PARENTERAL SOLUTIONS CONTAINING 7-HALO-1,2,3,4- TETRAHYDRO-3-ARYL-6-QUINA20LINE SϋLFONAMIDES

BACKGROUND OF THE INVENTION

Field of the Invention This application is a continuation-in-part of pending U.S. application Serial No. 08/299,493 filed September 1, 1994.

The present invention relates to parenteral solutions containing 7-Halo-l, 2,3, 4-tetrahydro-3-aryl-6-qinazoline sulfonamide. Description of the Related Art

Metolazone is a guinazoline diuretic approved for use in an oral tablet form (MYKROX®) for the treatment of hypertension, alone or in combination with other anti-hypertensive drugs of a different class. This compound acts primarily to inhibit sodium reabsorption at the cortical diluting site and to a lesser extent in the proximal convoluted tubule. Sodium and chloride ions are excluded in approximately equivalent amounts. The increased delivery of sodium to the distal-tubular exchange site results in increased potassium excretion. To treat hypertension, the compound may be administered in oral dosage forms such as in the form of a tablet containing from 0.5-10 mg of metolazone, or it may be administered in the form of an intravenous solution.

Metolazone is also indicated for use in treating heart failure and renal disease. Further, when metolazone is combined with furosemide (lasix) , the effectiveness of the diuretics is greatly enhanced. Furosemide can be administered intravenously to obtain the best and most rapid effect in emergencies. However, there is no intravenous formulation available of metolazone since metolazone is sparingly soluble in most solvents. Metolazone is only sparingly soluble in water, but is said to be somewhat more soluble in plasma, blood, alkali and organic solvents.

U.S. Patent Nos. 3,360,518 and 3,557,111 disclose methods for preparing metolazone.

SUBSTITUTE SHEET (RULέ 26)

DESCRIPTION OF THE INVENTION The present invention provides parenteral solutions comprising as an active ingredient a 7-Halo-i,2,3,4-tetrahydro-3- aryl-6-quinazoline sulfonamide of the following formula:

wherein X is a halogen;

R _1# R ₂ , R ₃ and R ₄ are independently selected from hydrogen and alkyl groups having from about 1 to 6 carbon atoms; and R ₅ is hydrogen or an alkyl group having from about 1 to 6 carbon atoms. More specifically, the present invention provides parenteral solutions suitable for intravenous administration containing as an active ingredient an effective anti-hypertensive amount of 7- chloro-1,2,3,4-tetrahydro-2-meth l-3-(-2-methylphenyl)-4-oxo-6- quinazoline sulfonamide (metolazone) in a sterile solvent comprising a [ bis- ( 2 -hydroxyethy1 ) -amino ] tris-

(hydroxymethyl)methane (Bis-Tris) buffer having a pH from about

10.5 to 12.5, and preferably from 11.5 to 12, i.e., metolazone-

Bis-Tris solutions.

The invention further provides parenteral solutions suitable for intravenous administration containing Metolazone as an active ingredient in a sterile solvent comprising a Tris-(hydroxymethyl) amino methane, hydrochloride (Tris) buffer having a pH of from about 10.5 to 12.5, and preferably from about 11.5-12, i.e., metolazone-tris solutions. The invention further provides solutions having extended stability that are suitable for parenteral administration comprising metolazone in a Bis-Tris or Tris buffer having a pH of from about 11.5 to 12.

Also included within the scope of the invention are methods for producing such solutions.

Still further, the invention provides solutions suitable for parenteral, e.g., intravenous, administration comprising an

effective anti-hypertensive amount of metolazone in a Bis-Tris or Tris buffer having a pH of from about 11.5 to 12.

Yet further, the invention provides solutions suitable for parenteral administration comprising furosemide and metolazone in Bis-Tris or Tris buffer at a pH of from about 11.5 to about 12. Further, the invention provides methods for treating an anti- hypertensive patient which comprises parenteral, e.g., intravenous, administration of an effective amount of a solution of metolazone in a Bis-Tris buffer. The invention also encompasses methods for treating patients suffering from or affected by edema or edematious states comprising parenteral, e.g., intravenous, administration of an effective amount of a solution of metolazone in Tris buffer. Representative edematious states include, for example, congestive heart failure and hypertension.

