Mucosal adhesive tablets for the treatment of oropharyngeal fungal infections

Abstract

The present invention relates to a sustained release buccal mucoadhesive tablet comprising 25 mg to 150 mg, preferably 35 mg to 135 mg of miconazole as active ingredient in combination with a milk protein concentrate and hydroxypropylmethylcellulose (HPMC) as excipients, characterized in that the tablet has a hardness of more than 20 N and an adhesiveness of more than 100 g. The present invention also relates to the use of said tablet for the treatment of oropharyngeal candidiasis, in particular for the treatment of biofilms.

Description

Technical Field

[0001] This invention relates to the field of therapeutic agents, and more particularly to mucosal adhesive compositions intended for treating oropharyngeal infections such as oropharyngeal candidiasis. Background Technology

[0002] Candidiasis is a fungal infection (also known as mycorrhizal candidiasis) caused by yeasts of the genus *Candida*. These yeasts are saprophytic, meaning they form part of a symbiotic microbiome. However, under certain conditions, they can transform into pathogenic filamentous forms capable of adhering to and colonizing mucous membranes. Approximately 23 species of *Candida* are pathogenic to humans, with *Candida albicans* being the leading cause of oropharyngeal candidiasis. Other *Candida* species may also be involved, such as *Candida tropicalis*, *Candida glabrata*, *Candida kefyr*, *Candida guilliermondii*, *Candida krusei*, *Candida lusitaniae*, and *Candida parapsilosis*.

[0003] Currently, several topical medications are used to treat oropharyngeal candidiasis. These medications are in the form of gels, such as... (Miconazole), drinkable suspension or mouthwash, such as (Amphotericin B) or (Nystatin), and gingival tablets such as (Miconazole)

[0004] However, antifungal drug treatment is sometimes insufficient to cure oropharyngeal candidiasis, and relapses require patients to use other classes of drugs to prevent systemic infection. The high sugar content of drinkable preparations or gels, combined with excessively fluctuating or transient local concentrations at the site of infection, has led to drug resistance and promoted relapses of oropharyngeal candidiasis.

[0005] Some oropharyngeal candidiasis cases exhibit primary or secondary resistance to antifungal drugs. Resistance may be related to multiple mechanisms, primarily mutations or overexpression of target enzymes and certain pump proteins involved in the efflux of antifungal agents. Multiple mechanisms often coexist, and cross-resistance between different antifungal agents is not uncommon. In addition to these resistance mechanisms, the ability of yeast to form biofilms has been reported in recent years, protecting them from external factors such as the host immune system or antifungal drugs.

[0006] Biomembranes are complex three-dimensional structures composed of a dense network of yeast, hyphae, and pseudohyphae surrounded by an extracellular polysaccharide matrix.

[0007] Biofilm oropharyngeal candidiasis, particularly buccal candidiasis, has a multifactorial etiology. Several factors contribute to the development of biofilm oropharyngeal candidiasis, such as wearing medical devices, age, physiological or iatrogenic reduction of saliva, oral trauma, high intake of antibiotics or corticosteroids, certain systemic diseases such as diabetes and cancer, and immunocompromised subjects, such as those with HIV or who have undergone radiation or chemotherapy.

[0008] Regarding medical devices, several studies have demonstrated that they constitute surfaces conducive to the formation of Candida biofilms. Therefore, dental prostheses, dentures, orthodontic systems, and other dental medical devices can be sources of oral candidiasis. This is because Candida readily adheres to the surfaces of these medical devices, which facilitates the formation of a biofilm capable of colonizing adjacent mucosa and then throughout the oral cavity and tongue. This infection can lead to acute candidal stomatitis (e.g., Candida-associated denture stomatitis (CaD)), characterized by inflammation of the oral mucosa, chronic erythema, and / or edema, making eating particularly painful and potentially leading to serious systemic complications in vulnerable individuals.

[0009] Several in vitro studies have demonstrated that Candida biofilms exhibit greater resistance to antifungal agents compared to their planktonic forms. This resistance has been observed with different classes of antifungals, such as polyene antifungals like amphotericin B or azole antifungals like fluconazole, itraconazole, miconazole, and voriconazole. These studies are consistent with clinical experience, indicating that biofilm-borne oropharyngeal candidiasis responds poorly to antifungal treatment, relapses frequently, and carries a high risk of systemic dissemination (Gebremedhin et al., Journal of Physiology and Pharmacology, 2014, 65, 4, 593-600).

[0010] Therefore, new strategies are needed to manage biofilm oropharyngeal infections. Summary of the Invention

[0011] According to a first aspect, an object of the present invention is a sustained-release buccal mucosa adhesive tablet comprising 25 to 150 mg, preferably 35 to 135 mg, of miconazole as an active ingredient, and a combination of a milk protein concentrate and hydroxypropyl methylcellulose (HPMC) as excipients, characterized in that it has an adhesiveness greater than 100 g, preferably 150 g to 500 g, and a hardness greater than 20 N, preferably 25 to 40 N. In some embodiments, the "hardness / adhesion ratio" of the tablet according to the invention is less than 0.4, preferably 0.04 to 0.4. Adhesion (i.e., the bioadhesion of the tablet to the gingival mucosa) and hardness are determined by conventional methods, as described below.

[0012] In some implementation methods, mucosal adhesion tablets are characterized by:

[0013] It is obtained through a granulation process, preferably wet granulation.

[0014] - It comprises primary particles containing miconazole, milk protein concentrate, and some HPMC, with the remaining HPMC in the outer phase of the primary particles and accounting for 45% to 55% by weight of the total HPMC present in the tablet.

[0015] The tablet may also contain a surfactant in the external phase, preferably dodecyl sulfate.

[0016] The tablets according to the invention may further contain a disintegrant, such as corn starch present in the primary granules, and one or more lubricants, such as talc and magnesium stearate present in the external phase.

[0017] The mucosal adhesion tablet preferably has the following in vitro release profile:

[0018] - Releases 20% to 45% of the miconazole present in the tablets within 4 hours.

[0019] - Releases 60% to 85% of the miconazole present in the tablets within 8 hours.

[0020] - To release at least 85% of the miconazole present in the tablets within 24 hours, by determining the in vitro dissolution profile under the following conditions, preferably as defined in Chapter 711 of the United States Pharmacopeia (USP):

[0021] - Basket dissolution apparatus: USP dissolution equipment 1

[0022] - Dissolution medium: 0.5% SDS in purified water, pH adjusted to 6.5 ± 0.5

[0023] - Dissolution volume: 1000 mL

[0024] -Temperature: 37±0.5℃

[0025] - Rotation speed: 60 rpm.

