NL192870C - Anti-hypertensive oral pharmaceutical preparation. - Google Patents

Description

1 192870

Anti-hypertensive oral pharmaceutical preparation

The present invention relates to an oral anti-hypertensive drug containing (D-3-mercapto-2-methylpropanoyl) -L-proline.

Such preparations are known from Dutch patent application 7701457 which relates to a process for the preparation of new proline derivatives and related compounds. These compounds, of which captopril, i.e. (D-3-mercapto-2-methylpropanoyl) -L-proline, is the most important, are inhibitors of the angiotensin converting enzyme. These compounds, also referred to as ACE inhibitors, are effective hypertension-reducing or relief agents. These compounds can be used in an oral dose of 0.1 to 100 mg / kg per day and are most effective when administered as a total daily dose of 60 to 600 mg. Doses within this range effect a significant reduction in arterial blood pressure and little or no significant reduction is usually achieved if the dose is further increased. Although certain peptides, for example teprotide (SQ 20,881), have been described as an ACE inhibitor, they are of no practical significance for such an indication, especially since these compounds are ineffective when administered orally (Rubin et al., 204, Jour. Pharm. Exper. Ther. 271-280 (1978); Laffan et al., Jour. Pharm. Exper. Ther. 204, 281-288 (1978); Brit. Med. Jour. 2 (6141): 866 (1978) ).

Hypertension is also often treated by the administration of a diuretic. Treatment with an anti-hypertensive agent usually results in a compensatory retention of sodium and water, which is prevented when a diuretic is co-administered. (Wollam et al., Drugs 14: 420-460 (1977). Administration of a compound of Dutch patent application 77-01457 alone, however, does not lead to sodium and water retention and may even cause sodium and diuresis on its own (Bengis et al. , Circulation Research, 43, I-45-I-53 (1978).

Duhne et al. Describe in The Lancet of March 9, 1974, page 408, that a combined administration of an ACE inhibitor, namely SQ 20,881, and the diuretic furosemide to a patient resulted in a nearly fatal drop in blood pressure. An McCaa article in IRCS Medical Science, Pharmacology: 5, 207 (1977) describes that SQ 20,881 and captopril are diuretics in themselves.

It was now found that administration of a preparation containing the ACE inhibitor captopril and a specific diuretic not only exhibited a surprising synergistic effect, but also did not present the expected problem of a severe drop in blood pressure.

The invention therefore provides a medicament as described in the preamble, characterized in that it additionally contains furosemide or hydrochlorothiamide, optionally in the form of a combination preparation, which allows for separate administration of the components.

Captopril can be prepared in the manner described in Dutch patent application 7701457.

Furosemide and hydrochlorothiazide are known compounds which can be prepared in a manner described in the literature.

Captopril and the diuretic are administered in an effective amount comprising a total daily dose of 30-600 mg, preferably 30-300 mg captopril and 15-300 mg, preferably 15-200 mg diuretic. Such daily total doses can be administered at once or in divided doses two to 40 to four times a day. Generally, three or four times a day is preferred. This preferred dose would then be 10-100 mg captopril and 5-75 mg diuretiaim three times a day or 5-125 mg captopril and 2.5-50 mg diuretic four times a day.

In a preferred embodiment, the two substances, namely captopril and furosemide or hydrochlorothiazide, are processed into a single 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 contains.

The active substances are present in the dosage unit in a ratio of 1: 2 to 12: 1, preferably from 2.5: 1 to 10: 1, based on the captopril relative to the diuretic and based on weight.

In general, 10-200 mg captopril and 2.5-100 mg diuretic can be easily incorporated into the preparation 50.

Tablets of various sizes can be prepared, for example, with a total weight of 50-700 mg, containing the active substances in the amounts indicated above, the remainder consisting of a physiologically acceptable carrier or other substances according to accepted pharmaceutical practice. These tablets can of course be scored to give dose fractions. 55 gelatin capsules can also be manufactured.

Liquid preparations can also be prepared by dissolving or suspending the combination of active substances in a conventional liquid carrier acceptable for pharmaceutical administration such that 192670 2 is supplied in the desired dose in 1-4 teaspoons.

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

Administration of captopril and the diuretic in a single pharmaceutical dosage form is the easiest and preferred.

