenge according to any one of claims 1-3, characterized in that, During preparation, the mass ratio of the sustained-release layer to the immediate-release layer is 1:

1.

5. The method for preparing the double-layered oral lozenge for preventing and treating oral ulcers according to any one of claims 1-4, characterized in that, Includes the following steps: S1: Mix selenium polysaccharide with carbomer, HPMC, chitosan and microcrystalline cellulose evenly to obtain powder; add binder to powder, make soft material, granulate, add lubricant, mix to obtain sustained-release layer particles. S2: Mix isoquercetin, sodium carboxymethyl starch, mannitol and microcrystalline cellulose evenly, add binder to granulate, dry and add lubricant to granulate to obtain immediate release layer particles; S3: The sustained-release layer particles are lightly compressed and pre-formed, then the immediate-release layer particles are added to cover the sustained-release layer particles, and the tablets are compressed into tablets.

6. The method for preparing a double-layered oral lozenge for preventing and treating oral ulcers according to claim 5, characterized in that, The mass ratio of the sustained-release layer particles to the immediate-release layer particles in step S3 is 1:

1.

7. The method for preparing a double-layered oral lozenge for preventing and treating oral ulcers according to claim 5, characterized in that, The pressure for tablet forming in step S3 is 10kN-15kN.

8. The method for preparing a double-layered oral lozenge for preventing and treating oral ulcers according to claim 5 or 7, characterized in that, The lubricant is magnesium stearate, sodium stearate fumarate, or polyethylene glycol; and / or the adhesive is a 5% PVP K30 ethanol solution or a 3% HPMC ethanol solution.

9. The use of the double-layered lozenge according to any one of claims 1-4 in the preparation of a medicament for the prevention or treatment of oral ulcers.

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