Parenteral solutions comprising metolazone in Bis-Tris or Tris buffer according to the invention are typically prepared by mixing the required amount of metolazone, which may be purified prior to use, is mixed with the buffer and adding to the resulting solution sodium hydroxide or other suitable base until a pH of about 12 to 12.5 is reached. To this highly basic solution is then added a protic acid, such as, for example, acetic acid, preferably about 1 molar acetic acid, to adjust the pH of the solution to that at which metolazone is completely soluble. The process is preferably carried out at room temperature, although other temperatures are acceptable.

Most preferred solutions of metolazone and Bis-Tris or Tris buffer contain about 1 mg of metolazone per ml of solution. The concentration of Bis-Tris or Tris buffer in the solution is typically about 0.05M. The resulting solutions after cooling to room temperature may be sterilized by known means, e.g., ultra- filtration preferably a 13 mm, 0.45 micron filter, terminal autoclave heating, or ethylene oxide treatment and may be packaged into vials suitable for dispensing as parenteral products. The preparation thus obtained at a pH of about 11.5 to 12 was found, quite unexpectedly, to remain in solution. The metolazone/Bis-Tris and metolazone/Tris aqueous formulations demonstrate remarkable stability when stored at room temperature

over at least a three week period without the formation of turbidity or precipitate.

The solutions thus formulated are indicated for the treatment of hypertension, heart failure, or renal disease. Solutions may also be prepared in a similar manner to contain furosemide and metolazone. As with any potent drug, the dosage must be individualized by the treating clinician.

One skilled in the art will recognize that modifications may be made in the present invention without deviating from the spirit or scope of the invention. The invention is illustrated further by the following examples which are not to be construed as limiting the invention or scope of the specific procedures described herein.

Example 1

To a mixture containing indicated quantities of metolazone (Research Biochemicals Inc., Lot # CC-1088E) , cyclodextrin (American Maize Products Co.), and with or without polyvinyl pyrrolidones (Sigma Chemical Co.), in differing amounts, as well as a quantity (as indicated) of different buffers at different concentrations, were added. This mixture was stirred, and 5N NaOH solution was added dropwise until a clear solution resulted. The pH of this solution was generally between 12.0-12.5. (It was allowed to stand at room temperature for 30 minutes in cases where cyclodextrins were used) . To this solution, 1M acetic acid was added in order to adjust to the desired pH at which the metolazone was completely soluble. The solution was filtered through 13 mm, 0.45 micron filter and stored in vials at room temperature and 40°C for several days. The results of these experiments are reported below in Table 1.

TABLEL± METOLAZONE SOLUBILITY

Observatioas on stability after standing for period of time

Buffer Used

CO (OJM unless Final pH otherwise Final cone. Metolazone of Temp, for

CD C staled) mg/ml Solution Storage 24 hr 48 hr 72 hr 96 hr I Wit 2 Wk 3 Wk

I

12 ml Na 6.7 RT ppt Acetate

C/5 +0.1 ml Tween 10 80

12 ml Na 9.0 RT PP

Acetate m +0.1 ml Tween ro 80 _o>

15 12 ml Na RT ppt

Acetate + 0.2 ml Tween 80

12 ml Na RT ppt 20 Acetate

+0.5 ml Tween 80

METOLAZONE SOLUBILITY

Observations on stability alter standing for period of time

Buffer Used

Acetate

+ 3 ml Tween m 80

12 ml Na 1.0 with 66 mg β CD 10.0 RT Clear Clear ppt

10 Acetate

+2 ml A PSO ¹

12 ml Na 1.0 with 66 mg β CD 10.0 RT Clear Clear ppt

Acetate

15 + 2 ml Bicine ²

¹ 3-[(l,| -dimethyl-2-hydroxyethyl)aminoJ-2-hydroxypropanesulfonic acid.

