Mucoadhesive tablet for the treatment of oropharyngeal fungal infections

Description

TECHNICAL FIELD

[0001] The present invention relates to the therapeutic field, more precisely to mucoadhesive compositions intended for the treatment of oropharyngeal infections such as oropharyngeal candidiasis. TECHNOLOGICAL BACKGROUND

[0002] Candidiasis is a fungal disease (also called mycosis) caused by yeasts of the genus Candida. Yeasts of the genus Candida are saprophytes, meaning they are part of the commensal flora. However, under certain conditions, they transform into a pathogenic filamentous form capable of adhering to and colonizing mucous membranes. There are approximately 23 species of Candida that can be pathogenic for humans, including Candida albicans which is the main pathogen responsible for oropharyngeal mycoses. Other species of Candida may be involved such as C . tropicalis, C. glabrata, C. kefyr, C. guilliermondii, C. krusei, C. lusitaniae and C. parapsilosis.

[0003] Currently, there are several topical medications for the treatment of oropharyngeal candidiasis. These medications come in the form of a gel such as Daktarin ®< (miconazole), an oral suspension or mouthwash such as Fungizone ®< (amphotericin B) or Mycostatin ®< (nystatin), or tablets for gingival administration such as Loramyc ®< (miconazole).

[0004] However, antifungal medical treatments are sometimes insufficiently effective in curing oropharyngeal candidiasis, and recurrences require retreatment with other classes of medications to prevent systemic infections. The high sugar content of oral formulations or gels, combined with excessively fluctuating or transient local concentrations at the site of infection, leads to the emergence of resistance and promotes relapses of oropharyngeal candidiasis.

[0005] Some oropharyngeal candidiasis exhibits primary or secondary resistance to antifungal drugs. Resistance can be linked to multiple mechanisms, primarily mutations or overexpression of the target enzyme and certain pump proteins involved in antifungal efflux. Multiple mechanisms frequently coexist, and cross-resistance between different antifungals is not uncommon. In addition to these resistance mechanisms, the ability of yeasts to form biofilms that protect them from external factors such as the host's immune system or antifungal drugs has been reported in recent years.

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

[0007] Oropharyngeal candidiasis with biofilm, particularly oral candidiasis, has a multifactorial etiology. There are several factors that promote the development of oropharyngeal candidiasis with biofilm, such as the use of a medical device, age, physiological or iatrogenic hyposialia, oral trauma, massive use of antibiotics or corticosteroids, certain systemic diseases such as diabetes and cancer, and immunocompromised individuals, for example those suffering from HIV or having undergone radiotherapy or chemotherapy.

[0008] Regarding medical devices, several studies have shown that they constitute surfaces conducive to the development of biofilms. to Candida. Thus, dental prostheses, dentures, orthodontic systems and other dental medical devices can be the cause of oral candidiasis. Indeed, species of Candidaadhere very easily to the surface of these medical devices, which facilitates the formation of a biofilm capable of colonizing the adjacent mucosa, then the entire mouth and tongue. This infection can lead to acute candidal stomatitis (for example, as in the case of stomatitis to Candida associated with wearing dentures - Candida-associated denture stomatitis (CaDs)) characterized by inflammation, chronic erythema and / or edema of the oral mucosa making eating particularly painful and potentially leading to serious systemic complications in vulnerable individuals.

[0009] Several studies in vitro have shown that biofilms at Candidaexhibit increased resistance to antifungals compared to planktonic forms. This resistance has been observed with different classes of antifungals, for example with polyenes such as amphotericin B or azole antifungals such as fluconazole, itraconazole, miconazole and voriconazole. These studies are consistent with clinical experience which shows that oropharyngeal candidiasis with biofilm responds poorly to antifungal treatments and that relapses are frequent with a high risk of systemic dissemination (Gebremedhin et al., Journal of Physiology and Pharmacology, 2014, 65,4,593-600).

[0010] US 2009 / 137477 A1 discloses an extended-release buccal mucoadhesive tablet comprising 30% to 50% by weight of miconazole, 18% to 28% milk protein, a surfactant, and HPMC. The document, in Table 1, discloses a composition comprising 43% miconazole, 18% HPMC, 24% milk protein, 8% corn starch, 0.34% lactose, 2% magnesium stearate and talc, 4.5% surfactant.

[0011] Document FR 2 827 517 A1 also discloses a mucoadhesive tablet for prolonged release of miconazole.

[0012] There is therefore currently a need for new strategies for the management of oropharyngeal biofilm infections. SUMMARY OF THE INVENTION

[0013] According to a first aspect, the subject of the invention is a prolonged-release buccal mucoadhesive tablet comprising from 25 to 150 mg, preferably from 35 to 135 mg, of miconazole as active ingredient in association with a milk protein concentrate and hydroxypropyl methylcellulose (HPMC) as excipients, characterized in that: the tablet has a hardness greater than 20 N and an adhesiveness greater than 100 g, the tablet is obtained by a granulation process, preferably by the wet method, the tablet comprises primary grains comprising miconazole, milk protein concentrate and a part of the HPMC, the remaining part of the HPMC being in the external phase of the primary grains and representing from 45% to 55% by weight of the total weight of the HPMC present in the tablet.

[0014] In some embodiments, the tablet according to the invention has a "hardness / adhesivity ratio" of less than 0.4, preferably ranging from 0.04 to 0.4. The adhesiveness, i.e. the strength of bioadhesion of the tablet to the gingival mucosa, and the hardness are determined by conventional methods, as illustrated below.

[0015] Said tablet may further comprise a surfactant, preferably a dodecyl sulfate salt, in the external phase.

[0016] The tablet according to the invention may also comprise a disintegrant such as corn starch present in the primary grains, and one or more lubricants such as talc and magnesium stearate present in the external phase.

[0017] The mucoadhesive tablet preferably has a release profile in vitro following: From 20% to 45% of the miconazole present in the tablet is released in 4 hours, From 60% to 85% of the miconazole present in the tablet is released in 8 hours, and At least 85% of the miconazole present in the tablet is released in 24 hours, the dissolution profile in vitro being determined by a dissolution test preferably as defined in the United States Pharmacopoeia (USP), Chapter 711 under the following conditions: Basket dissolution device: USP Dissolution Apparatus 1 Dissolution medium: 0.5% SDS in purified water at pH adjusted to 6.5±0.5 Dissolution volume: 1000 mL, temperature: 37±0.5°C and rotation speed: 60 rpm.

