Wet-adhesion dolpang oral patch for treating chemotherapy-induced oral mucosa ulcer and preparation method of wet-adhesion dolpang oral patch

Abstract

The invention relates to the field of oral medicine, relates to a duofiping oral patch for treating chemotherapy-induced oral mucosa ulcer, and in particular relates to a wet adhesion duofiping oral patch for treating chemotherapy-induced oral mucosa ulcer and a preparation method of the wet adhesion duofiping oral patch. The bonding layer and the medicine carrying layer of the Duofiping oral patch are manufactured through the 3D printing technology, the oral patch manufactured through the 3D printing technology is uniform in medicine content, and the difference between different production batches is small; an in-vitro drug release test shows that the patch can slowly release doxepin within 4 hours.

Description

Technical Field

[0001] This invention relates to the field of oral medicine, and specifically to a doxepin oral patch for treating chemotherapy-induced oral mucosal ulcers, particularly a wet-adhesive doxepin oral patch for treating chemotherapy-induced oral mucosal ulcers, its preparation method, and its uses. Background Technology

[0002] Chemotherapy-induced oral mucositis (CIOM) refers to lesions on the oral mucosa of cancer patients after treatment with chemotherapy drugs, molecularly targeted drugs, or immunotherapies. These lesions are characterized by hyperemia, erosion, ulceration, pseudomembrane formation, and atrophy. In recent years, with the development of novel anti-tumor treatment strategies such as molecularly targeted therapy and immunotherapy, the resulting oral mucositis has gradually attracted attention. For example, the incidence of immune checkpoint inhibitor-related oral mucositis is approximately 1.5-5.4%. As one of the most common complications in cancer treatment, oral mucositis can cause pain, difficulty eating, dry mouth, and taste disturbances, severely impacting patients' quality of life and even forcing treatment interruption, thus affecting the efficacy of cancer treatment. Therefore, effective treatment of oral mucositis in cancer chemotherapy patients is of great clinical significance.

[0003] Multiple randomized controlled trials have suggested that doxepin mouthwash can effectively relieve pain caused by ulcers in patients with clinically active oral cavity (CIOM) and has been listed as a recommended treatment for CIOM. However, its effect on the healing of CIOM ulcer lesions and its mechanism of action are currently unknown, and the current form of mouthwash administration is not conducive to the long-term effective retention of the drug locally. Local administration, due to its advantages of minimal trauma, fewer side effects, and direct action, has gradually become the mainstream approach for local oral mucosal administration. However, we have not yet seen doxepin patches for the treatment of CIOM. Researchers have discovered that the catechol groups of L-3,4-dihydroxyphenylalanine (DOPA) can achieve strong adhesion through various covalent and non-covalent interactions, such as oxidative crosslinking, electrostatic interactions, and coordination. Based on this principle, researchers in the field of biomaterials have created many biomimetic wet adhesive materials and verified their reliable adhesive properties, indicating that they are good excipients for oral topical preparations. This project utilizes 3D printing technology to prepare doxepin into an oral mucosal patch, incorporating a bio-adhesive, gelatin-dopa, allowing for prolonged local application and sustained drug release. The resulting patch is thin, flexible, and conforms to the shape of the oral mucosa, thus enhancing its therapeutic effect on CIOM. This invention not only expands the dosage form of doxepin, providing a new option for clinical treatment of CIOM, but also offers new insights into the preparation of oral mucosal patch drugs.

[0004] 3D printing, also known as additive manufacturing, is a technology that manufactures solid parts by adding materials layer by layer based on three-dimensional CAD data. It currently has wide applications in aerospace, construction, and medicine. 3D printed patches offer unique advantages such as the ability to customize drug size and shape, and precisely control drug release. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing a wet-adhesive oral mucosal patch containing doxepin hydrochloride. This method has the characteristics of being able to be applied locally in a moist environment and enabling targeted and sustained release of the drug, thereby achieving the effect of promoting the healing of chemotherapy-induced oral mucosal ulcers.