² N,N-bis-(2-hydroxyethyl)glycine

METOLAZONE SOLUBILITY

Observations on stability after standing for period of time

Buffer Used

1.0 with 66 m ø CD 10.0 RT Clear Clear ppt

1.0 with 66 mg β CD 10.0 RT Clear Clear ppt

10 12 ml Na 1.0 with 66 mg β CD 10.0 RT Clear Clear ppt

Acetate

+2 ml Glycine

12 ml Na 1.0 with 66 mg } CD 10.0 RT Clear Clear ppt

Acetate

15 +2 ml TAPS ⁵

³ 3-(cyclohexylamino)propanesulfonic acid

⁴ 2-(cyclohexylantino)ethanesulfonic acid

METOLAZONE SOLUBILITY

Observations on stability alter standing for period of time

Buffer Used

(OJM unless Final pH otherwise Final cone. Metolazone of Temp, for staled) mg/ml Solution Storage 24 hr 48 hr 72 hr % hr I Wk 2 Wk 3 Wk

12 ml Na 1.0 with 66 mg β CD 10.0 RT Clear Clear ppt

Acetate

O-J + 2 ml Tricine

CD CO 12 ml Na 1.0 with 66 mg /ϊ CD 10.0 RT Clear Clear ppt

Acetate

+2 ml TEA O 12 ml Na 1.0 with 66 mg /) CD 10.0 RT Clear Clear ppt

Acetate

-X) 00 I 10 5% NaHCO _] 1.5 I I

AMPSO 2 9.5 ro

AMPSO 2 10.0

AMPSO 2 10.5

AMPSO I 10.0

15 AMPSO 1.0 with 66 mg β CD 10.0 ppt

⁵ 3-(|tris-hydroxymethyl)methylIamino)propanesulfonic acid

METOLAZONE SOLUBILITY

Observations on stability after standing for period of time

CO c CD: 3 Wk CO

I

CZ e¬ CO

in ro

10

METOLAZONE SOLUBILITY

METOLAZONE SOLUBILITY

Observations on stability alter standing for period of tbne

Buffer Used

(OJM unless Final pH otherwise Final cone. Metolazone of Temp, for stated) mg/ml Solution Storage 24 hr 48 hr 72 hr 96 hr I Wk 2 Wk 3 W O

CD Bis-Tris 1.0 12.0 RT Clear Clear Clear Clear Clear Clear Clea CO¬ 0.05M

Bis-Tris 1.0 12.0 40°C Clear Clear Clear Clear Clear Clear Clea O.OSM

CO

Bis-Tris • 2.0 1 1.5 RT Clear Clear Clear Clear Clear ppt 0.05M

Bis-Tris 2.0 1 1.5 40°C Clear Clear Clear Clear Clear ppt O.OSM ro Bis-Tris 2.0 12.0 RT Clear Clear Clear Clear Clear ppt

10 O.OSM

Bis-Tris 2.0 12.0 40"C Clear Clear Clear Clear Clear ppt 0.05M

CAPS 9.5

CAPS 10.0

15 CAPS 10.5

CAPS 10.0

METOLAZONE SOLUBILITY

Observations on stability after standing for period of time

co

ED CO

CO

-X

33

ro

10

METOLAZONE SOLUBILITY

Observations on stability after standing for period of time

Buffer Used

(OJM unless Final pH O Z otherwise Final cone. Metolazone of Temp, for CD CO stated) mg/ml Solution Storage 24 hr 48 hr 72 hr 96 hr I Wk 2 Wk 3 W

CHES 1.5 10.4 RT ppt

CHES in D5W 2 9.5 RT ppt

CO

.X CHES in D5W 2 10.0 RT ppt

CHES in D5W 2 10.5 RT ppt

37

CZ CHES in D5W I 10.0 RT ppt ι— rπ ro CHES in D5W 1.0 with 66 mg β CD 10.0 RT Clear Clear ppt <3?

CHES in D5W 9.3 RT ppt

CHES in D5W 1 1.5 RT Clear ppt 0.05

10 CHES in D5W 1 1.5 40"C Clear ppt 0.05

CHES in D5W 12.0 RT Clear ppt 0.05

CHES in D5W 12.0 4σ'C Clear ppt

15 0.05

METOLAZONE SOLUBILITY

Observations on stability after standing for period of time

O cr cσ co 72 hr 96 hr 1 Wk 2 Wk 3 W

O rr I

_u

ιo

10

15

METOLAZONE SOLUBILITY

Observations on stability after standing for period of time

CO

CZ CD O

96 hr I Wk 2 Wk 3 W

O

IT

ro o

METOLAZONE SOLUBILITY

Observations on stability after standing for period of time

Buffer Used

(OJM unless Final pH otherwise Final cone. Metolazone of Temp, for co stated) mg/ml Solution Storage 24 hr 48 hr 72 hr 96 hr I Wk 2 Wk 3