[0018] In certain embodiments, the mucoadhesive tablet according to the invention is characterized in that it establishes a salivary concentration of miconazole 24 hours after its application to the subject's gum (C 24h ) of at least 100 µg / mL, preferably at least 140 µg / mL. According to certain embodiments, the tablet according to the invention comprises 50 mg of miconazole and has the following pharmacokinetic properties: a mean salivary Cmax of 300 to 500 µg / , a mean salivary Tmax of approximately 13 to 15 hours and a mean salivary AUCinf of 2000 to 3000 µg.h / mL.

[0019] In other embodiments, the tablet according to the invention is characterized in that the milk protein concentrate is in the form of an atomized powder and has a protein content of at least 85%, preferably at least 87% by weight and a calcium content of at least 1% by weight, preferably about 2.2% by weight and / or the HPMC has an apparent viscosity in water at 20°C of 11,000 to 22,000 cPs. In addition, the mucoadhesive tablet according to the invention may comprise: from 35% to 50% miconazole, from 10% to 25%, preferably from 15% to 20% HPMC, from 15% to 30%, preferably from 20% to 26% of a milk protein concentrate, from 5% to 15%, preferably from 6% to 10% of a disintegrant, preferably a corn starch, from 0% to 3% lactose, preferably from 0.1% to 0.8% lactose, from 2% to 8% surfactant, preferably from 3% to 6% sodium dodecyl sulfate, and from 1% to 3% lubricant, preferably from 1.5% to 2.5% magnesium stearate and talc, the percentages being expressed by weight relative to the total weight of the tablet.

[0020] Typically, the amount of miconazole is 50 mg or 100 mg in the tablet.

[0021] The tablet according to the invention can be obtained by a wet granulation process comprising the following steps: a) mixing miconazole with milk protein concentrate, part of the HPMC and the disintegrant b) wet granulating the mixture of step a) by adding water including lactose, c) drying and sizing the grains obtained in step b), d) adding the remainder of the HPMC, the surfactant and the lubricants to the grains obtained in step c), and e) compressing and shaping the mixture of step d) so as to obtain a tablet.

[0022] Typically, 45% to 55%, preferably about 50% by weight of the total weight of HPMC present in the final tablet is added in step a). Step e) is carried out so that the hardness of the tablet is at least 20N, preferably 20N to 60N, for example 25N to 50N. In a particular embodiment, the tablet according to the invention is intended for subjects suffering from or predisposed to oropharyngeal biofilm infections.

[0023] The present description also discloses the use of a tablet as defined above in the treatment and prevention of an oropharyngeal biofilm infection in a subject. Said infection may be an oral candidiasis associated, preferably with one or more species of Candida chosen from C . albicans, C. tropicalis, C. glabrata, C. kefyr, C. guilliermondii, C. krusei, C. lusitaniae and C. parapsilosis. In certain embodiments, the subject treated has one or more risk factors chosen from high age, preferably greater than 75 years, diabetes, cancer, physiological or iatrogenic hyposialia, immunosuppression, malnutrition, cigarette consumption, overconsumption of oral antiseptics, wearing an oral medical device, and medical treatments such as corticosteroid therapy, in particular by inhalation, antibiotics, immunosuppressants, radiotherapy in particular of the neck and head and chemotherapy.

[0024] In a particular embodiment, the tablet is used in the treatment and prevention of an oropharyngeal biofilm infection, the subject wearing an oral medical device preferably selected from a denture, a fixed or removable dental prosthesis and an orthodontic appliance. The oropharyngeal biofilm infection may be, in particular, candidal stomatitis associated with wearing a dental medical device.

[0025] A method of treating an oropharyngeal biofilm infection in a subject, comprising administering orally a mucoadhesive tablet as defined above, is also described but does not form part of the invention. The present description also discloses the use of miconazole for the preparation of a medicament for the treatment of an oropharyngeal biofilm infection, said medicament being in the form of a mucoadhesive tablet as defined above.

[0026] Finally, the subject of the invention is a method for manufacturing a mucoadhesive miconazole tablet according to the invention by wet granulation comprising the following steps: a) mixing miconazole with a portion of the HPMC, the milk protein concentrate and the disintegrant b) wet granulating the mixture of step a) by adding water including the lactose, c) drying and sizing the grains obtained in step b), d) adding the remainder of the HPMC, the surfactant and the lubricants to the grains obtained in step c), and e) compressing and shaping the mixture of step d) so as to obtain a tablet, wherein from 45% to 55%, preferably about 50% by weight of the total weight of HPMC present in the final tablet is added in step a) and wherein step e) is carried out in such a way that the hardness of the tablet is at least 20N, preferably from 20N to 60 N, for example from 25N to 50 N. DESCRIPTION OF FIGURES

[0027] There Figure 1 shows the in vitro dissolution profiles of the tablet according to the invention (form B) and the reference tablet (form A). Figure 2 shows the evolution of the average salivary concentration over time for the tablets according to the invention (form B) versus that obtained from the reference tablet (form A). The Figure 3 shows the effect of the distribution of HPMC between external phase and internal phase on the amount of miconazole released in vitro at T 24h for tablets obtained with a high compression force or a lower compression force. DETAILED DESCRIPTION OF THE INVENTION

[0028] Gebremedhin et al. (supra) tested the antifungal activity of miconazole on a biofilm model of different species of Candida in vitro. Gebremedhib et al.observed antifungal activity of miconazole against these biofilms. Nevertheless, the authors showed that a miconazole concentration of approximately 100 µg / ml is necessary to reduce the metabolic activity of biofilms by at least 50% in all species tested, namely C . albicans, C. glabrata, C. tropicalis, and C. parapsilosis.

[0029] Based on this observation, the Applicant analyzed that it is necessary to achieve a salivary concentration greater than 100 µg / ml, in a prolonged manner, to hope to treat oral candidiasis with biofilm.

[0030] International application WO03 / 009800 describes a mucoadhesive miconazole tablet comprising, in particular, as excipients milk proteins, hydroxypropyl methyl cellulose (HPMC) and sodium dodecyl sulfate (SDS). This tablet is obtained by a wet granulation process in which miconazole is mixed with HPMC and milk proteins. The mixture thus obtained is granulated with an aqueous solution containing lactose so as to obtain a primary grain to which SDS and other excipients (lubricants) are added. After mixing, the tablet is obtained by compression. HPMC is essentially present in the internal phase (i.e. in the primary grains). International application WO03 / 009800 does not provide any information regarding the hardness and bioadhesivity of the tablets obtained but describes that these tablets have a salivary Cmax of 15.07 µg / ml, a salivary tmax of 7h and a salivary AUC 0-12h of approximately 43 µgl.h / ml.Clearly, the tablet described in application WO03 / 009800 does not allow for the establishment of a prolonged salivary concentration of 100 µg / ml necessary to effectively treat oral candidiasis with biofilm.

