Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-01-27
2004-07-20
Qazi, Sabiha (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S501000, C424S465000, C424S464000, C424S440000, C424S489000
Reexamination Certificate
active
06764694
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to stable formulations of ACE inhibitors and similar drugs, especially enalapril maleate. The present invention also relates to methods for the preparation of stable formulations of ACE inhibitors.
BACKGROUND OF THE INVENTION
ACE inhibitors, or inhibitors of Angiotensin Converting enzymes, are drugs useful in the treatment of cardiovascular disorders, especially hypertension. However, it has been widely observed that ACE inhibitors are susceptible to breakdown, especially due to degradation and/or cyclization between the time of manufacture and the time of desired usage. Breakdown of ACE inhibitors has been found to occur both in solid and in liquid states. As breakdown of ACE inhibitor increases, the concentration of available, functional ACE inhibitor decreases. Also, at least some of the degradation products of such breakdown are believed to be deleterious. Accordingly, such breakdown is to be avoided.
ACE inhibitors include, but are not limited to, enalapril maleate and similar salts; quinapril hydrochloride and similar salts; benazepril hydrochloride and similar salts; moexipril hydrochloride and similar salts; lisonopril hydrochloride and similar salts; and indopril hydrochloride and similar salts. Typical breakdown products of ACE inhibitors include, but are not limited to, enalaprilat and/or enalapril-diketopiperazine (DKP) for enalapril species, quinalaprilat and/or quinapril-DKP for quinapril drugs, and other breakdown products well-known to those of skill in the art.
Methods for the formulation of ACE inhibitors into stable solid dosage forms have been previously described. For example, Merslavic et al., in U.S. Pat. No. 5,350,582, describe the formulation of enalapril sodium through the suspension of enalapril maleate in water with certain metal compounds. Full conversion to enalapril sodium is said to be indicated by a final “clear” solution. However, the suspension of enalapril maleate in water is extremely time-consuming due to the low wetability of enalapril maleate. Consequently, the residence time of the drug in the water is high. A high residence time is believed to facilitate significant hydrolysis of the product and lead to a drop in drug purity. Further, following the procedures described by Merslavic et al., high unit dose weights of lactose and starch are required.
Sherman et al., in U.S. Pat. Nos. 5,690,962 and 5,573,780, have described methods for the formulation of enalapril sodium. Instead of dispersing enalapril maleate in water, Sherman et al. describe “dry-blending” the enalapril maleate with an alkaline sodium powder and another powder excipient such as lactose. This “blend” is then granulated with water to initiate the acid-base conversion of enalapril maleate to enalapril sodium. Unlike the process described by Merslavic et al., Sherman provides no easily determinable endpoint of complete conversion of enalapril maleate to enalapril sodium Therefore, it is likely that significant batch-to-batch variations in purity of the product, i.e., amount of enalapril sodium, will exist in large scale production scenarios. Additionally, the Sherman et al. process may involve a time-consuming conversion of enalapril maleate to enalapril sodium, such that the product is vulnerable to breakdown and a drop in drug purity.
Sherman et al., in U.S. Pat. No. 5,562,921, also describe the manufacture of enalapril sodium formulations with improved resistance to decomposition. These formulations are said to be more resistant to decomposition due to restrictions in the excipients used in the process. However, the excipients set forth by Sherman as offering improved resistance to decomposition lead to formulations which lack sufficient hardness, an important quality in pharmaceutical formulations.
Harris et al., in U.S. Pat. No. 4,743,450, describe the use of stabilizers to minimize the cyclization, hydrolysis, and coloration of ACE inhibitors.
There remains a long-standing need for stable formulations and methods of preparation of ACE inhibitors. There is a further need for formulations and methods of preparation of ACE inhibitors that minimize breakdown of the product, that are inexpensive and time-efficient, and that have improved uniformity from batch to batch. Additionally, there is a need for methods of preparation and formulations of ACE inhibitors which are greatly reduced in breakdown products during preparation and/or subsequent storage.
SUMMARY OF THE INVENTION
The present invention relates to stable formulations of ACE inhibitors, especially enalapril sodium and similar drugs. The present invention also relates to time-efficient methods of preparing stable formulations thereof. Further, the present invention provides formulations and methods of preparation of ACE inhibitors that minimize breakdown of the products during preparation and/or subsequent storage thereof. The present invention also relates to products of the methods of preparing stable formulations of ACE inhibitors. The present invention also provides formulations of ACE inhibitors substantially free of harmful and/or undesired breakdown products. It is now possible to prepare such formulations which are substantially free of these contaminants. These and other embodiments of the present invention will readily occur to those of ordinary skill in the art in view of the disclosure herein.
REFERENCES:
patent: 4743450 (1988-05-01), Harris et al.
patent: 5350582 (1994-09-01), Merslavic et al.
patent: 5350584 (1994-09-01), McClelland et al.
patent: 5562921 (1996-10-01), Sherman
patent: 5573780 (1996-11-01), Sherman
patent: 5637730 (1997-06-01), Murthy et al.
patent: 5690962 (1997-11-01), Sherman
patent: 6153223 (2000-11-01), Apelian et al.
patent: 6555551 (2003-04-01), Spireas
patent: 2003/0225124 (2003-12-01), Spireas
patent: 2028665 (1991-04-01), None
patent: 0 425 892 (1990-10-01), None
patent: PCT/US00/23539 (2000-12-01), None
Hawley's Condensed Chemical Dictionary, Thirteenth Edition, p. 229.*
Liberman et al. (eds.),Theory&Practice of Industrial Pharmacy, 3rd Edition, Philadelphia, PA, 1986.
Remington's Pharmaceutical Sciences, 18th Edition, Easton, PA, Mack Publishing Co., 1990.
Mutual Pharmaceutical Co., Inc.
Qazi Sabiha
Woodcock & Washburn LLP
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