In preparing the compositions of the invention, the active ingredients are mixed in the amounts described above according to accepted pharmaceutical practice with one or more physiologically acceptable additives such as a carrier, excipient, binder, preservative, stabilizer, flavor, etc., to the type of dosing unit involved.

Captopril forms known pharmaceutically acceptable salts, known basic salts, or acid addition salts, etc. Whenever reference is made to captopril, this also includes these known salts.

The following examples illustrate the invention.

Example I

6000 tablets are prepared, each having the following composition: (D-3-mercapto-2-methylpropanoyl) -L-proline 100 mg.

Avicel (microcrystalline cellulose) 100 mg.

Hydrochlorothiazide 12.5 mg.

Lactose U.S.P. 113 mg.

20 Corn Starch U.S.P. 17.5 mg.

Stearic Acid U.S.P. 7 mg.

350 mg.

by processing (D-3-mercapto-2-methylpropanoyl) -L-proline, Avicel and part of the stearic acid into pellets. The pellets are ground and sieved through a No. 20 screen and then mixed with hydrochlorothiazide, lactose, corn starch and the rest of the stearic acid. The mixture is pressed in a tablet press into 350 mg capsule-shaped tablets. The tablets are scored to cut them in half.

Example II

10,000 tablets are prepared, each having the following composition: (D-3-mercapto-2-methylpropanoyl) -L-proline 200 mg.

Corn starch U.S.P. 17.5 mg.

Lactose U.S.P. 215.4 mg.

Acacia Gum U.S.P. 10.6 mg.

35 Water as needed (approx. 0.03 ml).

Hydrochlorothiazide 25 mg.

Corn starch U.S.P. 17.5 mg.

Avicel 200 mg.

Stearic acid 14 mg.

40,700 mg.

from sufficient quantities of starting material in the following way:

The acacia is dissolved in water and 17.5 mg of corn starch, (D-3-mercapto-2-methylpropanoyl) -L-proline and lactose are thoroughly mixed. The latter mixture is granulated using the acacia gum solution in water. The granulated product is sieved wet, dried at 49 ° C and crushed. The crushed, dry granulated product is mixed with hydrochlorothiazide, the remaining excipients are added and mixed. The mixture is pressed into 700 mg tablets.

Example III

50 tablets are produced, each with the following composition: (D-3-mercapto-2-methylpropanoyl) -L-proline 100 mg.

Lactose U.S.P. 211.8 mg.

Magnesium stearate 3.2 mg.

Hydrochlorothiazide 10 mg.

55 325 mg.

by dry mixing the starting materials (except the magnesium stearate) in a Hobart mixer, after which the mixture is sieved through a No. 20 sieve. The sieved material 3 192870 is then mixed again in the Hobart mixer, now with the magnesium stearate. The mixture is then filled into two-part gelatin capsules.

Example IV

Capsules containing furosemide and (D-3-mercapto-2-methylpropanoyl) L-proline are similarly prepared using 10 mg of furosemide in place of the hydrochlorothiazide of Example IV.

Example V

According to the procedure of Example II, but using 20 mg of furosemide instead of the hydrochlorothiazide and using 220.4 mg of lactose, tablets of 700 mg, each containing 20 mg of furosemide and 200 mg (D) are similarly prepared. -3-mercapto-2-methylpropanoyl) -L-proline.

Example VI

Using 10 mg furosemide in place of the hydrochlorothiazide and using 115.5 mg lactose in the method of Example 1, similarly notched 350 mg tablets each containing 10 mg furosemide and 100 mg (D-3-) are prepared. mercapto-2-methylpropanoyl) -L-proline.

20

Example VII

5000 incised tablets of 180 mg each containing the following ingredients are prepared in the manner described in Example 1. (D-3-mercapto-2-methylpropanoyl) -L-proline 10 mg.

Avicel 50 mg.

Hydrochlorothiazide 5 mg.

Lactose U.S.P. 101 mg.

Corn starch U.S.P. 10 mg.

Stearic acid 4 mg.

180 mg.

The effect of the invention can be seen from the data obtained in studies on spontaneously hypertensive rats and two renally hypertensive rats.

A. In an acute study on spontaneously hypertensive rats, 10-14 week old spontaneously hypertensive male Wistar-Kyoto rats (190-210 g) of the Okamoto-Aoki strain were given food and water ad libitum and incubated according to the method of Weeks and Jones, Proc. Soc. Exp. Biol, Med. 104, 646-648 (1960), in order to prepare them for blood pressure and heart rate determination by implantation of internal abdominal aortic catheters under anesthesia with pentobarbital sodium.

