ORAL COMPOSITIONS CONTAINING FLUOCINONIDE

Abstract: A topical composition containing fluocinonide in a base of glyceryl monooleate with a water content of less than about 20 % W/W is provided for the treatment of oral ulcerations, inflammation and lesions of the oral cavity. The composition is smeared thinly over the ulcer and forms a very mucoadhesive film which holds the fluocinonide in contact with the ulcer for a prolonged period. The composition is particularly useful for the treatment of oral aphthous ulcers, oral mucositis (including mucositis neuroticans agranulocytica), oral Crohn's disease, orofacial granulomatosis, and cicatricial pemphigoid, oral erosive lichen planus, gingivitis such as desquamative gingivitis and gingivitis associated with lichen planus, and oral vesiculerosive diseases.

Description: ORAL COMPOSITIONS CONTAINING FLUOCINONIDE This invention relates to the use the glyceryl monooleate in the preparation of a spreadable, topical composition for the treatment or prophylaxis of oral ulcerations, inflammation and lesions of the oral cavity. In particular the invention relates to a topical composition comprising fluocinonide and glyceryl monooleate . Oral ulceration (or mouth ulcers) other lesions and inflammation in the oral cavity can be very painful. There are various preparations for the treatment of oral ulcerations. For example carbenoxolone sodium can be helpful in promoting healing of mild oral lesions, lozenges and oral pastes containing corticosteroids are used for treating apthous non-specific ulcers, salicylates can be used in mild inflammatory and painful oral lesions, and benzydamine hydrochloride has a topical anti-inflammatory and analgesic effect and is used as a mouthwash or spray for oral ulcerations. A difficulty of treating oral ulcerations with preparations such as sprays, lozenges and mouthwash is that the active agent of the preparation is only transiently in contact with the ulcer. Even with gelatin based pastes, which have a protective effect for non-infected ulcers, it is difficult to keep them on the lesion for a prolonged period. TM An example of a mucoprotectant is orabase which contains carboxymethyl cellulose sodium, pectin and gelatin. This composition, however, has an uncomfortable gritty mouth feel. Fluocinonide is a corticosteroid used topically in the treatment of various skin disorders. It is usually employed as a cream, gel, lotion, ointment, or scalp application containing 0.05%. In Arch. Dermatol . Vol 116, Aug 1980, pp. 98 to 901 fluocinonide is used in an adhesive base to effectively treat oral vesiculoerosive diseases. The adhesive base was orabase. In Oral Surg. Med. Oral Pathol . 1993; 75: 181 -5, fluocinonide is again used in adhesive base, this time to treat oral lichen planus. The adhesive base was 40% hypromellose (hydroxypropyl methyl cellulose) in white soft paraffin. The present inventor has now surprisingly found an effective medicament for treating oral ulcerations, inflammation, and lesions of the oral cavity which comprises fluocinonide or a physiologically acceptable derivative thereof and glyceryl monooleate, such as monoolein, as a spreadable mucoadhesive base. The glyceryl monooleate is conveniently spread in a thin film over, for example, the ulcer and forms an adhesive bond with the mucous of the ulcer, which in turn maintains the active agent in contact with the ulcer for a prolonged period.. Monoolein is a mixture of the glycerides of oleic acid and other fatty acids, consisting mainly of the glyceryl monooleate. A commercial form of monoolein is sold by Eastman Chemicals (e.g. at Hemel Hempstead, UK or Denver, TM USA) under the trade name Myverol . The manufacturers recommended uses of Myverol™ are: for sustained release formulations, for topical permeation enhancement, for solubilisation of a water soluble drug into an oil matrix, and for sustained release microspheres . Monoolein is normally formulated in its fully hydrated cubic phase (which contains up to about 40% water) to produce its advantageous sustained release properties (J. Phy. Chem.1989 , 93, 7304-7314 and EP-A-0 314 689). A composition comprising monoolein and an active such as metronidazole (an anti-bacterial) is described in EP-A-0 671 175 and equivalent US-A-5 261 164 as a sustained release product for treating periodontal disease. The composition is injected into the periodontal pocket, preferably by a syringe. Such a product is sold under the trade name elyzol™ which is issued with a disposable applicator for the treatment of chronic periodontal disease. A similar periodontal type application of monoolein is disclosed in J.Clin. Periodontal 1992; 19:687- 692. In Pharmaceutical Technology Europe Feb 1995, pl4-16, various phases of monoolein are described. Primarily there is the fully hydrated cubic phase which consists of about 2/3 lipid and 1/3 water by water, and is used in the sustained release of drugs. The lamellar phase has a water content of about 5 to 20% w/w and in a water-rich environment will spontaneously swell to the cubic phase. The mucosal adhesion force (to a pig's tongue) is twice as great for the lamellar phase as for the cubic phase. Other precursor phases to the fully swelled cubic phase are pure monoolein (substantially zero water content) and the reversed micellar phase (0% to 5% w/w water) . If such a precursor phase is applied to a wet surface for example the gums or any mucosa, the system will absorb water from the surroundings . It is an object of the present invention to provide an effective treatment for oral ulceration, inflammation and lesions of the oral cavity, in particular of the tongue, gingivae, lips, palate and buccal mucosa. Accordingly in a first aspect of the present invention there is provided use of fluocinonide or a physiologically acceptable derivative thereof together with glyceryl monooleate having a water content of less than about 20% w/w in the preparation of a spreadable topical medicament for the treatment or prophylaxis of oral ulcerations, inflammation and lesions of the buccal mucosa, tongue, palate, gingivae, and lips. By physiologically acceptable derivative, we mean a derivative which is metabolised in vivo, such as by the enzymes in the oral cavity, to the same active metabolite as fluocinonide, and in particular includes physiologically acceptable salts. Preferably, monoolein (CAS Registry No. 25496-72-4) is used in the composition of the invention. By monoolein, we mean a product which consists predominantly of glyceryl monooleate, although various other glycerides of oleic acid and other fatty acids could be present. Hereinafter references to glyceryl monooleate should be construed also as a reference to monoolein and visa versa. A particularly preferred form of monoolein is sold by Eastman Chemical under the trade name of Myverol™. Preferably the glyceryl monooleate (or monoolein) has a water content of less than about 5% w/w, more preferably less than about 2% w/w and optimally has a water content of substantially zero (i.e. pure glyceryl monoleate/monoolein) . By lesion we mean to include papule, nodule, weal, vesicle, bulla, pustule, plaque, scale, excoriation, scar, and lichenification. Most oral ulcerations or lesions should respond to treatment with a composition of the present invention particularly including the following: oral aphthous ulcers, oral mucositis (including mucositis neuroticans agranulocytica) , oral Crohn's disease, orofacial granulomatosis, and cicatricial pemphigoid, oral erosive lichen planus, gingivitis such as desquamative gingivitis and gingivitis associated with lichen planus, and oral vesiculerosive diseases. The composition of the invention is of particular benefit in the treatment or prophylaxis of cicatricial pemphigoid, oral erosive lichen planus, gingivitis such as desquanative gingivitis and gingivitis associated with lichen planus. Oral mucositis is an inflammation of the oral mucous surface and, for example, can result from chemotherapy. Symptoms of oral Crohn's disease can include thickening of the mucous membranes of the mouth and lip. Symptoms of orofacial granulomatosis can include furrowing of the tongue, thickening of the lower lip and buccal mucosa, and recurrent aphthous ulcers. Cicatricial pemphigoid is a chronic vesiculobullous disease that primarily involves the mucous membranes. It is an autoimmune condition and is characterised by the formation of subepithelial bullae. Oral erosive lichen planus is a common condition of the oral mucosa, usually of no identifiable aetrology. However a variety of drugs may provoke such a condition and certain of these drugs notably NSAIDs favour the induction of erosions. The composition of the invention is ideally suited for treating oral ulceration, inflammation and lesions of the tongue, palate, lips, gingivae and the buccal mucosa. Optional components which can also be used in the composition include flavourings, surfactants, penetration enhancers, antioxidants, polymers, opacifiers, viscosity modifying agents including hydrocarbon waxes or oils such as glycerol . In a preferred embodiment white soft paraffin wax is used to improve the rheological behaviour of glyceryl monooleate (i.e. improve its spreadability) . Other preferred optional components are titanium dioxide as an opacifier, lidocaine hydrochloride as an anaesthetic, benzyl alcohol as a penetration enhancer and ascorbyl palmitate as an antioxidant. The amount of each component in a formulation can vary. Thus for example fluocinonide could be used at 0.01 to 0.05% w/w, preferably 0.015 to 0.035% w/w and most preferably about 0.025% w/w. Glyceryl monooleate can be present at 30% to 90% w/w, preferably 50% to 70% w/w and most preferably about 60% w/w. Where the total weight is less than 100% w/w, the formulation would be made up with other optional components. For example, a hydrocarbon wax, such as white soft paraffin, is desirably used at 20% to 60% w/w, preferably 30% to 50% w/w, most preferably about 40% w/w. If an anaesthetic agent, such as lidocaine, is present, it is desirably used at 1% to 5% w/w, preferably about 3% w/w. A particularly preferred embodiment of the invention includes fluocinonide or a physiologically acceptable salt thereof, at 0.015% to 0.035% w/w, glyceryl monooleate at 40% to 60% w/w, hydrocarbon wax, preferably white soft paraffin, at 39.965% to 39.985% w/w. The composition of the invention is typically supplied from a tube or pump dispenser and spread topically using the finger tip in a smearing action over, for example, the oral ulcer. In this way a thin and very mucoadhesive film is formed which is comfortable and convenient for the patient. In addition, the glyceryl monooleate film