Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1999-04-05
2001-04-17
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S435000
Reexamination Certificate
active
06217897
ABSTRACT:
This invention relates to a 5-aminosalicylate acid (5-ASA) composition for the treatment or prophylaxis of oral ulcerations, inflammation and lesions of the oral cavity, and in particular the use the glyceryl monooleate in the preparation of such compositions.
Oral ulceration (or mouth ulcers) can be very painful and the resulting lesions can be mild or severe. 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.
An example of a mucoprotectant is orabase™ which contains carmellose sodium, pectin and gelatin. This composition, however, has an uncomfortable gritty mouthfeel.
5-aminosalicylic acid (5-ASA) is a known compound and is currently used in the treatment of inflammatory bowel disease such as Crohn's disease and ulcerative colitis. For these indications, 5-ASA is administered rectally as an enema, or orally as a controlled release capsule. EP-A-0 352 826 relates to the use of 5-ASA for detmatological disorders associated with therapy-resistant loss of epithelium, such as pyoderma gangrenosum, leg ulcers, mouth ulcers, decubitus, bullous dermatoses and burns. In addition, 5-ASA is water sensitive and therefore it is desirable to formulate it in a substantially water free composition.
Topical 5-ASA in a guaze poultice has also been reported as treating oral and genital lesions resulting from Behcet's disease (British J. Dermatol., 1989, 120:471-72).
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.
We have now surprisingly found an effective medicament for treating oral ulcerations inflammation, and lesions of the oral cavity which comprises 5-ASA as active agent or a physiologically acceptable derivative thereof, and glyceryl monooleate. The glyceryl monooleate is conveniently spread in a thin film over the ulcer and forms an adhesive bond with the mucous of the ulcer, which in turn maintains the 5-ASA in contact with the ulcer for a prolonged period. Furthermore, we have found that the glyceryl monooleate can be used in a substantially water free state, which helps to stabilise the 5-ASA and prolong the shelf life of the composition.
Preferably, monoolein (containing glyceryl monooleate) is used in the composition of the invention.
By monoolein we mean a product which consists predominantely of glyceryl monooleate, although various other glycerides of oleic acid and other fatty acids could be present. Hereinafter refernces to glyceryl monooleate should be construed also as a reference to monoolein (CAS Registry No. 25496-72-4) and visa versa.
Preferably glyceryl monooleate (and monoolein) is formulated in a substantially water-free state. This enhances the shelf life of the compositon.
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 Hemstead, UK or Denver, 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 antibacterial) is described in EP-A-0 671 175 and equivalent U.S. Pat. No. 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. Similar periodontal type applications of monoolein are disclosed in Pharmaceutical Technology Europe February 1995, p14-16, and J.Clin. Periodontal 1992; 19:687-692.
Accordingly in a first aspect of the present invention there is provided a spreadable mucoadhesive topical pharmaceutical composition comprising 5-ASA or a physiologically acceptable derivative thereof, and glyceryl monooleate.
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 5-ASA, and in particular includes physiologically acceptable salts and esters of 5-ASA.
An example of a derivative of 5-ASA ia an N-acetyl derivative and its salts. Some esters have similar activity, e.g. alkyl esters, especially lower alkyl esters such as methyl, ethyl, propyl or isopropyl; alkenyl esters; cycloalkyl esters; aryl esters; alicyclic esters; and aralkyl esters.
Examples of physiologically acceptable salts of 5-ASA and its derivatives include salts derived from an appropriate base, such as an alkali metal (for example sodium or potassium), an alkaline earth metal (for example magnesium), ammonium or NX4
+
, wherein X is a C
1-4
alkyl group.
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, ulcers in patients with ulcerative colitis, orofacial granulomatosis, denture stromatitis, oral ulcers associated with Behet's Disease, oral lichen planus, pemphigus of the mouth, herpetic ulcers and traumatic lesions. By lesion we mean to include papule, nodule, weal, vesicle, bulla, plaque, scale, excoration, scar, and lichenification.
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.
The composition of the invention is ideally suited for treating oral ulceration, inflammation and lesions of the tongue, palate, lips, gingivae and most preferably the buccal mucosa.
Optional components which can also be used in the composition include anaesthetic agents, 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 Theological behaviour of glyceryl monooleate (i.e. improve its spreadability). Surprisingly, the white soft paraffin also helps prevent sedimentation of solids in the formulation as compared to other oils such as paraffin, glycerol, and arachis oil.
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. Ascorbyl palmitate is a particularly good antioxidant in a substantially water-free composition of the invention.
The amount of each component in a formulation can vary. Thus 5-ASA could be used at up to 20% w/w, more preferably 1%
Page Thurman K.
Tillotts Pharma AG
Ware Todd D
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