Double-layer buccal tablet for preventing and treating oral ulcer as well as preparation method and application thereof

Abstract

The invention relates to a double-layer buccal tablet for preventing and treating oral ulcer and a preparation method of the double-layer buccal tablet. The double-layer buccal tablet is prepared from a quick release layer containing isoquercetin and a slow release layer containing selenium polysaccharide, wherein the weight part ratio of the dosage of the isoquercetin to the dosage of the selenium-containing polysaccharide is (7.5-20): (17.5-5), and the total weight part of the dosage of the isoquercetin to the dosage of the selenium-containing polysaccharide is 25. By controlling the quick release of the isoquercetin, the use amount of the selenium polysaccharide and the release sequence of slow release adhesion, the selenium polysaccharide forms an adhesion layer on the wound surface pretreated by the isoquercetin, so that the advantages of improving the curative effect on the oral ulcer, regulating the balance of oral flora and preventing the recurrence of the oral ulcer can be realized.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and in particular relates to a double-layer buccal tablet for preventing and treating oral ulcer and a preparation method and application thereof. BACKGROUND

[0002] Oral ulcer is a common oral mucosa disease, which causes obvious local burning pain and repeated illness, and brings great inconvenience to daily life. Although the cause has not been completely clear, studies have shown that it is closely related to local inflammatory storm, oxidative stress and immune imbalance. Although traditional treatment drugs such as antibacterial drugs and hormones can relieve symptoms, they have problems such as large side effects, easy recurrence and inability to consider multiple pathological links.

[0003] Isoquercitrin is a derivative of quercetin, which is a flavonol compound with significant anti-inflammatory and antioxidant capacity, can quickly neutralize free radicals and inhibit inflammatory pathways, but its water solubility is poor, the oral retention time is short, and it is difficult to sustain the effect alone; selenium polysaccharide is an organic selenium compound formed by the combination of selenium and polysaccharide, which can promote mucosa repair and regulate immunity, but it takes effect slowly, and the protein liquid in the unprocessed wound exudate in the acute stage of ulcer may hinder the adhesion of selenium polysaccharide, and the bioavailability is low. Both of them have certain limitations in treating oral ulcer when used alone.

[0004] Although the current oral ulcer compound preparation attempts to combine multiple active ingredients, it is a disordered synchronous release, and the existing technology does not recognize the pathological stage adaptability of "first removing inflammation / oxidative damage, then starting repair", and cannot maximize the potential of the components.

[0005] Bilayer Buccal Tablets is an advanced dosage form combining the characteristics of immediate release (IR) and sustained release (SR), which realizes rapid onset or local treatment through oral mucosa. Bilayer Buccal Tablets is usually composed of two layers: the immediate release layer (IR layer): fast disintegration or dissolution, rapid drug release; the sustained release layer (SR layer): slow drug release through hydrophilic gel, hydrophobic matrix or membrane control technology, maintaining long-acting effect. Commonly prepared by tabletting process, high-precision layering and compression are realized by double-layer tabletting machine (such as GEA Courtoy, Korsch XM), ensuring the bonding force and integrity between layers.

[0006] Although the bilayer tablet technology has been used for taste masking or gastrointestinal split release, it has never been applied to the time-sequential drug release design targeting specific pathological mechanisms in oral ulcer treatment. Moreover, there is no double-layer buccal tablet for treating oral ulcer by combining isoquercitrin and selenium polysaccharide. SUMMARY

[0007] Based on this, the purpose of the present application is to provide isoquercitrin-selenium polysaccharide double-layered buccal tablets with time-release function and a preparation method and application thereof, which can be used for treating oral ulcers and regulating oral flora balance and improving the microenvironment of the oral cavity.

[0008] The first aspect of the present application is to provide a double-layered buccal tablet for preventing and treating oral ulcers, which is prepared from a rapid-release layer containing isoquercitrin as an active ingredient and a sustained-release layer containing selenium polysaccharide as an active ingredient.

[0009] The mass ratio of isoquercitrin to selenium polysaccharide is (7.5-20):(17.5-5).

[0010] In some embodiments, the mass fraction of isoquercitrin in the rapid-release layer is 3 / 76-2 / 19.

[0011] In some embodiments, the mass fraction of selenium polysaccharide in the sustained-release layer is 1 / 38-7 / 76.

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

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

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

[0015] In more preferred embodiments, the weight ratio of the dosage of isoquercitrin to selenium polysaccharide is (10-15):(15-10), and the dosage ratio of sodium carboxymethyl starch to mannitol is (12.5-15):(87.5-85). The isoquercitrin-selenium polysaccharide double-layered buccal tablet prepared by this formula not only has good rapid-release and sustained-release properties, but also has superior drug activity.

[0016] In some embodiments, the excipients of the sustained-release layer include carbomer, HPMC, penetration enhancer, and filler.

