NO784357L - PROCEDURE FOR PREPARING A PHARMACEUTICAL PREPARATION - Google Patents

Description

"Procedure of manufacture

of a pharmaceutical preparation"

This invention relates to a method for the preparation of a pharmaceutical preparation, which comprises that an effective amount of a compound with the formula:

where

R is hydroxy, lower alkoxy or NH 2 ;

and - R 1 is each hydrogen, lower alkyl or phenyl-lower alkyl; R 2 is hydrogen or R 2 -CO;

R 1 is hydrogen, hydroxy or lower alkyl;

R 1 - is lower alkyl, phenyl or phenyl-lower alkyl; and

n is 0, 1 or 2,

•combined with an effective amount of a diuretic compound. The compounds of formula I are described as angiotensin-converting enzyme inhibitors that intervene in the angiotensinogen -> renin -»• angiotensin I -+ angiotensin II mechanism, and are effective in reducing or alleviating hypertension. See US Patent 4,046,889, and Science 196, 441-443 (1977). Such compounds can be used in an oral dose range from approx. 0.1 to .100 mg/kg per day and are most effective when administered in a total daily dose of

about. 60 to 600 mg. Doses within this range result in a substantial reduction in arterial blood pressure, and in most cases little or no further reduction is achieved by increasing the dose further. Although certain peptides, e.g. teprotide (SQ20,881), have been reported to have angiotensin-converting enzyme activity, they are not of practical use for such use because of the price and especially

since they are ineffective when administered orally [Rubin et al, 204, Jour. Pharm. Exper. Ther. 271-280, 1978; Laffan et al.,

Duty. Pharm. Exper. Ther. 204, 281-288, 1978; Brit. With. Duty. 2 (6141); 866, 1978].

Hypertension is also often treated by administration of

a diuretic. Typically, treatment with an antihypertensive agent alone results in a compensatory retention of sodium and water which concomitant administration of a diuretic prevents (Wollam et al., Drugs 1_4: 420-460, 1977). However, administration of a compound of formula I does not result in sodium and water retention when administered alone and in fact may itself cause natriuresis and diuresis (Bengis et al, Circulation Research, Vol. 4_3 I-45-I-53, 1978 ). It would therefore be expected that a diuretic would not enhance the antihypertensive effect of compounds of formula I. However, administration of a diuretic in combination with compounds of formula I has been found to be more effective than either agent alone. The combination of such compounds with a diuretic as described below results

in one reinforcement of blood pressure reduction significantly beyond that

level that each of the substances itself entails at a dose within the acceptable range and also in higher doses.

According to the invention, preparations are made for relief

of hypertension by combining a compound of the above formula I with a diuretic from the group consisting of the thiazide class, e.g. chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, metyclothiazide, trichlormethiazide, polythiazide or benzthiazide, as well as ethacrynic acid, ticrynafen, chlorthalidone, furosemide, bumetanide, triamterene,

amiloride and spironolactone and salts of such compounds. It is preferred to use the compounds of formula I where R is hydroxy or lower alkoxy, especially C₁-C₂-lower alkoxy;

R 2 is hydrogen or lower alkyl, especially methyl, R 2 is hydrogen or lower alkanoyl, especially C 1 -C 4 -lower alkanoyl; R 1 is hydrogen or hydroxy, especially 4-hydroxy; R 1 is hydrogen or lower alkyl, especially C 1 -C 2 -lower alkyl; and n is 0 or 1. Within this group, compounds of formula I where R is hydroxy are particularly preferred; R 1 is hydrogen or methyl; is hydrogen or acetyl; R 1 is hydrogen; R 1 is hydrogen or methyl; and n is 0 or 1. The use of a compound of formula I is particularly preferred

where R is hydroxy; R 1 is methyl; R 2 , R 1 and R 2 are each hydrogen;

and n is 1, in particular (D-3-mercapto-2-methylpropanoyl)-L-proline.

As the second component, it is preferred to use chlorothiazide, hydrochlorothiazide, furosemide, ticrynafen or triamterene, especially hydrochlorothiazide or furosemide.

It is particularly preferred that (D-3-mercapto-2-methylpropanoyl)-L-proline is combined with either hydrochlorothiazide or furosemide.

The compounds of formula I can be prepared as described in US patent 4,046,889. The diuretics used are known compounds which are produced by methods described in the literature.