[0031] The Applicant therefore sought to modify the pharmaceutical form described in international application WO03 / 009800 so as to obtain, in a stable and rapid manner, a salivary concentration of at least 100 µg of miconazole per ml of saliva in patients while reconciling a simple dosage regimen, namely the administration of this pharmaceutical form once a day.

[0032] Surprisingly, the Applicant has shown that it is possible to improve the release profile of miconazole by increasing the hardness of this tablet.

[0033] Such a result is entirely surprising since the skilled person would have expected that an increase in hardness would impair the integrity of the tablet, prevent or delay salivary penetration and therefore the dissolution of the active ingredient, and also hinder its adhesion to the patient's mucosa. The skilled person could also have expected that an increased hardness of the tablet would prevent rapid release of the active ingredient locally and / or promote significant systemic release of the active ingredient, which is undesirable, in particular due to the associated side effects. In other words, the skilled person would also have expected that the increase in hardness would significantly impair the release profile of the active ingredient by reducing its initial release rate and preventing its prolonged release over time due to incomplete disintegration of the tablet in the oral cavity.However, surprisingly, the Applicant has shown that a tablet with a hardness greater than 20 N exhibited a dissolution profile. in vitro improved compared to a control tablet, of similar composition but having a hardness of approximately 17N.

[0034] Surprisingly, the Applicant also showed that this difference in vitro was translated in vivoin humans by a longer tablet adhesion time (24 h versus 15 h for the reference tablet) and a clear change in the pharmacokinetic profile: The mucoadhesive tablet according to the invention comprising a dose of 50 mg of miconazole allows a prolonged release of miconazole characterized by a salivary Cmax of 346 µg / ml, a Tmax of 14 h, and an AUC of 2630 µg.h / mL. Notably, the salivary miconazole concentration at 24 h is approximately 150 µg / ml, which is well above the concentration determined by Gebremedhin et al. to cause an inhibition of at least 50% of the metabolic activity in all the strains of Candida tested. These pharmacokinetic characteristics are significantly better than those observed for the control tablet and those of the tablet described in application WO03 / 009800,

[0035] In other words, the prolonged-release mucoadhesive tablet according to the invention makes it possible to establish a salivary concentration greater than 100 µg / ml, continuously, over 24 hours, which is not observed with the reference tablet or other usual pharmaceutical forms such as miconazole-based gels and mouthwashes.

[0036] The Applicant has also observed that the “hardness / adhesivity” ratio is an important parameter for obtaining an improved release profile of miconazole. Preferably, the “hardness / adhesivity” ratio is greater than 0.04 and less than 0.4 in the tablet according to the invention. Finally, the Applicant has shown that it is advantageous to prepare the tablet according to the invention by wet granulation, as described in application WO03 / 009800, but by fractionating the addition of HPMC so that approximately half of the HPMC is present in the primary grains and the remainder is present in the external phase. Such fractionation makes it possible to obtain tablets with optimized hardness and bioadhesivity. Furthermore, this fractionation makes it possible to make the manufacturing process more robust, by improving the compressibility of the tablet and minimizing the effect of the compression step on the total proportion of miconazole released during in vitro dissolution tests.

[0037] Without wishing to be bound by any theory, the Applicant is of the opinion that the mucoadhesive tablet according to the invention makes it possible to establish very high and prolonged salivary concentrations of antifungal, which would have the major clinical advantage of treating oropharyngeal candidiasis, in particular those with biofilm or resistant to usual treatments.

[0038] Thus, by making it possible to establish a salivary concentration of miconazole significantly higher than 100 µg / ml during its application period (24 hours), the mucoadhesive miconazole tablet according to the invention is particularly suitable for the treatment and prevention of oropharyngeal biofilm infections, unlike the usual pharmaceutical forms available commercially.

[0039] Thus, the subject of the invention is a prolonged-release mucoadhesive tablet characterized in that it comprises from 25 mg to 150 mg of miconazole as active ingredient, a milk protein concentrate and hydroxypropyl methylcellulose as excipients and in that it has a hardness greater than 20 N. Preferably, the tablet according to the invention has an adhesiveness greater than 100 g and a “hardness / adhesiveness” ratio greater than 0.04.

[0040] The tablet according to the invention is preferably obtained by granulation and comprises primary grains comprising miconazole, milk proteins, and a portion of the HPMC, and an external phase comprising the remainder of the HPMC, the HPMC present in the primary grains representing from 45% to 55% by weight of the total weight of the HPMC present in the tablet.

[0041] The tablet according to the invention is particularly suitable for subjects suffering from or predisposed to oropharyngeal biofilm infections.

[0042] The use of said tablet for treating or preventing oropharyngeal biofilm infections is described but does not form part of the present invention, in particular oral biofilm candidiasis.

[0043] A method of treating an oropharyngeal biofilm infection is described but does not form part of the present invention, in particular oral biofilm candidiasis in a subject comprising the application of a mucoadhesive tablet according to the invention to the patient's gum, said application being able to be renewed after 24 hours, preferably over a period of at least 7 days. 1. The prolonged-release mucoadhesive tablet according to the invention :

[0044] As indicated above, the invention relates to a prolonged-release mucoadhesive miconazole tablet as described in the claims.

[0045] We understand by "mucoadhesive tablet" a tablet capable of adhering to a mucosa for an extended period of time, namely several hours. In the context of the present invention, the mucosa refers to the oral mucosa, preferably to the gum. The mucoadhesive tablet according to the invention is capable of adhering to the surface of the gum for a period of at least 18 hours, preferably at least 20 hours, and even more preferably for a period of at least 24 hours.

[0046] The route of administration of the tablet according to the invention is therefore the mucosal route, more precisely the buccogingival mucosa.

[0047] We understand by "extended release" the fact that a pharmaceutical form allows the release of an active ingredient in a controlled manner over a prolonged period, namely over several hours.

[0048] We understand by "miconazole" the compound of CAS No. 22916-47-8 with the following chemical formula: including racemic mixtures, enantiomers and pharmaceutically acceptable salts thereof.

[0049] A preferred pharmaceutically acceptable salt is miconazole nitrate.

[0050] Miconazole is present in the tablet according to the invention in an amount ranging from 25 mg to 150 mg. Preferably, miconazole is present in an amount of 50 mg or 100 mg in the tablet according to the invention.