[0006] Zein possesses unique solubility; it is insoluble in water and anhydrous alcohols, but soluble in 60%–95% (v / v) aqueous solutions of alcohols, exhibiting excellent film-forming properties after dissolution. Furthermore, as a natural plant protein, it boasts excellent biocompatibility and possesses certain antioxidant properties. Currently, zein is widely used in food packaging and the preparation of sustained-release pharmaceutical materials.

[0007] This invention provides a wet-adhesive doxepin oral patch for treating chemotherapy-induced oral mucosal ulcers, characterized in that it comprises zein, wet-adhesive adhesive gelatin polydopamine (Gel-DOPA), doxepin, carboxymethyl propyl cellulose (HPMC), and a thickener.

[0008] Furthermore, the thickener includes carbomer 974p.

[0009] Furthermore, the weight ratio of Gel-DOPA, doxepin hydrochloride, carboxymethyl propyl cellulose HPMC, and thickener is 1:(1-2):(1-10):(1-10).

[0010] A method for preparing a wet-adhesive doxepin oral patch for treating chemotherapy-induced oral mucosal ulcers includes the following steps:

[0011] (1) Preparation of patch backing layer:

[0012] Using zein as the substrate solution, a patch backing layer was further obtained;

[0013] (2) Preparation of the drug-carrying layer and adhesive layer of the patch:

[0014] A mixture of wet adhesive materials, including gelatin polydopamine (Gel-DOPA), doxepin, carboxymethyl propyl cellulose (HPMC), and a thickener, was used. The drug-loaded layer and the adhesive layer were sprayed onto the patch backing layer prepared in step (1) using a 3D printer. The patch was then dried at room temperature to obtain the patch.

[0015] Furthermore, in step (1), zein is added to glycerol to form a liner solution, wherein the mass ratio of zein to glycerol is (5-15):1.

[0016] Further, step (1) specifically involves dissolving 2g of zein in 80% ethanol and adding 0.2g of glycerol to a 50ml beaker. The mixture is then magnetically stirred at room temperature for 5 minutes to ensure uniform mixing of all components and form a backing solution. Subsequently, following the solvent casting method, 6ml of the backing solution is added to a 90mm diameter Petri dish and dried in a 65℃ oven for 3 hours to form the hydrophobic material layer of the patch, i.e., the patch backing layer.

[0017] Furthermore, in step (2), gelatin polydopamine Gel-DOPA is formed by dissolving gelatin in 2-morpholine ethanesulfonic acid MES buffer, adding 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EDC and N-hydroxysuccinimide NHS for cross-linking.

[0018] Furthermore, in step (2), the wet adhesive material Gel-DOPA, doxepin hydrochloride, carboxymethyl propyl cellulose HPMC, and thickener carbomer 974p are added to an ethanol solution and magnetically stirred to mix evenly as "ink". The drug-loaded layer and adhesive layer are sprayed onto the backing layer prepared in step (1) using a biomaterial 3D printer and allowed to dry naturally overnight at room temperature to finally prepare a wet adhesive double-layer oral mucosal patch loaded with doxepin.

[0019] Furthermore, in step 2, the weight ratio of Gel-DOPA, doxepin hydrochloride, carboxymethyl propyl cellulose HPMC, and thickener is 1:(1-2):(1-10):(1-10).

[0020] This invention provides a wet-adhesive doxepin oral patch for treating chemotherapy-induced oral mucosal ulcers, characterized in that it is prepared according to the above-described preparation method.

[0021] The use of the wet-adhesive doxepin oral patch of the present invention is characterized in that it is used to treat chemotherapy-induced oral mucosal ulcers.

[0022] Technical effects of the present invention:

[0023] The adhesive layer and drug-loaded layer of the doxepin oral patch were fabricated using 3D printing technology. The oral patch produced by 3D printing technology has a uniform drug content with little difference between different production batches. In vitro drug release tests showed that the patch can release doxepin within 4 hours. Attached Figure Description

[0024] Figure 1 Schematic diagram of the preparation of the oral patch of the present invention;

[0025] Figure 2This invention presents a photograph of the 3D printing process of a wet-adhesive doxepin bilayer oral patch, wherein (A) the patch backing layer is made using a solvent casting method; (B) the prepared bio-adhesive Gel-DOPA with wet-adhesion properties; and (C) the doxepin-loaded bilayer patch is finally made using 3D printing technology.

[0026] Figure 3 The in vitro dissolution test effect (A) and the in vitro permeation test effect (B) of the drug doxepin hydrochloride are shown in the following figures:

[0027] Figure 4 The present invention characterizes the performance of the doxepin hydrochloride patch, including (A) the contact angle of the backing layer and the adhesive drug-loaded layer of the doxepin bilayer oral patch; (B) and (C) the comparison of the relative weight and thickness of the doxepin bilayer oral patch (doxepin patch) with commercially available propolis oral ulcer patch (propolis patch) and dexamethasone acetate patch (dexamethasone patch); (D) the analysis of drug content uniformity of the three batches of doxepin bilayer oral patch; (E) the application of doxepin patch, propolis patch and dexamethasone patch to the buccal mucosa of rats; and (F) the comparison of the in vivo and in vitro adhesion time of doxepin patch, propolis patch and dexamethasone patch.

[0028] Figure 5 Comparison of CIOM lesion area in rat cheeks after treatment with different patches over time;

[0029] Figure 6 H&E staining images of the lesion areas in rats of each group during the healing process. Detailed Implementation

[0030] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention. The specific embodiments described herein are merely illustrative of the present invention and are not intended to limit the present invention.

[0031] Example 1:

[0032] (1) Fabrication of patch backing layer

[0033] Dissolve 2g of zein in 80% ethanol and add 0.2g of glycerol to a 50ml beaker. Stir magnetically at room temperature for 5 minutes to ensure homogeneous mixing and form a backing solution. Then, using the solvent casting method, add 6ml of the backing solution to a 90mm diameter Petri dish and dry in a 65℃ oven for 3 hours to form the hydrophobic material layer (backing layer) of the patch.

[0034] (2) Preparation of drug-loaded layer and adhesive layer of patch

[0035] First, 1g of type A gelatin was dissolved in 50ml of 2-morpholinoethanesulfonic acid MES buffer, and 500mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 427mg of N-hydroxysuccinimide (NHS) were added. The mixture was reacted under vacuum and nitrogen protection for 24 hours to crosslink the two substances and form a wet adhesive material with a DOPA-containing structure—gelatin polydopamine (Gel-DOPA). Subsequently, the adhesive material Gel-DOPA was dialyzed to remove impurities and then freeze-dried under vacuum for storage. 200 mg of wet adhesive material Gel-DOPA, 250 mg of drug doxepin hydrochloride, 800 mg of 3D printing matrix material carboxymethyl propyl cellulose HPMC with sustained-release drug properties, and 800 mg of thickener carbomer 974p were added to 50 ml of 50% ethanol solution and magnetically stirred at 1200 r / min for 3 h to mix evenly as "ink". The nozzle pressure parameter was set to 42 kPa and the spraying shape was set to a 90 mm diameter circle. The drug-loaded layer and adhesive layer were sprayed onto the backing layer prepared in step (1) using a CELLINK BIO X biomaterial 3D printer. The layer was allowed to dry naturally at room temperature overnight to finally prepare a wet adhesive double-layer oral mucosal patch loaded with doxepin.

[0036] Application example: To evaluate the therapeutic effect of this patch on CIOM ulcers, we also conducted animal experiments. The results confirmed that the oral patch loaded with doxepin in rats with experimental CIOM could reduce the degree of inflammation in the lesion tissue (inflammatory factor score), promote the regeneration and migration of epithelial cells, and accelerate ulcer healing. Its effect on promoting tissue healing was not significantly different from that of the commercially available classic ulcer drug propolis patch.