A preparation of a compound of formula I and a diuretic is administered in an effective amount comprising a total daily dose of about 30 to 600 mg, preferably 30 to 300 mg of a compound of formula I and approx. 15 to 300 mg, preferably 15 to 200 mg, of the diuretic agent to a mammal having elevated blood pressure. Such total daily doses can be used by a single administration of the entire amount or in divided doses two to four times a day. In general, administration 3 or 4 times daily is preferred. The preferred dose is approx. 10 to 100 mg of the compound of formula I and approx. 5 to 75 mg of the diuretic 3 times a day or approx. 5 to 125 mg of compound of formula I and approx. 2.5 to 50 mg diuretic 4 times a day. The preferred form of administration is oral.

According to a preferred embodiment, the components are mixed in a simple pharmaceutical dosage form for oral administration such as a tablet, capsule, solution or suspension containing an effective amount of each of the active ingredients, in a physiologically acceptable carrier.

The active substances in the preparation are used in a ratio

of approx. 1:2 to approx. 12:1, preferably approx. 2.5:1 to approx. 10:1,

. of the compound of formula I relative to the diuretic (by weight). In general, approx. 10 to 200 mg of a compound of formula I and approx. 2.5 to 100 mg of the second component in the preparation.

Tablets of different sizes can be produced, e.g. with a total weight of approx. 50 to 700 mg, containing the active substances in the ranges described above, the rest being a physiologically acceptable carrier or other materials according to accepted pharmaceutical practice. These tablets can of course be provided with notches to facilitate dividing the doses.

Gelatin capsules can be produced in a similar way.

Liquid preparations can also be prepared by dissolving or suspending the combination of active substances in a common liquid carrier which is accepted for pharmaceutical administration, so that the desired dosage is obtained in 1 to 4 full teaspoons.

Such dosage forms can be administered to the patient in a course of 1 to 4 doses per day.

According to another modification, in order to further fine-tune the dosage, the active substances can be administered, separately in single doses simultaneously or at carefully coordinated times. Since blood levels are built up and maintained using a regulated timetable for administration, the same result is achieved with the simultaneous presence of the two substances.

The respective substances can be prepared separately in unit doses as described above.

Mixed preparations of the compound of formula I and diuretic are more appropriate and preferred, especially i

tablet or capsule form for oral administration.

In the preparation of the preparations, the active substances, in the amounts described above, are mixed in accordance with normal pharmaceutical practice with a physiologically acceptable carrier, excipient, binder, preservative, stabilizer, flavoring etc., in the particular type of unit dose that is desired.

Illustrative examples of additives that can be introduced into the tablets are the following: a binder, such as tragacanth gum, acacia gum, corn starch or gelatin; an auxiliary such as dicalcium phosphate or cellulose, an explosive such as corn starch, potato starch, alginic acid or the like; a lubricant such as stearic acid or magnesium stearate; a sweetener such as sucrose, lactose or saccharin; a flavoring such as orange, peppermint, wintergreen oil or cherry. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or agents that otherwise modify the physical form of the unit dose. E.g. tablets or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, water, alcohol or the like as a carrier, glycerol as a solubilizing agent, sucrose as a sweetener, methyl and propyl parabens as preservatives, a coloring agent and a flavoring agent such as cherry or orange.

Many of the active substances described above form commonly known, pharmaceutically acceptable salts such as alkali metal or other common basic salts or acid addition salts, etc. Reference to the bases should therefore be understood to include the common salts known to be approximately equivalent to the output connection.

The following examples shall serve to illustrate the invention in more detail, and represent particularly preferred embodiments. They also serve as a model for the preparation of other preparations which can be prepared by suitable replacement of the constituents as described above.

Example 1

6,000 tablets, each containing the following ingredients:

is produced (from sufficient starting quantities) by forming (D-3-mercapto-2-methylpropanoyl)-L-proline, "Avicel" and some of the stearic acid into pieces. The pieces are ground and passed through a No. 2 sieve, then mixed with hydrochlorothiazide, lactose, corn starch and the remainder of the stearic acid. The mixture is pressed into 350 mg capsule-shaped tablets in a tablet press. The tablets are provided with a notch for splitting in two.

