A mucoadhesive material having single-sided bioadhesion and a method of preparing the same

Abstract

The application belongs to the technical field of medical materials, and discloses a mucous membrane adhesive material with single-face biological adhesion and a preparation method thereof.The mucous membrane adhesive material comprises the following components: an ion cross-linking aggregate and a water storage material; the ion cross-linking aggregate is formed by pre-crosslinking raw materials comprising a cationic polymer and an anionic polymer; the water storage material comprises at least one of hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxymethyl starch, hyaluronic acid and gelatin; and the mass ratio of the anionic polymer, the cationic polymer and the water storage material is (2-5) : 1 : (2-5). The mucous membrane adhesive material has the characteristics of single-face biological adhesion and good adhesion performance, can play a good role in protecting and promoting repair of mucous membrane wounds, has excellent use experience, and has a wide application prospect in the field of mucous membrane wound treatment preparations.

Description

Technical Field

[0001] This invention belongs to the field of medical materials technology, and in particular relates to a mucosal adhesive material with single-sided bioadhesion and its preparation method. Background Technology

[0002] Bioadhesion is the property of some adhesive materials to adhere to biological tissues, especially mucus-covered epithelial tissues such as the gastric, oral, vaginal, and rectal mucosa. Oral ulcers, also known as canker sores, are superficial ulcers that occur on the oral mucosa and commonly appear on the tongue, lips, cheeks, vestibule, and soft palate, exhibiting a cyclical pattern. Currently, there are numerous oral ulcer preparations on the market, including solid powders, ointments, gels, films, and sprays. Most existing technologies employ adhesive substances to cover the mucosal wound, but this approach presents two main problems:

[0003] (1) Most oral ulcer preparations have poor bioadhesion. For example, chitosan oral ulcer films can quickly adhere to the oral mucosa, but they dissolve within minutes in the moist oral environment. Oral ulcer sprays, for instance, utilize the principle of soluble polymer film formation, but film formation only occurs on dry mucosal surfaces where the spray liquid evaporates. In reality, the moist oral environment makes film formation difficult. Therefore, most oral ulcer preparations struggle to achieve continuous protection and prolonged wound treatment.

[0004] (2) Some researchers have used materials with strong adhesion to make ointments and gels, such as preparations with acrylic acid as the main component. Although these can adhere quickly to the mucosa and dissolve slowly, thus prolonging the retention time, such medical adhesive preparations not only adhere to the mucosa of the wound surface, but also adhere to other mucosal surfaces in the oral cavity, causing the mucosa to stick together and pull on the protective film, resulting in a poor user experience.

[0005] In view of the shortcomings of existing mucosal wound treatment agents, the present invention aims to propose a mucosal adhesion material that can achieve single-sided mucosal adhesion and has good bioadhesion performance. Summary of the Invention

[0006] This invention aims to solve at least one of the technical problems existing in the prior art. To this end, this invention proposes a mucosal adhesive material with single-sided bioadhesion and its preparation method. The mucosal adhesive material proposed in this invention possesses both single-sided bioadhesion and good adhesion performance, enabling it to effectively protect and promote the repair of mucosal wounds, and providing an excellent user experience. It has broad application prospects in the field of mucosal wound treatment preparations.

[0007] This invention provides a mucosal adhesive material with single-sided bioadhesive properties, comprising the following components: an ionic cross-linked aggregate and a water-retaining material; the ionic cross-linked aggregate is formed by pre-cross-linking raw materials containing cationic polymers and anionic polymers;

[0008] The water storage material includes at least one of hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxymethyl starch, hyaluronic acid, and gelatin;

[0009] The mass ratio of the anionic polymer, cationic polymer, and water storage material is (2-5):1:(2-5).

[0010] The cationic and anionic polymers form ionic cross-linked aggregates through a "pre-cross-linking" process. These aggregates spontaneously form stable and robust hydrogels on the mucosal surface, preventing easy loss or detachment, thus exhibiting excellent bioadhesion and acting as a very effective mucosal barrier. Furthermore, although the anionic and cationic polymers have good mucosal adhesion while the water-storage material has weaker adhesion, the addition of a specific ratio of water-storage material can create a synergistic effect with the anionic and cationic polymers, thereby effectively enhancing adhesion performance.

