Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-13
2001-09-25
Rose, Shep K. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S872000
Reexamination Certificate
active
06294548
ABSTRACT:
This invention relates to improved formulations of endo-N-(9-methyl-9-azabicyclo[3.3.1.]non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride.
The compound is represented by Structure I:
The formulations of this invention are useful as anti-emetics, particularly in the treatment of cytotoxic agent induced emesis.
DETAILED DESCRIPTION OF THE INVENTION
Endo-N-(9-methyl-9-azabicyclo[3.3.1.]non-3-yl)-1-methyl-1H-indazole-3-carboxanide hydrochloride is a compound which is disclosed and claimed, along with pharmaceutically acceptable salts, hydrates and solvates thereof, as being useful as an anti-emetic, particularly in the treatment of cytotoxic agent induced emesis, in U.S. Pat. No. 4,886,808, the entire disclosure of which is hereby incorporated by reference. Endo-N-(9-methyl-9-azabicyclo[3.3.1.]non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride can be prepared by methods such as described in U.S. Pat. No. 4,886,808. Endo-N-(9-methyl-9-azabicyclo[3.3.1.]non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride is commercially available under the trade name Kytril and is also known by the generically as granisetron hydrochloride.
As indicated in the
Physicians' Desk Reference
®, 1997 edition, published by Medical Economics Company, Inc. at Montvale, N.J., an injectable dosage form of endo-N-(9-methyl-9-azabicyclo[3.3.1.]non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride is commercially available in a 1 ml single use vial containing an aqueous solution comprising 1.12 mg of granisetron hydrochloride equivalent to granisetron 1 mg. The recommended dosage for granisetron hydrochloride is 10 mcg/kg infused intravenously over 5 minutes, beginning within 30 minutes before initiation of chemotherapy.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as though fully set forth.
The prior 1 mg/ml single dose vial has proved undesirable in a number of ways. The recommended dose is 10 mcg/kg of body weight. Thus, the 1 ml vial is not ideal for patients weighing greater than 100 kg as a portion of a second vial will have to be utilized and the remaining medication discarded. Further, product wastage will occur when administering to lighter patients who do not require the full 1 ml dose. Numerous advantages would be realized if a suitable multidose vial comprising endo-N-(9-methyl-9-azabicyclo[3.3.1.]non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride could be prepared. The advantages of a multidose vial of endo-N-(9-methyl-9-azabicyclo[3.3.1.]non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride include: making weight-based dosing more efficient thereby minimizing wasted product, conserving resources, containing costs, making better use of storage space and more cost effective to produce and transport.
Numerous difficulties were encountered in preparing multidose aqueous formulations of endo-N-(9-methyl-9-azabicyclo[3.3.1.]non-3-yl)-1-methyl-1H-indazole-3-carboxanide hydrochloride. Included in the difficulties encountered is the need for and the selection of an antimicrobial preservative. Further, the multidose formulation experienced a shift in pH during the sterilization process. The pH of the solution was stabilized by the addition of a buffer. The previous single dose vial did not contain an antimicrobial preservative or a buffer.
The difficulties encountered in preparing multidose aqueous formulations of endo-N-(9-methyl-9-azabicyclo[3.3.1.]non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride were over come and suitable multidose formulations prepared based on the Experimental data presented below.
All of the pharmaceutical excipients utilized herein are known and are commercially available. Before carrying out the Examples of the invention described herein, the test solutions were placed into glass vials and autoclaved for about 15 to 60 minutes at about 121° C. to provide sterile solutions.
REFERENCES:
patent: 4886808 (1989-12-01), King
patent: 5225407 (1993-07-01), Oakley et al.
Remington: The Science and Practice of Pharmacy, Mack Publishing Co., Chapter 87, p. 1529, 1995.*
Ettinger, et al.; Cancer, vol. 78, No. 1, 1996, pp. 144-151.
Cassidy, et al.; Br. Journal of Cancer, vol. 58, 1988, pp. 651-653.
Carmichael, et al.; Cancer Chem. Pharm., vol. 24, 1989, pp. 45-49.
Allen, et al.; Eur. J. Clin. Pharm., vol. 46, 1994, pp. 159-162.
Allen, et al.; Eur. J., Clin. Pharm., vol. 48, 1995, pp. 519-520.
Addelman, et al., J. Clin. Oncology, vol. 8, No. 2, 1990, pp. 337-341.
Remington: The Science and Practice of Pharmacy, 1995, 19th edition, Chapter 87, pp. 1529.
Hoffmann-La Roche Inc.
Jagoe Donna
Johnston George W.
Rocha-Tramaloni Patricia S.
Rose Shep K.
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