GB1584089A

GB1584089A - Antihypertensive pharmaceutical compositions

Info

Publication number: GB1584089A
Application number: GB35524/77A
Authority: GB
Original assignee: Roehm Pharma GmbH; ICI Pharma SA
Current assignee: Roehm Pharma GmbH; AstraZeneca SAS
Priority date: 1976-08-27
Filing date: 1977-08-24
Publication date: 1981-02-04
Also published as: JPS5350340A; FR2362636B1; FR2362636A1; DE2638716A1

Description

(54) ANTIHYPERTENSIVE PHARMACEUTICAL QOMPOSITIONS (71) We, RÖHM PHARMA G.m.b.H. a German Body Corporate of Darmstadt, Germany; and ICI - Pharma Arzneimittelwerk Plankstadt, Niederlassung der Deutsche ICI G.m.b.H., a German Body Corporate, of Plankstadt, Germany do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The invention relates to pharmaceutical compositions possessing an anti-hypertensive action.

Hypertension, especially as a chronic diagnosis, is a disorder well-known in human medicine. To combat high blood pressure, diuretic medicines have, for example, been previously employed. A group of substituted 1,2,4-benzothiadiazin-l.l-dioxides. for example chlorothiazide (6-chloro-7-sulfamoyl-2H-1,2.4-benzothiadiazin-1,1-dioxide) and hydrochlorothiazide ((i-chloro-3 .4-dihydro-7-sulfamoyl-2H- 1 ,2,4-benzothiadiazin- 1,1- dioxide), have been employed in such therapy as saluretic agents in combination with other anti-hypertensives. However. owing to their influence on the electrolytic regime of the patients, the use of such saluretic agents is subject to important restrictions. For example, if there is liver and/or kidney disease, thereapy with chlorothiazide or hydrochlorothiazide usually presents a very serious risk. Also, with continued application of the drugs mentioned dangerous disturbances of the electrolytic and acid-base regime (hypochloraemia, hypocalcaemia. hypokaliemia and alkalosis) can occur. The loss of potassium ions in the monotherapeutic use of saluretic agents is especially undesirable. Consequently, research into "potassium retaining" diuretics has been undertaken. One such product which has been used in anti-hypertensive therapy is triamterene (2.4,7-triamino-6-phenyl- pteridine) which serves to regulate blood pressure partly in an analogous way to that of hydrochlorothiazide and similar saluretic agents (i.e. by increasing natriuresis, reducing plasma volume, stimulating renin activity) and partly in the opposite way (i.e. by increasing the peripheral resistance). Further. triamterene reduces cardiac output whereas hydrochlorothiazide has no such effect. Other 'potassium-retaining" diuretic agents include, for example, the compounds amiloride (N-amidino-3,5-diamino-6-chlorpyrazin-carboxamide) and spironolactone (3-(3-oxo-7a-acetylthio-17i3-hydroxy-4-androsten- 17a-yl )-a-lactone), the latter being an aldosterone antagonist in contrast to triamterene and amiloride.

A further advance in anti-hypertensive therapy was the introduction of ss-receptor blockers. The property of blocking the adrenergic ss-receptors is shown by a series of substances having different chemical structures: for example, compounds of formula I:

[wherein n is () or 1; Ar represents. in the case where n is 1. a homo- or heterocvclic radical which contains at least one six-membered aromatic ring (preferably a phenyi. naphthyl, tetrahydronaphthyl. indolvl or indanyl radical) connected directly to the rest of the molecule and which can be substituted by one or more lower alkyl. alkoxy. alkenyl, alkenoxy, alkynyl. alkynoxy. alkvlmercapto. alkylsulfonyl. hydroxyalkyl, aminoalkyl, alkylamino. dialkylamino. alkinoyl. alkanoyloxy. benzamido. alkanoylamino, aryl, aryloxy, arylamino. arylmercapto. arylsulfonyl. arylsulfonylamino. arylamino, arylalkoxy, haloalkyl alkoxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, nitro, hydroxy, amino and/or cyano groups and/or halogen atoms, or in the case where n is O, a phenyl, naphthyl, tetrahydronaphthyl or indanyl radical which can also be substituted by lipophilic substituents, such as halogen atoms, nitro groups, lower alkyl and/or alkoxy radicals; and R represents a lower alkyl or hydroxyalkyl radical, preferably branched, e.g. tert- butyl, sec-butyl or more preferably iso-propyll and their non-toxic acid addition salts, especially the hydrochlorides.

The term "non-toxic" is used herein in relation to the above acid addition salts to denote those salts the anionic moieties of which are physiologically acceptable at the dosage at which the salts are administered. The expression "lower alkyl" is used herein with reference to alkyl radicals containing not more than six carbon atoms, such as methyl, ethyl, propyl or isopropyl as well as straight-chain or branched butyl, pentyl or hexyl radicals. The expression "lower alkenyl" is used herein with reference to alkenyl radicals containing not more than six carbon atoms, especially allyl or methallyl radicals. Similarly the expression "lower alkynyl" is used herein with reference to alkynyl radicals containing not more than six carbon atoms. The propargyl radical is particularly preferred as a lower alkynyl radical.

Alkanoyl substituents include the propionyl and butyryl radicals, the acetyl radical being preferred. Aryl substituents include naphthyl and more preferably the phenyl radical.

Halogen substituents are preferably fluorine or chlorine atoms. Examples of the above compounds of formula I include t-(3,4-dichlorophenyl)-i-hydroxy-2-isopropylaminoethane (dichloro-isoproterenol) and t-isopropylamino-3-(2-allylphenoxy)-propan -2-ol (alprenolol) and their physiologically compatible acid addition salts, especially the hydrochlorides.

An especially interesting representative of the class of ss-receptor blockers has proved to be l-iso-propylamino-3-(1-naphthyloxy)-propan -2-ol (propranolol). especially in the form of its physiologically compatible salts, particularly its hydrochloride. Propranolol has an anti-hypertensive action by reducing the cardiac output. The peripheral resistance is first increased and after longer treatment it then drops. Also a reduction in renin activity is recorded.

On the basis of experience a practical treatment pattern has been developed, which can be characterised as follows: on the principle of a general dietetic therapy, saluretic agents are used in the basic treatment. If treatment does not have the desired effect on blood pressure, then other anti-hypertensives e.g. Rauwolfia-alkaloids, dihydralazine, clonidine andNr a-methyl dopa, sympathicus blockers and/or ss-receptor blockers, are introduced into the therapy. In view of the frequently wide individual differences in response, the treating physician can first increase the dosage of individual or combined medicines in this therapy and then continue treatment with another medicine if there is no sign of success from the therapy. In everv case the aim of the therapy is to normalise blood pressure, allowing for the age and general health of the patient.

Therapy is further complicated when hypertension is associated with other internal diseases. Reference has already been made to complications in the treatment of liver and kidney diseases with saluretic agents. Such agents can also have an effect on the blood sugar level-revealed by hyperglycaemia. With diabetics simultaneous administration of propanolol and insulin or oral anti-diabetic drugs can set off or aggravate hypoglycaemia.

Generally, ss-receptor blockers can be used with the necessary degree of safety only if it is certain that the patient is not suffering from decompensation of the heart or from obstrctive diseases of the wind pipe. Consequently. therapy with ss-receptor blockers was primarily applied to juvenile hypertensive patients.

In converting the results of recent clinical research in this field into recommendations for practical therapy a certain dilemma arises. (C.J. Hollifield et al. in New England J. Med.

295 (2) 68-73 (l976)J. On the assumption that the renin level of the patient is known, it is recommended that on patients with a high and a normal renin level propranolol therapy should be started at a moderate dosage. the dosage being increased to a specific value and, if there is an adverse effect. diuretics being given in addition. Conversely for patients with a low renin level. therapy should begin with the administration of diuretics and. if unsuccessful, be continued with the addition of propanolol. Usually. however. the precondition for the therapy. i.e. knowledge of the renin level. is not met.

