Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-06-29
2002-12-31
Pryor, Alton (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
active
06500867
ABSTRACT:
This application claims the benefit of foreign priority under 35 U.S.C. §119 to Finnish patent application no. FI 991485, filed on Jun. 30, 1999. The contents of that priority document are specifically incorporated by reference herein.
FIELD OF THE INVENTION
The present invention relates to new pharmaceutical compositions comprising entacapone, levodopa, and carbidopa, or pharmaceutically acceptable salts or hydrates thereof, to a preparation method of the compositions and to a use of the compositions in a therapeutic method. The invention also relates to the use of entacapone, levodopa, and carbidopa, or their pharmaceutically acceptable salts or hydrates, in the manufacture of an oral solid fixed dose combination.
BACKGROUND OF THE INVENTION
The chemical names of entacapone, levodopa and carbidopa are (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide, (−)-L-&agr;-amino-&bgr;-(3,4-dihydroxybenzene)propanoic acid, and (−)-L-&agr;-hydrazino-&agr;-methyl-&bgr;-(3,4-dihydroxybenzene)propanoic acid, e.g. as the monohydrate, respectively. Entacapone is described in U.S. Pat. No. 5,446,194 as a catechol-O-methyltransferase (COMT) inhibitor. Enteral and parenteral routes of administration of entacapone are discussed in U.S. Pat. No. 5,446,194. An oral compacted composition containing entacapone and croscarmellose sodium is commercially available in the European market under the trademarks COMTESS® and COMTAN® manufactured by Orion Corporation, Finland. Levodopa and carbidopa are the most commonly used drugs in the treatment of Parkinson's disease. Levodopa and carbidopa are commercially available as combination tablets sold in Europe under, for instance, the following trademarks: NACOM® (distributed by DuPont Pharma), ISICOM® (distributed by Isis-Chemie), SINEMET® (distributed by DuPont Pharma), SINEMET® PLUS (distributed by DuPont Pharma in the UK) and SINEMET® LP 25 (distributed by DuPont Pharma).
Parkinsonism medication needs to be taken several times a day to keep the patients without symptoms. Therefore, patient compliance can be improved significantly by using a fixed dose combination of entacapone, levodopa, and carbidopa instead of taking two separate tablets, i.e., an entacapone tablet and a levodopa-carbidopa tablet, several times a day. This is especially important for parkinsonism patients with tremor and old age.
We have found that entacapone, levodopa, and carbidopa, or their pharmaceutically acceptable salts or hydrates, are preferably released from the oral composition as soon as possible after ingesting it.
Furthermore, it is very difficult to adjust the absorption of three different active agents from one and the same oral solid composition. Usually in practice, the absorption of one of the active agents may decrease while that of the other one increases. When selecting the pharmaceutical excipients, disintegrants and other auxiliary agents to be used in a pharmaceutical composition in combination with several active agents, numerous factors have to be considered, e.g., the chemical and physical characteristics of the active agents and the auxiliary agents, the bioavailabilities of the active agents, the method of preparing the composition, the stability of the composition , etc.
None of the above-cited patents nor any other patent or publication, of which applicants are aware, describes an oral solid composition comprising entacapone, levodopa, and carbidopa, or pharmaceutically acceptable salts or hydrates thereof.
SUMMARY OF THE INVENTION
Applicants have discovered that entacapone, levodopa and carbidopa, or their pharmaceutically acceptable salts or hydrates, can be combined into one oral solid composition with particularly interesting properties.
The invention thus provides an oral solid fixed dose composition comprising pharmacologically effective amounts of entacapone, levodopa, and carbidopa, or pharmaceutically acceptable salts or hydrates thereof, and comprising at least one pharmaceutically acceptable excipient (hereinafter referred to as a composition according to the invention), which has preferable stability and bioavailability characteristics and which is easy to swallow.
Particularly, the present invention provides an oral solid composition comprising pharmacologically effective amounts of entacapone, levodopa, and carbidopa, or pharmaceutically acceptable salts or hydrates thereof, and comprising at least one pharmaceutically acceptable excipient being a sugar alcohol, starch or sugar alcohol and starch. Preferably, the sugar alcohol is mannitol, and the starch is maize starch.
The present invention also provides a stable oral solid composition comprising pharmacologically effective amounts of entacapone, levodopa, and carbidopa, or pharmaceutically acceptable salts or hydrates thereof, and comprising at least one pharmaceutically acceptable excipient other than microcrystalline cellulose.
Applicants have found that a particularly interesting way to increase the bioavailability of carbidopa from an oral solid composition comprising entacapone, levodopa, and carbidopa is to add carbidopa separately, for instance by granulating first levodopa and entacapone together and then adding carbidopa to these granules separately.
Accordingly, the invention further provides an oral solid composition comprising pharmacologically effective amounts of entacapone, levodopa, and carbidopa, or pharmaceutically acceptable salts or hydrates thereof, and a pharmaceutically acceptable excipient, wherein a substantial portion of carbidopa is separated from entacapone and/or levodopa.
There are several different techniques to accomplish the separation of carbidopa from entacapone and levodopa, for instance, by mixing, e.g. granulating, entacapone and levodopa together and adding carbidopa separately. Carbidopa can be added as such or in a form of granules.
Therefore, the invention also provides a method for producing an oral solid pharmaceutical composition comprising pharmacologically effective amounts of entacapone, levodopa, and carbidopa, or pharmaceutically acceptable salts or hydrates thereof, and a pharmaceutically acceptable excipient, which comprises mixing first entacapone and levodopa separately and adding carbidopa separately.
The oral solid composition according to the invention includes a tablet, a capsule and the like. Preferably, the oral solid composition according to the invention is in the form of a tablet.
Furthermore, the invention provides a method for treating Parkinson's disease, e.g. at end of dose “wearing-off”, by administering to a patient in need thereof an oral solid composition according to the invention, e.g. up to 8-10 times a day.
The invention also provides the use of entacapone, levodopa, and carbidopa, or pharmaceutically acceptable salts or hydrates thereof, in the manufacture of an oral solid composition for the treatment of Parkinson's disease in different stages of the disease.
Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objects and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and do not restrict the invention, as claimed.
REFERENCES:
patent: 4190672 (1980-02-01), Fahn
patent: 5389653 (1995-02-01), Bernauer et al.
patent: 5446194 (1995-08-01), Bäckström et al.
patent: 5532274 (1996-07-01), Wenzel et al.
patent: 253490 (1988-01-01), None
patent: 2321190 (1998-07-01), None
patent: WO 98/31355 (1998-07-01), None
patent: WO 00/15196 (2000-03-01), None
patent: WO 01/01984 (2001-01-01), None
Davis, “Catechol-O-Methyltransferase Inhibitrors in Parkinson's Disease,” CNS Drugs, vol. 10, No. 4, pp. 239-246 (1998).
Copy of co-pending application No. 09/152,263, filed on Sep
Kallioinen Sari
Kervinen Lasse
Laaksonen Marja
Lintulaakso Jarmo
Niskanen Mervi
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Orion Corporation
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