[0026] In some embodiments, the mucosal adhesion tablet according to the invention is characterized by producing a salivary miconazole concentration (C0.05) 24 hours after its application to the gingiva of the subject. 24hThe concentration of miconazole is at least 100 μg / mL, preferably at least 140 μg / mL. According to certain embodiments, the tablets according to the invention contain 50 mg of miconazole and have the following pharmacokinetic characteristics: a mean salivary Cmax of 300 to 500 μg / mL, a mean salivary Tmax of about 13 to 15 hours, and a mean salivary AUC∞ of 2000 to 3000 μg / mL.

[0027] In other embodiments, the tablets according to the invention are characterized in that the milk protein concentrate is in the form of an atomized powder, having a protein content of at least 85% by weight, preferably at least 87% by weight, a calcium content of at least 1% by weight, preferably about 2.2% by weight, and / or the apparent viscosity of the HPMC in water at 20°C is 11,000 to 22,000 cP. Furthermore, the mucosal adhesion tablets according to the invention may comprise:

[0028] -35% to 50% miconazole,

[0029] -10% to 25%, preferably 15% to 20% HPMC,

[0030] -15% to 30%, preferably 20% to 26% milk protein concentrate,

[0031] -5% to 15%, preferably 6% to 10%, of disintegrant, preferably corn starch.

[0032] -0% to 3% lactose, preferably 0.1% to 0.8% lactose.

[0033] -2% to 8% surfactant, preferably 3% to 6% sodium dodecyl sulfate,

[0034] -1% to 3% lubricant, preferably 1.5% to 2.5% magnesium stearate and talc,

[0035] The percentage is expressed by weight relative to the total weight of the tablets.

[0036] Typically, the amount of miconazole in the tablets is 50 mg or 100 mg.

[0037] The tablets according to the present invention can be obtained by a wet granulation process, which includes the following steps:

[0038] a) Mix miconazole with milk protein concentrate, some HPMC, and disintegrant.

[0039] b) Wet granulation of the mixture from step a) by adding water containing lactose.

[0040] c) Dry and calibrate the particles obtained in step b).

[0041] d) Add the remaining HPMC, surfactant, and lubricant to the particles obtained in step c), and

[0042] e) Compress the mixture from step d) to obtain tablets.

[0043] Typically, in step a), 45% to 55% by weight, preferably 50% by weight, of HPMC is added relative to the total weight of HPMC present in the final tablet. Step e) is performed to give the tablet a hardness of at least 20 N, preferably 20 N to 60 N, for example 25 N to 50 N. In one specific embodiment, the tablet according to the invention is intended for use in subjects suffering from or susceptible to biofilm-related oropharyngeal infections.

[0044] Another objective of the invention is the use of the tablets as defined above in the treatment and prevention of biofilm oropharyngeal infections in subjects.

[0045] The infection may be oral candidiasis, preferably associated with one or more Candida species selected from Candida albicans, Candida tropicalis, Candida glabrata, Candida lactis, Candida guillimon, Candida krusei, Candida Portugueseia, and Candida parapsilosis. In some embodiments, the treated subject has one or more risk factors selected from advanced age (preferably 75 years or older), diabetes, cancer, physiological or iatrogenic pharyngeal candidiasis, immunosuppression, malnutrition, smoking, excessive use of oral disinfectants, wearing oral medical devices, and medical treatments such as corticosteroid therapy (especially by inhalation), antibiotics, immunosuppressants, radiation therapy (especially neck and head radiation therapy), and chemotherapy.

[0046] In one specific embodiment, the tablet according to the invention is used for the treatment and prevention of biofilm oropharyngeal infections, wherein the subject wears an oral medical device, preferably selected from dentures, fixed or removable dental prostheses, and orthodontic instruments. The biofilm oropharyngeal infection may be, in particular, candidal stomatitis associated with wearing dental medical devices.

[0047] Another object of the present invention is a method for treating a biofilm-borne oropharyngeal infection in a subject, the method comprising oral administration of a mucosal adhesive tablet as defined above. Another subject of the present invention is the use of miconazole in the preparation of a medicament for treating biofilm-borne oropharyngeal infections, said medicament being in the form of a mucosal adhesive tablet as defined above.

[0048] Finally, the objective of this invention is a method for manufacturing miconazole mucosal adhesion tablets according to the invention by wet granulation, the method comprising the following steps:

[0049] a) Mix miconazole with some HPMC, milk protein concentrate and disintegrant.

[0050] b) Wet granulation of the mixture from step a) by adding water containing lactose.

[0051] c) Dry and calibrate the particles obtained in step b).

[0052] d) Add the remaining HPMC, surfactant, and lubricant to the particles obtained in step c), and

[0053] e) Compress the mixture from step d) to obtain tablets.

[0054] In step a), 45% to 55% by weight, preferably 50% by weight, of HPMC present in the final tablet is added.

[0055] Step e) is performed to make the tablet hardness at least 20N, preferably 20N to 60N, for example 25N to 50N. Attached Figure Description

[0056] Figure 1 In vitro dissolution profiles of the tablet (Form B) and the reference tablet (Form A) according to the present invention are shown.

[0057] Figure 2 The evolution of average saliva concentration over time is shown for the tablet (Form B) according to the invention and the reference tablet (Form A).

[0058] Figure 3 The effect of HPMC distribution between the external and internal phases of tablets obtained under high and low compression forces on the in vitro release of miconazole at T 24 hours is shown. Detailed Implementation

[0059] Gebremedhin et al. (see above) tested the antifungal activity of miconazole against various Candida biofilm models in vitro. They observed antifungal activity of miconazole against these biofilms. However, the authors demonstrated that a miconazole concentration of approximately 100 μg / ml was necessary to reduce biofilm metabolic activity by at least 50% in all tested species, namely Candida albicans, Candida glabrata, Candida tropicalis, and Candida parapsilosis.

[0060] Based on this finding, the applicant believes that it is necessary to maintain a saliva concentration greater than 100 μg / ml over a long period in order to treat oral candidiasis of biofilms.