[0011] Meanwhile, another function of the water storage material is that it can not only accelerate the formation of hydrogel during use, but also form a "hydration layer" on the interface of the external environment. This "hydration layer" has a lubricating effect and weak adhesion, and will not re-adhere to other mucous membranes, thus preventing the mucous membranes from sticking to each other, thereby achieving the effect of one-sided bioadhesion. It can also effectively prevent external forces from damaging the hydrogel film layer formed by the mucous membrane adhesion material, and can slow down the dissolution and erosion of the coating by more external liquids, playing a barrier and protective role.

[0012] Preferably, the cationic polymer is selected from at least one of chitosan, carboxymethyl chitosan, cellulose quaternary ammonium salt, and polyethyleneimine.

[0013] Preferably, the anionic polymer is selected from at least one of polyacrylic acid or its salt, polymethacrylic acid or its salt, polyvinyl sulfonic acid or its salt, anionic polyacrylamide or its salt, carbomer, and polycarbofil.

[0014] Preferably, the adhesive material further contains a solvent.

[0015] When solvent-free, the mucosal adhesive material is in powder form, which can be easily sprayed onto the mucous membranes of internal cavities of the human body, such as the mucous membranes of the upper and lower digestive tracts and the nasal cavity. However, when the solvent is an oil-based solvent, the mucosal adhesive material is a fluid or semi-fluid paste, which can be easily applied to exposed mucous membranes, such as the oral cavity and vagina. When the solvent is an aqueous solvent, the mucosal adhesive material is a semi-solid gel, which can be easily applied to mucous membranes with high water content, such as the eye mucous membranes.

[0016] More preferably, the solvent is selected from at least one of water, liquid paraffin, and petrolatum.

[0017] More preferably, the solvent is a combination of liquid paraffin and petroleum jelly, with a mass ratio of liquid paraffin to petroleum jelly of 10:1. Using this oily solvent allows the formed "hydration layer" to have better lubrication and improved single-sided adhesion.

[0018] Preferably, the mucosal adhesion material further comprises a therapeutic drug. The types of therapeutic drugs include, but are not limited to, penicillin, chlorhexidine, dexamethasone, and oxytinidin. The addition of a therapeutic drug can improve the effectiveness of wound repair and treatment.

[0019] The present invention also provides a method for preparing the above-mentioned mucosal adhesion material, comprising the following steps:

[0020] (1) Dissolve the cationic polymer and the anionic polymer in water respectively to obtain a cationic polymer solution and an anionic polymer solution; add the anionic polymer solution dropwise to the cationic polymer solution during stirring to obtain a pre-crosslinked solution;

[0021] (2) Dissolve the water storage material in water to obtain a water storage material solution; mix the water storage material solution with the pre-crosslinking solution and dry to obtain the mucosa adhesion material.

[0022] Preferably, the viscosity of the anionic polymer solution in step (1) is 100-1000 mPa·s, and the viscosity of the cationic polymer solution is no more than 10 mPa·s. The above viscosity values ​​were measured at room temperature (25°C).

[0023] Preferably, the drying method in step (2) is freeze drying.

[0024] This invention also provides the application of the above-mentioned mucosal adhesive material in the preparation of mucosal wound treatment agents. Mucosal wound treatment agents prepared using the above-mentioned mucosal adhesive material can effectively protect the wound, isolate the mucosal wound, prevent the mucosal wound from contacting the external environment, reduce irritation, relieve ulcer pain, and promote ulcer repair.

[0025] Preferably, the mucosal wound treatment preparation is a wound treatment preparation for any one of the mucosa of the mouth, vagina, or eye.

