Controlled release oral appliance, medicine

Abstract

To provide a controlled-release oral appliance for stably holding a medicine within an oral cavity and sustainably sending the medicine to an affected part in the oral cavity.SOLUTION: A controlled-release oral appliance includes a medicine controlled-release part for performing controlled-release of a medicine within an oral cavity, with the controlled-release surface of the medicine controlled-release part arranged on an external surface.SELECTED DRAWING: Figure 4

Description

[Technical Field]

[0001] The present disclosure relates to a drug delivery system (DDS), and more particularly to a sustained-release oral appliance that sustainably releases a drug into the oral cavity. [Background technology]

[0002] A drug delivery system is a drug administration system designed to deliver the required amount of drug to the required site for the required period of time. A typical DDS is a sustained-release formulation, which is designed to maintain an appropriate drug concentration by controlling the release of the drug from the dosage form.

[0003] Patent Document 1 discloses a drug delivery system that delivers drugs at a constant sustained rate over an extended period of time, and discloses an example of its application to the eye. The DDS in Patent Document 1 is a DDS for treating the eyes of mammals with ocular disorders or diseases. It can be safely and easily implanted into the eye and can deliver drugs into the eye over an extended period of time without an initial burst (paragraph 0005). Specifically, the DDS in Patent Document 1 comprises a box-shaped PEG (polyethylene glycol) containing a therapeutic drug solution, collagen impregnated with a therapeutic drug, or a PEG pellet containing collagen impregnated with a therapeutic drug. The box-shaped PEG is then covered with a porous PEG sheet and implanted into the eye. The drug inside is gradually released through the porous PEG sheet.

[0004] Patent Document 2 discloses an example of an orthodontic appliance in the shape of a mouthpiece, containing a drug on its surface or inner layer, which allows for sustained release of the drug. Patent Document 2 also describes a system that enables drugs or therapeutic agents to be delivered via the mouth, providing ideal drug delivery for periodontal disease, tooth surfaces, specific diseases related to endodontic treatment, and diseases related to cancer and other medical conditions (paragraph 0007). For example, Figures 2B-2C disclose a DDS having multiple delivery nozzles 18A-18C protruding from an appliance 17 so that the appliance 17 contacts the patient's gingival tissue on the side of the gums or within a periodontal pocket.

[0005] As an intraoral DDS for treatments other than dental and periodontal disease, Non-Patent Document 1 discloses that a device for oral mucosal diseases, a fiber membrane (patch formulation) made by electrospinning and consisting of a hydrophilic polymer, a bioadhesive polymer, and a hydrophobic polymer layer, is currently under development. The patch formulation is designed to be attached to the cheek, tongue, gums, etc., and releases the drug from the patch formulation over several hours.

[0006] Non-Patent Document 2 describes a Phase 2 trial conducted by AFYX Therapeutics, Inc., aimed at treating oral lichen planus, an oral mucosal disease. According to Non-Patent Document 2, treatment with a patch formulation was carried out twice daily for four weeks (with a two-week follow-up period), and it is reported that the patch formulation remained in the affected area for an average of 90 minutes per treatment.

[0007] Although oral administration is relatively easy, the dynamic oral environment, including the tongue, teeth, and saliva, presents challenges in sustained drug delivery to affected areas. For example, oral lichen planus, a difficult-to-treat oral mucosal disease, causes reticular or patchy white lesions to form locally on the oral mucosa, accompanied by discomfort and pain. For this reason, topical steroid therapy is commonly used. However, ointments and oral mucosal patches applied to the affected area can peel off due to irritation from saliva or the tongue. Therefore, it is crucial to develop treatments other than patch formulations that allow for stable drug delivery to the affected area. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2011 / 021594 [Patent Document 2] Special Publication No. 2008-521514 [Non-patent literature]

[0009] [Non-Patent Document 1] HE Colley, et. al. “Pre-clinical evaluation of novel mucoadhesive bilayer patches for local delivery of clobetasol-17-propionate to the oral mucosa” Biomaterials 178 (2018) 134-146, Internet<https: / / pubmed.ncbi.nlm.nih.gov / 29929183 / > [Non-patent document 2] AFYX Therapeutics, OLP Phase 2 Study Results, Presented by Prof. Mike Brennan at AAOM - April 2021, Internet <chrome-extension: / / efaidnbmnnnibpcajpcglclefindmkaj / https: / / afyxtx.com / wp-content / uploads / 4623f2d8d800-Phase_II_OLP_AFYX_AAOM_FINAL.pdf> Summary of the Invention [Problem to be solved by the invention]

[0010] The present disclosure aims to provide a sustained-release oral appliance that stably retains a drug in the oral cavity and continuously delivers the drug to an affected area in the oral cavity. [Means for solving the problem]

[0011] The present inventors have conducted extensive research to solve the above problems and have found that when an oral appliance is configured to have a sustained drug-release portion formed from a drug-permeable material and a drug-impermeable material, the drug can be stably retained in the oral cavity and the drug can be continuously released into the oral cavity. Furthermore, they have found that the sustained drug-release portion can be positioned at any position on the oral appliance, making it effective for local therapy as well, and have completed the present invention.