Example 2

10,000 tablets each containing the following ingredients:

is prepared from sufficient starting quantities as follows: The acacia gum is dissolved in water. 17.5 mg corn starch, (D-3-mercapto-2-methylpropanoyl)-L-proline and lactose are mixed, carefully. The dry mixture is granulated using the aqueous solution of gum acacia. The granulate is sieved in a wet state, dried at 49°C and reduced. The reduced, dry granules are mixed with the hydrochlorothiazide, and the rest of the excipients are then added and mixed. The mixture is pressed into tablets of 700 mg each.

Example 3

Tablets each containing the following ingredients are prepared as described in Example 2:

Example 4

1000 capsules, each containing the following ingredients:

is prepared by dry mixing of the starting materials (except for the magnesium stearate) in a Hobart mixer, after which the mixture is passed through a No. 20 sieve. The materials are mixed again in the Hobart mixer with the magnesium stearate. The mixture is then filled into No. 2 two-part gelatin capsules.

Example 5

By using 10 mg of furosemide instead of the hydrochlorothiazide in example 4, capsules containing furosemide and (D-3-mercapto-2-methylpropanoyl)-L-proline are prepared in a similar manner.

Example 6

By following the procedure according to example 2', but by

using 20 mg furosemide instead of hydrochlorothiazide and using 220.4 mg lactose, 700 mg tablets each containing 20 mg furosemide and 200 mg (D-3-mercapto-2-methylpropanoyl)-L-proline are prepared in a similar manner.

Example 7

By using 10 mg of furosemide instead of hydrochlorothiazide and using 115.5 mg of lactose in the method according to example 1, one obtains in a similar way 350 mg of scored tablets, each containing 10 mg of furosemide and 100 mg of (D-3-mercapto-2-methyl -propanoyl)-L-proline.

Example 8

6000 scored tablets, each 400 mg and containing the following ingredients:

is produced as described in example 2.

Example 9

6000 scored tablets, each 350 mg and containing the following ingredients:

is produced as described in example 1.

Example 10

5000 scored tablets, each 180 mg and containing the following ingredients:

is produced as described in example 1.

Example II

By using the same amount of ticrynafen instead of hydrochlorothiazide according to example 1, tablets containing 100 mg of (D-3-mercapto-2-methylpropanoyl)-L-proline and 12.5 mg of ticrynafen are prepared in a similar manner.

Representative examples of the results obtained with the preparations produced according to the invention are data obtained from examinations of spontaneously hypertensive rats and two renally hypertensive rats.

A) In an acute study with spontaneously hypertensive rats, 10-14-week-old spontaneously hypertensive male Wistar-Kyoto rats (190-210 g) of the Okamoto-Aoki strain (obtained from Taconic Farms, Germantown, N.Y.) were given food and water after desire

and intubated by the method of Weeks and Jones, Proe. Soc. Exp. Biol. With. 104, 646-648 (1960), to prepare them for blood pressure and heart rate determination by implantation of permanent abdominal aortic catheters under sodium pentobarbital anesthesia. 3 weeks later, their direct blood pressure and heart rate were recorded by the method of Laffan et al., Cardiovasc. Res. 6_, 319-324 (1972), modified as follows. The signal from the transducer was digitized in a 10 bit A/D converter and fed to a PDP 11/05 computer. The computer was programmed to sense and store samples at a rate of 125/sec for each rat, as well as the number of taps during 10 seconds of scanning on each rat. The average of these parameters was calculated and stored as.-MBP (mean blood pressure, mm Hg) and heart rate (beats/min.) at this time. Data were obtained from each rat every 5 min. The average of 6 such sets of data was found to obtain a mean value representing a 30 minute sample, and this 30 minute value was stored for subsequent analysis. Each time a 48 hour cycle was completed (or earlier if desired) the data obtained was serially transferred to a host machine (PDP 11/40) for further analysis and the data obtained was printed on a Versatec Printer/Plotter for at least 16 hours after each dose.

The spontaneously hypertensive rats were divided into four groups of 5 rats each (except for group 3 which included 6 rats). The following were administered to the rats in the respective groups:

1. (Control) Agar - 5 ml/kg + agar - 5 ml/kg

2. Water - 5 ml/kg + Compound A - 30 mg/kg

3. Compound F - 50 mg/kg + agar - 5 ml/kg

4. Compound F - 50 mg/kg + Compound A 30 mg/kg.

Compound A = (D-3-mercapto-2-methylpropanoyl)-L-proline

Compound F = Furosemide

Compound F was suspended in 0.25% agar and Compound A was in aqueous solution. All drugs were administered by means of a stomach tube, and there was an interval of 1 hour between the drugs. The test results were assessed 2.5 hours after single oral doses.

