The bioadhesive therapeutic systems of the invention contain at least one active principle.

When the bioadhesive therapeutic systems are intended to prevent and treat fungal infections, a preferred active principle is a compound from the broad spectrum azole family preferably selected from miconazole, clotrimazole, ketoconazole, fluconazole, itraconazole, isoconazole, econazole, saperconazole, genaconazole, terconazole, butoconazole, tioconazole, oxiconazole, bifonazole, fenticonazole, omoconazole, sertaconazole, voriconazole and sulconazole. It is advantageously triazoles such as fluconazole, itraconazole or saperconazole; or imidazoles preferably selected from miconazole, clotrimazole and ketoconazole.

Particularly preferred azole compounds in the present invention are miconazole, ketoconazole and itraconazole, and unitary doses are then in the range 10 to 150 mg per tablet.

A still more preferred compound is miconazole whose chemical denomination is (RS)-1-[-2-(2,4-dichlorobenzyloxy)-2-(2,4-dichlorophenyl)-ethyl]-1H-imidazole, present in a dose of 10 to 150 mg per tablet, preferably 25 to 75 mg and more preferably 50 mg per tablet.

Azole compounds are known to act on the synthesis of a constituent of the fungal membrane: ergosterol.

The bioadhesive therapeutic systems of the invention and containing substantially 50 mg per tablet ensure a continuous and prolonged presence of the active principle above the MIC at the site of action in a single daily dose as well as the various advantages described above, and in the absence of systemic passage.

A further advantage of bioadhesive therapeutic systems essentially comprising 50 mg of miconazole is the excellent tolerance of the active principle as the useful dose per day in the 50 mg preparation is ten times lower than the usual dose of the same product in the reference formulation, Daktarin buccal gel formulation (500 mg/d) while surprisingly, the local concentrations are considerably increased (7 to 10). An important advantage is the reduction in the risk of acquiring resistance to the fungi. Indeed, the appearance of resistance to a compound often occurs if the local concentration is less than the MIC allowing the yeast to grow again. The useful dose in the tablets of the invention can also reduce or even eliminate certain undesirable effects resulting from a dose of 500 mg/d, such as intestinal problems (nausea, vomiting, diarrhea) or allergic reactions. Transaminase elevations are rarely observed.

The various advantages of the bioadhesive therapeutic systems of the invention will become clear from the following examples that essentially described the pharmaceutical forms and the results of comparative clinical tests.

The azole miconazole type compound can be associated with a further active principle selected, for example, from an antifungal with a different spectrum, of the polyene type, an analgesic, a salivation agent, a saliva substitute, an antiseptic, an anti-inflammatory (corticoid), thalidomide or a mixture thereof.

Polyenes have a different action mechanism to azoles. They bond to sterol groups, principally ergosterol, present in the fungal membrane and induce the appearance of pores and channels. These pores and channels substantially increase cell permeability and the loss of small molecules, leading to cell death.

From polyenes, preferred polyenes for use in the compositions of the invention are broad spectrum polyenes, preferably tetraenes. Nystatin and amphotericin B can in particular be cited.

Advantageously, nystatin is used in the bioadhesive therapeutic systems of the invention.

Polyenes are advantageously used in doses in the range 10 to 100 mg, preferably in the range 20 to 90 mg. By way of illustration, amphotericin is advantageously used in doses in the range 20 to 60 mg. Nystatin is used in an amount of 10 mg to 100 mg, preferably 20 mg to 40 mg, more preferably about 25 mg.

The doses can be recommended in units knowing that 1 mg corresponds to 4400 units. A preferred composition of the invention comprises 50 to 400 mg of an imidazole or triazole compound and 20 to 90 mg or 100 000 to 200 000 units of a polyene. More preferably, the azole compound is miconazole and the polyene is nystatin. The compositions of the invention are generally intended for use in one or two daily doses. Preferably, they are administered at intervals that allow them to be taken daily in amounts of 20 to 200 mg of azole and 50 000 to 500 000 units of polyene (10 to 110 mg).

Further, to improve the treatment efficacy, the bioadhesive therapeutic systems of the invention applied to mucosal administration can also comprise one or more other active principles. More particularly, the bioadhesive therapeutic systems of the invention can comprise one or more active principles that ensure hydration and local acceptance, an indication of compliance in this type of treatment. The use of this type of active principle is particularly advantageous in acute application and in maintenance treatment.

The associated excipients and other active principles can, for example, advantageously be selected from one or more anaesthetic compounds, salivation agents, antiseptics, anti-inflammatories, thalidomide, antibiotics, saliva substitutes or flavour masking agents, used alone or in combination.

The combined use of an active principle with anaesthetic properties is particularly advantageous since, as indicated above, candidiasis is often accompanied by severe pain, in particular during ingestion. An example of a suitable anaesthetic for use in the context of the invention is lidocaine or tetracaine. Preferably, the anaesthetic is used in doses in the range 0.1% to 10% of the total weight of the active ingredients of the compositions of the invention, more preferably in the range 1% to 7%.

A typical composition in accordance with the invention comprises about 1% to 5% of anaesthetic, for example lidocaine.

The combined use of an agent facilitating salivation is also advantageous for treating candidiasis, which frequently causes dry mouth. In a further aspect, then, the invention concerns a bioadhesive therapeutic system or a composition comprising at least one active principle and a salivation agent.

The active principle can be an antifungal compound as described below, an antiviral for the treatment of HIV infections (human immunodeficiency virus), EBV (Epstein-Barr virus, infectious mononucleosis, hairy leukoplakia), CMV (cytomegalovirus), herpes simplex virus (HSV) or the varicella zoster virus (VZV). The active principles contained in the bioadhesive therapeutic systems are then zidovudine, aciclovir, valaciclovir or ganciclovir. It can also be an insoluble or only slightly soluble analgesic for which other administration modes pose precisely those solubility problems. An example that can be cited is low solubility fentanyl base which is important in treating severe resistant pain in particular associated with cancer.

An example of a suitable salivation agent for use in the context of the invention is pilocarpine. Pilocarpine is currently used in treating xerostomia in patients receiving irradiation when treating cancers of the head and neck. An example of another salivation agent is bethanechol.

The salivation agent is preferably used in doses in the range 0.1% to 10% by weight of the total weight of the active constituents in the compositions of the invention, more preferably between 0.1% and 5%.

A composition of the type defined in the invention comprises about 0.5% to 3% of a salivation agent, for example pilocarpine.

More preferably, a particular association of the invention comprises at least one antifungal compound, an anaesthetic and a salivation agent. More preferably, an advantageous composition of the invention comprises:

Further, to improve observance of the treatment, a flavour masking agent can be used if necessary, for example with antifungals. However, in a dose of 50 mg of miconazole, the bioadhesive tablet is characterized by an absence of disagreeable flavour. This agent is preferably free of sugar to avoid possible complications in the mouth, in particular dental problems (caries). In a further embodiment, the bioadhesive therapeutic systems of the invention comprise at least one antifungal compound and a flavour masking agent. This latter comprises mentholated type derivatives, for example. The flavour masking agent is advantageously used in combination with the anaesthetic and the salivation agent as described above.

Further, as indicated above, the combined use of an antiseptic also has major advantages, in particular when used in prophylactic treatment or for maintenance treatment. The use of this type of compound can ensure better oral hygiene for patients afflicted with candidiasis infections. In particular, the use of this type of agent can reduce the bacterial populations present in the oral cavity. A suitable antiseptic is either the alkali metal alkylsulphate alone, or associated with chlorexidine (0 to 5%), an antibiotic (fusafungin, 500 mg, for example) or with an anti-inflammatory, or with a corticoid.

The combined use of said symptomatic active principles endows the compositions of the invention with supplementary properties, in particular:

Thus, the present invention shows that it is possible to combine in the active compositions different agents with complementary properties, ensuring more effective treatment of candidiasis infections in patients. In particular, the compositions of the invention allow global treatment of these diseases, in contrast to early or local systemic treatments using azoles, the efficacy of which is high but which can cause resistance.

