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Prolonged release bioadhesive therapeutic systemsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Preparations Characterized By Special Physical Form, Tablets, Lozenges, Or Pills, Sustained Or Differential Release TypeProlonged release bioadhesive therapeutic systems description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070160668, Prolonged release bioadhesive therapeutic systems. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present invention relates to the medical field, in particular the field of mucosal infections. More particularly, the present invention relates to novel prolonged release bioadhesive therapeutic systems for treating local mucosal infections or the mucitis and candidiasis type. The invention also relates to methods for treating such symptoms and to novel release forms for improving their efficacy. The bioadhesive therapeutic systems of the invention can be used for curative or preventative treatment of such disease types. [0002] Candidiasis is a disease resulting from a local proliferation of fungal species (Candida). Such proliferation can have a number of origins, in particular a local physico-chemical imbalance (modification of pH, etc) associated, for example, with taking antibiotics, steroids or other physical treatments (irradiation, chemotherapy, immunodepressors, etc.). The increase in immunodepression situations (related to immunodepression consecutive upon chemotherapy in the treatment of cancer or the AIDS epidemic) was the cause of a re-emergence of oral candidiasis and severe parodontal disease (Hermant et al., 1997, Med. Mal. Infect. 27: 715-718). Buccal candidiases are routinely detected even in HIV seropositive subjects who are apparently in good health. They are often the first manifestation of an HIV infection. More than 90% of patients with AIDS develop oral candidiasis (Vasquez, 1999, Pharmacotherapy, 19 (1): 76-87). The prevalence approaches 20% in certain populations; it increases with the reduction in the number of CD4 (Greenspan & Greenspan, 1996, Lancet 348: 729-733). Further, candidosa is a common characteristic of infection by the immunodeficiency virus HIV and cancer. The fungal species responsible for those candidiases are Candida such as C. albicans, C. glabrata, C. tropicalis or C. krusei. [0003] Particular signs associated with candidiasis are dry mouth, pain on ingestion, loss of taste, burns, etc. A change in the condition of the buccal cavity has serious implications for the general condition of the patient. Buccal infections that are poorly treated can be the cause of odynophagia and dysphagia, can interfere with speech, mastication and deglutition. Further, the pain caused by those infections leads patients to reduce their food intake; this results in a loss of weight, dehydration and malnutrition. Prevention and treatment of oral candidiasis is thus an essential concern in maintaining quality of life and in preventing more severe complications in those patients (Weinert et al., 1996, Amn. Intern. Med. 125: 485-496). [0004] Candidiasis is also a frequent complication in anticancer treatments. In particular, chemotherapy, bone marrow graftings or local irradiation are all factors encouraging the development of local candidiasis type infections. The secondary oral effects of chemotherapy are a major source of morbidity in cancerology. Out of 27 clinical tests: 14 with mucitis (945 randomized cases) and 15 with oral candidiasis (1164 randomized cases), the incidence of mucitis was 50% to 80% and that of candidiasis was 30% to 70% and varied as a function of the location of the cancer. In view of that analysis, partially absorbed treatments appear to be more effective than those which are totally absorbed by the intestinal tract as regards prophylaxis (Clarkson et al., 2000, Cochrane Database Syst Rev. (2): CD000978). [0005] More generally, a further factor encouraging the development of candidiasis is an alteration in the integrity of the mucosa, for example by local or diffuse desquamation. Mucitis is one of such conditions: it involves an erythema generally followed by local desquamation. The alteration in the mucosa (generally buccal) that is induced is the early stage forming the bed of infection, in particular a fungal infection in ADS or cancer (chemotherapy, bone marrow grafting, local irradiation with tumours to the head and neck, etc). Patients suffer locally from salivary hypofunction, which itself is responsible for an alteration in dental hygiene (Greenspan et al., The Lancet 348 (1996) 729). [0006] Candidosa infections are currently treated in the first intention in a local manner, essentially using antifungals: magistral preparations, lozenges, mouthwashes, azoles, polyenes (Greenspan et al., Lancet 348: 729-733). Azole derivatives are proposed in the second intention, by systemic route, in the case of oesophageal candidiasis (ketoconazole, fluconazole, itraconazole). Such treatments are effective in prevention but are risky (interactions with drugs, resistance, intolerance) . . . . Such systemic azoles are reserved for short therapies in confirmed candidiasis (Kovacs et al., 2000, The New England Journal of Medicine, May 11, 1416-1429). [0007] A further disadvantage of these treatments resides in frequently observed relapses. Some studies observed 60% recurrence in the three months following treatment (Imam et al., Amer. J. of Medicine 89 (1990) 142). [0008] Considering the physiopathology of candidiasis, Candida albicans and also C. krusei, C. tropicalis and C. glabrata are the agents responsible for the local infection (mouth, oesophagus, skin, nails, vagina). It can be more or less profound depending on the host's defenses. It is a cutaneo-mucous affection that can induce complications and become systemic. Effective local treatment