[0026] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0027] This invention combines anionic and cationic polymers that form a "pre-crosslinked" network with a water-retaining material. The resulting mucosal adhesive material not only significantly improves adhesion performance but also prevents mucosa from sticking together, thereby achieving one-sided bioadhesion. It demonstrates good mucosal wound protection and promotes repair, and provides an excellent user experience. Detailed Implementation

[0028] To enable those skilled in the art to more clearly understand the technical solutions described in this invention, the following embodiments are provided for illustration. It should be noted that the following embodiments are merely preferred embodiments of this invention and do not constitute a limitation on the scope of protection claimed by this invention. Any modifications, substitutions, or combinations made without departing from the spirit and principle of this invention are included within the scope of protection of this invention.

[0029] Unless otherwise specified, the raw materials, reagents or devices used in the following examples are available from conventional commercial sources or can be obtained by existing known methods.

[0030] Example 1

[0031] This embodiment provides an adhesive film material, the preparation method of which includes the following steps:

[0032] Dissolve 1 g of carboxymethyl chitosan in 20 mL of water, stir at 200 rpm for 6 hours, sonicate for 30 min, and let stand overnight to obtain a carboxymethyl chitosan solution (viscosity approximately 5 mPa·s); dissolve 5 g of carbomer in 500 mL of water, stir at 200 rpm for 6 hours, sonicate for 30 min, and let stand overnight to obtain a carbomer solution (viscosity approximately 600 mPa·s).

[0033] Carbomer solution was added dropwise to carboxymethyl chitosan solution while stirring at 2000 rpm. After the addition was complete, stirring was continued overnight to obtain a solution in which anions and cations were pre-crosslinked. The liquid in this solution was then evaporated using a vacuum rotary evaporator to form a concentrated composite solution.

[0034] Dissolve 5g of hydroxypropyl methylcellulose in water, add 0.1g of oxytinididine powder, stir at low speed of 200rpm for 6 hours, and let stand overnight to obtain a hydroxypropyl methylcellulose solution.

[0035] The concentrated composite solution was added to the hydroxypropyl methylcellulose solution, stirred at low speed of 500 rpm for 6 hours, and ultrasonically dispersed for 30 minutes. The mixture was then frozen at -20℃ for 2 hours, freeze-dried under vacuum, ground, and sieved to obtain a powdered adhesive film material.

[0036] Example 2

[0037] This embodiment provides an adhesive film material, the preparation method of which includes the following steps:

[0038] Take 10g of liquid paraffin and 1g of petroleum jelly, heat and stir at 80°C for 30 minutes, add 9g of the powdered adhesive film material prepared in Example 1, and stir while cooling at a speed of 800rpm. After stirring for 2 hours, cool to room temperature to obtain the paste-like adhesive film material.

[0039] Example 3

[0040] This embodiment provides an adhesive film material, the preparation method of which includes the following steps:

[0041] Dissolve 2.5 g of carboxymethyl chitosan in 50 mL of water, stir at 200 rpm for 6 hours, sonicate for 30 min, and let stand overnight to obtain a carboxymethyl chitosan solution (viscosity approximately 5 mPa·s); dissolve 5 g of carbomer in 500 mL of water, stir at 200 rpm for 6 hours, sonicate for 30 min, and let stand overnight to obtain a carbomer solution (viscosity approximately 600 mPa·s).

[0042] Carbomer solution was added dropwise to carboxymethyl chitosan solution while stirring at 2000 rpm. After the addition was complete, stirring was continued overnight to obtain a solution in which anions and cations were pre-crosslinked. The liquid in this solution was then evaporated using a vacuum rotary evaporator to form a concentrated composite solution.

[0043] Dissolve 5g of hydroxypropyl methylcellulose in water, add 0.1g of oxytinididine powder, stir at low speed of 200rpm for 6 hours, and let stand overnight to obtain a hydroxypropyl methylcellulose solution.

[0044] The concentrated composite solution was added to the hydroxypropyl methylcellulose solution, stirred at low speed of 500 rpm for 6 hours, and ultrasonically dispersed for 30 minutes. The mixture was then frozen at -20℃ for 2 hours, freeze-dried under vacuum, ground, and sieved to obtain a powdered adhesive film material.