[0017] The filler can 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] The second aspect of the present application provides a preparation method of the double-layered buccal tablet for preventing and treating oral ulcer.

[0021] The preparation method of the double-layered buccal tablet for preventing and treating oral ulcer comprises the following steps:

[0022] S1: uniformly mixing selenium polysaccharide, carbomer, HPMC, chitosan and microcrystalline cellulose to obtain a powder; adding a binder to the powder to prepare a soft material, granulating, adding a lubricant, mixing, and obtaining slow-release layer granules;

[0023] S2: uniformly mixing isoquercitrin, sodium carboxymethyl starch, mannitol and microcrystalline cellulose, granulating by adding a binder, drying, and granulating by adding a lubricant to obtain quick-release layer granules;

[0024] S3: lightly pressing the slow-release layer granules to pre-form, then adding the quick-release layer granules to cover the slow-release layer granules, and tabletting to form.

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

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

[0027] In some embodiments, the binder is various binders commonly used in the pharmaceutical field, and preferably 5% PVPK30 ethanol solution and 3% HPMC ethanol solution.

[0028] In some embodiments, the lubricant is various lubricants commonly used in the pharmaceutical field, and preferably the lubricant is magnesium stearate, sodium stearyl fumarate and polyethylene glycol.

[0029] The third aspect of the present application provides the use of the double-layered buccal tablet in the preparation of a medicine for preventing or treating oral ulcer.

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

[0031] We found that controlling the ratio and the release sequence of isoquercitrin and selenium polysaccharide can obtain good quick-release and slow-release properties, thereby obtaining an isoquercitrin-selenium polysaccharide double-layered buccal tablet with time-release function. The present application controls the release sequence of quick-release of isoquercitrin and slow-release adhesion of selenium polysaccharide, so that the selenium polysaccharide forms an adhesion layer on the wound surface pretreated by isoquercitrin, solves the problems of low synergistic efficiency and poor pathological stage adaptability of the two drugs, improves the curative effect on oral ulcer, and can regulate the balance of oral flora and prevent the recurrence of oral ulcer. BRIEF DESCRIPTION OF DRAWINGS

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

[0033] Figure 2 is a schematic diagram of the dissolution test results of selenopolysaccharide. DETAILED DESCRIPTION

[0034] For the purpose of promoting the understanding of the present application, a more comprehensive description of the present application will be provided below. The present application can be realized in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present application more thorough and comprehensive.

[0035] The experimental methods in the following examples, unless otherwise specified, are generally carried out according to the conventional conditions, for example, in the fourth edition of Molecular Cloning: A Laboratory Manual edited by Green and Sambrook, which was published in 2013, or according to the conditions recommended by the manufacturer. The various common chemical reagents used in the examples are commercially available products.

[0036] Unless otherwise defined, all technical and scientific terms used in the present application have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. The terms used in the specification of the present application are only for the purpose of describing specific embodiments and are not intended to limit the present application. The term "and / or" used in the present application includes any and all combinations of one or more related listed items.

[0037] Definitions In order to facilitate the understanding of the present technology, some terms and phrases are defined below.

[0038] Isoquercitrin, also known as isoquercitrin, is a natural flavonoid compound, and its chemical name is 3,3',4',5,7-pentahydroxyflavone-3-β-glucoside.

[0039]

[0040] In this paper, the term "prevention and / or treatment" is the prevention and / or treatment in conventional medicine, and the double-layered buccal tablet of the present application can be used for the prevention and / or treatment of oral ulcer.

[0041] The present application will be further described in detail below in combination with specific embodiments.

[0042] The sources of the materials involved in the following examples are as follows:

[0043] Selenopolysaccharide, organic selenium accounts for 96% of the total selenium mass percentage, Guangdong Fengjing Element Technology Co., Ltd.

[0044] Isoquercitrin: Guangdong Jinjun Kang Biotechnology Co., Ltd.

[0045] Sodium Carboxymethyl Starch: Xi'an Tianzheng Pharmaceutical Auxiliary Material Co., Ltd.

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

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

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

[0049] Carbomer 971P: Shandong Hulinqing New Material Co., Ltd.

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

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

[0052] Magnesium Stearate: Huzhou Linghu Xinyang Chemical Co., Ltd.

[0053] Microcrystalline Cellulose: Huzhou Linghu Xinyang Chemical Co., Ltd.