The active principles used in the context of the invention can be conditioned in the same homogeneous or heterogenous bioadhesive therapeutic system with two phases with two release rates, or separately depending on whether administration is carried out simultaneously or at intervals. Further, they can be formulated in different manners, depending on the nature of the compounds, and the dosage. The formulation can be in the form of homogeneous or double-layer tablets, or in the form of micro- or nano-spheres. In general, packaging and formulation are defined to allow compatibility of the associated products, reduced or facilitated administration frequency (one or two doses a day), easy delivery system (preferably an oral bioadhesive form), a masked taste if necessary, local hydration, an absence of systemic passage and good acceptability.

A further aspect of the bioadhesive therapeutic systems of the invention can be found in the excipients and the fillers. Adhesiveness is conferred by natural proteins, which represent at least 50% by weight of the active principle. Types of natural proteins that can be used are those described in EP 0 542 824. A particular example is a milk protein concentrate titrating a minimum of 85% of proteins such as Prosobel L85, LR85F or, preferably either Promilk 852A sold by Armor Protéines, or from the Alaplex range (4850, 1180, 1380 or 1395) from NZMP. The relative concentration of the natural proteins in a bioadhesive tablet of the invention is 15% to 50%, preferably 20% to 30%.

The bioadhesive therapeutic systems of the invention also comprise excipients which are normal in bioadhesive systems, as will be shown in the examples below.

A particular characteristic of the compounds of the invention is that they contain between 3.5% and 10% of a metal alkylsulphate. Preferably, it is selected from the group formed by sodium laurylsulphate and diethylsulphosuccinate. More preferably, it is sodium laurylsulphate in a concentration of 4% to 6% by weight of the total tablet weight.

The presence of a dose of more than 3.5% of an alkali metal alkylsulphate and more particularly sodium laurylsulphate can, as will be shown in the following examples, increase the release of miconazole from the tablet in vitro, namely more than 80% over 8 hours as opposed to the active principle being impossible to dissolve in the absence of alkali metal alkylsulphate including over short periods. Thus, it increases the solubility of insoluble or low solubility active principles. This is essential to food availability of the active principle locally. Further, it allows better swelling of the tablet, which has the advantage of producing a constant release of the active principle into the site of action of pathogenic agents. It should be noted that such a concentration of sodium laurylsulphate associated with the adhesive tablet is completely unusual for a tablet in which the concentration of this product rarely exceeds 3%.

Thus in the present invention, the solubilizing function of the sodium laurylsulphate as regards a low solubility active principle has an essential role for its in situ liberation. The examples below indicate good coherence between the in vitro dissolution test and the cumulative salivary concentration over time measured in vivo.

Thus, the presence of sodium laurylsulphate in a concentration of 4% to 6% is an essential element in the composition of tablet and in the qualities of tablet cited above: good availability, a single dose per day, etc.

Sodium laurylsulphate in the minimum concentration of 3.5%, and preferably in the range 3.5% to 10%, also has the advantage of having antiseptic properties per se. Thus, it not only acts as an excipient, but it also acts as an active principle, in particular when treating mucitis.

Finally, the bioadhesive therapeutic systems of the invention can comprise between 0.1% and 1% of a sugar monohydrate, preferably lactose monohydrate or saccharose. The presence of lactose is not, a priori, indispensable per se, provided that the concentration of milk proteins is high. However, the presence of lactose monohydrate or saccharose results in a substantial modification of a step of the preparation process as described in EP 0 542 824-B1, which consists of eliminating a granulation step in the presence of alcohol and replacing it with a wetting liquid composed of lactose or saccharose in purified water, as will be indicated below.

This absence of ethanol has the particular advantage of enabling large scale production of the bioadhesive systems of the invention without using explosion-proof apparatus, which are obligatory when alcohol is present in any step in an industrial process.

The bioadhesive systems of the invention are prolonged release systems and can also be coated with a soluble layer containing the same active principle with immediate release; this is particularly important with analgesic treatments for which a double effect-immediate and prolonged-is sought.

The present invention also concerns a process for preparing a mucosal controled release bioadhesive therapeutic system containing at least one active principle, with an active principle dissolution percentage of more than 70% over 8 hours, comprising at least: