Abstract:
A method for the treatment of a variety of cardiovascular disorders and related conditions in a mammal having at least one such disorder or condition is disclosed comprising treating the mammal with cotherapy comprising benazepril and amlodipine or pharmaceutically acceptable salts of either or both. Combination formulations of benazepril and amlodipine for use in the method are also disclosed.

Description:
FIELD OF THE INVENTION 
     The present invention relates to cardiovascular disease states, whether the underlying problem is cardiovascular in nature or secondary to some other condition, and their treatment. It further relates to the treatment of underlying cardiovascular problems which lead to, or present as, non-cardiovascular disease states as well. In addition, the invention relates to angiotensin coverting enzyme inhibitors (ACEI) and the conditions for which treatment therewith is known to be useful. Still further, the invention relates to calcium channel blockers (CCB) and the conditions for which treatment therewith is known to be useful. More specifically, the invention is concerned with the field of combination therapy of an ACEI and a CCB. 
     BACKGROUND OF THE INVENTION 
     Cardiovascular disease treatment has evolved rapidly over the last few decades from the early diuretics and natural products such as rauwolfia serpentina to the newest agents such as angiotensin converting enzyme inhibitors (ACEI) of the last few years and the even more recent calcium channel blockers (CCB). In efforts to achieve improved therapy (primarily for the treatment of hypertension, its sequelae, reversible conditions secondary to hypertension, and hypertension secondary to other conditions), a number of agents in each of these classes have been tested both alone as well as in combination with other agents. Some of the conditions for which at least one of these agents has been used or is believed useful include, without limitation, hypertension, angina, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, and headache. Others will be apparent to those of ordinary skill in the art based on a knowledge of the underlying mechanisms involved as well as on general clinical and pre-clinical experience. 
     Benazepril, benazeprilat, and their pharmaceutically acceptable salts are disclosed in U.S. Pat. No. 4,410,520, along with pharmaceutically acceptable dosage forms thereof, dosage ranges and suitable routes of administration therewith, and uses therefor, all of which are incorporated herein by reference. Amlodipine and its pharmaceutically acceptable salts are set forth in U.S. Pat. No. 4,572,909, incorporated herein by reference. Phamaceutically acceptable dosage forms, dosage ranges, suitable routes of administration, and uses of amlodipine and its salts are set out there. U.S. Pat. No. 4,879,303 is directed to the besylate salt of amlodipine, and it too is incorporated herein by reference. More specific dosages, routes of administration, formulations, and uses for amlodipine besylate can be found there. An excellant review of amlodipine is Burges et al, Cardiovas Drug Dev. 8(1) 25-44, 1990. 
     Recently, particular combinations of an ACEI and a CCB have appeared in the literature. See generally for example EP 334,264 A2 (corresponding to U.S. application Ser. No. 171,068, filed Mar. 21, 1988), EP 180,785-B and EP 257,485; J. Cardiovas. Pharm 1988, 12(5) p.600-607; J. Cardiovas. Pharm, 1988, 12, Suppl 6, p.S104-108 and Suppl 4, p.S80-85; and Diabetologia 1/89 32(1), p.40-44. More specific references which have appeared include: J. Hum. Hypertens. Aug 1988 2(2) p.127-132 and J. Cardiovas Pharmacol 1988 12 Suppl 7 p S85-88, each of which discloses combination usage of amlodipine with captopril; and Br. J. Clin. Pharmac. 1987, 24, 465-472, disclosing combination usage of benazepril and nicardipine; and J. Amer. Coll. Cardiol. 17 (2) 188A, 1991, disclosing combination usage of benazepril and nifedipine. In this last reference, the authors conclude that there is no advantage in combining benazepril and nifedipine over the use of nifedipine alone. Hence, the art has mixed teachings as to the benefits of combination therapy between ACEIs and CCBs generally, and especially with the use of benazepril as the ACEI in such combinations. 
     OBJECTS OF THE INVENTION 
     It is an object of the invention to provide a synergistic combination therapy for the treatment of cardiovascular diseases and their sequelae which are responsive to antihypertensive therapy. 
     It is another object of the invention to provide combination products suitable for carrying out the aforementioned object. 
     SUMMARY OF THE INVENTION 
     Surprisingly, these and other objects of the present invention are accomplished by a method of treating a condition responsive to co-therapy with an angiotensin converting enzyme inhibitor (ACEI) and a calcium channel blocker (CCB), in a mammal in a need thereof comprising administering to said mammal cotherapy of 
     (1) an ACEI selected from the group consisting of benazepril, benazeprilat, and pharmaceutically acceptable salts thereof, and 
     (2) A CCB selected from the group consisting of amlodipine and pharmaceutically acceptable salts thereof, 
     said ACEI and said CCB being administered in synergistically effective amounts to treat said condition. 
     DETAILED DESCRIPTION OF THE INVENTION 
     More specifically, the invention is a method of treating a condition responsive to co-therapy with an angiotensin converting enzyme inhibitor (ACEI) and a calcium channel blocker (CCB), 
     said condition selected from the group consisting of 
     hypertension, angina, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, and headache, 
     in a mammal in need thereof comprising 
     administering to said mammal cotherapy of 
     (1) an ACEI selected from the group consisting of benazepril, benazeprilat, and pharmaceutically acceptable salts thereof, and 
     (2) a CCB selected from the group consisting of amlodipine and pharmaceutically acceptable salts thereof, 
     said ACEI and said CCB being administered in synergistically effective amounts to treat said condition. 
     Preferably, the ACEI is benazepril or a salt thereof, most preferably a salt thereof. Suitable salts of benazepril and benazeprilat can be found in U.S. Pat. No. 4,410,520 mentioned above. For purposes of the present invention, the hydrochloride salt of the ACEI is most advantageous, with the most prefered specific ACEI compound being benazepril hydrochloride. 
     The present invention CCB is limited to amlodipine or its salts, which are set forth in the above cited U.S. Pat. No. 4,572,909, with the most suitable salt being the besylate salt (the subject matter of U.S. Pat. No. 4,879,303). 
     While the ACEI and the CCB can be administered at different times, they are most preferably administered at the same time. Most conveniently, this is via a single, fixed combination dosage form. However, the ACEI can be administered at times different from the administration of the CCB and the invention benefits still be realized. When administered at different times, the ACEI and the CCB should be given within about 16 hours of each other, preferably within about 12 hours of each other, more preferably within about 8 hours of each other, most preferably within about 4 hours of each other. Of course, these time periods can be extended if the dosage form is one which will &#34;administer&#34; the agents for extended periods. 
     When the ACEI and the CCB are given substantially simultaneously, they may be given by a single fixed combination dosage form or by different dosage forms, whichever is convenient. When given by different dosage forms, it is irrelevant whether the route of administration is the same for each agent or different for each agent. Any route of administration known for the individual agents is acceptable for the practice of the present invention. Most preferably, the agents are given in a fixed combination, or at least substantially simultaneously, i.e. within about 1 hour of each other. Also, the most suitable dosage form is an oral dosage form, where oral administration is a clinically suitable route. 
     Dosages of the two agents include all dosages at which the agents are used individually. Typically, the dosage of the ACEI is from about 2 to about 80 mg, preferably about 3 to about 40 mg, more preferably about 5 to about 20 mg (based on benazepril hydrochloride). Generally the dosage of the CCB is about 1 to about 20 mg, more preferably about 2 to about 10 mg, more preferably about 2.5 to about 5 mg (based on amlodipine free base). Corresponding dosages for other salts of amlodipine, for free benazepril and other salts of benazepril, and benazeprilat and its salts will be readily apparent to those of ordinary skill in the art. In each of the dosages set forth here, the range is the acceptable range based an adult mammal of approximately 50 to about 70 kg. Modified dosage ranges for mammals of other sizes and stages of development will be apparent to those of ordinary skill. In the practice of the present invention, the weight ratio of the ACEI to CCB (based upon benazepril hydrochloride:amlodipine free base) is from about 0.5:1 to about 10:1, more preferably 1:1 to 8:1. The precise weight ratios when using salts other than those set forth above may change, but only because the corresponding amount of the active agents have different weights. Those of ordinary skill in the art will be able to make the appropriate calculations. Particularly advantageous ratios of benazepril hydrochloride:amlodipine free base are 1:1, 2:1, 4:1, and 8:1. 
     Benazepril and amlodipine are physically incompatible substances. Hence, if incorporated into a single dosage form they must be kept physically separated. This may be accomplished in any of the myriad ways known in the art, such as bi-layered tablets, coated pellets of one agent incorporated into a tablet of the other, separately coated pellets of each agent in a capsule or tablet, coated pellets of one agent in capsule together with powder of the other agent, each agent microencapsulated separately and then blended together for use in a tablet or capsule, use of a dual or multiple compartment transdermal device, etc. Due to the incompatibility, combination products of the two agents in an injectable solution are not really acceptable. For convenience purposes, a coated compressed tablet of benazepril together with amlodipine powder in a capsule has been found to be the most desirable oral form. 
     For purposes of the present invention, the synergy referred to throughout this description relates primarily to blood pressure, either systolic or diastolic, or both. The conditions for which the instant invention is useful includes, without limitation, hypertension (whether of the malignant, essential, reno-vascular, diabetic, isolated systolic, or other secondary type), congestive heart failure, angina (whether stable or unstable), myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction (such as Alzheimer&#39;s, etc), stroke, headache, and life extension. 
     For the present purposes, preferred mammals are rabbits, dogs, goats, hogs, sheep, horses, cattle, and primates, more preferably primates, most preferably humans. 
    
    
     EXAMPLES 
     The following examples are presented to exemplify, but not to limit the invention. 
     Example 1 
     One thousand capsules containing 20 mg of benazepril hydrochloride and amlodipine besylate equivalent to 5 mg of amlodipine base for use in the present invention were prepared as follows: 
     Benazepril hydrochloride cores are prepared using the following: 
     
         ______________________________________1. Benazepril HCL  20.000 g2. Lactose, monohydrate              32.920 g3. Pregelatinized Starch              5.000 g4. Colloidal SiO.sub.2              1.000 g5. Crospovidine    2.000 g6. Microcrystalline Cellulose              10.000 g7. Hydrogenated Castor Oil              4.000 g8. Purified Water  as needed______________________________________ 
    
     Components 1-3 are milled and blended together and water is added to granulate the blend. The wet granules are screened and oven dried. The dried granules are then milled together with components 5-7. Component 4 is screened and then mixed with the other ingredients. The resulting mixture is then compressed into a core. 
     The thus made cores are coated with a coating solution prepared as follows: 
     
         ______________________________________9.     Hydoxypropyl Methylcellulose                        4.881 g  2910, 3 cps10.    Polysorbate 80        0.119 g11.    Purified Water        as needed12.    Talc                  trace______________________________________ 
    
     Component 10 is dissolved in the water and component 9 is added thereto. The previously made cores are then coated with this solution and the wet coated tablets are dried. The dried tablets are then dusted with component 12. 
     Amlodipine besylate for incorporation into the formulation is prepared as follows: 
     
         ______________________________________13. Amlodipine Besylate               6.944 g14. Microcrystalline Cellulose               124.056 g15. Calcium Phosphate Dibasic               63.000 g16. Sodium Starch Glycolate               4.000 g17. Magnesium Stearate               2.000 g______________________________________ 
    
     Components 13-16 are mixed together and the blended mixture is screened and reblended. Component 17 is separately screened and then blended with the reblended mixture containing the amlodipine. 
     No. 1 hard gelatin capsules are used to encapsulate one benazepril hydrochloride containing coated core along with 200 mg of the amlodipine besylate containing powder per capsule.