Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-11-30
2001-06-12
Seaman, D. Margaret (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06245785
ABSTRACT:
BACKGROUND OF INVENTION
1. Field of the Invention
The present invention relates to pharmaceutical compositions comprising triprolidine, and more particularly to tablets containing triprolidine hydrochloride and processes for producing and assaying such tablets.
2. Background of the Invention
Triprolidine hydrochloride monohydrate is a monograph/compendial antihistamine contained in a variety of pharmaceutical products. The compound and methods for producing it are disclosed by Adamson in U.S. Pat. Nos. 2,712,020 and 2,712,023 and by Adamson et al.,
J. Chem. Soc.
312 (1958). A more recent publication describing triprolidine and methods for producing it is
Analytical Profiles of Drug Substances
, Vol. 8, pp. 509-528 (Florey, Ed., Academic Press, N.Y., 1979).
Triprolidine demonstrates unusual behavior when used in certain pharmaceutical preparations. Due to its low dose and to insure content uniformity, triprolidine is normally wet processed with standard pharmaceutical excipients, then dried and tableted. The commonly used excipients are starches, sugars and celluloses. The formulations prior to tableting contain the expected level of triprolidine with good content uniformity.
However, when the tablets are evaluated using the required United States Pharmacopeia dissolution assays (
United States Pharmacopeia
23/
The National Formulary
18, pp. 1606-1608 (1994)), only 85% to 90% of the triprolidine appears to dissolve. This behavior is noted even though all of the individual components of the tablet are extremely water soluble. This type of dissolution has even been observed with simple triprolidine granulations prior to compressing them into a tablet. In the past, this 85%-90% release level was largely acceptable because the USP dissolution S-1 acceptance criterion (i.e., tolerance) was 80%. However, as USP is raising the minimum tolerance level to 85%, batches formally considered acceptable will now be borderline at best.
Thus, a need exists to improve the performance of triprolidine compositions in USP testing. A need also exists to improve the availability of triprolidine hydrochloride in tablets prepared by, e.g., wet granulation or direct compression, and tested according to USP standards.
All references cited herein are incorporated by reference herein in their entireties.
SUMMARY OF THE INVENTION
The present invention addresses at least the foregoing problems in the art by providing a pharmaceutical composition comprising triprolidine and an ionic additive effective to increase triprolidine availability indicated by a dissolution assay.
Also provided are a process for preparing the composition of the invention and a process for improving a performance of a pharmaceutical composition in a dissolution assay measuring triprolidine availability, said process comprising incorporating into said composition an ionic additive in an amount effective to increase said triprolidine availability measured by said dissolution assay.
DEFINITIONS
The term “ionic additive” denotes a highly ionic, water soluble material added to triprolidine compositions to improve the triprolidine availability in standard assays.
The term “highly ionic” denotes a compound that is substantially completely ionized in aqueous solution.
The term “water soluble” is defined in accordance with the USP definition for solubility at page 2071 of USP23/NF18. That is, a solute is water soluble for purposes of this disclosure if not more than about 30 parts of solvent are required to dissolve 1 part of solute.
The term “triprolidine” as used herein encompasses the compound itself and salts thereof, including, e.g., triprolidine hydrochloride, triprolidine sulfate and triprolidine citrate. This disclosure largely focuses on triprolidine hydrochloride, as the form of triprolidine presently approved by USP for pharmaceutical use.
REFERENCES:
patent: 2712020 (1955-06-01), Adamson
patent: 2712023 (1955-06-01), Adamson
patent: WO9207559 (1992-05-01), None
patent: WO9621431 (1996-07-01), None
patent: WO9746243 (1997-12-01), None
Chemical Abstracts 121:148233, Jung, 1992.*
Chemical Abstracts 89:204231, Augstein, 1978.*
Chemical Abstracts 129:8597, abstract of VanLengerich, WO 9818610, May 1998.*
Chemical Abstracts 120:315629, Gibson, abstract of Br. J. Pharmacol., vol. 111(4), pp1262-1268, 1994.*
Chemical Abstracts 116:147517, abstract of EP 459387, 1991, Dubler.*
“Rote Liste 1996”; 1996; Edition Cantor; Aulendorf, Germany.
Bess William
Cruz Victor A.
Kulkarni Neema
Nichols W. Michael
Sorg Albert F.
Federman Evan J.
Seaman D. Margaret
Warner & Lambert Company
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