[0045] Example 4

[0046] This embodiment provides an adhesive film material, the preparation method of which includes the following steps:

[0047] Take 10g of liquid paraffin and 1g of petroleum jelly, heat and stir at 80 degrees for 30 minutes, add 9g of the powdered adhesive film material prepared in Example 3, and stir while cooling at a speed of 800 rpm. After stirring for 2 hours, cool to room temperature to obtain the paste-like adhesive film material.

[0048] Comparative Example 1

[0049] This comparative example provides an adhesive film material, the preparation method of which includes the following steps:

[0050] Dissolve 1g of carboxymethyl chitosan in 20mL of water, stir at 200rpm for 6 hours, sonicate for 30min, and let stand overnight to obtain a carboxymethyl chitosan solution (viscosity approximately 5mPa·s); evaporate the liquid of the solution using vacuum rotary evaporation to form a concentrated solution.

[0051] Dissolve 5g of hydroxypropyl methylcellulose in water, add 0.1g of oxytinididine powder, stir at low speed of 200rpm for 6 hours, and let stand overnight to obtain a hydroxypropyl methylcellulose solution.

[0052] The concentrated solution was added to the hydroxypropyl methylcellulose solution, stirred at low speed of 500 rpm for 6 hours, and ultrasonically dispersed for 30 minutes. The mixture was then frozen at -20℃ for 2 hours, freeze-dried under vacuum, ground, and sieved to obtain a powdered adhesive film material.

[0053] The difference between Comparative Example 1 and Example 1 is that Comparative Example 1 does not contain carbomer (i.e., anionic polymer).

[0054] Comparative Example 2

[0055] This comparative example provides an adhesive film material, the preparation method of which includes the following steps:

[0056] Dissolve 5g of carbomer in 500mL of water, stir at 200rpm for 6 hours, sonicate for 30min, and let stand overnight to obtain a carbomer solution (viscosity approximately 600mPa·s); evaporate the liquid of the solution using vacuum rotary evaporation to form a concentrated solution.

[0057] Dissolve 5g of hydroxypropyl methylcellulose in water, add 0.1g of oxytinididine powder, stir at low speed of 200rpm for 6 hours, and let stand overnight to obtain a hydroxypropyl methylcellulose solution.

[0058] The concentrated solution was added to the hydroxypropyl methylcellulose solution, stirred at low speed of 500 rpm for 6 hours, and ultrasonically dispersed for 30 minutes. The mixture was then frozen at -20℃ for 2 hours, freeze-dried under vacuum, ground, and sieved to obtain a powdered adhesive film material.

[0059] Compared to Example 1, Comparative Example 2 differs in that it does not contain carboxymethyl chitosan (i.e., a cationic polymer).

[0060] Comparative Example 3

[0061] This comparative example provides an adhesive film material, the preparation method of which includes the following steps:

[0062] Dissolve 1 g of carboxymethyl chitosan in 20 mL of water, stir at 200 rpm for 6 hours, sonicate for 30 min, and let stand overnight to obtain a carboxymethyl chitosan solution (viscosity approximately 5 mPa·s); dissolve 5 g of carbomer in 500 mL of water, stir at 200 rpm for 6 hours, sonicate for 30 min, and let stand overnight to obtain a carbomer solution (viscosity approximately 600 mPa·s).

[0063] Carbomer solution was added dropwise to carboxymethyl chitosan solution while stirring at 2000 rpm. After the addition was complete, stirring was continued overnight to obtain a solution in which anions and cations were pre-crosslinked. The liquid in this solution was evaporated using a vacuum rotary evaporator to form a concentrated composite solution. The solution was then frozen at -20°C for 2 hours, freeze-dried under vacuum, ground, and sieved to obtain a powdered adhesive film material.

[0064] Compared to Example 1, Comparative Example 3 differs in that it does not contain hydroxypropyl methylcellulose (i.e., a water-retaining material).