CD O H ₂ 0

H ₂ 0

CO

-X H,0 1

I

30 H ₂ 0 2

CZ ro H ₂ 0 2

H ₂ 0 2

H ₂ 0 2

K Phosphate 1.5 I .OM

10 Na Acetate I Buffer in D5W

Na Acetate 2 Buffer

METOLAZONE SOLUBILITY

Observations on stability alter standing for period of time

Buffer Used

(OJM unless Final pH otherwise Final cone. Metolazone of Temp, for

CO suted) mg/ml Solution Storage 24 hr 48 hr 72 hr 96 hr 1 Wk 2 Wk 3 W

CZ CD O Na AceUle 10.0 RT ppt Buffer m Na Acetate 10.5 RT ppt Buffer

Na AceUte 10.5 RT Clear Clear Clear Clear ppt Buffer

JO

CZ Na Acetate 10.0 RT ppt Buffer to

Na Acetate 9.5 RT ppt

10 Buffer

Na AceUte 10.5 RT Clear Clear Clear Clear ppt Buffer

Na AceUte 10.5 4tf'C Clear Clear Clear Clear ppt Buffer

15 Na AceUte 1.0 with 88 mg βCD I I RT Clear Clear ppt Buffer

METOLAZONE SOLUBILITY

Observations on stability after standing for period of lime

Buffer Used

(OJM unless Final pH otherwise Final cone. Metolazone of Temp, for O suted) mg/ml Solution Storage 24 hr 48 hr 72 hr 96 hr I Wk 2 Wk 3

CD O Na AceUte 1.0 with 88 mg I I RT Clear ppt ppt Buffer Encapcine

Na AceUte 1.0 with 88 mg ϊ CD I I RT Clear ppt ppt m

CO 00 Buffer

I

Na AceUte 1.0 with 88 mg γ CD I I RT Clear ppt Buffer

3D

Na AceUte 1.0 with I76 mg γ-CD 9.8 RT Clear Clear ppt Buffer ro

CT> Na AceUte 1.0 with 440 mg γ-CD 9.8 RT Clear ppt

10 Buffer

Na AceUte 1.0 with 44 mg /?-CD 10.5 RT Clear Clear Clear Clear ppt Buffer

Na AceUte 1.0 with 44 mg 0CD 10.5 40"C Clear Clear Clear Clear ppt Buffer

15 Na AceUte 1.0 with 66 mg 0 CD 10.0 RT Clear Clear Clear Clear ppt Buffer

METOLAZONE SOLUBILITY

Observations on stability after standing for period of time

CO 24 hr 48 hr 72 hr 96 hr I Wk 2 Wk 3

CD O Clear Clear Clear Clear ppt

I ppt

CO

ppt

3D CZ ro ppt en

ppt

10 ppt

METOLAZONE SOLUBILITY

Observations on stability after standing for period of time

72 hr 96 hr I Wk 2 Wk 3 o z

CD CO

CZ

I O r>

X I

33 Z ro Color

10 ppt

METOLAZONE SOLUBILITY

Observations on stability after standing for period of time

CO. 3 W

CD CO

I l-

CO

I

-3

10

METOLAZONE SOLUBILITY

Observations on stability after standing for period of time

72 hr 96 hr I Wk 2 Wk 3 o Z CD

I O I

5 33

ro ppt

10

15

METOLAZONE SOLUBILITY

Observations on stability after standing for period of time

Buffer Used

(OJM unless Final pH otherwise Final cone. Metolazone of Temp, for suted) mg/ml Solution Storage 24 hr 48 hr 72 hr 96 hr 1 Wk 2 Wk 3 W

CO

CD TEA +1.8% 9.5 RT ppt NaCI(l.l) Z TEA +1.8% 10.0 RT ppt —I m I NaCI(l.l) O m TEA + 1.8% 10.5 RT Pl»t NaCI(l l)

__D TEΛ+1.8% 10.0 RT ppt NaCI(l:l) ro TEA +1.8% 11.5 RT Clear Clear ppt

10 NaCI(IJ)

TEA +1.8% 11.5 40"C Clear ppt NaCI(l l)

TEA +1.8% 12.0 RT Clear ppt NaCI(l:l)

