IE43955B1 - Pharmaceutical composition and dosage units thereof - Google Patents

Abstract

1509778 Antihypertensive compositions LEO PHARMACEUTICAL PRODUCTS Ltd AS 12 Oct 1976 [7 Nov 1975] 44677/75 Heading A5B Pharmaceutical compositions having antihypertensive activity comprise bendroflumethazide and S-(-)-1-tert-butylamino-3-(4-morpholino-1, 2, 5-thiadiazol-3-yloxy) - 2 - propanol (timolol) or an acid addition salt thereof, optionally together with a pharmaceutically acceptable carrier, the ratio by weight of the bendroflumethazide to the timolol being between 1:5 and 5:1.

Description

The present invention relates to a pharmaceutical preparation containing as one therapeutically active component the diuretic bendroflumethiazide and as another therapeutically active component the β-adren5 ergic blocking agent S( - ) - 1 - tert.butylamino - 3 (4 - morpholino - 1,2,5 - thiadiazol - 3 - yloxy) - 2 propanol, with the generic name timolol, or salts of timolol; to methods of preparing said composition; and to dosage units thereof.

Timolol is a base capable of forming mono- and dibasic salts with acids among which may be mentioned the non-toxic, pharmaceutically acceptable salts with hydrochloric and hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, p-toluenesulfonic acid, methanesulfonic acid, formic acid, acetic acid, propionic acid, citric acid, tartaric acid and maleic acid.

The preferred salt is timolol maleate.

By administering bendroflumethiazide together with timolol maleate to dogs a prolonged and marked decrease of both the systolic and the diastolic blood pressure has been observed. This finding is highly surprising as the single compounds are substantially ineffective in so far as the above criterion is concerned.

Thus the compounds of the composition of the present invention show a synergistic effect.

As a further feature it has been found that - 3 potassium excretion (resulting in hypo kalemia) and the hyperreninemia induced by bendroflumethiazide is almost completely inhibited by simultaneous administration of timolol maleate.

The synergism mentioned above has been demonstrated in animal experiments as follows: Mongrel dogs of both sexes (body weight 15-20 kg) were made hypertensive according to the Goldblatt technique. They were used at least 2 months after surgery and maintained on a standard diet.

The compounds were administered in soft gelatin capsules at 09.00 a.m. after 18 hours fasting.

The blood pressure was measured in conscious animals, in the lying position with Roche Arteriosonde 10l0R at the time of administration of the compounds and then 3 and 5 hours later.

The plasma potassium was measured by standard flame photometry methodology.

The plasma renin activity was measured by radioimmunoassay using radioiodinated angiotension I, in normotensive dogs.

TABLE 1 Systolic and diastolic blood pressure in renal hypertensive dogs treated orally with: A=bendroflumethiazide, 2 mg/kg B=timolol maleate, 8 mg/kg C=bendroflumethiazide, 2 mg/kg+timolol maleate, 8 mg/kg Daily administration, once a day, from day 0 to day 12 - 4 Blood Pressure (systolic/diastolic) mmHg A . B C Before 186/95 178/98 182/93 Day 5 0 hr (*) 188/95 168/90 146/70 3 hr 184/90 165/94 148/70 5 hr 182/94 172/90 133/58 Day 12 0 hr (*) 182/94 174/92 155/68 3 hr 184/90 170/94 147/72 5 hr 180/96 175/95 137/55 (*) 0 hr=tlme of administration Each value is the mean of 4 dogs TABLE 2 Plasma potassium levels in renal hypertensive dogs treated orally with; A=bendroflumethiazide, 2 mg/kg B=timolol maleate, 8 mg/kg C=bendroflumethiazide, 2 mg/kg+timolol maleate, 8 10 mg/kg Daily administration, once a day, from day 0 to day 12 K+ mmoles/1 of plasma A B C Before 4.79 4.61 4.19 bay 5 4.02 4.50 3.85 Day 12 3.74 4.32 3.95 Determination performed 4 hrs after drug administration. 439 55 - 5 Each value is the mean of 4 dogs.

TABLE 3 Plasma renin activity in renal normotensive dogs treated orally with: A=bendroflumethiazide, 2 mg/kg B=timolol maleate, 8 mg/kg C=bendroflumethiazide, 2 mg/kg timolol maleate, 8 mg/kg Daily administration, once a day, from day 0 to day 12 Plasma renin activity ng angiotensin I/ml/hr A B C Before 0.7 0.6 0.7 Day 5 1.8 0.5 1.1 Day 12 2.1 0.7 1.2 Determination performed 4 hr after drug administration.

Each value is the mean of 4 dogs.

The synergistic effect by the combined treatment with bendroflumethiazide and timolol maleate has also been demonstrated in clinical trials where the modest antihypertensive activity of timolol maleate was increased when given together with bendroflumethiazide to patients suffering from hypertension.

As is well known the recommended dose of timolol maleate for treatment of e.g. angina pectoris in its capacity of being a β-adrenergic blocking agent is of the order of 30 mg per day, whereas higher doses, e.g. 60 mg per day is recommended when it is applied as an antihypertensive agent. With such higher doses, however its 8-adrenergic blocking activity may cause a β43353 - 6 adrenergic blockade in other organs e.g. the lungs thereby resulting in bronchoconstriction as an undesired side-effect.

Therefore, it is a further and advantageous feature of the combined therapy with bendroflumethiazide and timolol maleate, that an antihypertensive effect Is obtainable with low doses of timolol maleate.

Thus it is one object of the present invention to provide a pharmaceutical composition which is useful, in the general treatment of patients suffering from cardiovascular diseases, and in the treatment of hypertension and related conditions.

With this object in view, the composition of the invention contains as one active component bendroflume15 thiazide and as another active compound timolol or a salt thereof with a non-toxic, pharmaceutically acceptable acid, optionally together with a solid or liquid pharmaceutical carrier and/or auxiliary agent.

In the composition of the invention the weight ratio of bendroflumethiazide to timolol may vary between 1:5 to 5:1. Preferably, however, timolol is present in amounts exceeding those of bendroflumethiazide and an appropriate weight ratio of bendroflumethiazide to timolol is found to be from 1:2 to 1:5.

Said composition preferably contains at least 1% by weight of the therapeutically active compounds and can be worked up in a manner known per se to various pharmaceutical forms of presentation, such as tablets, pills, dragees, capsules, sustained release tablets, suspensions, suppositories and injectable preparations, containing the bendroflumethiazide and the β-adrenergic blocker used according to the invention, optionally mixed with carriers and/or auxiliary agents. 3 9 5'ΰ - 7 Pharmaceutical organic or inorganic, solid or liquid carriers and/or auxiliary agents suitable for oral, or enteral administration can be used to make up compositions containing the present compounds. Gelatine, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, gum, polyalkylene glycol, buffers or other known carriers and/or auxiliary agents for medicaments are all suitable.

Another object of the invention resides in the selection of a dose of the composition of the invention which dose can be administered so that the desired activity is achieved without simultaneous secondary effects.

In human therapy, the composition can conveniently be administered (to adults) in dosage units containing not less than 1 mg and up to 100 mg, preferably from 10 mg to 50 mg, of bendroflumethiazide plus timolol calculated in its free form, in a weight ratio from Is2 to Is5.

By the term dosage unit is meant a unitary, i.e. a single dose which is capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically stable unit dose comprising either the active material as such, or a mixture of it with solid or liquid pharmaceutical diluents or carriers.

In the form of dosage units, the composition may be administered once or more times a day at appropriate intervals, always depending, however, on the condition of the patient, and in accordance with the prescription made by the medical practitioner.

The adequate daily dose of the composition as defined above is within the range from 10 mg to 100 mg for treatment of adults. - 8 In continuous therapy, tablets or capsules may be the appropriate form of pharmaceutical preparation owing to the long-lasting effects obtained when the drug is given orally, or sustained release formul5 ations can also support the long-lasting effect.

The invention will now be described by the following examples which are illustrative of the invention.

Example 1.

Tablet: Timolol maleate Bendroflumethiaz ide Lactose Corn starch Gelatin solution 4% Magnesium stearate 100 g 25 g 1000 g 534 g 400 ml g Sieve the mixed timolol maleate, bendroflumethiazide and corn starch through a 0.3 mm. sieve. Moisten the powder with the gelatin solution and dry the granules in a fluid bed dryer at 40°C. Pass the dry granulate through a 0.7 mm sieve, add magnesium stearate and mix for 15 minutes. Compress into 10,000 tablets, diameter 8 mm, each having a weight of 0.18 g.