[0061] International patent application WO 03 / 009800 describes a miconazole mucosal adhesion tablet, which specifically comprises milk protein, hydroxypropyl methylcellulose (HPMC), and sodium dodecyl sulfate (SDS) as excipients. The tablet is obtained by a wet granulation process of mixing miconazole with HPMC and milk protein. The resulting mixture is then granulated with an aqueous solution containing lactose to obtain primary granules, to which SDS and other excipients (lubricants) are added. After mixing, tablets are obtained by compression. HPMC is primarily present in the internal phase (i.e., in the primary granules). International patent application WO 03 / 009800 does not provide any description of the stiffness or bioadhesiveness of the obtained tablets, but describes these tablets with a salivary Cmax of 15.07 μg / ml, a salivary tmax of 7 hours, and a salivary AUC of approximately 43 μg / ml for 0-12 hours. Clearly, the tablets described in patent application WO 03 / 009800 cannot establish the long-term saliva concentration of 100 μg / ml required for effective treatment of oral candidiasis with biofilm.

[0062] Therefore, the applicant sought to modify the form of the drug described in International Patent Application WO 03 / 009800 in order to obtain a salivary concentration of at least 100 μg miconazole / ml in patient saliva in a stable and rapid manner, while coordinating a simple dosing regimen of administering the drug once daily.

[0063] Surprisingly, the applicant has demonstrated that increasing the hardness of the tablet can improve the release profile of miconazole.

[0064] This result was entirely unexpected, as those skilled in the art would expect that increased tablet hardness would alter tablet integrity, prevent or delay saliva penetration, and thus prevent or delay the dissolution of the active ingredient, as well as hinder its adhesion to the patient's mucous membranes. Those skilled in the art would also expect that increased tablet hardness would prevent the rapid local release of the active ingredient and / or facilitate substantial systemic release of the active ingredient, which is particularly undesirable due to the associated side effects. In other words, those skilled in the art would also expect that increased hardness would significantly alter the release profile of the active ingredient by reducing the initial release rate and preventing its subsequent release over time due to incomplete disintegration of the tablet in the oral cavity.

[0065] Surprisingly, the applicant has demonstrated that tablets with a hardness greater than 20 N have improved in vitro dissolution profiles compared to control tablets with similar composition but a hardness of approximately 17 N.

[0066] Surprisingly, the applicant also demonstrated that this in vitro difference was reflected in vivo through a longer duration of tablet adhesion (24 hours compared to 15 hours for the reference tablet) and significantly altered pharmacokinetic profiles. The mucosal adhesion tablets of the present invention, containing a 50 mg dose of miconazole, allow for sustained release of miconazole, characterized by a salivary Cmax of 2630 μg / h / ml, a Tmax of 14 hours, and an AUC of 2630 μg / mL. Specifically, the salivary miconazole concentration at 24 hours was approximately 150 μg / ml, significantly higher than the concentration determined by Gebremedhin et al., resulting in at least a 50% inhibition of metabolic activity against all tested Candida strains. These pharmacokinetic properties are significantly superior to those observed against the control tablet and the tablets described in patent application WO 03 / 009800.

[0067] In other words, the sustained-release mucosal adhesion tablets according to the present invention can continuously produce a saliva concentration greater than 100 μg / ml for 24 hours, which has not been observed in reference tablets or other commonly used drug forms such as miconazole gels and mouthwashes.

[0068] The applicant also observed that the "hardness / adhesion" ratio is an important parameter for obtaining improved miconazole release profiles. Preferably, the "hardness / adhesion" ratio of the tablets according to the present invention is greater than 0.04 and less than 0.4.

[0069] Finally, the applicant has demonstrated that it is advantageous to prepare tablets according to the invention by wet granulation as described in patent application WO 03 / 009800, but by fractionating the addition of HPMC such that approximately half of the HPMC is present in the primary granules and the remainder in the external phase. This fractionation process allows for the production of tablets with optimal hardness and bioadhesion. Furthermore, this fractionation process makes the manufacturing process more robust, thereby improving the compressibility of the tablets and minimizing the impact of the compression step on the total proportion of miconazole released in in vitro dissolution tests.

[0070] Without being bound by any theory, the applicant believes that the mucosal adhesion tablets according to the present invention can establish extremely high and long-term salivary antifungal concentrations, which will have a major clinical advantage in treating oropharyngeal candidiasis, especially biofilm candidiasis or candidiasis resistant to conventional treatment.

[0071] Therefore, unlike conventional commercially available drug forms, the miconazole mucosal adhesion tablets according to the invention are particularly suitable for the treatment and prevention of biofilm oropharyngeal infections by enabling the production of salivary miconazole concentrations significantly greater than 100 μg / ml during the course of administration (24 hours).

[0072] Therefore, one object of the present invention is a sustained-release mucosal adhesion tablet characterized in that it contains 25 mg to 150 mg of miconazole as an active ingredient, a milk protein concentrate and hydroxypropyl methylcellulose as excipients, and has a hardness greater than 20 N. Preferably, the tablet according to the invention has an adhesion of greater than 100 g and a "hardness / adhesion" ratio greater than 0.04.

[0073] The tablets according to the invention are preferably obtained by granulation and comprise primary granules containing miconazole, milk protein and some HPMC, with the outer phase containing the remaining HPMC, wherein the HPMC present in the primary granules accounts for 45% to 55% by weight of the total HPMC present in the tablet.

[0074] The tablets according to the invention are particularly suitable for subjects suffering from or susceptible to biofilm-related oropharyngeal infections.

[0075] Another objective of this invention is the use of the tablets for the treatment or prevention of biofilm oropharyngeal infections, particularly biofilm oral candidiasis.

[0076] Another objective of the invention is a method for treating biofilm oropharyngeal infections, particularly biofilm oral candidiasis, in subjects, the method comprising applying a mucosal adhesion tablet according to the invention to the patient's gingiva, the application being repeatable after 24 hours, preferably over a period of at least 7 days.

[0077] 1. The sustained-release mucosal adhesion tablet according to the present invention:

[0078] As noted above, one object of the present invention is a sustained-release miconazole mucosal adhesion tablet.

[0079] The term "mucosal adhesion tablet" refers to a tablet capable of adhering to a mucosa for an extended period (i.e., several hours). In the context of this invention, mucosa refers to the oral mucosa, preferably the gingiva. The mucosal adhesion tablet according to the invention is capable of adhering to the gingival surface for a period of at least 18 hours, preferably at least 20 hours, and even more preferably at least 24 hours.

[0080] Therefore, the administration route of the tablets according to the present invention is the mucosal route, more precisely the buccal mucosa.

[0081] The term "sustained release" refers to a drug form that allows the active ingredient to be released in a controlled manner over a long period of time, i.e., within several hours.

[0082] The term "miconazole" refers to a compound with CAS number 22916-47-8, which has the following chemical formula:

[0083]

[0084] This includes its racemic mixtures, enantiomers, and pharmaceutically acceptable salts.

