Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-12-30
2004-09-14
Padmanabhan, Sreeni (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S315000, C514S279000, C424S078050
Reexamination Certificate
active
06790847
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising the non-sedating H
1
antihistamines cetirizine, loratadine, mixtures, or pharmaceutically acceptable salts thereof for topical application in the form of a gel.
Histamine is a biogenic amine formed by decarboxylation of the amino acid histidine and is present as a tissue hormone in human and animal organisms, especially in the skin and in the lung. However, it is also contained in bee poison, in the salivary secretion of biting insects, in stinging nettles, and such like. In the human body, histamine is stored in the basophilic granulocytes and the mastocytes. When allergic skin reactions occur, excess histamine is released and is then one of the factors responsible for itching and the formation of skin weals and flares. This release takes place whenever human and animal cells are damaged and causes reactions of the surrounding tissue. Even though histamine is rapidly metabolised in the human body, the effects caused by the release may last for a considerable period of time which severely affects the well-being of the person concerned. At present, antihistamines are primarily administered orally to treat these effects of histamine releases.
Antihistamines are pharmaceutical agents which competitively displace histamine from its receptors and are therefore able to counteract its effects. Depending on the histamine receptors they effect, they are classified as H
1
antihistamines and H
2
antihistamines. In addition to their antihistaminic characteristics, almost all H
1
antihistamines also have a spasmolytic and locally anaesthetising effect. In addition, most of these preparations have a sedating effect on the central nervous system.
In general, H
1
antihistamines are indicated for all diseases based on the release of histamine, substances with a stronger sedating effect also being used as antiemetics or sleeping drugs. In any case, the most important side effect is the influence on the central nervous system, i.e. the sedating effect. Because this sedating effect prevented general application, for example in case of colds or hay fever, second generation H
1
antihistamines with fewer sedating side effects have been developed of late. In general and for the purposes of the present application, these are called “non-sedating H
1
antihistamines”. Typical examples of non-sedating H
1
-antihistamines are terfenadine, astemizole, antazoline, cetirizine, loratadine, ketotifen, acrivastine, ebastine, efletirizine, epinastine, fexofenadine, levocabastine, mizolastine, oxatomide, sebastine, temelastine and azelastine.
For example, H
1
antihistamines are typically administered orally and sometimes nasally in the form of a spray to treat hay fever. Cetirizine or loratadine are preferably used as active ingredients.
According to the American Drugdex Drug Evaluations, cetirizine, a metabolite of hydroxyzine, is a H
1
antagonist with non-sedating characteristics. The recommended oral dose for cetirizine is 10 mg once per day for adults or 2.5 to 5 mg once per day for children. In general, cetirizine is used to treat hay fever, allergic rhinitis, chronic urticaria and asthma. Usually, it is administered orally. The intranasal application of a cetirizine spray is also known, even though such formulations are not available commercially.
U.S. Pat. No. 4,525,358 describes the preparation of cetirizine and other hydroxizine derivatives as well as the use as an anti-allergic, anti-histaminic, bronchio-dilatory and anti-spasmodic agent. In a general form, the document also describes a possible oral, parenteral or topical use of the hydroxyzine derivatives disclosed. However, no examples for a topical formulation are given. In case of the above-mentioned indications, cetirizine has, on the whole, been administered only orally or, for experimental purposes, nasally.
Likewise, other second generation H
1
antihistamines such as loratadine are exclusively formulated and administered orally in practical applications. According to the American Drugdex Drug Evaluations, loratadine is also a non-sedating anti-histamine. The active ingredient is administered to adults in one oral dose of 10 mg per day and to children in one dose of 5 mg per day. Oral combination products, for example with pseudoephedrine, are also known. Similar to cetirizine, areas of indication for the use of loratadine are allergic rhinitis, asthma and chronic idiopathic urticaria.
The preparation of the substance is described in U.S. Pat. No. 4,282,233, which also describes pharmaceutical preparations for enteral or parenteral administration, but not topical administration of the active ingredient.
European patent application 0 903 151 describes the use of combinations of non-sedating antihistamines and &agr;-adrenergic active ingredients for the topical treatment of rhinitis or conjunctivitis and of symptoms of a cold. The topical preparations described contain the antihistamine in an amount of 0.001% to 0.5%, preferably 0.05% to 0.1%. Apart from that, the application describes only topical formulations for administration via the mucous membranes, namely nose sprays, nose drops or eye drops. Topical application to the skin is not disclosed or intended.
WO 01/87 236 discloses a spray containing a pharmacologically active compound such as an antihistamine to treat insect bites, insect stings, nettle rash, atopical dermatitis and contact dermatitis, as well as sunburn, neurodermatitis, urticaria and eczema. At the same time, the document discloses creams, gels, foams, ointments or lotions containing hydroxyzine. No details concerning these compositions are provided.
U.S. Pat. No. 5,993,833 discloses topical compositions containing an antihistamine, an interleukin-1 antagonist and/or an TNF&agr; antagonist. These preparations may be provided in any topical form possible including anhydrous or lipophilic gels, creams, emulsions, foams and such like. However, this document primarily teaches the addition of an antihistamine to a cosmetic, dermatological or pharmaceutical preparation instead of such as composition per se, the antihistamine not being the actual active ingredient, but merely improving toleration of the latter.
As components of said preparations all customary components such as oils, emulsifiers, solvents (lower alcohols and propylene glycol), hydrophilic gelatinising agents (carbomer, acryl copolymers, polysaccharides such as hydroxy propyl cellulose as well as lipophilic gelatinising agents such as ethyl cellulose and polyethylene) are mentioned. The examples illustrate the use of the antihistamine cetirizine or loratadine as a cream, gel or lotion.
WO 01/39 774 discloses a preparation containing ketotifen which may be used for the treatment of allergic conditions including insect bites and stings, nettle rash, atopical and contact dermatitis as well as eczema, urticaria, neurodermatitis, dry skin and sunburn and may be present in the form of a gel, a lotion, a spray, a foam, a cream, an ointment and different fluids. Even though the preparations may contain various customary components, gels are not especially preferred. Instead, a cream preparation is preferred.
EP 0 484 529 discloses a w/o skin cream preparation comprising an active ingredient such as, among others, ketotifen and a cream base containing a diglycerol fatty acid ester and/or sorbitan fatty acid ester having a HLB of 3 to 7, a polyvalent metallic salt of a fatty acid having 10 to 12 carbon atoms, a salt of an inorganic or organic acid, an oil phase component and water.
The oral administration described above has the disadvantage of a slow onset of the effect. In addition, oral administration is accompanied by the known sedating side effects since the active ingredient is evenly distributed throughout the entire organism. These side effects also occur with second generation H
1
antihistamines, albeit in a less severe form. Especially in situations where the person taking it must be fully alert, for example when driving a car, operating complicated machine
Kim Jennifer
Oramon Arzneimittel GmbH
Padmanabhan Sreeni
Ratner & Prestia
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