We have now found that a substantially improved anti-hypertensive effect can be achieved with a pharmaceutical composition comprising at least one ss-receptor blocker of general formula I (as hereinbefore defined) and at least one potassium-retaining diuretic agent.

According to the present invention we therefore provide pharmaceutical compositions having an antihypertensive action and comprising: (a) At least one lS-reccptor blocking agent of general formula I

[wherein n isO or 1; Ar represents, in the case where n is 1, a homo- or heterocyclic radical which contains at least one six-membered aromatic ring (preferably a phenyl, napthyl, tetrahydronapthyl, indolyl or indanyl group) connected directly to the rest of the molecule and optionally substituted, e.g. by one or more lower alkyl, alkoxy, alkenyl, alkenoxy, alkynyl, alkynoxy, alkymercapto, alkylsulfonyl, hydroxyalkyl, aminoalkyl, alkylamino, dialkylamino, alkanoyl, alkanoyloxy, benzamido, alkanoylamino, aryl, aryloxy, arylamino, arylmercapto, arylsulfonyl, arylsulfonylamino, arylamino, arylalkoxy, haloalkyl, alkoxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, nitro, hydroxy, amino and/or cyano groups and/or halogen atoms, and, in the case where n is 0, Ar represents a phenyl, napthyl, tetrahydronapthyl or indanyl group optionally substituted by a lipophilic group such as, for example, a halogen atom, a nitro group or a lower alkyl or alkoxy group; and R represents a lower alkyl or hydroxyalkyl group, preferably branched, such as, for example, tert - butyl, sec - butyl or more preferably iso - propyl or a non-toxic acid addition salt thereof, preferably a hydrochloride; (b) at least one potassium-retaining diuretic agent; and (c) at least one pharmaceutical carrier or excipient, components (a) and (b) being present in sufficient amounts to provide the said antihypertensive effect.

It will be appreciated that the ss-receptor blocking agent should be employed in an amount sufficient to maintain a blocking effect on the (3-receptors. The amount of the potassium-retaining diuretic agent incorporated into the pharmaceutical compositions according to the invention is, in general, lower than the dosage hitherto normally used for the compound in question and is preferably lower than that necessary to provide an effective antihypertensive action in the absence of the ss-receptor blocking agent. In this way, it is possible to come very close to the intended aim of normalizing blood pressure with a minimum of therapeutically harmful side effects and risks. With the combination of anti-hypertensive compounds employed in the above-described compositions a synergistic therapeutic effect is obtained. If desired, the compositions can also contain one or more saluretic agents as further physiologically active ingredients.

The active ingredients in the compositions according to the invention are preferably employed in as low a dosage as possible.

ss-Blockers of general formula I, and preferably propranolol, which have previously been proposed for use in hypertensive therapy may be employed in the compositions according to the invention. Recommended dosages for maintaining blockage of ss-receptors have been defined by clinical research. With propranolol hydrochloride the recommended daily dose is approximately 160 mg (two administrations of 80 mg doses).

The reference here to "potassium-retaining" diuretic agents denotes compounds which are diuretically active and which simultaneously reduce potassium ion secretion. Antikaliuretic agents are advantageously employed in the compositions according to the invention, these agents serving to reduce the potassium ion secretion to a value 80% below the normal figure. Triamterene is a particularly preferred example of a potassium-retaining diuretic for use in accordance with the invention. In the pharmaceutical compositions according to the invention comprising propranolol hydrochloride as the ss-blocker and triamterene as the potassium-retaining diuretic agent, the weight ratio is advantageously 1.2:1 to 2:1, preferably 1.6:1.

In the case of 'potassium-retaining" diuretic agents the dosages should advantageously be considerably below the dosages normal in conventional hypertensive thereapy, for example 50-80C/e of the conventional doses employed in monotherapy. Thus, instead of a normal dose of 200 mg triamterene daily. a dose of 100 mg daily is sufficient for anti-hypertensivetherapy (in combination with propranolol) according to the present invention, while at the same time giving a superior therapeutic result.

The possibility of being able to reduce the dosage of the active ingredients in the pharmaceutical compositions according to the present invention also extends to the saluretic agent which may be employed as a optional ingredient. Here, also, it is generally sufficient to use quantities below those conventionally used in mono-therapy and, generally. also for combination hypertensive thereapy. The dosage can. for example, be around 50 mg hydrochlorothiazide per day, if desired, in combination with triamterene and propranolol hydrochloride. Preferably such compositions contain propranolol hydrochlor ide, triamterene and hydrochlorothiazide in a-weight ratio of from 1 l0.2:tl. 1 to 1:0.8:0.4, for example about 1:0.3:0.15 or about 1.6:1:0.5.

The compositions according to the present invention are formulated in dosage unit form, for example. as tablets, dragees or capsules. Such dosage units may for example contain about 80 mg propranolol hydrochloride and 25-50 mg triamterene.

It will however be appreciated that individual therapy is needed for hypertensive diseases, and that very wide differences in response may occur. It is all the more desirable to have an anti-hypertensive preparation whose application does not require an exact measurement of the renin level before and during treatment. Further, there is no need for the exploratory (mono-therapeutic) treatment stage which, as the dosage increases in steps, demands continuous monitoring of the patient, apart from the fact that increasing the dosage in stages is not an ideal therapy.

An important advance over mono-therapy is also to be seen in the generally considerably higher response rate for blood pressure using compositions according to the present invention. This result is unexpected since, as previously mentioned, physiological factors which have a considerable bearing on blood pressure are partly nullified by the active ingredients employed in the compositions according to the invention.

In experiments which we have carried out we have found that certain undesirable side effects or adverse subsequent symptoms known from therapy with individual components of the compositions of the invention are repressed or completely eliminated in therapy on hypertension using the compositions according to the invention. Thus. the not always obvious, negative-inotropic effect of propranolol is favourably effected by triamterene (with a certain positive-inotropic effect).

Conversely, desirable therapeutic effects, e.g. the anti-arrhythmic properties of propranolol known from mono-therapy, are enhanced by the concomitant use of triamterene.

The pharmaceutical compositions according to the invention are preferably adapted for oral administration but may, if desired be adapted for parenteral administration.

The carriers or excipients which may be employed in the compositions according to the invention may be physiologically acceptable organic or inorganic materials. Examples of water-soluble carrier materials which may be used include sugar and sugar alcohols while examples of water-insoluble polymeric carrier substances which may be used include cellulose and cellulose derivatives. Other conventional additives such as e.g. tablet disintegrating agents can also be employed. The compositions can be prepared in conventional manner.

The following comparative tests illustrate the advantageous therapeutic effect which may be achieved by pharmaceutical compositions according to the invention.

Comparative test: effect of a composition according to the invention as compared with that of propranolol in patients with high blood pressure: TEST Treatment Dosage Average arterial blood pressure Lying Standing mm Hg I week. placebo 131 130 3 weeks with 160 mg propranolol 1) per day 115 112 3 weeks with propranolol HCI 160 mg plus Triamterene 100 mg plus hydrochlo- 103 10 thiazide 2) 50 mg per day I) One 8() mg tablet twice a day 2) One tablet containing 80 mg propranolol HCI. 50 mg triamterene and 25 mg hvdrochlorothiazide twice a dav.

The tests show that even with a low dosage a very high response rate is achieved.

The following Example illustrates the present invention.

a) Manufacture of a granulate with propranolol hydrochloride: Propranolol hydrochloride is granulated when moist with polyvinylpyrrolidone. The composition of the granulate is: 97coo by weight propranolol HCI and 3'-Xr by weight polyvinvlpyrrolidone.

b) