Vasopressin antagonist and diuretic combination

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C514S471000, C514S249000, C514S255060, C514S259500, C514S416000, C514S562000, C514S571000

Reexamination Certificate

active

06656931

ABSTRACT:

This invention relates to new methods of increasing urine flow in humans while controlling the loss of electrolytes, the method comprising administering N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)-3-chlorophenyl]-5-fluoro-2-methylbenzamide (or a pharmaceutically acceptable salt thereof) and a diuretic, such as furosemide. Particularly, this invention provides useful means for removing excess water, such as in the case of congestive heart failure, while maintaining a desirable blood osmolality in the recipient.
BACKGROUND OF THE INVENTION
The art describes many methods of producing liquid or semi-solid encapsulated pharmaceutical formulations. In Bull. Tech./Gattefosse Rep. (1996), 89, 27-38, authors Shah et al. describe hard gelatin capsule technology, particularly for use in enhancing the bioavailability of poorly soluble or poorly absorbed drugs.
U.S. Pat. No. 4,620,974 (Hersh et al.) teaches a hard gelatin capsule comprising a telescoping two-piece cap with a lubricant comprising a polyethylene glycol of a molecular weight between about 200 and about 900 present in admixture with the composition at a concentration of from about 0.5 to about 25 weight percent.
WO 96/40071 (Lamberti) discloses methods and devices for producing minimal volume capsules. WO 96/41622 (Tanner et al.) teaches suspensions suitable for encapsulation in gelatin capsules, particularly including a solid phase of solid particles and a liquid phase capable of suspending the solid phase.
U.S. Pat. No. 5,641,512 (Cimiluca) teaches soft gelatin encapsulated analgesics in which the shell contains a xanthine derivative, such as caffeine.
EP 0 815 854 A1 discloses a substantially translucent, semi-solid fill material for a soft gelatin capsule, the semi-solid material being sufficiently viscous that it cannot be expelled from the capsule with a syringe at room temperature.
U.S. Pat. No. 4,744,988 (Brox) teaches soft gelatin capsules comprising a shell of gelatin, a softener and a filling of a polyethylene glycol and a low polyhydric alcohol and at least one active substance, characterized in that the shell contains 4 to 40 percent sorbital or sorbitanes, at least half of the weight of polyethylene glycol used is a polyethylene glycol having a mean molecular weight of 600, and the capsule filling comprises up to 20% by weight of glycerol and/or 1,2-propylene glycol.
WO 95/19579 (Dhabhar) teaches a process for solubilizing difficulty soluble pharmaceutical agents in a mixture of polyethylene glycol and propylene glycol by using a polyvinylpyrrolidone with a specific viscosity average molecular weight of from about 5,000 to about 25,000.
SUMMARY OF THE INVENTION
Diuretics are commonly used in the treatment of hypertension and management of edema, such as with congestive heart failure. Of significant concern in such treatments is the loss of ions or electrolytes, particularly including sodium and potassium, with the increased volume of urine.
This invention provides methods of increasing urine flow in humans while minimizing, inhibiting or limiting loss of electrolytes or ions, the methods comprising administering to a human in need thereof a combination of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)-3-chlorophenyl]-5-fluoro-2-methyl-benzamide (or a pharmaceutically acceptable salt thereof), also known as VPA-985, and one or more diuretic agents. The active agents of this invention are preferably given orally, but may be administered intravenously or parenterally, as needed.
This invention may also be seen as an improved method of increasing urine flow in a human by administering one or more diuretics to the human, the improvement comprising administering in conjunction with the diuretic a pharmacologically effective amount of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)-3-chlorophenyl]-5-fluoro-2-methylbenzamide, or a pharmaceutically acceptable salt thereof. Similarly, this invention may be characterized as an improved method of retaining electrolytes or ions in the blood during diuretic administration, the method comprising the coadministration of VPA-985 with the diuretic.
N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)-3-chlorophenyl]-5-fluoro-2-methylbenzamide can be seen as Example 482 in U.S. Pat. No. 5,516,774, which is incorporated herein by reference and fully explains the production of VPA-985 and its salts, which has the structure:
Preferably, this active compound is formulated with a carrier system herein and encapsulated for oral administration by methods known in the art, preferably with a soft or hard gelatin capsule.
Among the diuretic agents useful for the combination regimens of this invention are thiazide and related sulfonamide diuretics bendroflumethiazide, benzthiazide, chlorothiazide, chlorthalidone, cyclothiazide, hydrochlorothiazide, hydroflumethiazide, indapamide, methylclothiazide, metolazone, polythiazide, quinethazone and thrichlormethiazide. Also useful are potassium-sparing diuretics, such as amiloride, spironolactone and triamterene. Among the more preferred diuretics for use with this invention are the Loop diuretics, such as bumetanide, ethacrynic acid, ethacrynate sodium, and furosemide (sold under the Lasix® tradename, Hoechst Marion Roussel). The diuretics herein are known in the art and can be administered in the fashion and at the concentrations known in the art.
In one embodiment of the present invention N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)-3-chlorophenyl]-5-fluoro-2-methyl-benzamide, or a pharmaceutically acceptable salt is administered to the recipient at a daily dose of from about 25 mg to about 400 mg, preferably from about 40 mg to about 200 mg, most preferably between about 50 mg and about 150 mg, in conjunction with furosemide administration at a daily concentration of from about 20 mg to about 100 mg, more preferably from about 20 mg to about 80 mg. The doses of this combination regimen are preferably administered at the same time(s) per day and may be administered once per day or divided into two or more doses, as required for the desired urine output.
Joint administrations with ethacrynic acid (tablets available under the tradename Edecrin®, Merck & Co., Inc.) are preferably at a daily dose range of from about 25 mg to 200 mg per day, more preferably at a daily dose range of from about 50 mg to about 100 mg per day if desirable urine output is maintained.
Bumetanide administrations with this invention are preferably maintained at a daily dose range of from about 0.25 mg to about 5 mg. Spironolactone may be combined in formulations of this invention preferably at a daily dose range of from about 50 mg to 400 mg/day, more preferably at a range of from about 100 mg to 300 mg/day, more preferably at a range of from 150 mg to about 250 mg/day. Hydrochlorothiazide may be administered in these formulations at a dose range of from about 10 mg to about 100 mg/day, preferably from about 25 to about 50 mg/day.
Coadministration of VPA-985 and a diuretic provides an additive urine output over either compound alone and provides retention of ions or electrolytes and osmolality maintenance over the administration of diuretics, alone.
VPA-985 formulations useful with this invention may comprise (by % w/w):
a) from about 1% to about 20% of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)-3-chlorophenyl]-5-fluoro-2-methylbenzamide, or a pharmaceutically acceptable salt thereof, preferably from about 5% to about 16% of this active ingredient;
b) from about 1% to about 15% of a surfactant component, preferably from about 5% to about 10% of the surfactant component;
c) from about 50% to about 80% of a component of one or more polyethylene glycols (PEG), preferably from about 55% to about 70% of one or more polyethylene glycols; and
d) from about 1% to about 20%, preferably from about 5% to about 15% and more p

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