Each tablet contains 10 mg of timolol maleate 25 and 2.5 mg of bendroflumethiazide.

Example 2.

Capsule; Timolol maleate 100 Bendroflumethiazide 25 Microcrystalline cellulose 2630 Magnesium stearate 30 Colloidal silicon dioxide 15 - 9 Mix the timolol maleate and bendroflumethiazide with 500 g of the microcrystalline cellulose and sieve the powder through a 0.3 mm. sieve. Add the remaining microcrystalline cellulose, magnesium stearate and silicon dioxide. Mix for 30 minutes. Fill the mixture into No. 1 capsules (Parke Davis) using a capsule fill weight of 0.28 g.

Each capsule contains 10 mg of timolol maleate and 2.5 mg of bendroflumethiazide.

Claims (11)

1. CLAIM S:~

1. A pharmaceutical preparation for treatment of hypertension containing as one therapeutically active component bendroflumethiazide and as another 5 therapeutically active component S( - ) -1tert.butylamino - 3-(4- morpholino - 1,2,5 thiadiazol - 3 - yloxy) - 2 - propanol or an atoxic pharmaceutically acceptable salt thereof with an inorganic or organic acid, the ratio by weight of the 10 bendroflumethiazide to the S( - ) - 1 - tert.butylaiiiino - 3 - (4 - morpholino - 1,2,5 - thiadiazol - 3 yloxy) - 2 - propanol being between 1:5 and 5:1.

2. A pharmaceutical preparation as claimed in Claim 1 containing S( - ) - 1 - tert.butylamino - 3 15 (4 - morpholino - 1,2,5 - thiadiazol - 3 - yloxy) - 2 propanol maleate.

3. A pharmaceutical preparation as claimed in Claim 2 in which the ratio by weight of bendroflumethiazide to S( - ) - 1 - tert.butylamino - 3 - (4 20 morpholino - 1,2,5 - thiadiazol - 3 - yloxy) - 2 propanol maleate is from 1:2 to 1:5.

4. A pharmaceutical preparation as claimed in claim 2 or 3 in which the ratio by weight of bendroflumethiazide to S( - ) - 1 - tert.butylamino - 3 25 (4 - morpholino - 1,2,5 - thiadiazol - 3 - yloxy) - 2 - propanol maleate is 1:4.

5. A pharmaceutical preparation as claimed in Claim 3 or 4 in dosage units each containing from 1 mg to 100 mg of bendroflumethiazide + S( - ) - 1 30 tert.butylamino - 3 - (4 - morpholino - 1,2,5 thiadiazol - 3 - yloxy) - 2 - propanol in total.

6. A pharmaceutical preparation as claimed in any one of claims 1 to 5 containing an atoxic pharmaceutically acceptable carrier in an amount not 43855 exceeding 99% by weight of the composition.

7. A pharmaceutical preparation as claimed in Claim 5 or 6 in the form of tablets or capsules each containing 2.5 mg of bendroflumethiazide + 10 mg of 5 S( — ) — X — tert.butylamino - 3 - (4 - morpholino - 1,2,5 - thiadiazol - 3 - yloxy) - 2 - propanol maleate.

8. A pharmaceutical preparation as claimed in any one of Claims 1 to 6 in injectable form.

9. 10 9. A pharmaceutical preparation as claimed in claim 8 containing up to 10 mg. in total of the therapeutically active ingredients. 10. A method of preparing a preparation according to any one of Claims 1 to 9 which comprises 15 mixing bendroflumethiazide with S( - ) - 1 - tert.butylamino - 3 - (4 - morpholino - 1,2,5 - thiadiazol - 3 - yloxy) - 2 - propanol or an atoxic pharmaceutically acceptable salt thereof with an inorganic or organic acid, optionally together with an atoxic 20 pharmaceutically acceptable carrier.

10.

11. A pharmaceutical preparation for the treatment of hypertension substantially as hereinbefore described in either of the foregoing Examples.