[0085] The preferred pharmaceutically acceptable salt is miconazole nitrate.

[0086] Miconazole is present in the tablets according to the invention in amounts from 25 mg to 150 mg. Preferably, miconazole is present in the tablets according to the invention in amounts of 50 mg or 100 mg.

[0087] As described above, the mucosal adhesion tablet according to the present invention is characterized by a hardness of at least 20 N, preferably 20 to 50 N or 25 to 40 N.

[0088] In the context of this invention, the hardness (also known as “crush resistance”) of the tablets is preferably determined according to Section 2.9.8 of the European Pharmacopoeia (European Pharmacopoeia 10.0, page 337, chapter: Resistance to crushing of tablets).

[0089] The mucosal adhesive tablets according to the invention are further characterized in that the adhesiveness is greater than 100g, preferably greater than 150g, for example in the range of 150g to 600g, 150g to 500g, 200g to 550g or 300g to 500g.

[0090] In the context of this invention, adhesiveness (also referred to herein as bioadhesion, adhesive strength, or bioadhesion) corresponds to the strength of adhesion between a tablet and a given surface (typically stainless steel). This adhesive strength can be determined using a consistency tester according to conventional methods.

[0091] Typically, a cyanoacrylate adhesive is used to bond the top surface of the tablet to a disposable probe of a consistency tester. The tablet is then contacted with a stainless steel holder in a crystallizer filled with purified water for a specified time. The lever arm of the consistency tester is then lifted at a set speed, and the force required to pull the tablet away is measured, thereby obtaining the adhesion strength. Preferably, the adhesion strength is determined according to the procedure given in the examples.

[0092] In another embodiment, the mucosal adhesive tablet according to the invention is characterized by a "hardness / adhesion" ratio greater than 0.04, where hardness is expressed in Newtons (N) and adhesion is expressed in units of acceleration (g), said hardness and adhesion being determined according to the method described above.

[0093] In one specific implementation, the "hardness / adhesion" ratio is in the range of 0.04 to 0.4, for example, in the range of 0.04 to 0.1.

[0094] According to certain embodiments, the sustained-release mucosal adhesion tablet according to the present invention is characterized by the following in vitro release profile:

[0095] - No more than 45% of the miconazole in the tablets is released within 4 hours.

[0096] - No more than 85% of the miconazole in the tablets is released within 8 hours.

[0097] - At least 85% of the miconazole in the tablets is released within 24 hours.

[0098] In some other embodiments, the sustained-release mucosal adhesive tablet according to the present invention is characterized by the following in vitro release profile:

[0099] - 20% to 45% of the miconazole in the tablets is released within 4 hours.

[0100] - 60% to 85% of the miconazole in the tablets is released within 8 hours, and

[0101] - At least 85% of the miconazole in the tablets is released within 24 hours.

[0102] In vitro dissolution profiles can be determined by dissolution testing, preferably according to Chapter 711 of the United States Pharmacopeia (USP), under the following conditions:

[0103] - Basket dissolution apparatus: USP dissolution equipment 1

[0104] - Dissolution medium: 0.5% SDS in purified water, pH adjusted to 6.5 ± 0.5

[0105] - Dissolution volume: 1000 mL

[0106] -Temperature: 37±0.5℃

[0107] - Rotation speed: 60 rpm (revolutions per minute).

[0108] The release of miconazole into the medium was monitored by HPLC analysis and UV detection (220 nm absorbance).

[0109] In additional or alternative embodiments, the mucosal adhesion tablet according to the invention is characterized in that it provides an average salivary miconazole concentration (C0.05) of at least 100 μg / ml, preferably at least 110, 120, 130 or 140 μg / ml, over 24 hours. 24h Typically, the average C of a tablet containing 50 mg of miconazole is... 24h The average C of a tablet containing 100 mg of miconazole is approximately 150 μg / ml. 24h It is approximately 425 μg / ml.

[0110] In some embodiments, the mucosal adhesion tablet according to the invention comprises 50 mg miconazole, characterized by an average salivary Cmax of 300 to 500 μg / ml (e.g., about 350 μg / mL), an average salivary Tmax of about 13 to 15 hours (e.g., about 14 hours), and an average salivary AUC. inf It is 2000 to 3000 μg·h / mL (e.g., about 2600 μg·h / mL).

[0111] In other embodiments, the mucosal adhesion tablet according to the invention comprises 100 mg miconazole, characterized by an average salivary Cmax of 500 to 700 μg / ml (e.g., about 600 μg / mL), an average salivary Tmax of about 15.5 to 17.5 hours (e.g., about 16 hours), and an average salivary AUC of inf It ranges from 4300 to 5500 μg·h / mL (e.g., about 4800 μg·h / mL).

[0112] The above pharmacokinetic parameters are averages obtained from a cohort of healthy subjects aged at least 18 years. The number of subjects included in this cohort was selected to ensure that the results were statistically significant.

[0113] Each subject received one tablet according to the invention (containing 50 mg or 100 mg miconazole), placed on the upper gingiva, preferably above the incisors. For each subject, saliva samples were collected at regular time intervals (usually hourly) over 24 hours for miconazole determination. For each individual, pharmacokinetic parameters could be determined from curves showing the change of miconazole saliva concentration over time in a conventional manner. Cp could be determined from the raw data of each individual by applying well-known statistical methods. 24h Cmax, Tmax, and AUC inf The average value.

[0114] As used in this article, C 24h The AUC represents the salivary miconazole concentration 24 hours after tablet administration to the subject's gums. Cmax represents the maximum salivary miconazole concentration reached after tablet administration. Tmax represents the time to reach Cmax. inf This represents the area under the curve where miconazole concentration is extrapolated to infinity over time.

[0115] As noted above, this sustained-release mucosal adhesion tablet is characterized by the presence of milk protein concentrate and HPMC as excipients. The inventors have demonstrated that using a combination of milk protein concentrate and hydroxypropyl methylcellulose as excipients has a significant impact on tablet adhesion and the release profile of the active ingredient.

[0116] Milk protein concentrate acts as a bioadhesive, thus ensuring the adhesion of the tablet to the gingival mucosa.

[0117] It is preferably a protein concentrate derived from cow's milk. In other words, it is an extract of at least partially purified cow's milk proteins, i.e., having a protein content of at least 80%. Milk proteins include casein, albumin, and globulins. Casein is the main protein in the concentrate according to the invention.