[0012] The present disclosure includes the following aspects. [1] A drug release section is provided for gradually releasing a drug into the oral cavity, The sustained-release surface of the sustained-release drug portion is disposed on the outer surface. Sustained-release oral appliance. [2] the sustained drug-release portion includes a main body having a recess formed therein and a lid portion that closes the recess; The main body is formed independently of the oral appliance. [1] A sustained-release oral appliance. [3] the sustained drug-release portion includes a main body having a recess formed therein and a lid portion that closes the recess; The main body is integrally formed with the oral appliance. [1] A sustained-release oral appliance. [4] the body is formed from a drug-impermeable material; [2] or [3]. A sustained-release oral appliance. [5] The lid portion is formed from a drug-impermeable material and a drug-permeable material. [2] - [4] The sustained-release oral appliance according to any one of [2] to [4]. [6] The thickness of the lid is 0.01 to 0.3 mm. [2] to [5]. The sustained-release oral appliance according to any one of [2] to [5]. [7] The recess accommodates a cured product of a drug, a drug-impermeable material, and a drug-permeable material. [2] to [6]. The sustained-release oral appliance according to any one of [2] to [6]. [8] The sustained drug release portion is placed at any position of the oral appliance. [1] - [7] The sustained-release oral appliance according to any one of the above. [9] The sustained-release oral appliance is applied to at least a portion of the wearer's dentition. [1] - [8] The sustained-release oral appliance according to any one of the above.

[10] The oral appliance is a mouthpiece or a bracket. [1] - [9] The sustained release oral appliance according to any one of the above.

[11] Drugs for oral mucosal diseases and a sustained-release oral appliance having a drug sustained-release portion that sustainably releases the drug for oral mucosal diseases. Pharmaceuticals. [Effects of the Invention]

[0013] According to the present disclosure, it is possible to provide a sustained-release oral appliance that stably retains a drug in the oral cavity and continuously delivers the drug to an affected area in the oral cavity. [Brief explanation of the drawings]

[0014] [Figure 1] FIG. 1 is an image diagram of wearing the sustained-release oral appliance 10 according to the first embodiment. [Figure 2] 1 illustrates each step (S1 to S8) of the method for producing the sustained release device 11. [Figure 3] 1 is a schematic diagram illustrating the shape of a sustained release device 11 and a sustained release oral appliance 10. FIG. [Figure 4] FIG. 1 shows an example of a sustained release oral appliance 10 in which a sustained release device 11 is attached to the outer surface of a mouthpiece 15 so as to be in the vicinity of a first molar. [Figure 5] 10 is a diagram for explaining the fastening structure of the sustained release device 11. FIG. [Figure 6a] FIG. 2 is a diagram illustrating the size of the sustained release device 11 attached to the mouthpiece 15. [Figure 6b] FIG. 6b is a diagram illustrating the size when FIG. 6a is viewed from the cheek side. [Figure 7] FIG. 10 is an image diagram of a sustained-release oral appliance 20 according to a third embodiment when worn. [Figure 8] FIG. 10 is an image diagram of a sheet-shaped sustained-release oral appliance 30 according to a fourth embodiment when it is attached. [Figure 9] 1 is a graph showing the amount of drug released over time in an example. [Figure 10a] 1 is a plan view (photograph) of the sustained-release oral appliance 10 taken from above. [Figure 10b]1 is a bottom view (photograph) of the sustained release oral appliance 10 taken from below. [Figure 10c] 1 is a perspective view (photograph) of the sustained-release oral appliance 10 taken obliquely from above and on the side. [Figure 10d] 1 is a perspective view (photograph) of the sustained-release oral appliance 10 taken from diagonally above the front. DETAILED DESCRIPTION OF THE INVENTION

[0015] Hereinafter, embodiments of the present invention will be described with reference to the drawings. Components indicated by the same reference numerals in the various drawings are the same components. Note that duplicated descriptions and reference numerals may be omitted in the following embodiments.

[0016] This application discloses a sustained-release oral appliance, which is a drug delivery system (DDS) equipped with a drug-releasing portion that sustainably releases a drug into the oral cavity from the outer surface of the oral appliance. The term "oral appliance" is a combination of "oral" and "appliance" and refers to an oral appliance (or device) such as a mouthpiece. Therefore, an oral appliance can also be called an oral device or oral apparatus. The drug refers to a chemical substance with a pharmacological effect and is not particularly limited.

