The invention provides numerous unexpected benefits. One such benefit relates to the pharmacokinetics of each drug. Both amlodipine and chlorthalidone have approximately 40-48 hour half-lives in normal adult patients; the half-lives of both drugs increase to approximately 72 hours in the elderly. Under steady state conditions, the combination will exhibit an enhanced pharmacodynamic activity. The composition comprising a combination of these active ingredients thus may have unexpected effects on duration and pharmacokinetic effect, such as improved peak-to-trough ratio and the Smoothness Index (SI). For example, if a 12.5 mg dose of chlorthalidone reduces systolic blood pressure by 10 mm Hg, adding a dose of amlodipine that typically also reduces systolic blood pressure 10 mm Hg will produce a greater reduction in systolic blood pressure than adding another 12.5 mg dose of chlorthalidone (i.e., doubling the dose of chlorthalidone to 25 mg). Peak-to-trough ratio and SI resulting from the combination of amlodipine and chlorthalidone will also improve as compared to doubling the dose of chlorthalidone.
Conversely, if the starting dose of amlodipine is, for example 2.5 mg, and lowers blood pressure 8 mm Hg, adding a 6.25 mg dose of chlorthalidone can provide a superior blood pressure-lowering effect as compared to adding a second 2.5 mg dose of amlodipine. Peak-to-trough ratio and SI can also be improved by use of the combination as compared to use of a first and second dose of amlodipine.
Another unexpected advantage of the subject invention is the ability of chlorthalidone to favorably ameliorate peripheral edema caused by amlodipine. It has been observed that the rate of edema triples or quadruples as the dose of amlodipine doubles from 5 to 10 mg daily. The additive, and at times synergistic, effects of the co-formulation of amlodipine and chlorthalidone can thus provide compositions and methods which result in fewer side effects than would be caused by giving a higher dose of either drug alone.
A hypertensive patient treated with a low daily dose of each drug in a co-formulation, such as chlorthalidone 12.5 mg and amlodipine 2.5 mg, dosed once daily can exhibit an anti-hypertensive effect equal to that of a daily dose of chlorthalidone 25 mg, taken alone or a daily dose of amlodipine 10 mg taken alone.
It is believed that ultra-low doses of each drug, such as 2 mg of amlodipine and 3-6 mg of chlorthalidone, which may be relatively ineffective when given separately, are effective in combination, which can support a synergistic benefit.
To manufacture the invention, different tablets have been disclosed above. In a standard tablet or capsule lacking an inactive segment, amlodipine or a suitable salt thereof, of which besylate is the most preferred salt, is provided with chlorthalidone and suitable excipients and either is placed in a capsule or utilized in a standard fashion, such as via direct compression or utilizing a wet granulation, into a tablet. It would be understood that the active ingredients, amlodipine and chlorthalidone, can be used as a free base, or as any suitable derivative, hydrate, metabolite, polymorphic form, or salt thereof.
In a preferred embodiment of the novel tablet, amlodipine and chlorthalidone are formulated separately with suitable excipients. A suitable inactive segment is formulated, and the tablet is prepared on a tri-layer or five-layer press, such as a commercially available multi-layer tablet press manufactured by Korsch AG of Germany. Alternatively, amlodipine and chlorthalidone are co-formulated with suitable excipients and compressed in an appropriate layer press with at least one other layer derived from an inactive composition, e.g., granulation. In the standard tablets and capsules well known in the art, a suitable co-formulation is prepared and either tabletted or encapsulated, and no separately formulated inactive granulation is utilized.
The invention also includes the method of treating hypertension by adding to an amlodipine dosage regimen an amount of chlorthalidone that is sufficient to then lower the blood pressure to below a desired upper limit, such as below 140 mm Hg systolic and below 90 mm Hg diastolic. Also included is the method of treating hypertension by adding to a chlorthalidone dosage regimen an amount of amlodipine that is sufficient to then lower the blood pressure to below the 140/90 mm Hg range described immediately above.
One of the specific embodiments of the invention is the method of treatment of hypertension with an initial dose of amlodipine that is a sub-maximal dose, such as 5 mg daily, in which either blood pressure response is inadequate or edema occurs. The method of the subject invention is to begin treatment with the novel composition of amlodipine plus chlorthalidone (or pack thereof). It has however been taught to begin treatment with a diuretic and follow it with a CCB if response to the diuretic is inadequate. In the case of chlorthalidone at doses of less than 25 mg, it has not been taught to begin with such a low dose and then add a CCB if BP response is inadequate, and it further has not been taught to co-administer, such as with a co-formulation or with the aid of a pack, a sub-25 mg dose of chlorthalidone plus a CCB such as amlodipine.