[0065] Comparative Example 4

[0066] This comparative example provides an adhesive film material, the preparation method of which includes the following steps:

[0067] Take 1g of carboxymethyl chitosan powder, 5g of carbomer powder, 5g of hydroxypropyl methylcellulose powder and 0.1g of oxytinidin powder, mix them evenly to obtain a powdered mucosal adhesion material.

[0068] Compared to Example 1, in this comparative example, carboxymethyl chitosan (i.e., cationic polymer) and carbomer (i.e., anionic polymer) did not form a pre-crosslinked network.

[0069] Comparative Example 5

[0070] This comparative example provides a mucosal adhesion material, the preparation method of which is basically the same as that of Example 1, the only difference being that the amount of components used in Comparative Example 5 is 1g of carboxymethyl chitosan, 5g of carbomer, and 9g of hydroxypropyl methylcellulose.

[0071] Comparative Example 6

[0072] Take 10g of liquid paraffin and 1g of petroleum jelly, heat and stir at 80 degrees for 30 minutes. Take 9g of each of the powdered adhesive materials prepared in Comparative Examples 1, 2, 3 and 4, add them to the mixture, and stir while cooling at a speed of 800 rpm. After stirring for 2 hours, cool to room temperature to obtain a paste-like adhesive material. The products obtained are named Comparative Example 6-1, Comparative Example 6-2, Comparative Example 6-3 and Comparative Example 6-4, respectively.

[0073] Product effectiveness test

[0074] 1. Erosion resistance test

[0075] Products from each embodiment and comparative example were tested, with porcine gastric mucosa selected to test the mucosal adhesion performance of the coating. Equal masses of powder were uniformly applied to porcine gastric mucosa, allowed to stand for 2 minutes, and then the coating was rinsed with water at the same flow rate. The time it took for the coating to peel off was tested (the upper limit of the test time was 10 minutes). This test characterizes the coating's adhesion ability to the mucosa, and the test results are shown in Table 1.

[0076] Table 1. Effluent Resistance Time

[0077] scouring time Example 1 10min Example 2 10min Example 3 10min Example 4 10min Comparative Example 1 34s Comparative Example 2 2min Comparative Example 3 268s Comparative Example 4 6min Comparative Example 5 144s Comparative Example 6-1 30s Comparative Example 6-2 111s Comparative Example 6-3 275s Comparative Example 6-4 5min

[0078] As shown in Table 1, the adhesive strength of the comparative examples is generally weaker than that of the embodiments. Comparative Examples 1, 2, 3, and 6-1, 6-2, 6-3 exhibit the weakest adhesive strength, indicating that anionic polymers, cationic polymers, and water-retaining materials must be present simultaneously to achieve a strong adhesive effect. Among these, compared to the embodiments, Comparative Examples 3 and 6-3 have shorter scouring times, suggesting that although the anionic and cationic polymers have better adhesive strength and the water-retaining material has weaker adhesive strength, their combination can produce an adhesive material with even better adhesion.

[0079] The results of Comparative Examples 4 and 6-4 show that although the simultaneous presence of anionic polymers, cationic polymers, and water-retaining materials can enhance the adhesion of the membrane, the adhesion ability is still not ideal compared to the examples because they lack a "pre-crosslinked" network.

[0080] The scouring resistance time of the adhesive film prepared in Comparative Example 5 was shorter, indicating that its adhesion was poor when there was too much water-retaining material. Furthermore, compared to Comparative Example 3, Comparative Example 5 had an even shorter scouring resistance time, suggesting that excessive water-retaining material may result in even worse scouring resistance than no water-retaining material. Therefore, the amount of water-retaining material added needs to be kept within an appropriate range.

[0081] 2. Double-sided adhesion test

[0082] The products of each embodiment and comparative example were tested, and the mucosal adhesion performance of the coating was tested on porcine gastric mucosa. The same mass of powder was taken and evenly coated on porcine gastric mucosa, while another layer of porcine gastric mucosa was covered on top to form a "sandwich" structure. After standing for 5 minutes, the double-sided adhesion performance was tested with a tensile tester. The test results are shown in Table 2.