or preventing buccal candidiasis can avoid systemic candidiasis and the appearance of resistant strains. [0009] Adhesion of the fungus to the mucosa is an essential element in its pathogenicity. The residency time of an antifungal product in the buccal cavity can be an essential element in its immediate and long term efficacy. [0010] Described or existing formulations or compositions are based on forms for systemic administration both as regards their galenic form and the active principles involved. [0011] The present invention provides a prolonged release bioadhesive therapeutic system that is essential for producing a long residence time in the locations of the infection in contrast to the usual local forms (mouthwashes, gel, pastils, lozenges) which have a transitional effect. [0012] By way of example, a buccal gel for local application based on miconazole is sold by Janssen-cilag (92787 Issy-les-Moulineaux, France) under the trade name Daktarin buccal gel.RTM. for the treatment of mycoses of the buccal cavity. Miconazole is an antifungal from the imidazole family. It acts in situ after application. As it is only very slightly re-absorbed, it is well tolerated. The dosage for treating buccal mycoses in adult is 125 mg of miconazole (two spoonfuls) applied 4 times a day for 7 to 15 days. The salivary concentration of the miconazole is a good reflection of the efficacy of the product. It varies from 5 to 0.4 .mu.g/ml 30 minutes to 3 hours after applying the gel. Its very rapid reduction is explained by the very short residency time of gel in the buccal cavity. Further, the MIC (minimum inhibitory concentration) of miconazole against Candidosa albicans is in the range 1 to 10 .mu.g/ml (Daktarin monograph, medical information from the Swiss Compendium of Medicinal Products). This concentration is only obtained achieved during the short period following application of the gel. As a result, the antimycotic coverage obtained with the buccal gel is mediocre. [0013] Bioadhesive forms and their preparation method have been described in patent EP-0 542 824 B1. They were designed for systemic passage and cannot be used for local action. They do not permit satisfactory in vitro dissolution, a criterion for determining local availability. Thus, they are incompatible with using an active principle such as an antifungal which necessitates local action and/or limited systemic passage. [0014] The present invention aims to overcome all of the disadvantages described above by providing novel prolonged release bioadhesive therapeutic systems by ensuring solubilisation of active principles to ensure its local efficacy. Indeed, prolonged release forms can reduce the number of doses and produce more stable levels of active principle over time. [0015] Throughout the text, the terms "bioadhesive" or "mucoadhesive" will be used equally, therapeutic systems of the invention are more particularly suitable for mucosal administration. [0016] Similarly, the term "therapeutic" encompasses both therapy and prophylaxis of the different pathologies mentioned above, and in particular mucitis and candidiasis. [0017] The bioadhesive therapeutic systems can be in the form of bioadhesive tablets, micro spheres or nanospheres. [0018] The present invention also provides a method for preparing said bioadhesive therapeutic systems in the form of tablets with the desired qualities for use on all types of mucosa. [0019] More precisely, the bioadhesive tablets and methods of the invention are suitable for treating mucitis and candidiasis in the context of diseases in immunodepressed subjects (elderly, malnourished, antibiotherapy, cancer, AIDS, radiotherapy, chemotherapy, grafting). [0020] Said tablets are also suitable for administering active principles for which mucosal administration has advantages as regards therapy or comfort, compared with buccal, transdermal or systemic administration. As an example, it may be antivirals such as aciclovir, valaciclovir, ganciclovir, zidovudine or insoluble analgesics such as fentanyl base. [0021] They enable favorable local use of insoluble or slightly soluble active principles. They also enable a number of active principles to be combined in the tablet to increase compliance and acceptability of the treatment, such as other antiflngals with a different spectrum, analgesics, salivation agents, etc. [0022] The tablets of the invention also enable that the dose can be reduced and thus, undesirable secondary effects which can accompany the normal use of such drugs can also be reduced. Further, the invention also describes compositions that are particularly advantageous clinically as they are active on the basis of a single (or two) daily dose(s). Finally, their novel formulation does not alter taste and appetite, which are essential elements in maintaining a good general condition in the immunodepressed patient. [0023] The present invention also provides a solution to the disadvantages of the prior art, enabling a more complete and better tolerated control of mucosal infections and associated symptoms (continuous and non-transient cover) and of certain viral diseases, pain or other diseases. [0024] In a first aspect, the invention provides a prolonged release bioadhesive mucosal therapeutic system containing at least one active principle, having an active principle dissolution test of more than 70% over 8 hours, comprising quantities of natural proteins representing at least 50% by weight of active principle and at least 20% by weight of said bioadhesive therapeutic system, between 10% and 20% of a hydrophilic polymer, compression excipients to reinforce the hardness of the bioadhesive therapeutic system, and comprising between 4% and 10% of an alkali metal alkylsulphate and optionally between 0.1% and 1% of a monohydrate sugar. 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