[0037] To evaluate the therapeutic effect of this patch on CIOM ulcers, we also conducted animal experiments. The results showed that the oral patch loaded with doxepin in rats with experimental CIOM reduced the degree of inflammation in the lesion tissue (inflammatory factor score), promoted the regeneration and migration of epithelial cells, and accelerated ulcer healing. Its effect on promoting tissue healing was not significantly different from that of the commercially available classic ulcer drug propolis patch.

[0038] Figure 1 The image shows the raw materials and reaction examples used in this application, which ultimately yielded an oral patch including a hydrophobic material layer, a drug reservoir, and an adhesive layer.

[0039] Figure 2 The image shows a 3D-printed wet-adhesive doxepin bilayer oral patch: (A) a patch backing layer made using a solvent casting method; (B) a bio-adhesive Gel-DOPA with wet-adhesion properties; and (C) a doxepin-loaded bilayer patch finally made using 3D printing technology.

[0040] Figure 3 The results show that the in vitro dissolution test of doxepin hydrochloride (A) can achieve local sustained release of doxepin hydrochloride double-layer oral patch for 0-250 minutes, and can release about 80% of the drug content within 100 minutes; the in vitro permeation test of doxepin hydrochloride (B) shows that doxepin hydrochloride can permeate into the mucosa in a time-dependent manner.

[0041] Figure 4 Performance characteristics of Doxepin Hydrochloride Patch: (A) Contact angle of the backing layer and adhesive drug-loaded layer of Doxepin bilayer oral patch; (B) and (C) Comparison of relative weight and thickness of Doxepin bilayer oral patch (Doxepin patch) with commercially available propolis oral ulcer patch (propolis patch) and dexamethasone acetate patch (dexamethasone patch); (D) Analysis of drug content uniformity of three batches of Doxepin bilayer oral patch; (E) Demonstration of application of Doxepin patch, propolis patch and dexamethasone patch to rat buccal mucosa; (F) Comparison of in vivo and in vitro adhesion time of Doxepin patch, propolis patch and dexamethasone patch. This figure illustrates that the doxepin hydrochloride bilayer oral patch involved in this patent has the characteristics of being thin and light, significantly lighter than commercially available dexamethasone acetate oral ulcer patches, and can better conform to the buccal mucosa morphology for drug delivery. At the same time, due to the addition of the wet adhesive substance Gel-DOPA, the in vivo and in vitro adhesion time of the doxepin bilayer oral patch is also longer than that of commercially available propolis patches.

[0042] Figure 5 The study compared the area of ​​CIOM lesions in the cheeks of rats treated with different patches over time. After 4, 8, and 12 days of treatment, the area of ​​CIOM lesions in the cheeks of rats in each group (natural healing, Duxepin double-layer oral patch (Duxepin patch), commercially available propolis oral ulcer patch (propolis patch), and dexamethasone acetate patch (dexamethasone patch)) was compared. It is evident that the Duxepin patch can promote the healing of CIOM lesions in rats, and this healing-promoting effect is not significantly different from that of the commercially available classic ulcer patch, propolis patch, indicating that the Duxepin double-layer oral patch involved in this patent has a good healing-promoting effect on CIOM.

[0043] Figure 6 H&E staining images of the lesion areas of rats in each group during the healing process. Each group consists of naturally healed tissue, tissue sections stained with hematoxylin and eosin ... Figure 6 Can be with Figure 5The evidence corroborates each other, and from a histopathological perspective, it is confirmed that the Duoluping double-layer oral patch involved in this patent can reduce the inflammatory infiltration of local lesions in CIOM, promote the regeneration and migration of oral mucosal epithelium, thereby exerting a healing-promoting effect.

[0044] The physicochemical properties of the prepared doxepin bilayer oral patch were measured. The results showed that the thickness of the doxepin patch was not significantly different from that of commercially available propolis patches, and both were thinner than dexamethasone acetate patches. Although the relative weight of the doxepin patch was heavier than that of the propolis patch, it was much lighter than that of the dexamethasone acetate patch, demonstrating its thinness and lightness, which makes it more conformable to the morphology of the oral mucosa. Furthermore, the addition of a wet adhesive substance and the backing layer structure of the patch enable strong local adhesion to the mucosa and targeted sustained release of doxepin hydrochloride. This resulted in a promotion of lesion healing in the CIOM animal model.