[0051] As indicated above, the mucoadhesive tablet according to the invention is characterized by a hardness of at least 20 N, preferably ranging from 20 to 50 N or from 25 N to 40 N.

[0052] For the purposes of this document, the tablet hardness (also called "crushing resistance") is preferably determined according to the European Pharmacopoeia § 2.9.8 (European Pharmacopeia 10.0, p. 337, section: Resistance to crushing of tablets).

[0053] The mucoadhesive tablet according to the invention is also characterized by an adhesiveness greater than 100g, preferably greater than 150g, for example ranging from 150g to 600g, from 150g to 500g, from 200g to 550g or even from 300g to 500g.

[0054] In the context of the present invention, adhesiveness (also referred to herein as bioadhesivity, adhesive strength or bioadhesion) corresponds to the adhesive strength of the tablet for a given surface, typically stainless steel. This adhesive strength can be determined using a texturometer according to a conventional methodology.

[0055] Typically, the upper surface of the tablet is glued to the disposable probe of the texturometer using a cyanoacrylate-based glue. The tablet is then brought into contact with a stainless steel support for a given time in a crystallizer filled with purified water. The lever arm of the texturometer is then raised at a defined speed and the force required to tear off the tablet is measured, thus providing access to the adhesive force. Preferably, the adhesive force is determined according to the protocol provided in the examples. In an additional embodiment, the mucoadhesive tablet according to the invention is characterized by a "hardness / adhesiveness" ratio greater than 0.04, the hardness being expressed in Newton (N) and the adhesiveness in acceleration units (g) and said hardness and adhesiveness being determined according to the methods described above.

[0056] In a particular embodiment, the “hardness / adhesiveness” ratio is in a range from 0.04 to 0.4, for example in the range from 0.04 to 0.1.

[0057] According to certain embodiments, the mucoadhesive extended-release tablet according to the invention is characterized by the release profile in vitro following : At most 45% of the miconazole present in the tablet is released in 4 hours, At most 85% of the miconazole present in the tablet is released in 8 hours, and At least 85% of the miconazole present in the tablet is released in 24 hours,

[0058] In certain additional embodiments, the mucoadhesive extended-release tablet according to the invention is characterized by the release profile in vitro following From 20% to 45% of the miconazole present in the tablet is released in 4 hours, From 60% to 85% of the miconazole present in the tablet is released in 8 hours, and At least 85% of the miconazole present in the tablet is released in 24 hours,

[0059] The dissolution profile in vitro can be determined by a dissolution test preferably as defined in the United States Pharmacopoeia (USP), Chapter 711 under the following conditions: basket dissolution device: USP Dissolution Apparatus 1 dissolution medium: 0.5% SDS in purified water at pH adjusted to 6.5±0.5 Dissolution volume: 1000 mL temperature: 37±0.5°C and rotation speed: 60 rpm (rotation per minute).

[0060] The release of miconazole into the medium is monitored by HPLC analysis with UV detection (absorbance at 220 nm).

[0061] In additional or alternative embodiments, the mucoadhesive tablet according to the invention is characterized in that it provides a mean salivary concentration of miconazole at 24h (C 24h ) of at least 100 µg / ml, preferably at least 110, 120, 130, or 140 µg / ml. Typically, the mean C 24h is about 150 µg / ml for a tablet comprising a 50 mg dose of miconazole and the mean C 24h is about 425 µg / ml for a tablet comprising a 100 mg dose of miconazole.

[0062] In certain embodiments, the mucoadhesive tablet according to the invention comprises 50 mg of miconazole and is characterized by a mean salivary Cmax of 300 to 500 µg / ml (eg approximately 350 µg / L), a mean salivary Tmax of approximately 13 to 15h (eg approximately 14h) and a mean salivary AUCinf of 2000 to 3000 µg.h / mL (eg approximately 2600 µg.h / mL).

[0063] In other embodiments, the mucoadhesive tablet according to the invention comprises 100 mg of miconazole and is characterized by a mean salivary Cmax of 500 to 700 µg / ml (eg approximately 600 µg / L), a mean salivary Tmax of approximately 15.5 to 17.5h (eg approximately 16h) and a mean salivary AUCinf of 4,300 to 5,500 µg.h / mL (eg approximately 4,800 µg.h / mL).

[0064] The above-mentioned pharmacokinetic parameters are mean values ​​obtained from a panel of healthy subjects aged at least 18 years. The number of subjects included in the panel is chosen so that the results obtained are statistically significant.

[0065] Each subject receives a single tablet according to the invention (50 or 100 mg of miconazole) which is placed at the level of the upper gum, preferably above the incisors. For each subject, saliva samples are taken at regular time intervals (typically every hour), for 24 hours, in order to measure the miconazole. For each individual, the different pharmacokinetic parameters can be determined in a conventional manner from the curve giving the salivary concentration of miconazole as a function of time. The mean values ​​C 24h , C max , Tmax, and AUCinf can be determined from the raw data of the individuals by implementing well-known statistical methods.

[0066] As used herein, C 24h represents the salivary miconazole concentration 24h after tablet application to the subject's gum, Cmax represents the maximum salivary miconazole concentration reached after tablet application, Tmax represents the time at which Cmax is reached, and AUCinf represents the area under the curve plotting miconazole concentration over time extrapolated to infinity.

[0067] As indicated above, the mucoadhesive extended-release tablet is characterized by the presence of a milk protein concentrate and HPMC as excipients. The inventors have shown that the use of a milk protein concentrate in combination with hydroxypropyl methyl cellulose as excipients has a major impact on the adhesive properties of the tablet and the release profile of the active ingredient.

[0068] The milk protein concentrate plays a bioadhesive role, ensuring the adhesion of the tablet to the gingival mucosa.

[0069] 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 majority protein in the concentrate according to the invention.

[0070] This protein concentrate is in the form of a powder and is typically obtained from cow's milk by a process typically comprising a skimming step, a pasteurization step, a diafiltration or ultrafiltration step and a spray drying step. Preferably, the milk protein concentrate has a protein content of at least 85%, preferably at least 86% or at least 87% by weight relative to the total dry weight of the concentrate. The milk protein concentrate also comprises a calcium content of at least 0.5%, preferably at least 1.0% or 1.5%, for example from 1.5% to 3.0% by weight relative to the total weight of the concentrate. For example, the calcium content may range from 2.0 g to 2.5 g per 100 g of milk protein concentrate.