[0017] The sustained-release portion may include a main body having a recess formed therein that functions as a drug reservoir, and a lid that closes the recess that functions as a sustained-release membrane. The recess is a space for filling with the drug, and the drug is retained in the recess of the sustained-release portion. The main body is formed from a drug-impermeable material. The lid is formed from a mixture of a drug-permeable material and a drug-impermeable material. The drug is mixed with the drug-permeable material and the drug-impermeable material and hardened, and is retained in the recess while being confined by the drug-permeable material and the drug-impermeable material. Therefore, the drug first permeates the mixture of the drug, drug-permeable material, and drug-impermeable material, and then permeates the lid formed from the drug-permeable material and drug-impermeable material, and is released into the oral cavity. Because the amount of drug permeation can be controlled by the mixing ratio of the drug-permeable material and the drug-impermeable material, the sustained-release oral appliance of the present disclosure can sustainably release a desired amount of drug into the oral cavity for a desired period of time. A sustained-release oral appliance configured in this manner makes it possible to stably and continuously deliver a drug to the affected area in the oral cavity in a highly dynamic oral environment caused by the tongue, teeth, saliva, etc.

[0018] The drug-permeable material may be any material that allows the drug to permeate. The drug-impermeable material may be any material that does not allow the drug to permeate alone, or that allows the drug to permeate only in small amounts so as not to interfere with the effectiveness of the sustained-release oral appliance of the present disclosure. For example, the drug-permeable material and the drug-impermeable material may be the same type of compound but with different molecular weights. Alternatively, they may be different types of compounds but with different molecular weights. The material forming the sustained-release portion is preferably a biocompatible material. For example, polyethylene glycol (PEG) and its derivatives may be used. Therefore, a combination of a drug-permeable material and a drug-impermeable material may be, for example, polyethylene glycol dimethacrylate (PEGDM) with different molecular weights.

[0019] The molecular weight of PEGDM is not particularly limited. PEGDM, as used here, refers to a compound formed by polymerizing two or more ethylene glycol monomers, and includes low-molecular-weight PEGDMs such as triethylene glycol dimethacrylate (TEGDM) with three monomers and tetraethylene glycol dimethacrylate with four monomers. By using a mixture of PEGDMs with different molecular weights, drug permeability, for example, permeability of small molecular weight drugs below 1 kDa, can be controlled by the molecular weight of the permeable PEGDM in the PEGDM. For example, a 100:0 mixture of TEGDM (Fw = 286.33) and PEGDM (Mn = 750) results in almost no drug permeability. Conversely, a 0:100 mixture facilitates permeation of small molecular weight drugs. While the TEGDM and PEGDM ratios shown here are "0," it is desirable for the TEGDM and PEGDM mixture to not fall below "1" in practice. That is, the TEGDM to PEGDM ratio is preferably between 99:1 and 1:99.

[0020] [First embodiment] A first embodiment will be described below. In the first embodiment, the oral appliance is a mouthpiece, and the sustained-release device has a drug-releasing portion formed independently of the mouthpiece. The drug-impermeable material is TEGDM, and the drug-permeable material is PEGDM, which has a higher molecular weight than TEGDM. The mouthpiece is not particularly limited as long as it can be manufactured using existing technology. FIG. 1 is an illustration of a sustained-release oral appliance 10 according to the first embodiment when worn. The mouthpiece is not limited to the upper jaw, and may be worn on the lower jaw. The mouthpiece may also be worn on a portion of the upper or lower jaw dentition.

[0021] (Method for producing sustained release devices) The sustained release device can be manufactured by molding. Figure 2 illustrates the steps (S1 to S8) of a method for manufacturing an example sustained release device 11. Transparent members I, II, and III, listed at the top of Figure 2, are used for manufacturing. Step S1: A mixture of TEGDM and a photopolymerization initiator is placed in a cavity of a mold (member I) having a cavity with the same shape as the main body of the sustained release device 11. Step S2: Insert the convex portion of member II, which has a convex portion on one side, into the cavity of member I. Step S3: The members I and II are irradiated with ultraviolet (UV) rays for 50 to 70 seconds, preferably 60 seconds, to harden the TEGDM and form the main body 12. The main body 12 with the recesses formed therein is removed from the member I. Step S4: A mixture of the drug, TEGDM, PEGDM, and photopolymerization initiator is placed in the recess of the main body 12. Step S5: The main body 12 is irradiated with ultraviolet (UV) light for 5 to 15 seconds, preferably 10 seconds, to cure the TEGDM and PEGDM, thereby obtaining a drug-containing cured material 13 (FIG. 3). Step S6: A mixture of TEGDM, PEGDM, and a photopolymerization initiator is further poured into the recess of the main body 12. Step S7: In order to make the top surface of the sustained release device 11 flat, a member III is placed on the main body 12. Step S8: The main body 12 is irradiated with ultraviolet (UV) light for 200 to 300 seconds, preferably 240 seconds, to harden the TEGDM and PEGDM, form the lid portion 14 (FIG. 3), and obtain the sustained release device 11.

