Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1998-03-18
2001-05-22
Webman, Edward J. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S470000, C424S474000
Reexamination Certificate
active
06235311
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition which includes a statin cholesterol lowering agent and aspirin in a manner to minimize interaction of aspirin with the statin, for use in lowering cholesterol and reducing risk of a myocardial infarction, and to a method for lowering cholesterol and reducing risk of a myocardial infarction employing such composition.
BACKGROUND OF THE INVENTION
The use of aspirin for reducing the risk of a myocardial infarction and the use of statins for lowering cholesterol and preventing or treating atherosclerosis and cardiovascular disease and cerebrovascular disease are well documented. In fact, it is not uncommon that patients having elevated cholesterol levels who are at high risk for a myocardial infarction take both a statin and aspirin. However, use of both a statin and aspirin may require special care to insure that drug interaction, including physical and chemical incompatibility, and side effects, are kept to a minimum while achieving maximum benefit from these drugs.
With regard to possible drug interaction, aspirin is an acid, while some of the statins, such as pravastatin, atorvastatin and cerivastatin, are alkali salts. Thus, mixing of such statins (alkali salts) with aspirin could result in aspirin hydrolysis as well as statin degradation. Pravastatin, on the other hand, is also a very acid labile compound. When pravastatin and aspirin are combined, the aspirin could cause pravastatin degradation which could result in lower bioavailability of pravastatin.
Aspirin is known for causing gastrointestinal bleeding when used for long-term therapy. It is therefore desirable in long-term aspirin therapy that the aspirin be provided in a form which minimizes side effects.
In view of the above, it is seen that there is a long-felt want in patients required to take both a statin and aspirin for a statin-aspirin formulation which provides for maximum cholesterol lowering and reduction of risk of a myocardial infarction without the undesirable side effects and drug interaction normally associated with use of such combination.
DESCRIPTION OF THE INVENTION
In accordance with the present invention, a pharmaceutical composition is provided which includes a statin cholesterol lowering agent and aspirin, which provides for maximum patient benefits including maximum cholesterol lowering and reduced risk of a myocardial infarction with minimal physical and chemical incompatibility (including minimal statin:aspirin interaction), and reduced side effects normally associated with use of such drugs.
In addition, in accordance with the present invention, a method is provided for lowering serum cholesterol, preventing or inhibiting or treating atherosclerosis, and/or reducing risk of or treating a cardiovascular event or disease including coronary artery disease and cerebrovascular disease, wherein a pharmaceutical composition containing a combination of a statin cholesterol lowering agent and aspirin in a single dosage form, in a manner so as to minimize interaction of the statin and aspirin, is administered to a patient in need of treatment.
Preferred pharmaceutical compositions of the present invention may take the form of several different embodiments. Thus, in one embodiment of the present invention, a pharmaceutical composition is provided wherein the statin (including any statin cholesterol lowering agent) and aspirin are formulated together in a single tablet. The tablet of the invention is preferably in the form of a bilayered tablet which includes a first layer and a second layer. Aspirin, in the form of granules of preselected size will be present in the first layer together with optional excipients as described hereinafter, while the statin will be present in the second layer which optionally may include one or more buffering agents (as necessary to prevent undesirable statin/aspirin interaction) and optionally one or more excipients as described hereinafter.
In addition, the bilayered tablet of the invention may include an outer protective coating or finishing layer as described hereinafter.
Another embodiment of the present invention comprises a cored tablet which includes a core and a buffering layer or outer coat which can be compressed onto the core as a dry coat. The core will preferably include compressed aspirin granules while the buffering layer or outer coat will include a statin (including any statin cholesterol lowering agent) together with one or more buffering agents and optional excipients.
Provision of aspirin in the core and statin in the buffering layer will effectively reduce the aspirin side effects and also minimize drug incompatibilities while providing maximum efficacy.
The so-described cored tablet may also optionally include an outer protective coating or finishing layer as described hereinafter.
In addition, in accordance with the present invention, a pharmaceutical composition is provided which is in the form of a tablet or capsule which includes a mixture of aspirin granules having an enteric coating and particles or granules of a statin. Such a combination will provide maximum efficacy while minimizing side effects resulting from prolonged aspirin therapy.
In the above embodiment containing enteric coated aspirin, the statin may include any statin cholesterol lowering agent, but preferably is simvastatin, lovastatin or cerivastatin.
In yet another embodiment of the pharmaceutical composition of the present invention, enteric coated aspirin granules as described above may be further coated with a protective coating or finishing layer. The double coated particles of aspirin can be mixed with any statins such as pravastatin, atorvastatin, simvastatin, lovastatin, and cerivastatin powders or granules, and the mixture can be encapsulated or tableted as described herein. In such case, further coating of the enteric coated aspirin particles is desired to minimize interaction of alkaline pravastatin, atorvastatin or cerivastatin with enteric coated aspirin. This combination will protect the integrity of the enteric coat and minimize the side effects normally resulting from prolonged aspirin therapy. The aspirin and the statin granules do not need to be mixed together; these can even be encapsulated separately into the same capsule shells in two shots.
Another embodiment of the pharmaceutical composition of the invention includes granules of enteric coated aspirin and enteric coated statin (including any statin cholesterol lowering agent), in the same dosage form such as compressed tablets or capsules.
The tablets containing the enteric coated granules of aspirin and statin may also include an outer protective coating or finishing layer.
In a further embodiment of the pharmaceutical composition of the invention, where aspirin side effects are not an issue, for example, where low dose aspirin is present (81 mg or less), the composition of the invention may comprise a mixture of aspirin granules and statin (including any statin cholesterol lowering agent, preferably, simvastatin, lovastatin or enteric coated particles of pravastatin or particles of pravastatin, atorvastatin and cerivastatin containing an outer protective coating or finishing layer); the above mixture may take the form of compressed tablets or capsules (where the mixture can be encapsulated separately in two shots in the same capsule shells).
DETAILED DESCRIPTION OF THE INVENTION
The pharmaceutical composition of the invention which includes a combination of a statin and aspirin is effective in preventing, reducing and/or treating elevated cholesterol levels (such as in hypercholesterolemia), atherosclerosis, cardiovascular events and disease including coronary events and cerebrovascular events, and coronary artery disease and/or cerebrovascular disease.
The terms “cardiovascular event(s)” and “cardiovascular disease” as employed herein refer to coronary and/or cerebrovascular event(s) and disease including primary myocardial infarction, secondary myocardial infarction, myocardial ischemia, angina pectoris (including unsta
Jain Nemichand B.
Ullah Ismat
Bristol--Myers Squibb Company
Webman Edward J.
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