[0071] Without wishing to be bound by any theory, the inventors are of the opinion that the presence of calcium ions contributes to the bioadhesive properties of the protein concentrate according to the invention.

[0072] The milk protein concentrate is typically present in a content ranging from 15% to 30% by weight, preferably from 18% to 28%, for example from 20% to 26% by weight relative to the total weight of the tablet.

[0073] Hydroxyl propyl methyl cellulose (HPMC) acts as both a binder and a hydrophilic matrix contributing to the controlled swelling of the tablet and release of the active ingredient and potentiates the effects of the milk protein concentrate. HPMC with an apparent viscosity ranging from 10,000 to 25,000 mPa.s, for example 11,000 to 22,000 cPs, can be used, typically at 2% in water at 20°C.

[0074] HPMC is typically present in a content ranging from 10% to 25% by weight, preferably from 15% to 20% by weight relative to the total weight of the tablet.

[0075] The tablet according to the invention may comprise other excipients.

[0076] Preferably, it also comprises a surfactant. The surfactant may be used as a wetting agent and to promote dissolution of the active ingredient. Surfactants include, but are not limited to, simethicone, triethanolamine, polysorbate derivatives such as Tween ®< 20 or Tween ®< 40, poloxamers, fatty alcohols such as lauryl alcohol or cetyl alcohol, or alkyl sulfates such as dodecyl sulfate salts (also known as lauryl sulfate). The surfactant is preferably sodium lauryl sulfate (also known as sodium dodecyl sulfate or SDS). It is typically present in a content ranging from 2% to 8% by weight of the total tablet weight.

[0077] Preferably, the tablet according to the invention is obtained by a granulation process, in particular by the wet method.

[0078] Typically, and as detailed below, the granulation process includes a step of preparing primary grains, to which other excipients are added in a subsequent step. The resulting mixture is then compressed to obtain the tablet. The excipients added in the subsequent step are present in the external phase, i.e. outside the primary grains.

[0079] Thus, in a particular embodiment, the tablet according to the invention is obtained by granulation and comprises primary grains comprising miconazole, milk protein concentrate and a portion of the HPMC, the remaining portion of the HPMC being in the external phase and representing from 45% to 55%, preferably from 46% to 54%, for example from 47% to 53%, from 48% to 52% or even approximately 50% by weight of the total weight of the HPMC present in the tablet.

[0080] Preferably, the tablet comprises a surfactant such as SDS, said surfactant being in the external phase.

[0081] The tablet according to the invention may further comprise a disintegrant and a lubricant.

[0082] The disintegrant may be used to improve the swelling of the tablet and / or the release of the active ingredient. It may be chosen, for example, from cross-linked polyvinyl pyrrolidone (crospovidone), cross-linked (such as croscarmellose sodium) or non-cross-linked carboxymethyl cellulose, starches and mixtures thereof. The disintegrant is preferably a starch, for example a corn starch. It is typically present in a content ranging from 5% to 15% by weight of the total weight of the tablet. The disintegrant is preferably present in the primary grains, when the tablet according to the invention is prepared by granulation.

[0083] The lubricant may be one or more compounds capable of preventing problems related to the preparation of dry dosage forms, such as sticking and / or seizure problems that occur in machines during filling and / or compression. Preferred lubricants are fatty acids or fatty acid derivatives such as calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, zinc stearate, or stearic acid, polyalkylene glycols, especially polyethylene glycol, sodium benzoate or talc. Preferred lubricants according to the invention are stearate salts and mixtures thereof. A suitable lubricant is, for example, magnesium stearate, talc and mixtures thereof. The lubricant is typically present in a content ranging from 1% to 3% by weight of the total weight of the tablet, and preferably in the external phase, when the tablet according to the invention is prepared by granulation.

[0084] Optionally, the tablet according to the invention comprises one or more excipients chosen from a diluent, a flavoring, a salivation agent and combinations thereof.

[0085] For example, the tablet according to the invention comprises from 0.1% to 3% by weight of a diluent or a binding agent preferably chosen from monosaccharides and polyols such as mannitol, lactose, xylose or galactose, preferably lactose.

[0086] In some embodiments, the tablet according to the invention comprises lactose, this lactose being used as a binding agent in the granulation process.

[0087] In some embodiments, the mucoadhesive tablet according to the invention comprises from 35% to 50% miconazole, from 10% to 25%, preferably from 15% to 20% HPMC, from 15% to 30%, preferably from 20% to 26% of a milk protein concentrate, from 5% to 15%, preferably from 6% to 10% of a disintegrant, preferably a corn starch, from 0% to 3% lactose, preferably from 0.1% to 0.8% lactose monohydrate, from 2% to 8% surfactant, preferably from 3% to 6% sodium dodecyl sulfate, and from 1% to 3% lubricant, preferably from 1.5% to 2.5% magnesium stearate and talc, the percentages being expressed by weight relative to the total weight of the tablet.

[0088] The dose of miconazole per tablet is 25 mg to 150 mg of miconazole, preferably 35 mg to 135 mg of miconazole, or 40 mg to 110 mg of miconazole, for example 50 or 100 mg of miconazole.

[0089] In some embodiments, the tablet according to the invention may be manufactured by a granulation process, preferably by wet granulation. Preferably, (i) the lubricant(s) (e.g. talc and magnesium stearate) are present in the external phase, (ii) the miconazole, the disintegrant, the milk protein concentrate and the lactose are present in the primary grains and (iii) the HPMC is distributed between the primary grains and the external phase in a mass ratio ranging from 45 / 55 to 55 / 45, preferably about 1 / 1.

[0090] In a particular embodiment, the tablet according to the invention is manufactured by a process comprising the following steps: a) mixing miconazole with a portion of the HPMC, the milk protein concentrate and the disintegrant b) wet granulating the mixture of step a) by adding water optionally comprising a diluent, preferably lactose, c) drying and sizing the grains obtained in step b), d) adding the remainder of the HPMC, the surfactant and the lubricants to the grains obtained in step c), and e) compressing and shaping the mixture of step d) so as to obtain a tablet.

[0091] The granulation step can be carried out in any type of granulator, for example a shear granulator.

[0092] Step c) is preferably carried out so as to obtain a water content of between 3% and 9% by weight, preferably 5% to 7% in the grains. Drying can be carried out at a temperature of between 40°C and 60°C, for example in a moving bed dryer.

[0093] An additional drying step may be introduced between step d) and e) so as to control the final water content of the tablets to a value below 8%.