15 TEA + 1.8% 12.0 40°C Clear ppt NaCI(IJ)

METOLAZONE SOLUBILITY

Observations on stability after standing for period of time

Buffer Used

(0.1 M unless Final pH otherwise Final cone. Metolazone of Temp, for

10 Tricine I 11.0

Tricine 1 10.4

Tricine 1.5 10.4

Tricine 2 9.5

N-(ιris-hydroxymethyl)methyl]glycine

METOLAZONE SOLUBILITY

Observations on stability after standing for period of time

co

CZ CD CO

CZ m — I

CO I ro

I

_H m r eon

10

METOLAZONE SOLUBILITY

Observations on stability after standing for period of time

10

METOLAZONE SOLUBILITY

Observations on stability after standing for period of time

ro en

1ABLZ1 METOLAZONE SOLUBILITY

CO

CD

<_Z

—I m I

CO ro 10 oo

I

33 CZ ro

15

20

As the above data demonstrates, Ketolazone is unexpectedly stable as a formulation in O.OSM Bis-Tris at pHs from about 11.5 to 12.0 and as a formulation in 0.05M Tris at pHs from about 11.5 to 12.0.

The activity of metolazone dissolved in the buffer systems of the invention is demonstrated by the following examples. In examples 2-4 below rats are deprived of food and water. After 24 hours, water only (25 ml/kg) is given orally and a solution of the drug, i.y.. lasix or metolazone, is given intraperitoneally. Urine is collected during the following 24 hours. The reβults of each example are shown in the accompanying table.

•S-fMP f ?

Metolazone Rat Experiment

Rats 450 gmβ received 2 g/kg Metolazone intraperitoneally in tris buffer. Group I Control received Tris containing no metolazone. Group II (rats originally used in saline control experiments) received l ml of a solution containing 1 mg/ml (2 mg/kg dose) metolazone in 0.05 M Tris at pH 11.5 to 12. Group III were animals (not previously treated) receiving 1 ml of a solution of 1 mg/ml (2 mg/kg dose) in Tris buffer metolazone. The volume of urine produced by the rats is shown below in Table III.

XλBLB ZIX Diuretic Effect of Metolasone (ZP rout* la Rat* (Value* indicate —ount (el) of urine collected)

Group III

Group II IP Metolazone

Group I ZP Metolazone 2 mg/kg 2 mg/kg

IP Trie buffer 1 ml (1 mg/ml) in Trie 1 ml (1 mg/ml) in Trie

Rat No. (1 ml) (control buffer (Rate from buffer (different rate

Group) control group used) ueed)

16 22

15 15

17 IS

10 18 12

10 17 13

Mean 9±1 17±1*» 16±3« ±SD

** Results from Goupβ II »nd III when compared to control Group I, were significantly different (p 0.01)

Example 3

Lasix Rat Experiment

Sprague-Dawley rats, 450-500g, received saline or furosemide (Lasix) in normal saline intraperitoneally at the concentrations listed below in a 1 ml volume. The volume of urine produced by the animals is shown in Table 2.

Group I (5 rats) was administered 1 ml of normal saline intraperitoneally. Group II (5 rats) was originally used in saline controls) administered 1 ml of a 2 mg/ml Lasix/saline solution intraperitoneally (4 mg/kg dose) .

Group III (5 previously untreated rats) was administered 1 ml of a 2 mg/ml Lasix/saline solution intraperitoneally (4 mg/kg dose) . Group IV (5 previously untreated rats) was administered l ml of a 1 mg/ml Lasix/saline solution intraperitoneally (2 mg/kg dose) . This diuretic effect of these formulations is shown below in Table IV.

CO

CZ αi n I

m Λ rπ

33 cr

10 ια> **P results from Groups II, III, and IV when compared to control Group I, were significantly different (p<0.01) .

Example 4

Diuretic Effects of Metolazone/Lasix Combination Therapy

Rats (450 g previously untreated) were intraperitoneally administered 0.5 ml of 4 mg/ml lasix solution (4 mg/kg dose) and 0.5 ml of 2 mg/ml metolazone/tris buffer solution, pH 11.5, (2 mg/kg dose) . The results are shown in Table V below.

TABLEV

Diuretic effect of Furosemide (Lasix) and Metolazone (IV route) combination therapy.

The results of these examples demonstrate that metalozone and lasix have distinctive action, increasing urine output. When lasix and metalozone are used in combination therapy the action is synergistic with more diuretic effect than with either drug alone.

From the foregoing it will bie appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention.