Probiotic oral colonization tablet

Abstract

The application discloses a probiotic oral cavity colonization tablet which is made of probiotic freeze-dried powder, biomaterial, filling agent, disintegrating agent, lubricant, biological mucous membrane adhesion material and adhesive. The application strengthens the biological adhesion of biomacromolecular material xanthan gum by modifying the biomacromolecular material xanthan gum with L-cysteine, improves the solubility of the tablet, and makes the tablet more fully dissolved in an effective time to meet the needs of the actual oral cavity environment. Meanwhile, the biomaterial is added in the tablet, and the biomaterial is applied in oral care products, so that the product can prevent and treat periodontitis and has a certain effect on local prevention of dental caries.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a probiotic oral colonization tablet. Background Technology

[0002] The primary cause of periodontal disease is bacterial infection. The oral cavity is a symbiotic environment for multiple bacterial genera. Pathogenic bacteria adhere to the tooth surface and gingival sulcus in the form of plaque, while even more pathogenic non-attached plaque exists within the periodontal pockets of diseased teeth. Therefore, anatomical variations, poor oral habits, defective dental restorations, and combined lesions can all contribute to the local retention and accumulation of pathogenic bacteria. If oral hygiene measures are not taken seriously or strengthened, regardless of whether systemic diseases or overall health conditions are present, the progression and severity of periodontal lesions will be exacerbated, thus affecting normal chewing and occlusion. Furthermore, a lack of awareness of oral health and the need for dental care among the population is also a significant contributing factor.

[0003] In the early stages of periodontitis, prevention and cleaning are the primary focus. General treatment for periodontitis includes: controlling oral plaque and maintaining oral hygiene; removing tartar and regular dental cleanings; and eliminating factors that lead to plaque retention, such as treating food impaction and filling cavities. Drug treatment for periodontitis: Drug treatment alone is not the main method of treating periodontal disease. For patients who do not respond to mechanical treatment, adjunctive medication may be considered. While antibiotics are effective in the short term, long-term use can lead to drug resistance, decreased efficacy, and disease recurrence. Surgical treatment for periodontitis: When periodontitis is severe, surgical treatment may be performed, mainly including flap surgery, bone grafting, guided tissue regeneration, and dental implantation.

[0004] To address the shortcomings of the aforementioned treatments, oral probiotic preparations can be used for the prevention and treatment of periodontitis, as well as as an adjunct to surgical treatment of periodontitis.

[0005] Lactobacillus rhamnosus (LGG) is a probiotic that has been widely and safely used in clinical gastrointestinal applications. Current research indicates that Lactobacillus rhamnosus not only affects the gut microbiota but also plays a crucial regulatory role in the oral microbial environment. It can regulate the balance of oral flora by inhibiting harmful bacteria, thereby treating periodontal diseases such as periodontitis caused by Porphyromonas gingivalis and dental caries caused by Streptococcus mutans. Currently, there are relatively few oral probiotic preparations on the market, and products that use or add oral probiotics are primarily health care products; dosage forms are mainly concentrated in lozenges, powders, mouthwashes, and chewing gum, with a large proportion being imported products. Ordinary probiotic lozenges have low bioavailability of live bacteria and are mostly used to treat halitosis and dental caries. There are few products specifically for the prevention and treatment of periodontitis, and they cannot penetrate deep into the periodontal pockets to colonize and effectively inhibit Porphyromonas gingivalis, thus failing to treat periodontitis.

[0006] Therefore, this application designs an oral colonization tablet based on the mucosal adhesion mechanism to promote the large-scale colonization of probiotics in the oral cavity, thereby regulating the oral flora and treating corresponding periodontitis, dental caries and other diseases. Summary of the Invention

[0007] The purpose of this invention is to provide a probiotic oral colonization tablet, comprising a tablet core and a bioadhesive coating layer, wherein the bioadhesive coating layer covers the outside of the tablet core;

[0008] The probiotic oral colonization tablets are prepared using the following steps:

[0009] Step 1: Mix a portion of the prescribed amount of lyophilized probiotic powder, biomineralized material, filler, disintegrant, and lubricant, and compress directly into tablets to obtain tablet cores;

[0010] Step 2: Mix the remaining amount of probiotic freeze-dried powder, biological mucosal adhesive material and adhesive evenly, take a portion of the mixture and fill it evenly at the bottom of the tablet press die, place the tablet core in the center and then fill it with the remaining amount of mixture to wrap it, and compress it directly again to obtain the final tablet.

[0011] The biomineralization material is casein phosphopeptide-amorphous calcium phosphate, and the biofilm adhesion material is L-cysteine-modified xanthan gum and guar gum.

[0012] Furthermore, the probiotic freeze-dried powder is Lactobacillus rhamnosus freeze-dried powder, the filler is selected from microcrystalline cellulose and lactose, the disintegrant is crospovidone, the lubricant is selected from magnesium stearate, sodium stearate and talc, and the binder is sodium carboxymethyl cellulose.

[0013] Further, the probiotic oral colonization tablet is made from the following raw materials in weight percentages: 1%–5% Lactobacillus rhamnosus lyophilized powder, 1%–5% casein phosphopeptide-amorphous calcium phosphate, 5%–10% microcrystalline cellulose, 20%–25% lactose, 0.5%–1% crosporinol, 0.5%–2% magnesium stearate, 5%–15% L-cysteine ​​xanthan gum, 2%–5% guar gum, and 10%–20% sodium carboxymethyl cellulose, with the sum of the weight percentages of all raw materials being 100%. Preferably, the weight ratio of L-cysteine ​​xanthan gum, guar gum, and sodium carboxymethyl cellulose is 5:2:8 or 8:5:8, more preferably 5:2:8.

[0014] Furthermore, the preparation method of the L-cysteine-modified xanthan gum is as follows: dissolve xanthan gum in water, adjust the pH to 5.5, add EDC and NHS to the solution, adjust the pH to 7.0, add L-cysteine ​​to the mixture under light-protected conditions, stir the reaction, dialyze with demineralized water after the reaction is completed, and freeze-dry after dialyzing to obtain L-cysteine-modified xanthan gum.

[0015] The proportions of xanthan gum, EDC, and NHS are as follows: 1.5g xanthan gum is dissolved in 200mL of water, and 0.28755g EDC (dissolved in 1mL of water) and 0.17264g NHS (dissolved in 4mL of water) are added to the solution. The proportions of xanthan gum and L-cysteine ​​are as follows: 1.5g xanthan gum is dissolved in 200mL of water, and then 1.45g L-cysteine ​​(dissolved in 25-35mL of water) is added to the solution for reaction.

[0016] In this invention, the casein phosphopeptide-amorphous calcium phosphate can be synthesized using the method described in this specification, or it can be prepared using commercially available products. This does not affect the efficacy of the implantation tablets of this invention.

[0017] Most existing oral probiotic preparations are ordinary lozenges, which suffer from low bioavailability, poor probiotic retention, and frequent administration. This invention designs and prepares an oral adhesive colonization tablet that significantly enhances the adhesion of tablets to the oral environment and significantly enhances the bioavailability of probiotics in the oral environment, thereby improving the effective colonization of probiotics. Compared with other ordinary probiotic preparations, it can achieve more stable release and longer retention time in vitro, improving the bioavailability of the drug in the local oral environment. Its preparation process is simple and feasible.

[0018] This invention enhances the bioadhesiveness and improves the solubility of xanthan gum by modifying it with L-cysteine, allowing for more complete dissolution within the effective time frame to meet the needs of the actual oral environment. However, the modified xanthan gum has poor stability. Therefore, guar gum is introduced into the formulation to improve the stability of the modified xanthan gum, thereby promoting tablet stability and further adjusting gel consistency. Simultaneously, casein phosphopeptide-amorphous calcium phosphate, a biomineralizing material used in oral care products, is added to the tablets. This biomineralizing material has a synergistic effect with probiotics in preventing and treating tooth decay without affecting the bioactivity of probiotics. This allows the product to provide local prevention of tooth decay while treating periodontitis.