[0083] Table 2 Double-sided adhesion test

[0084] Double-sided adhesion Example 1 1.9N Example 2 1.4N Example 3 1.7N Example 4 1.3N Comparative Example 1 0.8N Comparative Example 2 1.1N Comparative Example 3 5.2N Comparative Example 4 0.9N Comparative Example 5 1.1N Comparative Example 6-1 0.8N Comparative Example 6-2 1.0N Comparative Example 6-3 4.9N Comparative Example 6-4 0.9N

[0085] As shown in Table 2, Comparative Examples 3 and 6-3 exhibit the strongest double-sided adhesion. This is because, without the addition of a water-retaining material, the coating fails to form an effective "hydration layer" after adhering to the mucosa, leading to easy adhesion between mucosa sections. This undoubtedly causes discomfort in the mucosal cavities. In contrast, Examples 1-4 show relatively low double-sided adhesion. Combined with the analysis of erosion resistance above, Examples 1-4 demonstrate extremely strong mucosal adhesion and low double-sided adhesion. This allows the mucosal adhesive material to stably cover the ulcer wound without adhering to other mucosa sections, providing excellent protection and promoting healing of the mucosal wound, and offering a superior user experience.

[0086] The embodiments of this application have been described in detail above. However, this application is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of this application. Furthermore, unless otherwise specified, the embodiments and features described in the embodiments of this application can be combined with each other.

Claims

1. A mucosal adhesion material, characterized in that, It consists of the following components: ion-crosslinked aggregates and water-storing materials; the ion-crosslinked aggregates are formed by pre-crosslinking raw materials containing cationic polymers and anionic polymers; The mass ratio of the anionic polymer, cationic polymer, and water storage material is (2-5): 1: (2-5); The anionic polymer is carbomer; the cationic polymer is carboxymethyl chitosan; and the water storage material is hydroxypropyl methylcellulose. The steps of the preparation method of the mucosal adhesion material are as follows: (1) Dissolve the cationic polymer and the anionic polymer in water respectively to obtain a cationic polymer solution and an anionic polymer solution; add the anionic polymer solution dropwise to the cationic polymer solution during stirring to obtain a pre-crosslinked solution; (2) Dissolve the water storage material in water to obtain a water storage material solution; mix the water storage material solution with the pre-crosslinking solution and dry to obtain the mucosa adhesion material.

2. The adhesive film material according to claim 1, characterized in that, The adhesive film also contains a solvent.

3. The adhesive film material according to claim 2, characterized in that, The solvent is selected from at least one of liquid paraffin and petrolatum.

4. The mucosal adhesion material according to claim 2, characterized in that, The solvent is a combination of liquid paraffin and petrolatum, with a mass ratio of liquid paraffin to petrolatum of 10:

1.

5. The adhesive film material according to any one of claims 1-4, characterized in that, The mucosal adhesion material also contains therapeutic drugs.

6. A method for preparing a mucosal adhesion material, characterized in that, The steps are as follows: (1) Dissolve the cationic polymer and the anionic polymer in water respectively to obtain a cationic polymer solution and an anionic polymer solution; add the anionic polymer solution dropwise to the cationic polymer solution during stirring to obtain a pre-crosslinked solution; (2) Dissolve the water storage material in water to obtain a water storage material solution; mix the water storage material solution with the pre-crosslinking solution and dry to obtain the mucosa adhesion material; The anionic polymer is carbomer; the cationic polymer is carboxymethyl chitosan; and the water storage material is hydroxypropyl methylcellulose. The mass ratio of the anionic polymer, cationic polymer, and water storage material is (2-5): 1: (2-5).

7. The preparation method according to claim 6, characterized in that, The viscosity of the anionic polymer solution in step (1) is 100-1000 mPa·s, and the viscosity of the cationic polymer solution is no more than 10 mPa·s.

8. The preparation method according to claim 6, characterized in that, The drying method described in step (2) is freeze drying.

9. The use of the mucosal adhesive material according to any one of claims 1-4 in the preparation of mucosal wound treatment formulations.