[0022] The photopolymerization initiator can be appropriately selected from known photopolymerization initiators depending on the wavelength of the light source used. Examples include 2-hydroxy-2-methyl-propiophenone, 4'-isopropyl-2-hydroxy-2-methyl-propiophenone, 1-hydroxycyclohexyl phenyl ketone, 2,2-diethoxyacetophenone, benzyl methyl ketal, benzyl-β-methoxyethyl acetal, benzoin (2-phenyl-2-hydroxyacetophenone), and benzoin alkyl ether. The photopolymerization initiator may be added in an amount of 1 to 100 μg / ml, preferably 10 μg / ml, per 1 ml of total volume. The UV light intensity is 1 to 50 mW / cm. 2 may be 38.5 mW / cm 2 may be.

[0023] The drug is released from the lid portion 14, which functions as a sustained-release membrane. In this way, the sustained-release device 11 can release the drug from one direction. Note that the release surface is not limited to the top in FIG. 3, but may be configured to release the drug from either of the sides of the main body 12, as needed. While FIG. 3 illustrates a configuration in which the lid portion is provided on the top, lid portions may be provided on both the top and side, or only the side without the top. In these cases, it is desirable that the portion of the mouthpiece 15 in FIG. 3 corresponding to the lid portion be open so that the drug can be released. Furthermore, if a longer sustained release period is required, the PEGDM composition of the PEGDM / TEGDM in the lid portion 14, which is the sustained-release surface, can be increased. On the other hand, if increasing the PEGDM composition reduces durability, the thickness of the sustained-release device 11, for example, the thickness of the recess containing the drug-containing cured material 13 in FIG. 3 and the lid portion 14 (the sum of E and F in FIG. 6a), may be adjusted to ensure the durability of the sustained-release device 11 during the treatment period. As an example, the sum of E+F may be 0.7 mm.

[0024] (Shape of sustained release device) The shape of the main body 12 of the sustained release device 11 may have a recess. For example, it may be a roughly cubic shape such as a box shape, a roughly disc shape, a roughly spherical shape, a roughly cylindrical shape, or the like. In the first embodiment, the shape of the sustained release device 11 is an inverted truncated square pyramid with the bottom surface (main body 12 side) smaller than the top surface (lid portion 14 side), as shown in FIG. 3. Making the bottom surface of the sustained release device 11 smaller than the top surface makes it easier to attach to the mouthpiece 15. In addition, a shape in which the top and bottom surfaces have different shapes, such as a trapezoidal vertical cross section, is preferable because it makes it easier to distinguish the sustained drug release surface. The shape of the recess formed in the main body 12 is also not particularly limited. It may be a space that can accommodate the drug-containing cured material 13. For example, it may be roughly cubic, or may be an inverted truncated square pyramid like the main body 12.

[0025] (How to attach the sustained release device) As shown in FIG. 3, the sustained release device 11 may be attached by forming a cavity in the mouthpiece 15 and embedding it in the cavity. Alternatively, the sustained release device 11 may be directly attached to the surface of the mouthpiece 15 without being embedded. Alternatively, the sustained release device 11 may be attached so that its top surface (the sustained release side) slightly protrudes from the surface of the mouthpiece 15. FIG. 4 shows an example of the sustained release device 11 attached to the outer surface of the mouthpiece 15. In FIG. 4, the sustained release device 11 is positioned near the outer side of the first molar. The attachment method is not particularly limited. For example, orthodontic adhesive can be used for attachment. Alternatively, the sustained release device 11 and the mouthpiece 15 may be attached using a fastening structure with recesses and protrusions. FIG. 5 is a diagram illustrating an example of a fastening structure, conveniently showing an example in which the sustained release device 11 is attached to member IV. In FIG. 5, recesses 16 are formed at the longitudinal center ends of the sustained release device 11, and protrusions 17 are formed on the inner side of the longitudinal center of member IV. In FIG. 5, the sustained release device 11 has a shape in which the bottom surface is smaller (narrower) than the top surface, so the sustained release device 11 can be inserted into the member IV without hitting the protrusion 17 of the member IV. The sustained release device 11 hits the protrusion 17 of the member IV just before snapping into place, and the protrusion 17 deforms slightly due to the flexibility of the protrusion material and the flexibility of the material of the sustained release device 11, so that the protrusion 17 snaps into place in the depression 16 of the sustained release device 11. In practice, the sustained release device 11 is attached directly to the mouthpiece 15, so the protrusion 17 is formed in the cavity of the mouthpiece 15 in which the sustained release device 11 is embedded. The positions of the depression 16 and the protrusion 17 are not particularly limited. In this way, the sustained release device 11 may be attached using a fastening structure. Furthermore, the sustained release device 11 can be attached to any position on the mouthpiece 15. This enables the sustained release of a drug to a specific site in the oral cavity. In this way, the drug contained in the sustained release device 11 can be placed only in any part of the mouthpiece that corresponds to the affected area in the oral cavity that is to be treated, allowing the drug to act on the necessary area.