protects the ulcer from further infection and, because it > is substantially insoluble in saliva, it prevents the active agent from being washed off the ulcer. As such, with intermittent applications a therapeutically effective amount of active agent can be maintained in continuous contact with the ulcer thereby accelerating healing. Further aspects of the invention are as follows: 1. The use of glyceryl monooleate having a water content of less than about 20% w/w as a mucoadhesive in the preparation of a spreadable fluocinonide medicament for the topical treatment of oral ulcerations, inflammation, or lesions of the oral cavity, particularly the buccal mucosa, tongue, palate, gingivae, and lips. 2. The use of fluocinonide or a physiologically acceptable derivative thereof and glyceryl monooleate having a water content of less than about 20% w/w in the preparation of a spreadable medicament for the topical treatment of oral ulcerations, inflammation, or lesions of the oral cavity. 3. A method of treating oral ulcerations, inflammation, or lesions of the oral cavity comprising spreading topically over the ulcer lesion, or inflammed mucosa, a pharmaceutical formulation comprising an effective amount of fluocinonide or a physiologically acceptable derivative thereof, and glyceryl monooleate- having a water content of less than about 20% w/w. 4. Since we have also discovered that fluocinonide can particularly treat oral cicatricial pemphigoid, oral erosive lichen planus, gingivitis such as desquemative gingivitis, and gingivitis associated with oral lichen planus, a yet further aspect of the invention relates to the use of fluocinonide in the preparation of a medicament (in any composition) for the treatment of these oral disorders. The invention will now be described by way of example with reference to the following compositions. Example 1 Active Constituent % w/w Fluocinonide 0.025 Other Constituents Myverol™ 18-99 60.0 (Monoglyceride) White Soft Paraffin (vasoline) 39.975 Total: 100.00 Example 2 : Childhood Cicatricial Pemphigoid Presenting as Desquamative Gingivitis A fourteen year old girl presented with painful erythematous gingivae and a history of blister formation. A diagnosis of benign mucous membrane cicatracial pemphigoid (localised to the gingivae) was made. The patient was initially treated with a mouth rinse containing triamcinolone and chlortetracycline . This treatment was subsequently replaced by the mucoadhesive fluocinonide composition according to Example 1 and the patient instructed to apply this composition to the gingivae 4 times daily for 6 weeks. The desquamative gingivitis responded well to the mucoadhesive fluocinonide gel. Example 3 : Oral Erosive Lichen Planus The fluocinonide gel of Example 1 was prescribed to patients with oral erosive lichen planus refractory to conventional topical steroid preparation. Patients were asked to apply the gel 3 times daily to the erosions for a period of 2 weeks . This limited study presents favourable results for that the use of the fluocinonide gel in the management of oral erosive lichen planus. Example 4 ; Desquamative Gingivitis associated with Lichen Planus The fluocinonide gel of Example 1 was prescribed to several patients with desquamative gingivitis associated with lichen planus, and was found to be extremely beneficial .

Claims: CLAIMS 1. A spreadable mucoadhesive topical pharmaceutical composition for application to the oral mucosa, comprising fluocinonide or a physiologically acceptable derivative thereof and glyceryl monooleate having a water content of less than about 20% w/w. 2. A composition as claimed in Claim 1 wherein the glyceryl monooleate is present as monoolein. 3. A composition as claimed in Claims 1 or 2 wherein the glyceryl monooleate has a water content of less than about 5% w/w. 4. A composition as claimed in Claim 3 wherein the glyceryl monooleate is substantially water free. 5. A composition as claimed in any of the preceding claims comprising 0.015 to 0.035% w/w fluocinonide, 50 to 70% w/w glyceryl monooleate and white soft paraffin to 100% w/w. 6. Use of fluocinonide or a physiologically acceptable derivative thereof together with glyceryl monooleate having a water content of less than about 20% w/w in the preparation of a spreadable topical medicament for the treatment or prophylaxis of oral ulcerations, inflammation and lesions of the buccal mucosa, tongue, palate, gingivae, and lips. 7. Use as claimed in Claim 6 for the treatment or prophylaxis of oral aphthous ulcers, oral mucositis (including mucositis neuroticans agranulocytica) , oral Crohn's disease, orofacial granulomatosis, and cicatricial pemphigoid, oral erosive lichen planus, gingivitis such as desquamative gingivitis and gingivitis associated with lichen planus, and oral vesiculerosive diseases. 8. A method of treating oral ulcerations, inflammation, or lesions of the oral cavity comprising spreading topically over the ulcer, lesion, or inflammed mucosa a pharmaceutical formulation comprising an effective amount of fluocinonide or a physiologically acceptable derivative thereof, and glyceryl monooleate having a water content of less than about 20% w/w.

Inventors: BUSER THOMAS, BUSER, THOMAS
Applicants: BUSER THOMAS, TILLOTTS PHARMA AG, BUSER, THOMAS
Application year: 1997
Main classification: A61K31
IPC codes: A61K9, A61K31, A61K47, A61P1