[0094] Step e) is carried out by conventional techniques and in such a way as to obtain a tablet having a final hardness of at least 20 N, preferably from 20 N to 50 N or from 25 N to 40 N. Typically this step can be carried out with a rotary tablet press applying a compression force ranging from 10 kN to 20 kN.

[0095] Without wishing to be bound by any theory, the inventors are of the opinion that the fractional addition of HPMC in steps a) and d) contributes to improving the physicochemical and controlled release properties of the active ingredient. It also makes it possible to improve the robustness of the manufacturing process. Typically, between 45% and 55% (e.g. 46% to 54%, 47% to 53%, 48% to 52%, 49% to 51%), preferably about 50% of the final quantity of HPMC present in the tablet is added in step a), the remainder being added in step d). The process may comprise additional steps such as sieving and / or drying the various raw materials or packaging the final tablet in a suitable package.

[0096] It goes without saying that the process for obtaining the tablet as described above also forms part of the subject of the present invention. 2. Uses and therapeutic methods according to the invention : (these uses and methods are not part of the invention)

[0097] The miconazole mucoadhesive tablet according to the invention is intended for subjects suffering from or likely to develop an oropharyngeal biofilm infection.

[0098] The present description discloses the use of a mucoadhesive tablet as described above for the treatment or prevention of oropharyngeal biofilm infections.

[0099] The term " treatment» as used herein covers any treatment of a disease in a subject of interest, to: reduce the incidence and / or risk of relapse of the disease or disorder during a symptom-free period; alleviate or reduce a symptom or disorder associated with the disease; prevent the disease or any of its associated symptoms or disorders or the disorder from occurring in a subject who is ill or predisposed to the disease; stop, slow down or delay the development of the disease or any of its associated symptoms or disorders; reduce the frequency and / or intensity of episodes of the disease, e.g., symptoms; and alleviate the disease or an associated symptom or disorder, i.e., cause a total or partial regression of said disease, symptom or associated disorder.

[0100] The term " prevention" as used herein refers to a prophylactic treatment aimed at preventing, slowing down or delaying the onset of a disease or any of its associated symptoms or disorders.

[0101] For the purposes of the invention, oropharyngeal infections concern infections affecting one or more mucous membranes of the oropharynx, in particular the mouth and throat. These infections may involve microorganisms of any type, in particular yeasts or bacteria. Biofilm infections are referred to when the presence of a three-dimensional structure composed of a community of pathogenic microorganisms surrounded by a protective and adhesive polysaccharide-type extracellular matrix developing on a surface of the oropharynx, for example on the gum, palate or tongue.

[0102] In a preferred embodiment, the oropharyngeal infection is candidiasis, preferably oral candidiasis. "Candidiasis" means an infection caused by one or more species belonging to the genus Candida. In some embodiments, the oropharyngeal infection involves at least one species of Candida chosen from C . albicans, C. tropicalis, C. glabrata, C. kefyr, C. guilliermondii, C. krusei, C. lusitaniae and C. parapsilosis.

[0103] The subject suffering or likely to suffer from an oropharyngeal biofilm infection can be a man or a woman of any age.

[0104] In a particular embodiment, it is a subject at risk, that is to say a subject presenting one or more factors favoring biofilm infections.

[0105] In a particular embodiment, the subject suffering or likely to suffer from an oropharyngeal biofilm infection is chosen from infants, elderly subjects, preferably at least 75 years old, diabetics, subjects suffering from cancer having in particular undergone radiotherapy in particular to the head and neck or chemotherapy, subjects suffering from physiological or iatrogenic hyposialia, subjects under corticosteroid therapy, in particular by inhalation, subjects under antibiotic treatment, subjects having over-used antibacterial mouthwashes, immunocompromised subjects, for example suffering from HIV or under immunosuppressants, smokers, subjects suffering from malnutrition or eating disorders and subjects wearing an oral medical device.

[0106] In the context of the present invention, the term “ oral medical device» any medical device that can be placed in the mouth, in particular fixed dental prostheses, for example crowns or implants with a pivot such as bridges, removable dental prostheses, in particular those clipped onto a pivot, dentures and orthodontic appliances such as aligners, appliances with brackets or rings or even appliances with a palatal plate.

[0107] In some embodiments, the subject wears a dental medical device.

[0108] For example, oropharyngeal biofilm infection can be candidal stomatitis, particularly associated with wearing dentures or prosthetics. Stomatitis can also be associated with thrush, particularly on the inside of the cheeks and on the tongue. It can also be chronic erythematous candidiasis or candidal uranitis.

[0109] In therapeutic uses and treatments, the mucoadhesive tablet is positioned on the gum, for example above an incisor or canine of the upper jaw. The tablet is renewed approximately every 24 hours. The dose to be administered (50 or 100 mg miconazole tablet) and the duration of treatment depend on the characteristics of the subject, including age, weight, severity of the oropharyngeal infection, general health and comorbidities. The duration of treatment is at least one week, generally 7 to 14 days. This treatment can be extended or repeated if necessary depending on the condition of the subject and the progression of the disease.

[0110] Other aspects and advantages of the present invention will appear on reading the following examples, which should be considered as illustrative and in no way as limiting. EXAMPLES EXAMPLE 1 Tablets according to the invention and reference tablets

[0111] 50 mg or 100 mg tablets of miconazole were manufactured according to the invention having the following composition: of 43.5% miconazole, 17.8% HPMC, 23.9% milk protein concentrate having a protein content of 87% and a calcium content of 2.2% by weight, 8.0% corn starch, 0.3% lactose, 4.5% sodium dodecyl sulfate, and 1.15% magnesium stearate and 0.9% talc, the percentages being expressed by weight relative to the total weight of the tablet

[0112] These tablets were manufactured using the following methodology: a) mixing miconazole with 50% HPMC, milk protein concentrate, and corn starch b) wet granulating the mixture from step a) by adding a lactose solution in purified water, with stirring, in a high shear wet granulator, c) drying in a moving bed dryer at a temperature of about 50°C and sizing the grains obtained in step b), d) adding the remaining HPMC, SDS, and lubricants to the grains obtained in step c), and e) compressing and shaping the mixture from step d) using a rotary tablet press with a compression force of 10 to 20 kN.

[0113] The tablets thus obtained have a hardness between 25N and 40 N and an adhesiveness between 150 g and 500 g.

[0114] Reference tablets have a composition qualitatively and quantitatively similar to that of the tablets according to the invention, and correspond to the tablets described in application WO03 / 009800. These tablets were manufactured according to a process analogous to that of the tablets according to the invention except that HPMC is added only in step a), and a different milk protein concentrate is used and step e). The compression force in step e) was adjusted so that the reference tablets have a hardness of approximately 18 N. The adhesiveness of these tablets is between 20 and 30 g.