[0118] This protein concentrate is in powder form and is typically obtained from cow's milk by a process generally including defatting, pasteurization, percolation or ultrafiltration, and spray drying. Preferably, the protein content of the milk protein concentrate is at least 85% by weight, preferably at least 86% by weight, or at least 87% by weight, relative to the total dry weight of the concentrate. The milk protein concentrate also contains at least 0.5% by weight, preferably at least 1.0% by weight, or 1.5% by weight, for example, from 1.5% to 3.0% by weight, relative to the total weight of the concentrate. For example, the calcium content can be in the range of 2.0g to 2.5g per 100g of milk protein concentrate.

[0119] Without being bound by any theory, the inventors believe that the presence of calcium ions contributes to the bioadhesion properties of the protein concentrate of this invention.

[0120] The content of milk protein concentrate relative to the total weight of the tablet is typically 15% to 30% by weight, preferably 18% to 28% by weight, for example 20% to 26% by weight.

[0121] Hydroxypropyl methylcellulose (HPMC) acts as both a binder and a hydrophilic matrix, participating in the control of tablet swelling and the controlled release of active ingredients, and enhancing the effects of milk protein concentrates. HPMC with an apparent viscosity in the range of 10,000 to 25,000 mPa·s, for example, 11,000 to 22,000 cPs, typically present at 2% in water at 20°C, can be used.

[0122] The HPMC content is typically 10% to 25% by weight, preferably 15% to 20% by weight, relative to the total weight of the tablet.

[0123] The tablets according to the present invention may contain other excipients.

[0124] Preferably, the tablet also contains a surfactant.

[0125] Surfactants can be used as wetting agents and promote the dissolution of active ingredients. Surfactants include, but are not limited to, simethicone, triethanolamine, and polysorbate derivatives such as Tween 20 (…). 20) or Tween 40 ( 40) Poloxamer, fatty alcohols such as lauryl alcohol or cetyl alcohol, or alkyl sulfates such as dodecyl sulfate (also known as lauryl sulfate) salts. The surfactant is preferably sodium lauryl sulfate (also known as sodium dodecyl sulfate or SDS). Its content is typically 2% to 8% by weight relative to the total weight of the tablets.

[0126] Preferably, the tablets according to the invention are obtained by a granulation process, particularly a wet granulation process.

[0127] Typically, and as detailed below, the granulation process includes the step of preparing primary granules, followed by the addition of other excipients in subsequent steps. The resulting mixture is then compressed to obtain tablets. The excipients added in subsequent steps are present in the external phase and therefore on the exterior of the primary granules.

[0128] Therefore, in one specific embodiment, the tablet according to the invention is obtained by granulation and comprises primary granules containing miconazole, milk protein concentrate and some HPMC, the remaining portion of HPMC being in the external phase and accounting for 45% to 55% by weight, preferably 46% to 54% by weight, for example 47% to 53% by weight, 48% to 52% by weight or even about 50% by weight, relative to the total weight of HPMC present in the tablet.

[0129] Preferably, the tablet contains a surfactant such as SDS, which is in the external phase.

[0130] The tablets according to the invention may also contain disintegrants and lubricants.

[0131] Disintegrants can be used to improve the swelling of tablets and / or the release of the active ingredient. For example, they can be selected from crospovidone (cross-linked polyvinylpyrrolidone), crospovidone (such as sodium crospovidone), or non-crospovidone carboxymethyl cellulose, starch, and mixtures thereof. Starch, such as corn starch, is preferred as the disintegrant. The content of the disintegrant is typically 5% to 15% by weight relative to the total weight of the tablet. When tablets according to the invention are prepared by granulation, the disintegrant is preferably present in the primary granules.

[0132] The lubricant can be one or more compounds that prevent problems associated with the preparation of dried herbal forms, such as sticking and / or jamming on the machine during filling and / or compression. Preferred lubricants are fatty acids or fatty acid derivatives such as calcium stearate, glyceryl monostearate, glyceryl palmitoyl stearate, magnesium stearate, zinc stearate or stearic acid, polyethylene glycol, especially polyethylene glycol, sodium benzoate or talc. Preferred lubricants according to the invention are stearates and mixtures thereof. Suitable lubricants are, for example, magnesium stearate, talc and mixtures thereof. When tablets according to the invention are prepared by granulation, the lubricant content is typically 1% to 3% by weight relative to the total weight of the tablet, and is preferably in the external phase.

[0133] Optionally, the tablets according to the invention comprise one or more excipients selected from diluents, flavoring agents, salivary agents, and combinations thereof.

[0134] For example, the tablets according to the invention contain 0.1% to 3% by weight of a diluent or binder, which is preferably selected from monosaccharides and polyols, such as mannitol, lactose, xylose or galactose, with lactose being preferred.

[0135] In some embodiments, the tablets according to the invention comprise lactose, which is used as a binder in the granulation process.

[0136] In some embodiments, the mucosal adhesion tablet according to the present invention comprises:

[0137] -35% to 50% miconazole,

[0138] -10% to 25%, preferably 15% to 20% HPMC,

[0139] -15% to 30%, preferably 20% to 26% milk protein concentrate,

[0140] -5% to 15%, preferably 6% to 10%, of disintegrant, preferably corn starch.

[0141] -0% to 3% lactose, preferably 0.1% to 0.8% lactose monohydrate.

[0142] -2% to 8% surfactant, preferably 3% to 6% sodium dodecyl sulfate,

[0143] -1% to 3% lubricant, preferably 1.5% to 2.5% magnesium stearate and talc, the percentages being expressed by weight relative to the total weight of the tablets.

[0144] Each miconazole tablet contains 25 mg to 150 mg of miconazole, preferably 35 mg to 135 mg of miconazole, or 40 mg to 110 mg of miconazole, such as 50 mg or 100 mg of miconazole.

[0145] In some embodiments, the tablets according to the invention can be manufactured by a granulation process, preferably wet granulation. Preferably, (i) a lubricant (e.g., talc and magnesium stearate) is present in the external phase, (ii) miconazole, a disintegrant, a milk protein concentrate, and lactose are present in the primary granules, and (iii) HPMC is distributed between the primary granules and the external phase in a mass ratio ranging from 45 / 55 to 55 / 45, preferably about 1 / 1.

[0146] In one specific embodiment, the tablet according to the invention is manufactured by a method comprising the following steps:

[0147] a) Mix miconazole with some HPMC, milk protein concentrate and disintegrant.

[0148] b) The mixture from step a) is wet-granulated by adding water, optionally containing a diluent (preferably lactose).

[0149] c) Dry and calibrate the particles obtained in step b).

[0150] d) Add the remaining HPMC, surfactant, and lubricant to the particles obtained in step c), and

[0151] e) Compress the mixture from step d) to obtain tablets.

[0152] The granulation step can be performed in any type of granulator, such as a shear granulator.

[0153] Step c) is preferably performed to obtain a water content of 3% to 9% by weight, preferably 5% to 7%, in the particles. Drying can be carried out at a temperature of 40°C to 60°C, for example in a moving bed dryer.

[0154] An additional drying step can be introduced between steps d) and e) to control the final moisture content of the tablets to below 8%.

[0155] Step e) is performed using conventional techniques to obtain tablets with a final hardness of at least 20 N (preferably 20 N to 50 N or 25 N to 40 N). Typically, this step can be performed using a rotary tablet press that applies a compressive force of 10 kN to 20 kN.

[0156] Without being bound by any theory, the inventors believe that the partial addition of HPMC in steps a) and d) helps improve the physicochemical properties and controlled release properties of the active ingredient. It also improves the robustness of the manufacturing process. Typically, 45% to 55% (e.g., 46% to 54%, 47% to 53%, 48% to 52%, 49% to 51%), preferably about 50%, of the final amount of HPMC present in the tablet is added in step a), with the remainder added in step d).

[0157] The method may include additional steps such as sieving and / or drying various raw materials or packaging the final tablets in suitable packaging.

[0158] It goes without saying that the method of obtaining tablets as described above also constitutes part of the objectives of this invention.

[0159] 2. The therapeutic uses and methods according to the present invention:

[0160] The miconazole mucosal adhesion tablets according to the present invention are intended for use in subjects who have or are susceptible to biofilm oropharyngeal infections.

[0161] Another objective of this invention is the use of the above-mentioned mucosal adhesion tablets in the treatment or prevention of biofilm oropharyngeal infections.

[0162] As used herein, the term “treatment” covers any treatment of a disease in a target subject to: reduce the incidence and / or risk of recurrence of the disease or condition during an asymptomatic period; alleviate or reduce symptoms or conditions associated with the disease; prevent the occurrence of the disease or any of its associated symptoms or conditions in a subject with or susceptible to the disease; terminate, slow or delay the development of one of the disease or its associated symptoms or conditions; reduce the frequency and / or intensity of disease (e.g., symptoms) attacks; and alleviate the disease or associated symptoms or conditions, i.e., cause the disease or associated symptoms or conditions to completely or partially subside.

[0163] As used in this article, the term "prevention" refers to preventive treatment aimed at preventing, mitigating, or delaying the onset of a disease or its associated symptoms or conditions.

[0164] For the purposes of this invention, oropharyngeal infections refer to infections affecting one or more mucous membranes of the oropharynx, particularly the oral cavity and pharynx. These infections may involve any type of microorganism, particularly yeasts or bacteria. The term "biofilm infection" is used when a three-dimensional structure composed of a pathogenic microbial community is observed growing on the surface of the oropharynx (e.g., on the gums, palate, or tongue), surrounded by a protective and adhesive polysaccharide extracellular matrix.

[0165] In a preferred embodiment, the oropharyngeal infection is candidiasis, preferably buccal candidiasis. The term "candidiasis" refers to an infection caused by one or more species belonging to the genus Candida. In some embodiments, the oropharyngeal infection involves at least one Candida species selected from Candida albicans, Candida tropicalis, Candida glabrata, Candida lactis, Candida guillimon, Candida krusei, Candida Portugueseia, and Candida parapsilosis.

[0166] Subjects who have or are susceptible to biofilm oropharyngeal infections can be men or women of any age.

[0167] In one specific implementation, the subject is a high-risk subject, i.e., a subject with one or more factors that contribute to biofilm infection.

[0168] In one specific implementation, subjects suffering from or susceptible to biofilm oropharyngeal infections are selected from infants, elderly subjects (preferably at least 75 years old), diabetic subjects, cancer subjects who have received radiation therapy (especially radiation therapy to the head and neck) or chemotherapy, subjects suffering from physiological or iatrogenic pharyngeal candidiasis, subjects receiving corticosteroid treatment (especially by inhalation), subjects receiving antibiotic treatment, subjects who overuse antibacterial mouthwash, subjects with compromised immune function (e.g., subjects with HIV or receiving immunosuppressive therapy), smokers, subjects suffering from malnutrition or eating disorders, and subjects wearing oral medical devices.

[0169] In the context of this invention, the term "oral medical device" means any medical device that can be placed in the mouth, particularly fixed dental prostheses, such as crowns or implants with pivots like bridges; removable dental prostheses, particularly clip-on dental prostheses with pivots; dentures and orthodontic appliances, such as braces, bracket-based or strut-based appliances, or appliances with palatal plates.

[0170] In some implementations, the subject wears dental medical devices.

[0171] For example, biofilm-related oropharyngeal infections can manifest as candidal stomatitis, particularly in cases associated with wearing dentures or dentures. Stomatitis can also be associated with thrush, especially on the inner cheeks and tongue. It can also be a lesion of chronic erythematous candidiasis or kissing candidiasis.

[0172] In the therapeutic use and treatment according to the invention, the mucosal adhesion tablet is placed on the gingiva, for example, above the upper incisors or canines. The tablet is changed approximately every 24 hours. The dosage (50 or 100 mg miconazole tablets) and duration of treatment depend on the patient's characteristics, particularly age, weight, severity of oropharyngeal infection, general health condition, and comorbidities. The duration of treatment is at least one week, generally 7 to 14 days. Depending on the subject's condition and disease progression, this treatment may be extended or repeated as necessary.

[0173] Other aspects and advantages of the invention will become apparent upon reading the following embodiments, which should be considered illustrative rather than restrictive.

[0174] Example

[0175] Example 1

[0176] Tablets and reference tablets according to the present invention

[0177] Miconazole tablets of 50 mg or 100 mg according to the present invention having the following composition:

[0178] -43.5% miconazole,

[0179] -17.8% HPMC

[0180] -23.9% milk protein concentrate, with a protein content of 87% by weight and a calcium content of 2.2% by weight.

[0181] -8.0% corn starch,

[0182] -0.3% lactose,

[0183] -4.5% sodium dodecyl sulfate,

[0184] -1.15% magnesium stearate and 0.9% talc,

[0185] The percentage is expressed by weight relative to the total weight of the tablets.

[0186] These tablets are manufactured using the following method:

[0187] a) Mix miconazole with 50% HPMC, milk protein concentrate, and corn starch.

[0188] b) The mixture from step a) is wet-granulated by adding a solution of lactose in purified water while stirring in a high-shear wet granulator.

[0189] c) Dry the particles in a moving bed dryer at approximately 50°C and calibrate the particles obtained in step b).

[0190] d) Add the remaining HPMC, SDS, and lubricant to the particles obtained in step c), and

[0191] e) The mixture from step d) is compressed and molded using a rotary tablet press with a compression force of 10 to 20 kN.

[0192] The tablets obtained in this way have a hardness between 25N and 40N and an adhesiveness between 150g and 500g.

[0193] The composition of the reference tablets is qualitatively and quantitatively similar to that of the tablets according to the invention, and corresponds to the tablets described in patent application WO 03 / 009800. These tablets are manufactured according to a method similar to that of the tablets according to the invention, but with HPMC added only in step a), and a different milk protein concentrate used in step e). The compression force in step e) is adjusted so that the hardness of the reference tablets is about 18 N. The adhesiveness of these tablets is between 20 and 30 g.

[0194] The hardness of tablets was determined according to section 2.9.8 (10.0 version) of the European Pharmacopoeia.

[0195] Adhesion strength is determined using a consistency tester according to the following method:

[0196] Equipment used:

[0197] - Consistency tester: This device consists of a test bench, a power socket, and a control keyboard connected to a computer for data acquisition;

[0198] - Disposable flat nylon probe, with its central groove screwed onto the movable part of the upper consistency measuring instrument (8.1mm diameter, 1mm depth);

[0199] - The lower part consists of a crystallizer with a diameter of 4cm, and its base is made of stainless steel test tubes similar in shape to tablets.

[0200] Reagents used:

[0201] -Purified water: the medium in the crystallizer.

[0202] - Cyanoacrylate adhesive (e.g., "Superglue 3" or equivalent) is used to adhere the tablet to the flat probe.

[0203] program:

[0204] The crystallizer contained 10 ml of demineralized water. A drop of cyanoacrylate adhesive was used to attach the tablet to the center of the nylon probe via its flat side. The flat nylon probe was screwed onto the moving part of the consistency tester. The probe was pressed against the surface of a stainless steel test tube. After 90 seconds, the probe was pulled out (force applied: 1100 g, pull-out speed: 0.2 mm / s). Thirty tablets were randomly selected from this batch for repeated testing.

[0205] For each measurement performed on a single tablet, the adhesive strength was calculated and expressed in grams (1 g is 9.81 × 10⁻⁶). -3 N). The results of the adhesion test are the average of 30 individual adhesion strength values.

[0206] In vitro dissolution curve

[0207] The in vitro dissolution profiles of each batch of tablets were determined under the following conditions according to the dissolution test specified in Chapter 711 of the United States Pharmacopeia (USP):

[0208] Sample quantity: 6

[0209] - Basket dissolution apparatus: USP dissolution equipment 1

[0210] - Dissolution medium: 0.5% SDS in purified water, pH adjusted to 6.5 ± 0.5

[0211] - Dissolution volume: 1000 mL

[0212] -Temperature: 37±0.5℃

[0213] - Rotation speed: 60 rpm (speed per minute).

[0214] The release of miconazole into the medium was monitored by HPLC analysis and UV detection (220 nm absorbance).

[0215] Figure 1 The obtained dissolution profiles are shown. The tablets according to the invention (form B) exhibit a more sustained miconazole release than the reference tablets.

[0216] Pharmacokinetic assessment

[0217] Two batches of tablets (based on the invention and a reference batch) were evaluated in two independent pharmacokinetic clinical studies (Study 1 and Study 2) conducted at two different time points. These were pharmacokinetic studies conducted in healthy subjects (men and women) aged 18 to 35 years. The aim of these studies was to determine the pharmacokinetics of salivary miconazole following once-daily administration of 50 mg or 100 mg mucosal adhesion tablets. The salivary and plasma pharmacokinetics of miconazole were evaluated over a 24-hour period.

[0218] For each subject, the tablet according to the invention or a reference tablet was placed in the buccal region (the upper gingiva directly above the incisors) until it eroded or fell off. Parameters assessed included: miconazole concentrations in saliva and plasma samples, time required for the bioadhesive tablet to erode or fall off, and tolerability assessment based on adverse event reports and local (buccal) examination. Saliva concentrations were assessed by collecting saliva samples before administration and at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, and 24 hours after administration. Plasma samples were collected before administration and at 0.5, 1, 4, 6, 8, 12, and 24 hours after administration. The limit of quantitation for the assay was 0.1 ng / ml.

[0219] Table 1 below summarizes the main results obtained:

[0220]

[0221] It should be noted that patent application WO 2003 / 9800 describes the saliva Cmax of a 50mg reference tablet as 15μg / ml, the Tmax as 7 hours, and the saliva AUC as... 0-12h It is 43 μg·h / mL.

[0222] The patients tolerated the tablets well.

[0223] The tablets according to the invention provide a higher and longer-lasting concentration of salivary miconazole, which will enhance therapeutic efficacy, particularly in the treatment of biofilm candidiasis. Simultaneously, lower plasma concentrations were observed, indicating lower systemic absorption and therefore a lower incidence of side effects.

[0224] Figure 2 The results show the change in average salivary concentration over time of the tablet according to the invention (Form B) compared to that of a reference tablet (Form A). It can be seen that, compared to the reference tablet, the tablet according to the invention establishes a stable, higher, and more sustained salivary concentration. Surprisingly, the high stiffness of the tablet according to the invention improves the in vivo pharmacokinetics of miconazole.

[0225] Example 2

[0226] The effect of HPMC distribution between the external and internal phases was investigated. Tablets were prepared according to the same method as in Example 1, with the following internal / external HPMC distributions: 0 / 100, 25 / 75, 50 / 50, 75 / 25, and 100 / 0. A first series of tablets was obtained under high compression (+ force). A second series of tablets was obtained under lower compression (- force). For each HPMC distribution, T was compared in the following in vitro dissolution test. 24h miconazole release:

[0227] In vitro dissolution of tablets (50 mg miconazole) under non-precipitation conditions (HPLC determination)

[0228] - pH 6.8 phosphate buffer: 20 ml, in a sealed bottle, without shaking, concentration 37%.

[0229] -Total duration: 24 hours

[0230] - Obtain samples at 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, and 24 hours.

[0231] - At each time point, take all the medium (without inverting the bottle) for the measurement and add 20 ml of medium.

[0232] For a given HPMC distribution, compare the T values ​​of tablets obtained under + force and tablets obtained under - force. 24h Average miconazole release.

[0233] The results are as follows Figure 3 As shown. Figure 3 The results showed that the effect of compression force on miconazole release was minimal when HPMC was uniformly distributed between the outer and inner phases. A 9% difference was then observed between tablets obtained by compression with + force and tablets obtained by compression with - force. On the other hand, when HPMC was non-uniformly distributed between the inner and outer phases, a very significant change in release was noted.

[0234] HPMC's uniform distribution between the internal and external phases minimizes the impact of compressive force on miconazole release, thus improving the stability of the manufacturing process.

Claims

1. A sustained-release buccal mucosa adhesive tablet comprising 35% to 50% miconazole as the active ingredient, 15% to 30% milk protein concentrate as an excipient, and 10% to 25% hydroxypropyl methylcellulose (HPMC), characterized in that: It has a hardness of 25 N to 40 N, an adhesion of 150 g to 500 g, and a "hardness / adhesion" ratio of 0.04 to 0.

4. It is obtained through wet granulation, and It comprises primary particles containing miconazole, milk protein concentrate, and some HPMC, with the remaining HPMC in the outer phase of the primary particles and accounting for 45% to 55% by weight of the total HPMC present in the tablet. The amount of miconazole in the tablets is 25 mg to 150 mg, and The mucosal adhesion tablet further comprises: The disintegrant present in 5% to 15% of the primary particles. Lactose present in the primary particles is 0% to 3%. The external phase contains 2% to 8% surfactant, and One or more lubricants comprising 1% to 3% of the external phase, and The milk protein concentrate is in the form of an atomized powder and has a protein content of at least 85% by weight and a calcium content of at least 1% by weight. The percentage is expressed by weight relative to the total weight of the tablets. The sustained-release buccal mucosal adhesive tablets produced a salivary miconazole concentration of at least 100 μg / mL 24 hours after administration to the gingiva of the subject (C 24h ).

2. The mucosal adhesion tablet according to claim 1, characterized in that HPMC has an apparent viscosity of 11,000 cPs to 22,000 cPs in water at 20°C.

3. The mucosal adhesion tablet according to claim 1, characterized in that it has the following in vitro dissolution profile: 20% to 45% of the miconazole in the tablets is released within 4 hours. 60% to 85% of the miconazole in the tablets is released within 8 hours. At least 85% of the miconazole in the tablets is released within 24 hours. In vitro dissolution profiles were determined by dissolution testing, which was performed under the following conditions according to Chapter 711 of the United States Pharmacopeia (USP): Basket dissolution apparatus: USP dissolution equipment 1 Dissolution medium: 0.5% SDS in purified water, pH adjusted to 6.5 ± 0.5 Dissolution volume: 1000 mL Temperature: 37 ± 0.5℃ Rotation speed: 60 rpm.

4. The mucosal adhesion tablet according to claim 1, characterized in that it comprises 50 mg miconazole and has the following pharmacokinetic properties: an average salivary Cmax of 300 µg / ml to 500 µg / ml, an average salivary Tmax of 13 to 15 hours, and a 2000 μg / ml cg / ml saturation. h / mL to 3000 μg Average salivary AUC h / mL inf .

5. The mucosal adhesion tablet according to claim 1, characterized in that the amount of miconazole in the tablet is 50 mg or 100 mg.

6. The mucosal adhesion tablet according to claim 1, characterized in that... The tablet contains 50 mg or 100 mg of miconazole and the tablet comprises: HPMC containing 15% to 20% has an apparent viscosity of 11,000 to 22,000 cPs in water at 20°C. A milk protein concentrate of 20% to 26%, containing at least 87% by weight protein and 2.2% by weight calcium. 6% to 10% disintegrant, which is corn starch. 0.1% to 0.8% lactose, 3% to 6% surfactant, which is sodium dodecyl sulfate, and A lubricant of 1.5% to 2.5%, which is a mixture of magnesium stearate and talc. The percentage is expressed by weight relative to the total weight of the tablets.

7. The mucosal adhesion tablet according to claim 1, wherein the wet granulation process includes the following steps: a) Mix miconazole with some HPMC, milk protein concentrate and disintegrant. b) Wet granulation of the mixture from step a) by adding water containing lactose. c) Dry and calibrate the particles obtained in step b). d) Add the remaining HPMC, surfactant, and lubricant to the particles obtained in step c), and e) Compress the mixture from step d) to obtain tablets. In step a), 45% to 55% by weight of HPMC, representing the total weight of HPMC present in the final tablet, is added.

8. Use of the buccal mucosal adhesive tablet according to any one of claims 1-7 in the preparation of a medicament for treating and preventing biofilm oropharyngeal infections in a subject.

9. The use according to claim 8, wherein the amount of miconazole in the tablet is 50 mg or 100 mg, and wherein the infection is oral candidiasis.

10. The use according to claim 9, wherein the oral candidiasis is related to one or more Candida species selected from: Candida albicans ( C. albicans ), Tropical Candida ( C. tropicalis ), Candida glabrata ( C. glabrata ), Candida albicans ( C. kefyr ), Candida albicans ( C. guilliermondii ), Candida krusei ( C. krusei ), Candida Portugueseum ( C. lusitaniae ) and Candida parapsilosis ( C. parapsilosis ).

11. The use according to claim 8, wherein the subject wears an oral dental medical device.

12. The use according to claim 11, wherein the oral dental medical device is selected from dentures, fixed or removable dental prostheses, and orthodontic instruments.

13. The use according to claim 8, wherein the biofilm oropharyngeal infection is candidal stomatitis associated with wearing dental medical devices.

14. The use according to claim 8, wherein the subject has one or more risk factors selected from: advanced age, diabetes, cancer, physiological or iatrogenic pharyngeal candidiasis, immunosuppression, malnutrition, smoking, overuse of oral disinfectants, wearing oral medical devices, and medical treatment.

15. The use according to claim 14, wherein the medical treatment is corticosteroid therapy, antibiotics, immunosuppressants, radiotherapy, and chemotherapy.

16. A method for manufacturing miconazole mucosal adhesion tablets according to any one of claims 1-7 by wet granulation, the method comprising the following steps: a) Mix miconazole with some HPMC, milk protein concentrate and disintegrant. b) Wet granulation of the mixture from step a) by adding water containing lactose. c) Dry and calibrate the particles obtained in step b). d) Add the remaining HPMC, surfactant, and lubricant to the particles obtained in step c), and e) Compress the mixture from step d) to obtain tablets. In step a), 45% to 55% by weight of HPMC, representing the total weight of HPMC present in the final tablet, is added. Step e) is performed to make the hardness of the tablet 25 N to 40 N.

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