[0045] Those skilled in the art will understand that the present invention is not limited to the details of the above embodiments, and that the present invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered as exemplary and non-limiting in all respects.

[0046] It should be noted that the above specific embodiments are merely illustrative examples of the present invention and are not intended to limit it. For those skilled in the art, based on an understanding of the core ideas of the present invention, various modifications, combinations, or equivalent substitutions can be made, such as adjusting specific borehole parameters, shaped charge types, detonation delay times, etc. These modifications, which do not depart from the spirit and scope of the present invention, should all be included within the protection scope of the present invention.

Claims

1. A wet-adhesive doxepin oral patch for treating chemotherapy-induced oral mucosal ulcers, characterized in that: Including zein, wet adhesive gelatin polydopamine (Gel-DOPA), doxepin, carboxymethyl propyl cellulose (HPMC), and thickeners.

2. A wet-adhesive doxepin oral patch for treating chemotherapy-induced oral mucosal ulcers as described in claim 1, characterized in that: The thickener is carbomer 974p.

3. A wet-adhesive doxepin oral patch for treating chemotherapy-induced oral mucosal ulcers as described in claim 1, characterized in that: The weight ratio of Gel-DOPA, doxepin hydrochloride, carboxymethyl propyl cellulose HPMC, and thickener is 1:(1-2):(1-10):(1-10).

4. A method for preparing a wet-adhesive doxepin oral patch for treating chemotherapy-induced oral mucosal ulcers as described in claim 1, characterized in that: Includes the following steps: (1) Preparation of patch backing layer: Using zein as the substrate solution, a patch backing layer was further obtained; (2) Preparation of the drug-carrying layer and adhesive layer of the patch: The patch is prepared by mixing a wet adhesive material, gelatin polydopamine (Gel-DOPA), doxepin, carboxymethyl propyl cellulose (HPMC), and a thickener. The drug-loaded layer and the adhesive layer are sprayed onto the patch backing layer prepared in step (1) using a 3D printer or solvent casting. The patch is then dried at room temperature to obtain the patch.

5. The preparation method according to claim 4, characterized in that: In step (1), zein is added to glycerol to form a liner solution, wherein the mass ratio of zein to glycerol is (5-15):

1.

6. The preparation method according to claim 4, characterized in that: Step (1) is as follows: First, dissolve 2g of zein in 80% ethanol and add 0.2g of glycerol to a 50ml beaker. Stir magnetically at room temperature for 5min to mix the components evenly and form a backing solution. Then, according to the solvent casting method, add 6ml of the backing solution to a 90mm diameter Petri dish and dry it in a 65℃ oven for 3h to form the hydrophobic material layer of the patch, i.e., the patch backing layer.

7. The preparation method according to claim 4, characterized in that: In step (2), gelatin polydopamine Gel-DOPA is formed by dissolving gelatin in 2-morpholine ethanesulfonic acid MES buffer, adding 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EDC and N-hydroxysuccinimide NHS for cross-linking.

8. The preparation method according to claim 4, characterized in that: In step (2), the wet adhesive material Gel-DOPA, doxepin hydrochloride, carboxymethyl propyl cellulose HPMC, and thickener carbomer 974p are added to an ethanol solution and magnetically stirred to mix evenly as "ink". The drug-loaded layer and adhesive layer are sprayed onto the backing layer prepared in step (1) using a biomaterial 3D printer and allowed to dry naturally overnight at room temperature to finally prepare a wet adhesive double-layer oral mucosal patch loaded with doxepin.

9. The preparation method according to claim 4, characterized in that: In step 2, the weight ratio of Gel-DOPA, doxepin hydrochloride, carboxymethyl propyl cellulose HPMC, and thickener is 1:(1-2):(1-10):(1-10).

10. The use of the wet-adhesive doxepin oral patch according to claims 1-3, characterized in that: Used to treat chemotherapy-induced oral mucosal ulcers.

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