[0019] The probiotic oral colonization tablets of the present invention use a bioadhesive material on the outer layer of the tablet, which allows the outer layer of the tablet to quickly adhere to the oral mucosa after short-term hydration, thereby gradually releasing the probiotics in the tablet near the oral lesion site, thus avoiding the large loss of probiotics in the oral cavity due to saliva flow, as with oral lozenges. Attached Figure Description

[0020] Figure 1 Standard curves for L-cysteine ​​and L-leucine.

[0021] Figure 2 Scanning electron microscope image of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP).

[0022] Figure 3 Images showing the swelling of modified xanthan gum tablets.

[0023] Figure 4 Swelling curves of tablets made for different mucosal adhesion materials.

[0024] Figure 5 The dissolution curves are for tablets with drug loading ratios of 1:0, 3:1, 2:1, and 1:1 between the tablet core and the outer mucosa.

[0025] Figure 6 The in vitro dissolution curves are for tablets with drug loading ratios of 2:1 and 1:1 between the tablet core and the outer mucosa.

[0026] Figure 7 This is an electron microscope image of a tablet with an internal and external drug loading ratio of 1:1 after swelling and coagulation.

[0027] Figure 8 These are photographs of the surface and cross-section of the oral implantation patch of the present invention. Detailed Implementation

[0028] The preferred embodiments of the present invention will now be described in detail with reference to specific examples. It should be understood that the following examples are given for illustrative purposes only and are not intended to limit the scope of the invention. Those skilled in the art can make various modifications and substitutions to the present invention without departing from its spirit and essence.

[0029] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0030] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0031] Example 1

[0032] 1. Preparation of L-cysteine-modified xanthan gum

[0033] Step 1: Dissolve 1.5g xanthan gum in 200mL of pure water and adjust the pH to 5.5;

[0034] Step 2: Add EDC (0.28755g dissolved in 1mL of pure water) and NHS (0.17264g dissolved in 4mL of pure water) to the solution to activate the carboxyl groups. After stirring for 20 minutes, adjust the pH to 7.0.

[0035] Step 3: Dissolve 1.45g of L-cysteine ​​in 25-35mL of pure water and slowly add it to the reactants (avoid light).

[0036] Step 4: Stir the reaction at room temperature for 6 hours, then collect the sample and dialyze it.

[0037] Step 5: Dialyze the product 10 times with 5L of demineralized water (10000~12000Da); after dialysis, take out the reaction product and place it in a -80℃ freezer for pre-freezing, and wait for freeze-drying.

[0038] 2. Determination of the amount of cysteine ​​modification in L-cysteine-modified xanthan gum

[0039] First, standard curves for thiol quantification were established using the Ellman thiol quantification assay and the OPA method for free amino group detection, respectively: Y = 0.2357*X - 0.04657 (R²). 2 =0.9981) and the standard curve for amino quantification: Y = 0.2971*X - 0.05725 (R = 0.9981) 2 =0.9998). For example Figure 1 As shown.

[0040] The thiol content was then quantitatively determined, as follows:

[0041] (1) Prepare sample solution: Weigh 10 mg of modified xanthan gum, dissolve it in Ellman buffer and bring the volume up to 5 mL;

[0042] (2) Prepare blank control solution: Weigh 10 mg xanthan gum, dissolve it in buffer solution and bring the volume up to 5 mL;

[0043] (3) Take two test tubes and add 50 μL of Ellman's reagent and 2.5 mL of sodium phosphate buffer solution to each test tube. Mix well, then add 50 μL of the sample to be tested to each test tube, mix well, and let stand at room temperature for 15 minutes. Use xanthan gum solution as a blank and measure the absorbance of the sample at 412 nm. The absorbance value is 0.31 A.

[0044] (4) The concentration of thiol was 151.28 μmol / g by substituting the absorbance into the standard curve Y = 0.2357*X - 0.04657.

[0045] Finally, the content of free amino groups in the system was determined, and the procedure is as follows:

[0046] (1) Prepare the sample solution: Weigh 50 mg of modified xanthan gum and dissolve it in 15 mL of water;

[0047] (2) Prepare blank control solution: Weigh 50 mg xanthan gum and dissolve it in 15 mL of water;

[0048] (3) Take two test tubes, add 40 μL of the sample to be tested and 4.8 mL of OPA / NAC reagent to each test tube, mix well, let stand at room temperature for 15 minutes, use xanthan gum solution as blank, and measure the absorbance of the sample to be tested at 340 nm. The absorbance value is 0.097 A.