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

[0055] Example 1

[0056] The double-layer tablet preparation method described in this example includes the following steps:

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

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

[0059] ②10 mg of 3% HPMC K4M ethanol solution is added to the mixed powder as a binder to prepare a soft material (hand into a ball, light pressure is scattered), and 24-mesh sieve granulation is performed;

[0060] ③The wet granules are dried in a 40℃ air-drying oven for 2 h;

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

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

[0063] ①Isorhamnetin, sodium carboxymethyl starch, mannitol and microcrystalline cellulose are respectively passed through a 100-mesh sieve and mixed for 10 min according to the prescription amount in Table 1;

[0064] Granulation: 10 mg 5% PVP K30 ethanol solution was added as a binder, and granulation was performed on a 24-mesh screen;

[0065] ③ The wet granules were dried in a 40°C air-drying oven for 1.5 h;

[0066] ④ The granules were sieved through a 20-mesh screen, 3 mg of magnesium stearate was added and mixed for 5 min to obtain the immediate-release layer granules.

[0067] 3. Compression molding

[0068] ① The sustained-release layer granules (190 mg) were weighed into a mold and lightly compressed (pressure 2 kN) to form a preform;

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

[0070] ③ The tablets were compressed at the pressure set in Table 1.

[0071] Table 1: Formulations of each group

[0072]

[0073]

[0074]

[0075] Note: The total amount of the immediate-release layer / sustained-release layer must satisfy the immediate-release layer 190 mg + sustained-release layer 190 mg = total 380 mg, including the amount of binder, lubricant, and filler (microcrystalline cellulose) added during preparation. The balance is adjusted according to the specific situation and changed according to the conventional method.

[0076] Example 2: Release characteristics determination

[0077] Each group of 6 tablets of the test drug in each example was placed in a sinker basket.

[0078] The dissolution cup was preloaded with 100 mL of artificial saliva (Hui Zhihe Source Biotechnology (Suzhou) Co., Ltd.), and the temperature was set at (37 ± 0.5) °C with a rotation speed of 50 rpm.

[0079] The dissolution instrument was started, and 2 mL of solution was taken at 2 min, 5 min, 30 min, and 60 min, and an equal volume of fresh medium was added.

[0080] The solution sample was filtered through a 0.45 μm filter membrane, and the dissolution of isoquercitrin and selenium polysaccharide was determined by HPLC and AFS detection after microwave digestion (HNO3-H2O2), respectively.

[0081] The dissolution (release) values at each time point were recorded. The results are shown in Table 2 and Figure 1 and Figure 2.

[0082] Table 2: Dissolution

[0083]

[0084]

[0085] The in vitro dissolution study results show that the double-layer tablets prepared in Examples 1-7, 10, 11 all exhibit good immediate-release and sustained-release properties: the dissolution of isoquercitrin in the immediate-release layer is over 95% in 5 minutes, while the sustained-release layer has almost no release in the first 5 minutes and then slowly releases for 1 hour. In contrast, the single-layer tablet prepared by mixing and pressing the same raw and auxiliary materials as in Example 5, isoquercitrin and selenium polysaccharide are simultaneously dissolved, and isoquercitrin is not completely dissolved in 5 minutes. Examples 8, 9 show that when the amount of disintegrating agent (sodium carboxymethyl starch) in the immediate-release layer is small, the amount of sustained-release matrix agent (HPMC) in the sustained-release layer is large, and the tablet pressing pressure is increased, the dissolution of the active ingredients will be slowed down, and the active ingredients in the immediate-release layer and the sustained-release layer cannot be fully dissolved in 5 minutes and 1 hour; on the contrary, the dissolution of the active ingredients will be accelerated, and the sustained-release layer cannot start to slowly release for 1 hour after 2 minutes.

[0086] Example 3 Oral Ulcer Efficacy Experiment

[0087] Select 84 SPF level SD golden hamsters that have passed quarantine, half male and half female, and randomly divide them into normal control group (6) and model group (78) according to gender and weight. The model group animals are lightly anesthetized with ether, and then 10g / m, of areca extract is injected subcutaneously into the upper oral mucosa of the golden hamsters, 0.1mL per animal on both sides. The oral ulcer model of the golden hamster is replicated. The next day after modeling, the oral ulcer area of the model golden hamster is measured, and 72 model golden hamsters are randomly divided into 12 groups according to gender, oral ulcer area, and body weight, 6 in each group. The model control group is not given any medication, the dexamethasone acetate oral patch group animals are given medication according to the ulcer area, and the patches are pressed until they melt (ensure that the patch area covers the entire ulcer surface, 1 patch per side per time, 2 times per day), and the remaining groups are given 1 tablet of the test drug per time, 3 times per day.