[0026] (Size of sustained release device) The size of the sustained release device 11 may typically be a top surface of 4 x 9 mm, a bottom surface of 3 x 8 mm, and a thickness (height) of 2 mm. The thickness may be 1.5 to 3 mm, and the minimum size of the top and bottom surfaces may be 3 mm square (in this case, the sustained drug release surface is 2 mm square). The maximum size of the top and bottom surfaces may be determined by the degree to which they protrude from the mouthpiece.

[0027] The size of the sustained release device 11 is illustrated in Figures 6a and 6b. Figure 6a is a schematic end view of a cut section taken along line PP in Figure 4, with tooth 1 added. Figure 6b is a schematic view of the sustained release device 11 viewed from the outside (cheek side) of Figure 6a. A is the distance between the sustained release device 11 and tooth 1 when the sustained release device 11 is embedded in the mouthpiece 15. A may be 0.8 to 1.2 mm, and is typically 1 mm. B is the thickness from the bottom to the top of the sustained release device 11. B may be 1.8 to 4 mm, and may be 1.8 to 2.2 mm, and is typically 2 mm. C is the thickness of the portion of the sustained release device 11 that protrudes from the outer surface of the mouthpiece 15. C is typically 0 mm. A thickness of 0 mm is preferable because the sustained release device 11 and the mouthpiece 15 are flush with each other, thereby reducing the discomfort felt by the wearer of the mouthpiece 15. D is the length in the short direction of the top surface (sustained release surface side) of the sustained release device 11. D may be 3 to 6 mm, and is typically 4 mm. E is the thickness of the recess that accommodates the drug-containing cured material of the sustained release device 11. E may be 0.4 to 0.8 mm, and is typically 0.6 mm. F is the thickness of the lid of the sustained release device 11. F may be 0 to 0.3 mm, and is typically 0.1 mm. G is the length in the short direction of the bottom surface of the sustained release device 11. G may be 2 to 5 mm, and is typically 3 mm. H is the length in the long direction of the top surface (sustained release surface side) of the sustained release device 11. H may be 6 to 12 mm, and is typically 9 mm. I is the length in the long direction of the bottom surface of the sustained release device 11. I may be 5 to 11 mm, and is typically 8 mm.

[0028] As described above, the cap 14 functions as a sustained-release membrane, and the sustained-release rate can be controlled by the thickness F of the cap 14. The oral environment of a living body can be subject to various conditions unique to the oral cavity, including individual differences in oral temperature, saliva volume, and the influence of chewed food when using a sustained-release device. The amount of drug released per unit time in a sustained-release device, i.e., the sustained-release rate, can be controlled by the combination of a drug-permeable material and a drug-impermeable material used for the cap. The inventors have found that the sustained-release rate can be controlled by the thickness F of the cap. The inventors investigated the thickness F of the cap 14 that achieves sustained drug release under these conditions unique to the oral cavity. The inventors have found that when the drug to be sustained-released is a low-molecular-weight drug, a thickness F of 0.01 mm or more and 0.3 mm or less functions well as a sustained-release membrane, regardless of the composition of the drug-permeable material and the drug-impermeable material. This is true regardless of the combination of the aforementioned materials, depending on the combination, as follows: That is, when F is 0.01 mm or more and 0.05 mm, the sustained release rate can be fast. When F is more than 0.05 mm and 0.1 mm, the sustained release rate can be moderate. When F is more than 0.1 mm and 0.2 mm, the sustained release rate can be slow. When F is more than 0.2 mm and 0.3 mm, the sustained release rate can be further slowed. On the other hand, the sustained release device 11 can also be configured without the lid portion 14. The sustained release device 11 without the lid portion 14 may also be used. Not having the lid portion 14 is particularly effective when the drug is a polymer. The molar mass of a drug that distinguishes between low molecular weight and high molecular weight drugs is approximately 10,000 g / mol. A typical molar mass of a low molecular weight drug is approximately 400 g / mol. Note that the manufacture of the sustained release device 11 without the lid portion 14 can be simplified compared to when it has the lid portion 14.

[0029] As described above, the sustained-release oral appliance of the first embodiment is a drug delivery system (DDS) composed of a mouthpiece equipped with a sustained-release device that sustains the release of a drug. The sustained-release oral appliance configured in this manner can embed the sustained-release device in the mouthpiece, allowing for sustained release of a drug without substantially changing the size or shape of the existing mouthpiece. This reduces the discomfort felt by the mouthpiece wearer. Furthermore, because it is a mouthpiece, it is minimally invasive and easy to remove. Furthermore, the mouthpiece can be easily stored (e.g., cleaned and dried), providing excellent convenience. The first embodiment can be a sustained-release oral appliance that utilizes a conventional mouthpiece, for example, in the treatment of oral mucosal diseases.