[0049] (4) By substituting the absorbance into the standard curve Y = 0.2971*X - 0.05725, the concentration of free amino group, i.e. cysteine ​​that was not dialyzed out, was found to be 51.92 μmol / g.

[0050] The final calculation showed that the amount of thiol modification on the synthesized L-cysteine-modified xanthan gum was 99.36 μmol / g.

[0051] Example 2

[0052] Synthesis and Identification of Casein Phosphopeptide-Amorphous Calcium Phosphate (CPP-ACP)

[0053] Casein phosphopeptide-amorphous calcium phosphate is a biomineralized material currently used in many new oral care products. Many well-known toothpaste brands (such as Lion) incorporate this material to prevent and alleviate tooth decay. The reaction principle mainly involves the aggregation of phosphate and calcium ions at both ends of the casein phosphopeptide structure, thereby making the calcium phosphate amorphous, resulting in casein phosphopeptide-amorphous calcium phosphate. The specific synthesis method is as follows:

[0054] First, add 10 mL of deionized water to a 50 mL beaker, weigh 100 mg of anhydrous calcium chloride and place it in the beaker. After completely dissolving it by stirring with a glass rod, add 300 mg of CPP and gently stir in a 25 °C water bath for 1 hour.

[0055] Add 10 mL of deionized water to another 50 mL beaker, weigh 100 mg of Na3PO4 and add it to the beaker, stirring with a glass rod until completely dissolved. Then, quickly pour the Na3PO4 solution into the previously prepared CaCl2 solution, continue the reaction with gentle stirring in a water bath for one hour, transfer to a 50 mL centrifuge tube, and centrifuge at 6000 rpm for 10 min. After decanting the supernatant, gently wash the precipitate surface with a small amount of deionized water. Disperse the precipitate with 10 mL of deionized water to obtain a CPP-ACP dispersion. For long-term storage, freeze-dry the solution.

[0056] Subsequently, the morphology of casein phosphopeptides and the synthetic product casein phosphopeptides-amorphous calcium phosphate was scanned using a Hitachi SU8010 scanning electron microscope (Japan). The results are as follows: Figure 2As shown in the image, scanning electron microscopy reveals a significant structural change in casein phosphopeptide-amorphous calcium phosphate compared to the reactants. Under the influence of calcium phosphate, casein phosphopeptides exhibited marked aggregation, indicating the successful synthesis of casein phosphopeptide-amorphous calcium phosphate.

[0057] Example 3

[0058] Regarding the proportions of xanthan gum, guar gum, and sodium carboxymethyl cellulose, the main components of the mucosal adhesive outer layer, this embodiment uses a minimum peel force test to screen formulations. By comparing the minimum peel force required to separate the tablet from the mucosal tissue, the bioadhesive strength of different formulations is evaluated, thus identifying the optimal content ratio. The specific experimental procedure is as follows: First, a peristaltic pump is set to a flow rate of 0.5 mL / min to simulate the normal flow rate of saliva in an oral environment. After the artificial saliva flows through the mucosal tissue, tablets of each formulation are placed on the mucosal tissue. After standing for 30 seconds, the tablets are peeled off the tissue using a tensile tester, and the tensile force (g) required to peel the tablet is recorded. Each experiment is repeated twice.

[0059] The formulation of the tablets in this embodiment is as follows:

[0060]

[0061] The experimental results are as follows:

[0062]

[0063] By comprehensively comparing the minimum peel force required for different ratios of prescription tablets (xanthan gum: guar gum: CMC), it can be seen that tablets with ratios of 8:5:8 and 5:2:8 have relatively optimal biofilm adhesion properties.

[0064] By observing the appearance and other properties of the tablets, it was found that tablets with a 5:2:8 ratio had a smoother and cleaner appearance. Therefore, a 5:2:8 ratio was selected as the outer layer formulation for the tablets. Since the polymer materials can interact and exert a physical bond, they enhance the gel strength of individual polymer materials. This improvement in gel strength is also reflected in the subsequent swelling experiment results.

