SE445173B - ORAL, ANTIHYPERTENSIVE COMPOSITION CONTAINING (D-3-MERCAPTO-2-METHYLPROPANOYL) -L-PROLINE AND CERTAIN DIURETIC - Google Patents

Description

7813277-6 have been shown to have angioLensin-converting enzyme activity, they are not practically useful for such an indication due to the cost-effectiveness nfh upr fl ivlll vllwrßom dr is inwfívktnvn when dv is administered orally! (RuhLn et al., 202, Jour. Pharm. Exper.

Thvr. l973, uid. 271-280; Laffan et al., Jour. Pharm. Expvr. 293, 1978, p. 281-288; Brit. With. Jour., Ä, 1978, 6l4l: 866).

Hypertension is also often treated by administering a diuretic. In general, treatment with an antihypertensive agent alone provides a compensatory retention of sodium and water, which is prevented by co-administration of dioxytic (Wullam et al., Drugs 1, 1077, pp. 420-460).

However, administration of a compound of formula I does not provide sodium and water retention when administered alone, and the drug itself may give rise to sodium and diuresis (Bongis et al., Circulation Research, Vol. Ii, 1978, I). 45-I-53). Therefore, one would not expect a diuretic to increase the antihypertensive effect of the compounds of formula I. However, administration of a diuretic in combination with compounds of formula I has been found to be more effective than any of the drugs themselves. The combination of such compounds with a diuretic, as described below, provides a potentiation of the reduction in blood pressure, which is substantially below the level that any of the substances can achieve in itself at a dose within an acceptable range and also at lower doses.

Particularly preferred compositions contain 30-300 mg of (D-3-mercapto-2-motylpropanoyl) -L-proline and 15-200 mg of hydrochlorothiazide or 30-300 mg (D-3-mercapto-2-methylpropanoyl) -L- proline and lo-200 mg furosemide.

(D-3-mercapto-2-methylpropanoyl) -L-proline can be prepared in the manner described in USP 4 H46 889. The diuretic precursors mmmx fi nmümmh mmlrmm fifl h fi according to the methods described in the literature. According to the present invention, a combination of a compound of formula I and a diuretic is administered in an effective amount, which comprises a total daily dose of about 30-600 mg, preferably 30-300 mg of a compound of formula I and about 15 mg. -300 mg, preferably 15-200 mg of the diuretic, for a mammalian species with high blood pressure. Such total daily doses may be used in a single administration of the total amount or in divided doses two to four times daily. In general, a T.i.d. or q.i.d. cure. This preferred dose is about 10-100 mg of the compound of formula I and about 5-75 mg of the diuretic three times daily or about 5-125 mg of the compound of formula I and about 2.5-50 mg of the diuretic four times daily. The preferred mode of administration is oral administration.

In a preferred embodiment, the substances may be formulated in simple pharmaceutical dosage form for oral administration, such as tablets, capsules, solutions or suspensions comprising an effective amount of each of the active ingredients in a physiologically acceptable carrier therefor.

The active substances in the dosage unit should be present in a ratio of about 1: 2 to about 12: 1, preferably about 2.5: 1 to about 10: 1, of the compound of formula I with respect to the diuretic (by weight). In general, about 10-200 mg of a compound of formula I and about 2.5-100 mg of the second component can be readily formulated in the composition.

Tablets of different sizes can be prepared, e.g. with a total weight of about 50-700 mg, containing the active substances in the above proportions and wherein the remainder is a physiologically acceptable carrier or other material according to accepted pharmaceutical practice. These tablets can, of course, be scored to give fractional doses. Gelatin capsules can be prepared in a similar manner.

Liquid formulations may also be prepared by dissolving or suspending the combination of active substances in a conventional liquid carrier acceptable for pharmaceutical administration to give the desired dose in an amount corresponding to one to four teaspoons. Such dosage forms may be administered to the patient in an amount of one to four doses per day.

According to another modification, the substances can be administered separately in individual dosage units simultaneously or at carefully coordinated times to more accurately regulate the dosage schedule.

Since the blood levels are built up and maintained through a regulated administration schedule, the same result can be achieved by the simultaneous presence of the two substances; The substances in question can be prepared individually in separate dosage unit forms in a manner similar to that described above.

Fixed combinations of the compound of formula I and the diuretic are more suitable and are preferred, especially in tablet and capsule form for oral administration. In preparing the compositions of the invention, the active substance is processed in the above amounts according to accepted pharmaceutical practice with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavoring agent, etc., into the particular type of unit dosage form.

