Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-31
2001-04-10
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S220000, C514S315000
Reexamination Certificate
active
06214837
ABSTRACT:
The present invention relates to a pharmaceutical composition for the treatment of so-called restless legs, the new use of certain compounds known to act as antihistamines, preferably in combination with quinine, for the preparation of a pharmaceutical composition for the treatment of restless legs, and a new method of treatment of restless legs.
There are several theories about the cause of the affliction experienced as tingling and feelings of crawling in the-lower legs which occurs particularly at night and affects especially older patients. This affliction is termed restless legs. Several methods of treatment have been tried for this affliction, some of which are described in Clinical Pharmacy, Volume 10, June 1991, pages 427-428. No treatment has, however, been particularly successful. This reference describes, among other things, attempts to treat leg cramps by the use of quinine, but does not mention the use of quinine for the treatment of restless legs.
In accordance with the present invention, the surprising observation has been made that certain substances known to be antihistamines can in certain cases give effective relief from the affliction of restless legs, and that a combination of such a substance with quinine gives extraordinary good relief.
Accordingly, the present invention relates to a pharmaceutical composition for the treatment of restless legs, which is characterised in that it comprises a combination of
A) quinine, preferably in the form of a pharmaceutically acceptable acid addition salt thereof, and
B) a compound selected from the group consisting of
B1) compounds of the general formula (I)
wherein R
1
is hydrogen or a straight or branched alkyl group, having 1-4 carbon atoms,
R
2
and R
3
, which are equal or different, each represents hydrogen, a halogen atom, a straight or branched alkyl or alkoxy group having 1-4 carbon atoms, or a trifluoromethyl group, preferably in the form of a pharmaceutically acceptable salt thereof, and
B2) compounds of the general formula (II)
wherein X is hydrogen or a halogen atom, preferably chlorine, and R
4
is a methyl, ethyl or phenyl group
together with conventional pharmaceutically acceptable carrier substances.
Compounds of the general formula (I) and their preparation are known, for example from U.S. Pat. No. 3,014,911. The compound most preferred for use in the present invention is cyproheptadine ~4-(5H-dibenzo[a,d]cycloheptene-5-ylidene)-1-methyl-piperidine]. This compound is a histamine H1 antagonist which is sold by Merck Sharp and Dohme under the trade name Periactin® with indications acute and chronic allergy, pruritis, and vascular headache.
Compounds of the general formula (II) and processes for their production are known, for example from U.S. Pat. No. 4,282,233. The compound most preferred for use in the present invention is loratadine [ethyl-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2b]pyridine-11-ylidene)-1-piperidine-carboxylate]. This compound is sold by Schering-Plough AB, Stockholm, Sweden as a histamine H1 antagonist under the trade name Clarityn, with indications allergic rhinitis and conjunctivitis, and histamine mediated pruritis and urticaria.
According to one embodiment of the pharmaceutical composition according to the invention, the two components A) and B) exist together in one and the same pharmaceutical preparation together with conventional pharmaceutically acceptable carriers in a suitable dosage unit form.
According to another embodiment, the pharmaceutical composition according to the invention exists in the form of a kit containing the components A) and B) each in a separate dosage unit. In this case the two components exist separately in tablet form with a known composition for the conventional use of the components in question.
According to a particularly preferred embodiment of the pharmaceutical composition according to the invention said composition consists of a kit with quinine hydrochloride in the form of a tablet containing 50-400 mg, preferably 100-250 mg, quinine hydrochloride, and loratadine in the form of a tablet containing 5-15 mg, preferably 10 mg, loratadine.
According to another aspect of the present invention there is provided the use of quinine for the preparation of a pharmaceutical composition for the treatment of restless legs in combination with a compound with the general formula (I) or (II), as has been defined previously. According to the same aspect, the present invention also relates to the use of a compound with the general formula (I) or (II) as has been defined previously for the preparation of a pharmaceutical composition for the treatment of restless legs in combination with quinine.
According to a preferred embodiment of this use, the quinine exists in the form of quinine hydrochloride, while loratadine is used as a compound with formula (II), the two substances being prepared separately as dosage units.
According to a further aspect of the invention there is provided the use of a compound of the general formula (II) as defined above for the preparation of a pharmaceutical composition for the treatment of restless legs.
According to a still further aspect of the present invention there is provided a method of treatment of restless legs, which method comprises the administration to a patient of a therapeutically effective amount of a compound of formula (I) or (II) as has been defined previously in combination with quinine. According to a preferred embodiment of this method, the quinine is administered in the form of a tablet containing 50-400 mg, preferably 100-250 mg, quinine hydrochloride, and loratadine in the form of a tablet containing 5-15 mg, preferably 10 mg, loratadine.
The present invention also provides a method of treatment of restless legs which method comprises administration to a patient of a therapeutically effective amount of a compound of the general formula (II) as defined above.
The invention will be further illustrated below by a number of examples of the treatment of restless legs using a pharmaceutical composition in accordance with the present invention and using a compound of the general formula (II), with no connection to quinine, respectively.
The following preparations have been used in the experiments: Kinin NM Pharma has been used as quinine. This is marketed by NM Pharma AB, Stockholm, Sweden in the form of tablets containing 100 mg or 250 mg quinine hydrochloride.
Loratadine, in the form of, Clarityn®, has been used as component B) in the composition in accordance with the present invention. This is sold by Schering-Plough AB, Stockholm, Sweden in the form of tablets containing 10 mg loratadine.
REFERENCES:
patent: 3014911 (1961-12-01), Engelhardt
patent: 4282233 (1981-08-01), Vilani
patent: 5759198 (1998-06-01), Karell
patent: 6100274 (2000-08-01), Kou
“Therapy Consulation”, by Walton, et al., Clinical Pharmacy, vol. 10, Jun. 1991, pp. 427-428.
“Randomised Double-Blind Trial of Quinine Sulphate for Nocturnal Leg Cramp”, by S. H. Lim,The British Journal of Clinical Practice, vol. 40, No. 11, Nov. 1986, p. 462.
“Cramps, Stiffness and Restless Legs”, by Alan M. Whiteley, Practitioner, No. 226, Jun. 1982,pp. 1085-1087.
“Anxietas Tibiarum: Restless Legs and Headache”, by M. L. Masterson, Journal of the Kansas Medical Society, No. 81, No. 12, 1980, pp. 566-567, 600.
McDermott & Will & Emery
Weddington Kevin E.
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