[0030] [Second embodiment] A second embodiment will be described below. In the second embodiment, the oral appliance is a mouthpiece, and a recess (a space for filling the drug) of the sustained drug-release portion is formed in the mouthpiece. That is, the mouthpiece and the main body of the sustained drug-release portion are integrally formed, the mouthpiece functions as the main body of the sustained drug-release portion, and the entire mouthpiece becomes a sustained release device. The drug-impermeable material is TEGDM, and the drug-permeable material is PEGDM, which has a larger molecular weight than TEGDM. Therefore, the mouthpiece having the recess is formed from TEGDM. In this way, the mouthpiece that functions as the main body of the sustained release device may be formed from a drug-impermeable material so as to accommodate the drug. As described above, the sustained-release oral appliance of the second embodiment is a drug delivery system (DDS), in which the mouthpiece itself is a sustained-release device that accommodates and sustainedly releases a drug.

[0031] (Method for producing a mouthpiece-type sustained release device) The mouthpiece-type sustained release device can be produced, for example, by the following method. Step S11: A mouthpiece is made from TEGDM using a 3D printer. At the same time, a recess is formed in the mouthpiece at the position where the drug will be stored. Step S12: A mixture of the drug, TEGDM, PEGDM, and photopolymerization initiator is placed in the recess of the mouthpiece that will become the main body. Step S13: The recessed portion of the mouthpiece is irradiated with ultraviolet (UV) light for 10 seconds to cure the TEGDM and PEGDM, thereby obtaining a drug-containing cured material. Step S14: A mixture of TEGDM, PEGDM, and a photopolymerization initiator is further placed in the recess of the mouthpiece. Step S15: To flatten the surface of the recess of the mouthpiece, a flat plate member is placed on the recess. Step S16: The recess of the mouthpiece is irradiated with ultraviolet (UV) light for 240 seconds to harden the TEGDM and PEGDM, thereby obtaining a mouthpiece-type sustained-release device.

[0032] [Third embodiment] A third embodiment will be described below. In the third embodiment, the oral appliance is a bracket. A bracket is a device attached to the surface of a tooth for use in wire orthodontics (or the like). The sustained-release portion can be a sustained-release device similar to that in the first embodiment. In this way, the sustained-release device may be attached to the bracket instead of the mouthpiece. The bracket is not particularly limited as long as it can be manufactured using existing technology. As with the mouthpiece, the main body of the sustained-release portion may be formed separately from the bracket, and the sustained-release device may be attached to the bracket, or a recess may be formed in the bracket itself and used as the main body of the sustained-release portion. The material of the bracket is not particularly limited. Figure 7 is an illustration of a case in which multiple sustained-release oral appliances 20 according to the third embodiment are worn. Note that the brackets are not limited to those attached to the upper jaw, but may also be those attached to the lower jaw. Furthermore, the brackets may be attached to all of the wearer's teeth, or may be attached to only a portion of the teeth, such as one, two, or three. In the third embodiment, the sustained-release device is sized to fit the size of the teeth, thereby reducing discomfort felt by the wearer. Furthermore, it is minimally invasive and does not need to be removed when brushing teeth or eating, making it highly convenient. As described above, the sustained-release oral appliance of the third embodiment is a drug delivery system (DDS) composed of brackets equipped with a sustained-release device that sustains the release of a drug.

[0033] [Fourth embodiment] A fourth embodiment will be described below. In the fourth embodiment, a member for holding the sustained drug release portion, such as a mouthpiece, is not used, and the sustained drug release portion is a sustained release device similar to that of the first embodiment. A sustained-release oral appliance can be formed by adhering a thin-shaped sustained drug release portion to a sheet-like oral appliance. This sustained-release oral appliance may be directly attached to the affected area. Existing technology can be used for the attachment method. Figure 8 is an image of the sustained-release oral appliance 30 according to the fourth embodiment when worn.

[0034] In the explanation of the first embodiment, it was stated that the sustained-release device 11 may have a configuration without a lid portion 14. This also applies to the second to fourth embodiments. It should be noted that the first to fourth embodiments described above may have a configuration without a recess, as long as the drug-containing cured material 13 can be placed therein. In particular, the fourth embodiment may be a sheet-like sustained-release oral appliance without a recess. For example, a sheet-like TEGDM may be layered on a sheet-like oral appliance, and the drug-containing cured material 13 may be placed thereon. Furthermore, the entire drug-containing cured material 13 may be covered with a sheet-like mixture of TEGDM and PEGDM.

[0035] [Pharmaceuticals] The sustained-release oral appliance with a sustained-drug release portion of the present disclosure is a "combination product" that combines a pharmaceutical product and a medical device. In practice, a specific pharmaceutical is contained in the sustained-drug release portion and distributed as a pharmaceutical product. The term "drug" refers to a drug prepared for a specific purpose. In other words, in distribution, the sustained-release oral appliance of the present disclosure is a pharmaceutical product that includes a drug for oral mucosal diseases and a sustained-release oral appliance with a sustained-drug release portion that sustains the release of the drug for oral mucosal diseases. There are no particular limitations on the type of drug included, and examples include triamcinolone acetonide as a treatment for oral lichen planus, triamcinolone acetonide as a treatment for stomatitis, cevimeline hydrochloride or pilocarpine hydrochloride as treatments for xerostomia, and fluorouracil, gimeracil, and oteracil potassium as treatments for oral cancer.

[0036] Oral diseases are on the rise due to the rise in cancer incidence, including treatment for stomatitis associated with cancer radiation therapy. Oral diseases are generally treated with patch preparations or ointment application. However, patch preparations can be burdensome to patients, such as peeling off, and there is a risk of accidental ingestion. In the case of ointment application, there are issues with medication being removed by contact with the tongue, etc. As such, patch preparations have the problem of causing discomfort in the oral cavity and accidental ingestion, and ointment application has the problem of difficulty retaining the medication in the oral cavity with saliva.

[0037] The sustained-release oral appliance of the present disclosure can be used in the oral cavity, causes little foreign body sensation when placed in the oral cavity, and can serve as a DDS that delivers drugs locally and sustainably to the affected area. In particular, the sustained-release can be maintained for a long period of time, providing unprecedented benefits. For example, while the sustained-release time of a single patch formulation disclosed in Non-Patent Document 2 is 90 minutes, the sustained-release oral appliance of the present disclosure can continue to release for 14 days or more. For oral hygiene reasons, sustained-release oral appliances placed in the oral cavity must be cleaned regularly. The 14-day period mentioned here is a period from the perspective of cleaning the sustained-release oral appliance, and the sustained-release oral appliance of the present disclosure itself can maintain its sustained-release performance for a period exceeding 14 days.

[0038] The sustained release oral appliance of the present disclosure further has the following advantages: - In the treatment of oral diseases, it is possible to release drugs locally and for a long period of time. The structure of the sustained release device enables unidirectional, sustained drug release in the oral cavity. - It is roughly the same size as a conventional oral appliance, but allows for more space for the sustained release device to be placed in an effective location. Depending on the location of each oral disease, the sustained release device can be placed not only on the entire surface of the oral appliance but also on a portion of it, allowing for treatment of diseases in specific areas of the oral cavity. By making the oral appliance thicker, the sustained-release device can be placed near the affected area, making it easier for the medication to reach the affected area. For example, by placing the sustained-release device near the first molar in the upper jaw, it is possible to slowly release the medication into the oral cavity through the saliva secreted by the parotid gland, one of the three major salivary glands. This oral appliance has a sustained drug-releasing portion that diffuses the drug into the oral cavity. That is, this oral appliance can diffuse the drug throughout the oral cavity or into a specific area. In other words, this oral appliance has a different function than an appliance that sustainedly releases the drug only to a specific area in the oral cavity, for example, a specific tooth. The shape of the sustained release device can be changed to fit the shape of the diseased area (circle, oval, etc.), enabling efficient delivery of drugs to the affected area. This oral appliance can be produced using a 3D printer based on intraoral shape data obtained by taking images of the oral cavity. This means it can be produced without taking a dental impression. Furthermore, compared to milling, 3D printing makes it possible to produce appliances for teeth with severe undercuts. If the oral appliance is a mouthpiece, it is easy to put on and reduces the foreign body sensation when worn. Compared to conventional technologies for oral mucosal diseases (ointments, oral mucosal adhesive tablets, patches, etc.), the sustained-release device itself can release drugs over a long period of time without peeling off from the affected area. - Because the drug can be retained in the mouth for a long time, it can be absorbed into the body through the blood vessels in the mouth, similar to sublingual immunotherapy, making it possible to treat the allergen by getting the patient used to the allergen. By changing the type of drug loaded on this device and the placement location, it is effective in treating various oral diseases that require long-term medication compliance, such as oral lichen planus, xerostomia, and recurrent aphthous stomatitis. It can also be applied to the treatment of oral cancer. [Example]

[0039] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples and can be practiced in various forms with various modifications and improvements based on the knowledge of those skilled in the art.

[0040] A sustained release device was fabricated as the sustained drug release portion of the sustained release oral appliance of the present disclosure, and an in vitro test was conducted to test the sustained drug release from the sustained release device. The results are shown below. The following sizes of sustained release devices were created to be easily embedded in oral appliances such as mouthpieces and to take usability (e.g., how well they fit on the cheek) into consideration. Top (lid side): 9mm x 4mm Bottom (body side): 8mm x 3mm Thickness: 2mm The ingredients are listed below. TEGDM: Fw=286.33, 3G, manufactured by Shin-Nakamura Chemical Co., Ltd. PEGDM: Mn=750, 14G, manufactured by Shin-Nakamura Chemical Co., Ltd. Photopolymerization initiator: 2-Hydroxy-2-methylpropiophenone, manufactured by Tokyo Chemical Industry Co., Ltd. The drug used was triamcinolone acetonide (TA), a prescription drug used to treat oral lichen planus. The total amount of TA filled was 4 mg. The TA suspension was 1 mg / μL. The production conditions were a volume ratio of PEGDM:TEGDM=8:2 (the sustained release device under these conditions is designated as P80).