The following results were obtained:

In these investigations, Compound F alone resulted in

50 mg/kg p.o., a 9.7% reduction of SHR blood pressure. Compound A alone, 30 mg/kg, caused a 6.5% reduction in blood pressure. The combination of Compound A, 30 mg/kg p.o. + Compound B,

50 mg/kg, p.o., reduced blood pressure in SHR rats by 27.7%.

B) In chronic studies with renal hypertensive rats, male rats (115-150 g) of the Charles River Sprague Dawley (COBS-CO) strain were anesthetized with ether, and a silver clip (0.22 mg i.d.) was placed on the left renal artery through an incision in the side. The contralateral kidney was left intact (two-kidney Goldblatt model: 2-K RHR). Each rat was fitted with a tail cuff for air inflation and a Korotkoff audio microphone for detection of arterial pulsation. An oscilloscope was used for visual appearance and disappearance of the pulse. Blood pressure measurements were determined after a minimum of 6 inflations with systolic pressure recorded on a Narco physiograph manometer. Blood pressure was determined at the beginning immediately before dosing and twice per week from 4 hours after dosing.

The number of rats in each group was 15. Simple daily treatments were carried out by stomach tube with crossover treatments as indicated in the following table. The control group received distilled water. Compound A was administered in distilled water, 30 mg/kg. Compound H was administered in 0.25% methyl cellulose. Mean blood pressure (mm Hg) for each group before dosing and on day 119 (4 hours after dosing) and the number of survivors on day 120 are shown in the table.

The previous data show that with long-term treatment, compound H does not cause a significant reduction in blood pressure. Compound A alone shows approximately a 10-15% reduction in blood pressure. The preparation containing Compound A and Compound H shows approximately a 30% reduction in blood pressure. Furthermore, this preparation is the only one that shows a survival rate of 100%.

Claims (8)

1. Method for producing a preparation with improved anti-hypertensive effect, containing a compound of the formula: where R is hydroxy, lower alkoxy or NH 2 ; R 1 and R 2 are each hydrogen, lower alkyl or phenyl-lower alkyl; R 2 is hydrogen or R 1 -CO; R 1 is hydrogen, hydroxy or lower alkyl; R 1 is lower alkyl, phenyl or phenyl-lower alkyl; and n is 0, 1 or 2,, characterized in that the compound of formula I is combined with a diuretic selected from chlorothiazide, hydrochlorothiazide, flumethiazide, amiloride, hydroflumethiazide, bendroflumethiazide, methyclothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid, ticrynafen, chlorthalidone, furosemide, bumetanide, triamterene and spirdnolactone and salts ay said compounds. 2. Method as stated in claim 1, characterized in that 30 to 600 mg of the compound of formula I and 15 to 300 mg of said diuretic are used. 3. Method as stated in claim 2, characterized in that 30 to 300 mg of the compound of formula I and 15 to 200 mg of said diuretic are used. 4. Method as stated in claims 1 to 3, characterized in that a compound of formula I is used where R is hydroxy or lower alkoxy; R 1 is hydrogen or lower alkyl; R 2 is hydrogen or lower alkyl; R 1 is hydrogen or hydroxy; R 1 is hydrogen or lower alkyl; and n is 0 or 1. 5. Method as stated in claim 4, characterized in that a compound of formula I is used where R is hydroxy; R 1 is hydrogen or methyl; 1*2 is hydrogen or acetyl; R., is hydrogen; R 1 is hydrogen or methyl; and n is 0 or 1. 6. Method as stated in claims 1 to 5, characterized in that a diuretic selected from chlorothiazide, hydrochlorothiazide, furosemide, ticrynafen and triamterene is used. 7. Method as stated in claim 6, characterized in that a diuretic selected from hydrochlorothiazide and furosemide is used. 8. Method as stated in claims 1 to 7, characterized in that (D-3-mercapto-2-methylpropanoyl)-L-proline and a diuretic selected from hydrochlorothiazide and furosemide are used.