The amounts of amlodipine and chlorthalidone that may be used in tablets of the above structure can vary depending on the dosage regimen which is adopted for a particular patient. In general the dose of amlodipine in this dosage form may be within 1 to 20 mg and a preferable dose range of chlorthalidone is 3 to 6 mg but a preferred dose of chlorthalidone may be 3 to 50 mg depending on the particular patient. The elongated segment 4 is long enough to be easily broken by hand and may optionally contain a score or printed indicia to facilitate optional tablet breaking through segment 4 without impinging upon segments 2 or 6.
The invention also includes treating hypertension by the administration of amlodipine, chlorthalidone, and one or more of the members of the group consisting of another anti-hypertensive agent, a potassium-retaining diuretic, a cholesterol lowering agent, or a vitamin, additional anti-hypertensive drug such as, without limitation, an angiotensin converting enzyme (ACE) inhibitor (e.g., enalapril, lisinopril, benazepril, ramipril, captopril), an angiotensin receptor blocker (ARB) (e.g., losartan, valsartan, candesartan, eprosartan), or an alpha blocker (e.g., prazosin, doxazosin, terazosin); a calcium antagonist (calcium channel blocker, CCB) (e.g., nifedipine, nicardipine, nisoldipine, amlodipine (racemic), S-amlodipine, lacidipine, lercanidipine, manidipine, azelnidipine); an aldosterone antagonist (e.g., spironolactone, potassium canrenoate, eplerenone); a beta blocker (e.g., carvedilol, nebivolol, atenolol, metoprolol, betaxolol, bisoprolol) at appropriate doses such as the doses that are disclosed in the Physicians' Desk Reference (2005) which is incorporated by reference. The potassium sparing diuretics include without limitation triamterene and amiloride which may be administered according the Physicians Desk Reference (2005). Cholesterol lowering agents include without limitations statins such as lovastatin, simvastatin, atorvastatin, rosuvastatin and pravastatin; ezetimide; and fibrates such as fenofibrate and gemfibrozil. Vitamins include water soluble and oil soluble vitamins such as the B-complex vitamins, folic acid, vitamin C, D, E, K and the like in doses generally acceptable for the prevention or treatment of vitamin deficiencies.
A. Formulation of Chlorthalidone Active Blend
Step 1. Mixing
Step 2. Roller Compaction
Step 3. Mixing of Final Active Blend
B. Formulation of Inactive Blend
Step 1. Mixing
Step 2. Roller Compaction
Step 3. Final Blending
C. Formulation of Amlodipine Besylate Active Blend
Step 1. Blending Procedure
Step 2. Roller Compaction
Step 3. Final Active Blend
The milled material from step e is placed in a suitably sized “V” blender. The remaining magnesium stearate is added to the blender and the material is mixed for 3 minutes to obtain the final active blend.
D. Formulation of Amlodipine Besylate Plus Chlorthalidone Active Blend
The following ingredients are used at the specified weight percentages to formulate an amlodipine besylate and chlorthalidone active blend composition:
Step 1. Blending Procedure
Step 2. Roller Compaction
Step 3. Final Active Blend
Step 1. Blending Procedure
Step 2, Tablet Compression
Tablet Compression
Tablets were compressed using a Korsch TRP 900 multi-layer tablet press, specifically, using a 5-layer configuration. The first layer (layer 1) and last layer (layer 5) each contained a volume of the final active blend (from Step 3.f., above) to provide 2.5 mg of amlodipine and 6 mg of chlorthalidone in each layer, making a total of 5 mg of amlodipine and 12 mg chlorthalidone for the final tablet.
Layers 2, 3 and 4 contain the inactive blend, as prepared in Example 1, above.
Oval tooling was used for the compression, and the final tablets were compressed to a hardness of approximately 20 Kp.
The resulting active/inactive/active segmented tablet provides a combination drug product having 5 mg amlodipine besylate and 12 mg chlorthalidone.
It is recognized that related inventions may be within the spirit of the disclosures herein. Also no omission in the current application is intended to limit the inventors to the current claims or disclosures. While certain preferred and alternative embodiments of the invention have been set forth for purposes of disclosing the invention, modifications to the disclosed embodiments may occur to those who are skilled in the art.
This is a continuation-in-part of U.S. Provisional Patent Application Ser. No. 60/790,002, filed Apr. 6, 2006.
Number | Date | Country | |
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60790002 | Apr 2006 | US |