[0041] An appropriate amount of photopolymerization initiator was weighed and mixed into TEGDM. The mixture was poured into the recess of member I shown in Figure 2 (S1) so that the sustained release device would have the above size, and the protrusion of member II shown in Figure 2 was inserted into the recess of member I (S2). An intensity of 38.5 mW / cm was applied to members I and II. 2 After the TEGDM was cured by irradiation with UV light for 60 seconds (S3), the main body 12 having the recesses formed therein was removed from the member I. An appropriate amount of photopolymerization initiator was weighed and mixed into the mixture of the drug, TEGDM, and PEGDM. The mixture was poured into the recess of the fabricated main body 12 (S4), and an intensity of 38.5 mW / cm was applied. 2The TEGDM and PEGDM were cured by irradiation with UV light for 10 seconds (S5), yielding a drug-containing cured material 13. An appropriate amount of photopolymerization initiator was weighed and mixed into the mixture of TEGDM and PEGDM. The mixture was further poured into the recess of the main body 12 (S6), and member III shown in Figure 2 was placed on the main body 12 to flatten the top surface of the sustained release device (S7). An intensity of 38.5 mW / cm was applied to the main body 12 and member III. 2 The device was irradiated with UV light for 240 seconds (S8) to cure the TEGDM and PEGDM, thereby obtaining P80 as a sustained release device 11.

[0042] The three sustained-release devices (P80) fabricated under the above conditions were immersed in a 1% Tween 80 aqueous solution at 37°C. The amounts of drug released from the three P80s over time are shown in the graph in Figure 9. Table 1 below shows the average release amounts for the three P80s shown in the graph in Figure 9.

[0043] [Table 1]

[0044] No initial burst was observed. The daily release of P80 was approximately 25 μg on the first day. The release gradually decreased over the course of the day, reaching 8.25 μg per day between days 8 and 14. Note that 25 μg corresponds to 25 μg of the active ingredient (triamcinolone acetonide) in one tablet of Aftach (an adhesive-type aphthous stomatitis treatment). As shown in Figure 9, linear sustained release was confirmed for the three P80s over a 14-day period. This period is sufficient to cover the replacement period of the mouthpiece.

[0045] Figures 10a to 10d are photographs showing the manufactured sustained release device 11 attached to a mouthpiece. In Figures 10a to 10d, the sustained release device 11 is placed near the second molar and on both outer sides of the mouthpiece. In this way, the sustained release device 11 can be placed at any position on the mouthpiece (i.e., oral appliance). [Explanation of symbols]

[0046] 1 tooth 10. Sustained-Release Oral Appliances 11. Sustained release devices 12 Main Unit 13 Drug-containing cured product 14 Lid 15 mouthpiece 16. Depression 17 Protrusion 20. Sustained-Release Oral Appliances 30 Sustained-Release Oral Appliances I member II. Materials III. Materials IV Member

Claims

1. A drug release section is provided for gradually releasing a drug into the oral cavity, The sustained-release surface of the sustained-release drug portion is disposed on the outer surface. Sustained-release oral appliance.

2. the sustained drug-release portion includes a main body having a recess formed therein and a lid portion that closes the recess; The main body is formed independently of the oral appliance.

10. The sustained release oral appliance of claim 1.

3. the sustained drug-release portion includes a main body having a recess formed therein and a lid portion that closes the recess; The main body is integrally formed with the oral appliance.

10. The sustained release oral appliance of claim 1.

4. the body is formed from a drug-impermeable material; 4. The sustained release oral appliance of claim 2 or claim 3.

5. The lid portion is formed from a drug-impermeable material and a drug-permeable material.

4. The sustained release oral appliance of claim 2 or claim 3.

6. The thickness of the lid is 0.01 to 0.3 mm.

4. The sustained release oral appliance of claim 2 or claim 3.

7. The recess accommodates a cured product of a drug, a drug-impermeable material, and a drug-permeable material.

4. The sustained release oral appliance of claim 2 or claim 3.

8. The sustained drug release portion is placed at any position of the oral appliance. The sustained release oral appliance according to any one of claims 1 to 3.

9. The sustained-release oral appliance is applied to at least a portion of the wearer's dentition. The sustained release oral appliance according to any one of claims 1 to 3.

10. The oral appliance is a mouthpiece or a bracket. The sustained release oral appliance according to any one of claims 1 to 3.

11. Drugs for oral mucosal diseases and a sustained-release oral appliance having a drug sustained-release portion that sustainably releases the drug for oral mucosal diseases. Pharmaceuticals.

Images