Examples of adjuvants that can be incorporated into tablets are the following: A binder such as gum, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate or cellulose; a disintegrant 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 agent, such as f-1 orange, peppermint, wintergreen or cherry oil. When the dosage unit 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 to otherwise modify the physical form of the dosage unit. For example, 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 sweetening agent, methyl and propyl parabens as a preservative, a coloring agent and a flavoring agent such as cherries or orange.

Many of the active substances described above form generally known pharmaceutically acceptable salts, such as alkali metal and other common basic salts or acid addition salts, etc.

References to the base substances should therefore include those common salts which are known to be substantially equivalent to the parent compound.

The invention is further illustrated by the following examples, in which the temperature refers to OC.

Example l. 6000 tablets, each containing the following ingredients: (D-3-mercapto-2-methylpropanoyl) - -L-proline 100 mg Avicel (microcrystalline cellulose) 100 mg Hydrochlorothiazide 12.5 mg Lactose U.S.P. ll3 mg Corn starch U.S.P. 17.5 mg Stearic Acid U.S.P. 7 mg 350 mg are prepared (with sufficient mass amounts) by suspending (D-3-mercapto-2-methylpropanoyl) -L-proline, avicel and a portion of the stearic acid. The slurry is ground and passed through a No. 2 sieve, then mixed with the hydrochlorothiazide, lactose, corn starch and the remainder of the stearic acid. The mixture is compressed into 350 mg capsule-shaped tablets in a tablet press. The tablets are cut to be split in half. 7813277-6 Exemgel 2. 10,000 tablets, each containing the following ingredients: (D-3-mercapto-2-methylpropanoyl) -L-proline 200 mg Maize starch U.S.P. 17.5 mg Lactose U.S.P. 215.4 mg Acacia U.S.P. 10.6 mg Water q.s. (ca. 0.03 ml) Hydrochlorothiazide 25 mg Maize starch 17.5 mg Avicel _ 200 mg 'Stearic acid _l§__ mg 700 mg is prepared from sufficient masses as follows: The acacia is dissolved in water. 17.5 mg of corn starch, (D-3-mercapto-2-methylpropanoyl) -L-proline and lactose are mixed thoroughly. The dry mixture is granulated using an aqueous solution of acacia. The granules are water sieved, dried at 490 and reduced. The reduced dry granulation product is mixed with the hydrochlorothiazide and the remaining excipients are then added and mixed. The mixture is compressed into tablets weighing 100 mg each.¿ H: Exemgel 3¿ 1000 capsules, each containing the following ingredients: (D-3-mercapto-2-methylpropanoyl) -L-proline 100 mg Lactose U.S.P. 211.8 mg Magnesium stearate 3.2 mg Hydrochlorothiazide 10 m9 '325 mg 7813277-6 is prepared by dry mixing the pulp materials (except 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 two-part gelatin capsules of size 2.

Exemgel 4.

Using 10 mg of furosemide, capsules containing furosemide and (D-3-mercapto-2-methylpropanoyl) -L-proline are similarly prepared.

Example 5.

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

Example 5.

Using 10 mg of furosemide instead of the hydrochlorothiazide and 115.5 mg of lactose in the procedure of Example 1, similarly scored tablets weighing 350 mg each containing 10 mg of furosemide and 100 mg of D-3-mercapto are prepared. -2-methylpropanoyl) -L-proline.

Exemgel 7-000 tablet tablets weighing 180 mg each and containing the following ingredients: (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 in 180 mg is prepared as described in Example 1. -_, ___..., ..... r, ..._.-..__- «~ .. ~ __.:-_. 7813277-6 Representative of the results obtained with combinations of the agents of the invention are data obtained from studies of spontaneous hypertensive rats and two renal hypertensive rats.

A) In an acute study in spontaneously hypertensive rats, ten to fourteen week old spontaneously hypertensive male Wistar-Kyoto rats (190-210 g) of the Okamoto-Aoki strain (obtained from Taconic Farms, Germantown, NY) were fed and water ad libitum and intubated according to the method of Weeks and Jones, Proc. Soc. Exp. Biol. With. lgg, l960, p. 646-648, to prepare them for blood pressure and heart rate determination by implanting internal abdominal aortic catheters under sodium pentobarbital anesthesia.

Three weeks later, direct blood pressure and heart rate were measured according to the method of Laffan et al., Cardiovasc. Res.