[0115] The hardness of the tablets was determined according to the European Pharmacopoeia § 2.9.8 (version 10.0).

[0116] The adhesion strength was determined using a texturometer according to the following methodology: Equipment used: A texturometer: This device consists of a test bench, an electrical outlet, and a control keyboard connected to a computer for data acquisition. A single-use flat nylon probe with a hollowed-out center screwed onto the moving part of the upper texturometer equipment (8.1 mm in diameter and 1 mm deep). A lower part consisting of a 4 cm diameter crystallizer whose base is made of a stainless steel test tube similar to the shape of a tablet. Reagents used:

[0117] Purified water: middle of the crystallizer Cyanoacrylate adhesive glue (e.g. Superglue 3 or equivalent) to stick the tablet to the flat probe. Procedure :

[0118] The crystallizer is filled with 10 ml of demineralized water. A tablet is fixed by the flat side to the center of the nylon probe with a drop of cyanoacrylate adhesive glue. The flat nylon probe is screwed onto the moving part of the texturometer. The probe is pressed onto the surface of the stainless steel test piece. The probe is raised after 90 seconds (Applied force: 1100 g - rising speed: 0.2 mm / s). The test is repeated for 30 tablets taken at random from the batch.

[0119] For each measurement made on an individual tablet, the adhesive strength is calculated and expressed in grams (1 g is 9.81 × 10 -3< N). The adhesive test result is the average of the 30 individual adhesive strength values. In vitro dissolution profile

[0120] The dissolution profile in vitro was determined for each lot of tablet by a dissolution test as defined in the US Pharmacopoeia (USP), Chapter 711 under the following conditions: number of samples: 6 basket dissolution device: USP Dissolution Apparatus 1 dissolution medium: 0.5% SDS in purified water at pH adjusted to 6.5±0.5 Dissolution volume: 1000 mL temperature: 37±0.5°C and rotation speed: 60 rpm (revolutions per minute).

[0121] The release of miconazole into the medium is monitored by HPLC analysis with UV detection (absorbance at 220 nm).

[0122] There Figure 1 shows the dissolution profiles obtained. The tablets according to the invention (form B) exhibit a more prolonged release of miconazole than that of the reference tablets. Pharmacokinetic evaluation

[0123] The two batches of tablets (inventive batch and reference batch) were evaluated in two separate clinical pharmacokinetic studies conducted at two different time points (study 1 and study 2). These are pharmacokinetic studies conducted on healthy subjects (male and female) aged 18 to 35 years. The aim of these studies was to determine the pharmacokinetics of salivary miconazole after once-daily application of a mucoadhesive tablet, 50 or 100 mg. The salivary and plasma pharmacokinetics of miconazole were evaluated over a 24-hour period.

[0124] For each subject, a tablet according to the invention or a reference tablet was placed in the buccal region (upper gum just above the incisor tooth) until its erosion or detachment. The parameters evaluated were: miconazole concentration in saliva samples, and in plasma samples, the time taken for erosion or detachment of the bioadhesive tablet, tolerability assessment based on adverse event reporting and local (oral) examination. Miconazole concentrations were evaluated in saliva by collecting saliva samples before drug administration and at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 h post-dose. Plasma samples were collected before and 0.5, 1, 4, 6, 8, 12, and 24 h post-dose. The lower limit of quantification of the assay was 0.1 ng / ml.

[0125] Table 1 below shows the main results obtained: Reference tablets Tablet according to the invention Duration of stickiness 15h >24h Mean salivary Cmax (µg / mL) 15 346 Average salivary C24h (µg / mL) 0.12* 148** Mean salivary AUCinf (µg.h / mL) 55 2630 Mean plasma Cmax (ng / mL) 180 2.2 Mean salivary Tmax (h) 7 14 * salivary concentrations not detectable in 15 out of 18 subjects (83%) **concentrations detectable and measurable in 100% of subjects

[0126] It should be noted that application WO20039800 describes for the 50 mg reference tablets a salivary Cmax of 15 µg / ml, a tmax of 7h and a salivary AUC 0-12h of 43 µg.h / mL.

[0127] The tablets were well tolerated by patients.

[0128] The tablet according to the invention provides a higher and longer-lasting salivary concentration of miconazole, which should increase therapeutic efficacy, particularly for the treatment of biofilm candidiasis. At the same time, a lower plasma concentration is observed, suggesting less systemic passage and therefore a lower incidence of side effects.

[0129] There Figure 2shows the evolution of the average salivary concentration over time for the tablets according to the invention (form B) versus that obtained with the reference tablet (form A). It can be seen that the tablets according to the invention make it possible to establish a stable, higher and more prolonged salivary concentration than that of the reference tablet. Surprisingly, the high hardness of the tablet according to the invention improved the pharmacokinetics of miconazole in vivo. EXAMPLE 2

[0130] The effect of HPMC distribution between the external phase and the internal phase was studied. Tablets were prepared using a method identical to that of Example 1 with the following HPMC distributions in internal phase / external phase: 0 / 100, 25 / 75, 50 / 50, 75 / 25, and 100 / 0. A first series of tablets was obtained with a high compression force (force +). A second series of tablets was obtained with a lower compression force (force -). For each HPMC distribution, the amount of miconazole released at T24h was compared in the following in vitro dissolution test: In vitro dissolution of tablets (50 mg Miconazole) under non-sink conditions (HPLC assay) Phosphate buffer medium pH 6.8: 20 ml, in a closed bottle without shaking and at 37°C. Total duration 24h Samples at 1h, 2h, 3h, 4h, 6h, 8h and 24h At each time, all of the medium was taken (without turning the bottle) for dosage, and 20 ml of medium was added.

[0131] For a given HPMC distribution, the mean amount of miconazole released at T 24h was compared for tablets obtained with strength + and that for tablets obtained with strength -.

[0132] The results are illustrated in the Figure 3 . There Figure 3shows that the effect of compression force on the amount of miconazole released is minimized when HPMC is distributed equally between the external and internal phases. A variation of 9% is then observed between tablets obtained by compression with force + versus tablets obtained with compression force -. On the other hand, a very significant variation in the amount released is noted when HPMC is distributed unequally between the internal and external phases.

[0133] An equitable distribution of HPMC between the internal and external phases makes it possible to reduce the impact of the compression force on the release of miconazole and therefore to increase the robustness of the manufacturing process.

Claims

1. A sustained-release buccal mucoadhesive tablet comprising from 25 to 150 mg, preferably from 35 to 135 mg, of miconazole as active principle in combination with a milk protein concentrate and hydroxypropylmethylcellulose (HPMC) as excipients, characterized in that: - the tablet has a hardness of greater than 20 N and an adhesiveness of greater than 100 g, - the tablet is obtained via a granulation process, preferably by wet granulation, - the tablet comprises primary grains comprising miconazole, the milk protein concentrate and some of the HPMC, the remainder of the HPMC being in the outer phase of the primary grains and representing from 45% to 55% by weight relative to the total weight of the HPMC present in the tablet.

2. The mucoadhesive tablet of claim 1, characterized in that the tablet has a "hardness / adhesiveness" ratio greater than 0.04, preferably a "hardness / adhesiveness" ratio ranging from 0.04 to 0.4, a hardness ranging from 25 to 40 N, and an adhesiveness ranging from 150 g to 500 g.

3. The mucoadhesive tablet of claim 1 or 2, characterized in that: - the tablet comprises a surfactant, preferably a dodecyl sulfate salt, in the outer phase and / or - the tablet comprises a disintegrant such as corn starch present in the primary grains, and one or more lubricants such as talc and magnesium stearate present in the outer phase.

4. The mucoadhesive tablet of any one of the preceding claims, characterized in that: - the milk protein concentrate is in the form of an atomized powder and has a protein content of at least 85%, preferably at least 87% by weight and a calcium content of at least 1% by weight, preferably about 2.2% by weight and / or - the HPMC has an apparent viscosity in water at 20°C of from 11 000 to 22 000 cPs.

5. The mucoadhesive tablet of any one of the preceding claims, characterized in that it has the following in vitro release profile: - from 20% to 45% of the miconazole present in the tablet is released within 4 hours, - from 60% to 85% of the miconazole present in the tablet is released within 8 hours, and - at least 85% of the miconazole present in the tablet is released within 24 hours, the in vitro dissolution profile being determined by a dissolution test preferably as defined in the US Pharmacopea (USP), chapter 711, under the following conditions: - basket dissolution device: USP Dissolution Apparatus 1 - dissolution medium: 0.5% SDS in purified water with pH adjusted to 6.5 ± 0.5 - Dissolution volume: 1000 mL - temperature: 37 ± 0.5°C and - rotation speed: 60 rpm.

6. The mucoadhesive tablet of any one of the preceding claims, characterized in that it establishes a salivary concentration of miconazole 24 hours after its application to the subject's gums (C24h) of at least 100 µg / mL, preferably at least 140 µg / mL.

7. The mucoadhesive tablet of any one of the preceding claims, characterized in that it comprises 50 mg of miconazole and has the following pharmacokinetic properties: a mean salivary Cmax from 300 to 500 µg / ml, a mean salivary Tmax of about 13 to 15h and a mean salivary AUCinf from 2000 to 3000 µg.h / mL.

8. The mucoadhesive tablet of any one of the preceding claims, characterized in that it comprises: - from 35% to 50% of miconazole, - from 10% to 25%, preferably from 15% to 20%, of HPMC, - from 15% to 30%, preferably from 20% to 26%, of a milk protein concentrate, - from 5% to 15%, preferably from 6% to 10%, of a disintegrant, preferably a corn starch, - 0% to 3% of lactose, preferably from 0.1% to 0.8% of lactose, - from 2% to 8% of surfactant, preferably from 3% to 6% sodium dodecyl sulfate, and - from 1% to 3% of lubricant, preferably from 1.5% to 2.5% of magnesium stearate and talc, the percentages being expressed on a weight basis relative to the total weight of the tablet.

9. The tablet of any one of the preceding claims, characterized in that the amount of miconazole in the tablet is 50 mg or 100 mg.

10. The tablet of any one of claims 1 to 9, characterized in that it is obtained by a wet granulation process comprising the following steps: a) mixing miconazole with some of the HPMC, the milk protein concentrate and the disintegrant, b) wet granulation of the mixture from step a) by adding water comprising the lactose, c) drying and calibrating the grains obtained in step b), d) adding the remaining HPMC, the surfactant and the lubricants to the grains obtained in step c), and e) compressing and shaping the mixture from step d) so as to obtain a tablet, in which from 45% to 55%, preferably about 50% by weight relative to the total weight of the HPMC present in the final tablet is added in step a).

11. The mucoadhesive tablet of any one of preceding claims, for use in the treatment and the prevention of a biofilm oropharyngeal infection, said infection being preferably a buccal candidiasis associated with one or more Candida species chosen from C. albicans, C. tropicalis, C. glabrata, C. kefyr, C. guilliermondii, C. krusei, C. lusitaniae and C. parapsilosis.

12. The mucoadhesive tablet of any one of claims 1 to 10, for use in the treatment and the prevention of a biofilm oropharyngeal infection in a subject wearing an oral dental medical device preferably chosen from dentures, a fixed or removable dental prosthesis and an orthodontic appliance.

13. The mucoadhesive tablet of any one of claims 1 to 10, for use in the treatment and the prevention of a biofilm oropharyngeal infection, in which the biofilm oropharyngeal infection is candidal stomatitis associated with the wearing of a dental medical device.

14. The mucoadhesive tablet of claim 11, for use in the treatment and the prevention of a biofilm oropharyngeal infection, the subject presenting with one or more risk factors selected from high age, preferably over 75 years old, diabetes, cancer, physiological or iatrogenic hyposialia, immunodepression, malnutrition, cigarette smoking, overuse of buccal antiseptics, wearing of an oral medical device, and medical treatments such as corticosteroid therapy, notably by inhalation, antibiotics, immunosuppressants, radiotherapy notably of the neck and head, and chemotherapy.

15. A process for manufacturing a miconazole mucoadhesive tablet of any one of claims 1 to 10 by wet granulation, comprising the following steps: a) mixing miconazole with some of the HPMC, the milk protein concentrate and the disintegrant, b) wet granulation of the mixture from step a) by adding water comprising the lactose, c) drying and calibrating the grains obtained in step b), d) adding the remaining HPMC, the surfactant and the lubricants to the grains obtained in step c), and e) compressing and shaping the mixture from step d) so as to obtain a tablet, in which from 45% to 55%, preferably about 50% by weight relative to the total weight of the HPMC present in the final tablet is added in step a) and in which step e) is performed so that the hardness of the tablet is at least 20 N, preferably from 20 N to 60 N, for example from 25 N to 50 N.