Their direct blood pressure and heart rate were recorded three weeks later by the method of Laffan et al., Cardiovasc. Res. 6, 319-324 (1972), subject to the following modification.

40 The signal from the transducer was digitized in a 10-bit analog to digital converter and input into a PDP 11/05 computer. The computer was programmed to detect and store samples at a rate of 125 / second for each rat, as well as the number of pressure pulses for 10 seconds from each study on each rat. These parameters were averaged and stored as the MBP (mean blood pressure in mm of mercury) and heart rate (beats / minute) for that time. The 45 data were collected for each rat for 5 minutes. Six such series of data were averaged to a mean value representing a 30 minute sample and this 30 minute number was retained for further analysis. Whenever a 48 hour program was completed (or faster if desired), the data was serially transferred to an auxiliary computer (PDP 11/40) for further analysis and the data was visualized on a Versatec Printer / Plotter for a period of 50 at least 16 hours after each dose.

The spontaneously hypertensive rats were separated into four groups of 5 rats each (except group 3, which included 6 rats). The rats in the respective groups were administered the following: 1. (Control) 5 ml./kg agar + 5 ml./kg agar 2.5 ml./kg water and 30 mg./kg captopril 55 3.50 mg./kg furosemide and 5 ml./kg agar 4.50 mg.Ag furosemide and 130 mg.Ag captopril

The furosemide was suspended in 0.25% agar and the captopril was dissolved in water. All fabrics

Claims (2)

192870 4 were administered with a throat probe, leaving an interval of 1 hour between drugs. The test results were evaluated 2.5 hours after a single oral dose. The following results were obtained: TABLE A Average blood pressure For 2.5 hours after single oral dose (mm / Hg) 10 (1) 173 169 (2) 175 158 (3) 184 172 (4) 177 128 15 B. At chronic examination of renal hypertensive rats, anesthetized male rats (115-150 g) of the Charles River Spraque Dawley (COBS-CO) strain with ether and applied a silver clamp (0.22 mm internal medially) to the left renal artery through a flank incision. The contra-lateral kidney was left intact (two-kidney Goldblatt model: 2-K RHR). Each rat was provided with an inflatable tail pad and a Korotkoff microphone for sensing the arterial pulsations. An oscilloscope was used to visualize the appearance and disappearance of the pulsation. Blood pressure measurements were taken after inflation at least 6 times until systolic pressures were observed on a Narco physiograph pressure gauge. Blood pressures were initially determined just before dosing and twice weekly, 4 hours after dosing. The number of rats in each group was 15. Single daily treatments were performed with a throat probe, however, sometimes changing treatment as indicated in the table below. The control group received distilled water instead of medicaments. Compound A was administered in distilled water, 30 mg / kg. Compound H (= hydrochlorothiazide) was administered in 0.25% methyl cellulose. The mean blood pressure in millimeters of mercury from each group before dosing and at day 119 (4 hours 30 after dosing) as well as the number of survivors at day 120 are shown in the table. Table B Treatment Group Other Avg. blood pressure Number of survivors - 35 treatment1 2 - th Day 119 1 Change of treatment occurred on days 28 through 33 and on days 91 through 96 (except group 6 - see below). 1 H20 H20 198 ± 4.9 207 + 6.6 1 0 2 HzO H20 + A 198 + 4.9 206 ± 5.2 10 40. H20 H20 + H 206 ± 7.5 207 + 4.8 11 4. A 197 ± 5.3 167 + 4.6 14 5. H20 197 ± 6.2 176 ± 5.1 14 A2 + H2 202 ± 6.6 140 ± 4.6 15 7. H 197 + 5.8 202 ± 8.4 8 45 --- 2 Daily dose maintained from day 109. 50 Oral anti-hypertensive drug containing (D-3-mercapto-2-methylpropanoyl) -L-proline, characterized in that it also contains furosemide or hydrochlorothiazide, optionally in the form 55 of a combination preparation which allows for separate administration of the components. Medicament according to claim 1, characterized in that it contains (D-3-mercapto-2-methylpropanoyl) -L-proline and furosemide or hydrochlorothiazide in a single pharmaceutical dosage form.