Q, 1972, p. 319-324, modified as follows. The signal from the sensor was digitized in a 10-bit A / D converter and input to a PDP 11/05 computer. The computer was programmed to sense and store samples at a speed of 125 / sec. for each rat, as well as the number of pressure pulses during 10 sec. for each scan on each rat. Mean calculation was performed on these parameters and stored as MBP (mean blood pressure, mm Hg) and heart rate (beats / min.) For this time. Data were obtained from each rat every five minutes. Mean calculation was performed for six such sets of data to determine a mean representing a 30 minute sample, and this 30 minute figure was stored for subsequent analysis. Each time a 48 hour cycle was completed fi or sooner if required), data were transferred in series to a host computer (PDP ll / 40) for further analysis and data was printed on a Versatec Printer / Plotter for at least 16 hours after each dose dose. the rats were divided into four groups of five rats each (except group 3, which included six rats).

The following compounds were administered to the rats in the respective group = 7813277-6 l. (Control) agar - 5 ml / kg + agar - 5 ml / kg 2. water - s mi / kg + compound AX - 3G mg / kg 3. Compound Fxx - 50 mg / kg + agar - 5 ml / kg 4. Compound FXX - 50 mg / kg + compound AX - 30 mg / kg X 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 substances were administered by gavage and an hour interval was maintained between the administration of the drugs.

The test results were assessed 2.5 hours after single oral doses.

The following results were obtained: Iêäâlii Mean blood pressure (mm / Hg) Before 2.5 hours after single oral dose (1) 173 169 (2) 175 158 (s) 184 '172 (4) 177 128 In these studies, only compound F, 50 mg / kg po, 9.7% decrease in SHR blood pressure. Compound A alone, 30 mg / kg, gave a 6.5% reduction in blood pressure. The combination of compound A 30 mg / kg, p.o., + compound F, 50 mg / kg, p.o., reduced the blood pressure in SHR rats by 27.7%.

B) In chronic studies in 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 mm id) 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 equipped with a tail cuff for air injection and a Korotkoff sound microphone to track arterial pulsation. An oscilloscope was used to observe when the pulse was visible and disappeared.

Blood pressure measurements were determined after a minimum of six breaths, observing the systolic pressure on a Narco physiograph manometer. Blood pressure was initially determined just before dosing and twice a week four hours after dosing.

The number of rats in each group was 15. Simple daily treatment was performed by gavage with control treatments as indicated in the table below. The control group received distilled water. Compound A was administered in distilled water, 30 mg / kg. Compound H was administered in 0.25% methylcellulose.

The mean blood pressure (mm / Hg) for each group before dosing and on day 119 (4 hours after dosing) and the number of surviving animals on day 120 are given in the table. 7813277-6 ll ^ m.mmv Åoo fl v ^ m ~ mmv ^ m.mmv ^ mm> v ^ ß.mmv ^ ß ~ moV ^ ww®øGm> wHHw> m umHwun4 w ma QH wa flfi o fl OH Hm www: oo mm www H44 »w ~ www wwwwxm mquw flfi oupnox« .wH ~ oN @. «Ho« ~ H.mHw> H @ .4fl> @ H w_ «H> oN N_mH @ 0 ~ @_wH> @ ~ maa mmm .fl mzøummun w fi um fl vuo fi xøuwwn N c flfi0 Hm | A | AH> 0: mm0HmHhßmE | Nlovmmxumšnmnüv H 4 mo fi mmw: www wc fifl wumw mnum>> m wøwmwmw MN Acmww fl mm I w mmønm Eon fl ußmv mm mm fl m w mm_mH ~> Moæuuøo fl n fl wwmä N H fi wâm fi vn mm vmvwm .T vnvná AN owm 4 4 4 m + omm owm 4 + owm owm omm omm X.HÜGM fl0 Q IAHOHQGOM mn flfl vcø fl wm r-l fi l ms l ms ï 6 ï 12 data 6 ï gives a significant reduction in blood pressure. Compound A alone gives an approximately 10-15% reduction in blood pressure. The combined dose of compound A and compound H results in an approximately 30% reduction in blood pressure. The combination is also the only one that shows a 100% survival.

Claims (3)

13 7813277-6 PATENT REQUIREMENTS 1. Oral, antihypertensive composition, characterized in that it contains 30f600 mg of (D-3-mercapto-2-methylpropanoyl) -L-proline of the formula v * Q HS. GHz -_- CH --CO - N COOH and 15-300 mg of a diuretic consisting of hydrochlorothiazide or furosemide as active ingredients and a physiologically acceptable carrier therefor. 2. A composition according to claim 1, characterized in that it contains 30-300 mg of (D-3-mercapto-2-methyl-propanoyl) -L-proline and 15-200 mg of hydrochlorothiazide. 3. A composition according to claim 1, characterized in that it contains 30-300 mg of (D-3-mercapto-2-methylpropanoyl) -L-proline and 15-200 mg of furosemide.