[0065] Example 4

[0066] Proper swelling behavior of the oral adhesive system is essential for uniform and effective adhesion. The swelling of tablets increases their weight and volume due to the absorption of fluid. Tablets were weighed and fixed onto 2×2 cm slides to measure the swelling index. The slides with the fixed tablets were immersed in 10 mL of artificial saliva (pH 6.8). The study was conducted at a constant temperature of 37 ± 0.5 °C. Tablets were removed from the petri dish at regular intervals, dried with filter paper to remove excess surface moisture, and then weighed again.

[0067] The formula is as follows: Swelling index (%) = (W2 - W1) / W1 × 100%, where W1 is the initial weight of the tablet and W2 is the final weight of the swollen tablet. Each experiment was repeated three times.

[0068] The formulation of the tablets in this embodiment is as follows:

[0069]

[0070] like Figure 3 As shown, during the formulation screening process, the modified xanthan gum tablets exhibit a large swelling volume and are mostly in a loose state. Under the influence of mechanical activity, the outer layer can be rapidly lost. For example... Figure 4 The figure shows the swelling curves of tablets made from different mucosal adhesion materials during the formulation screening process. As can be seen from the figure, the swelling performance of modified xanthan gum (L-XG) is still at a higher level than that of xanthan gum (XG), but lower than that of xanthan gum. Moreover, the swelling performance of modified xanthan gum is higher than that of other biological mucosal adhesion materials such as chitosan and sodium carboxymethyl cellulose (HPMC).

[0071] Example 5

[0072] In vitro dissolution study on the drug loading ratio of the inner and outer layers of Lactobacillus rhamnosus colonized tablets.

[0073] 1. Prepare 20 tablets of Lactobacillus rhamnosus oral colonization formulation with an inner-outer layer drug loading ratio of 1:1.

[0074] The prescription is as follows:

[0075] Chip:

[0076]

[0077]

[0078] Preparation method: The lyophilized Lactobacillus rhamnosus powder and excipients were passed through an 80-mesh sieve separately. The prescribed amounts of Lactobacillus rhamnosus and excipients were weighed and thoroughly mixed using an equal-incremental mixing method. The mixture was then sieved and thoroughly mixed. An appropriate amount of magnesium stearate was added externally, and the mixture was thoroughly mixed. The Lactobacillus rhamnosus tablet core was prepared using the direct powder compression method. Alternatively, the prescribed amounts of lyophilized Lactobacillus rhamnosus powder, L-cysteine ​​xanthan gum, guar gum, and sodium carboxymethyl cellulose were passed through an 80-mesh sieve and thoroughly mixed using an equal-incremental mixing method. After sieving and mixing, half of the bioadhesive coating material was evenly filled into the bottom of the die. The tablet core was placed in the center, and the other half of the bioadhesive coating material was filled in. The tablets were then directly compressed a second time to obtain the final tablet.

[0079] 2. Preparation of 20 tablets of Lactobacillus rhamnosus oral colonization formulation with an inner-outer layer drug loading ratio of 1:0.

[0080] Chip:

[0081]

[0082] Outer layer:

[0083]

[0084] Preparation method: The lyophilized Lactobacillus rhamnosus powder and excipients were passed through an 80-mesh sieve separately. The prescribed amounts of Lactobacillus rhamnosus and excipients were weighed and thoroughly mixed using an equal-incremental mixing method. The mixture was then sieved and thoroughly mixed. An appropriate amount of magnesium stearate was added externally, and the mixture was thoroughly mixed. The Lactobacillus rhamnosus tablet core was prepared using the direct powder compression method. Alternatively, the prescribed amounts of lyophilized Lactobacillus rhamnosus powder, L-cysteine ​​xanthan gum, guar gum, and sodium carboxymethyl cellulose were passed through an 80-mesh sieve and thoroughly mixed using an equal-incremental mixing method. After sieving and mixing, half of the bioadhesive coating material was evenly filled into the bottom of the die. The tablet core was placed in the center, and the other half of the bioadhesive coating material was filled in. The tablets were then directly compressed a second time to obtain the final tablet.

[0085] 3. Prepare 20 tablets of Lactobacillus rhamnosus oral colonization formulation with an inner-outer layer drug loading ratio of 3:1.

[0086] Chip:

[0087]

[0088] Outer layer:

[0089]

[0090] Preparation method: The lyophilized Lactobacillus rhamnosus powder and excipients were passed through an 80-mesh sieve separately. The prescribed amounts of Lactobacillus rhamnosus and excipients were weighed and thoroughly mixed using an equal-incremental mixing method. The mixture was then sieved and thoroughly mixed. An appropriate amount of magnesium stearate was added externally, and the mixture was thoroughly mixed. The Lactobacillus rhamnosus tablet core was prepared using the direct powder compression method. Alternatively, the prescribed amounts of lyophilized Lactobacillus rhamnosus powder, L-cysteine ​​xanthan gum, guar gum, and sodium carboxymethyl cellulose were passed through an 80-mesh sieve and thoroughly mixed using an equal-incremental mixing method. After sieving and mixing, half of the bioadhesive coating material was evenly filled into the bottom of the die. The tablet core was placed in the center, and the other half of the bioadhesive coating material was filled in. The tablets were then directly compressed a second time to obtain the final tablet.

[0091] 4. Prepare 20 tablets of Lactobacillus rhamnosus oral colonization formulation with an inner-outer layer drug loading ratio of 2:1.

[0092] Chip:

[0093]

[0094] Outer layer:

[0095]

[0096]

[0097] Preparation method: The lyophilized Lactobacillus rhamnosus powder and excipients were passed through an 80-mesh sieve separately. The prescribed amounts of Lactobacillus rhamnosus and excipients were weighed and thoroughly mixed using an equal-incremental mixing method. The mixture was then sieved and thoroughly mixed. An appropriate amount of magnesium stearate was added externally, and the mixture was thoroughly mixed. The Lactobacillus rhamnosus tablet core was prepared using the direct powder compression method. Alternatively, the prescribed amounts of lyophilized Lactobacillus rhamnosus powder, L-cysteine ​​xanthan gum, guar gum, and sodium carboxymethyl cellulose were passed through an 80-mesh sieve and thoroughly mixed using an equal-incremental mixing method. After sieving and mixing, half of the bioadhesive coating material was evenly filled into the bottom of the die. The tablet core was placed in the center, and the other half of the bioadhesive coating material was filled in. The tablets were then directly compressed a second time to obtain the final tablet.

[0098] According to the dissolution test method in the 2020 edition of the Chinese Pharmacopoeia, the paddle method was used to conduct dissolution tests on tablets with core-to-mucosal drug loading ratios of 1:0, 3:1, 2:1, and 1:1 in 1 L of artificial saliva at 37℃. Samples were collected at 0.5h, 1.0h, 1.5h, 2.0h, 3.0h, 4.0h, 6.0h, and 8.0h after the start of the experiment and plated. Each time point was plated three times in parallel. After incubation at 37℃ under aerobic conditions for 48h, the number of *Lactobacillus rhamnosus* was counted, and dissolution curves were plotted. The dissolution results are as follows: Figure 5 As shown, when the drug loading ratio of the inner and outer layers is 1:0 and 3:1, the dissolution rate of probiotics is low and the release after six hours is too low. Further screening and comparison will be conducted on formulations with drug loading ratios of 2:1 and 1:1.

[0099] To simulate the actual dissolution of oral patches on the oral mucosa as closely as possible, and to further screen and compare formulations with drug loading ratios of 2:1 and 1:1 between the core and the outer mucosa, a 50mL EP tube was used as the dissolution test container. Glass beads from the flow cell method were filled at the bottom of the container to simulate the oral mucosa. The tablet was adhered to the beads, and 15mL of artificial saliva was added. The container was placed in a shaker at 37℃ and 50rpm for dissolution testing. Samples were collected at 0.5, 1, 1.5, 2, 3, 4, 5, and 6 hours, and after complete mixing at the end of the experiment, for plate coating. Each time point was coated three times in parallel. After 48 hours of incubation at 37℃ under aerobic conditions, the number of *Lactobacillus rhamnosus* was counted, and a dissolution curve was plotted. The dissolution results are as follows: Figure 6As shown, the formulation with a drug loading ratio of 2:1 between the inner and outer layers had an average cumulative release of 65.1% over 6 hours, while the formulation with a drug loading ratio of 1:1 had an average cumulative release of 78.3% over 6 hours. Furthermore, repeated experimental comparisons revealed that when the drug loading ratio of the tablet core to the outer layer was 1:1, the cumulative release rate and amount were better, and the curve was smoother. Moreover, the release was more complete at 4, 5, and 6 hours, reaching 48%, 63%, and 78%, respectively. Therefore, the formulation with a drug loading ratio of 1:1 is considered the optimal formulation.

[0100] The morphology of tablets with a drug loading ratio of 1:1 after full swelling was analyzed using a Hitachi SU8010 scanning electron microscope (Japan). The results are as follows: Figure 7 As shown in the scanning electron microscope images, the probiotic oral colonization tablets, after fully swelling in the simulated oral environment, exhibit a dense network macromolecular structure resembling a gel. This structure allows for the sustained release of probiotics, and the high viscosity after gelation enables the tablets to remain in the oral cavity for an extended period, thereby promoting the colonization of probiotics in the oral cavity.

[0101] like Figure 8 As shown, the surface and cross-section of the final prescription tablets were photographed and recorded using a digital camera. The images show that the tablets have a round and smooth appearance, and the cross-sectional photographs also show that they have a regular double-layer tablet structure.

Claims

1. A probiotic oral colonization tablet, characterized in that, The tablet comprises a tablet core and a bioadhesive coating layer, and the bioadhesive coating layer is coated on the tablet core; The probiotic oral colonization tablet is prepared by the following steps: Step 1: mixing part of the prescription amount of probiotic freeze-dried powder, biomaterial, filler, disintegrant and lubricant, and directly compressing to obtain a tablet core; Step 2: mixing the remaining prescription amount of probiotic freeze-dried powder, biomembrane adhesive material and adhesive, taking part of the mixture to uniformly fill the bottom of the tablet press die, placing the tablet core in the center position, and then filling the remaining amount of mixture to wrap, and directly compressing again to obtain the final tablet; The probiotic freeze-dried powder is Lactobacillus rhamnosus freeze-dried powder, the biomaterial is casein phosphopeptide-amorphous calcium phosphate, the filler is microcrystalline cellulose and lactose, the disintegrant is cross-linked polyvinylpyrrolidone, and the lubricant is magnesium stearate; The biomembrane adhesive material is L-cysteine-modified xanthan gum and guar gum, and the adhesive is sodium carboxymethyl cellulose; the weight ratio of the L-cysteine-modified xanthan gum, guar gum and sodium carboxymethyl cellulose is 5:2:8; The prescription of the probiotic oral colonization tablet is as follows: Tablet core: Lactobacillus rhamnosus freeze-dried powder 40 mg Casein phosphopeptide-amorphous calcium phosphate 100 mg Microcrystalline cellulose 237 mg Lactose 711 mg Cross-linked polyvinylpyrrolidone 22 mg Magnesium stearate 12 mg Bioadhesive coating layer: Lactobacillus rhamnosus freeze-dried powder 40 mg L-cysteine xanthan gum 580 mg Guar gum 232 mg Sodium carboxymethyl cellulose 928 mg Magnesium stearate 20 mg.

2. The probiotic oral colonisation tablet according to claim 1, characterised in that, The preparation method of the L-cysteine-modified xanthan gum is as follows: dissolving xanthan gum in water, adjusting the pH to 5.5, adding EDC and NHS to the solution, adjusting the pH to 7.0, adding L-cysteine to the mixture under light-proof conditions, stirring and reacting, dialyzing with demineralized water after the reaction is completed, and freeze-drying after the dialysis is completed to obtain the L-cysteine-modified xanthan gum.

3. The probiotic oral colonizing tablet according to claim 2, characterized in that, The dosage ratio of xanthan gum, EDC and NHS is: 1.5 g of xanthan gum is dissolved in 200 mL of water, and 0.2875 g of EDC and 0.1726 g of NHS are added thereto; the dosage ratio of xanthan gum and L-cysteine is: 1.5 g of xanthan gum is dissolved in 200 mL of water, and then 1.45 g of L-cysteine is added for reaction.

Images