[0088] The oral ulcers of the animals in each group were scored before administration and on D1, D2, D3, D5, D7, D10, D14 after administration. On the day of scoring, the animals in each group except the normal control group were photographed at the same angle and using the same ruler, and the ulcer area of each group of golden hamsters was measured using ImageJ software, and the ulcer healing rate was calculated according to the ulcer area. Ulcer healing rate (%) = (initial ulcer area - ulcer area on the day) / initial ulcer area. The next day after the last administration, the oral flora was collected, and bacterial 16S rDNA high-throughput sequencing (Guangzhou Huateng Biomedicine 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: Number of bacteria

[0100]

[0101] The experimental results show that the buccal tablet of the embodiment of the present application can significantly reduce the oral ulcer score of rats, improve the ulcer healing rate, and 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 the model control group on D1, D2, D3, D5, D7, D10, D14 after administration were significantly increased; compared with the model control group, the scores of examples 1-6 on D3, D5, D7, D10, D14 after administration were significantly reduced (P ≤ 0.05); compared with examples 1, 6, dexamethasone patches, single-layer isoquercitrin tablets, single-layer selenium polysaccharide tablets, mixed single-layer tablets, examples 7, 10, and 11, the scores of examples 2-5 on D7, D10, D14 after administration were significantly reduced (P ≤ 0.05).

[0103] Compared with the model control group, the healing rates of embodiments 1-6 were significantly increased (P≤0.05) on D5, D7, D10 and D14 after administration; compared with embodiments 1, embodiment 6, dexamethasone patches, single-layer isoquercitrin tablets, single-layer selenium polysaccharide tablets, mixed single-layer tablets, embodiments 7, 10 and 11, the healing rates of embodiments 2-5 were significantly increased (P≤0.05) on D5, D7, D10 and D14 after administration.

[0104] Compared with the normal control group, the number of Staphylococcus aureus in the model control group was significantly increased (P≤0.05), and the number of Bifidobacterium was significantly reduced (P≤0.05); compared with the model control group, the number of Staphylococcus aureus in embodiments 1-6 was significantly reduced (P≤0.05), and the number of Bifidobacterium was significantly increased (P≤0.05); compared with embodiments 1, embodiment 6, dexamethasone patches, single-layer isoquercitrin tablets, single-layer selenium polysaccharide tablets, mixed single-layer tablets, embodiments 7, 10 and 11, the number of Staphylococcus aureus in embodiments 2-5 was significantly reduced (P≤0.05), and the number of Bifidobacterium was significantly increased (P≤0.05).

[0105] The single-layer tablet experiment confirmed that isoquercitrin and selenium polysaccharide alone or only in combination could not achieve significant therapeutic effect. Comparative study found that if the release order of the two was reversed (embodiment 7) or the ratio was changed (embodiments 10 and 11), the therapeutic effect was not as good as that of embodiment 5 with optimized ratio and order. This shows that controlling isoquercitrin and selenium polysaccharide according to a certain ratio, and releasing isoquercitrin first to treat the ulcer surface with anti-inflammatory and antioxidant effect, and then releasing selenium polysaccharide to play its immune repair role on the ulcer surface pretreated by isoquercitrin, can achieve unexpected treatment effect on oral ulcer, and can increase the number of probiotics and reduce the number of harmful bacteria in the oral cavity, and regulate the oral microecology.

[0106] The present application realizes the "anti-inflammatory and antioxidant to immune repair" oral ulcer healing chain by designing a double-layer structure of "isoquercitrin immediate release + selenium polysaccharide sustained release adhesion", optimizing the formula, and can regulate the oral flora to prevent the recurrence of oral ulcer.

[0107] The above-described embodiments only express several embodiments of the present application, and the description is more specific and detailed, but it cannot be understood as limiting the scope of the patent. It should be noted that for ordinary skilled persons in the art, without departing from the concept of the present application, a number of modifications and improvements can be made, which are within the scope of protection of the present application. Therefore, the protection scope of the patent of the present application should be subject to 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 isoquercitrin to selenium-containing polysaccharide is (7.5-20):(17.5-5), and the total weight of the dosage is 25.

2. The double-layer oral lozenge according to claim 1, characterized in that, The isoquercitrin has a mass ratio of 3 / 76 to 2 / 19 in the immediate-release layer; and / or the selenium polysaccharide has a mass ratio of 1 / 38 to 7 / 76 in the sustained-release layer.

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

4. The double-layer oral lozenge according to claim 1, characterized in that, 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; and / or 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.

5. The double-layer oral lozenge according to claim 1, characterized in that, The weight ratio of isoquercitrin 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).

6. The double-layered lozenge according to any one of claims 1-5, characterized in that, During preparation, the mass ratio of the sustained-release layer to the immediate-release layer is 1:

1.

7. The method for preparing the double-layered oral lozenge for preventing and treating oral ulcers according to any one of claims 1-6, 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.

8. The method for preparing a double-layered oral lozenge for preventing and treating oral ulcers according to claim 7, characterized in that, The mass ratio of the sustained-release layer particles to the immediate-release layer particles in step S3 is 1:

1.

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

10. The use of the double-layered lozenge according to any one of claims 1-6 in the preparation of a medicament for the prevention or treatment of oral ulcers.

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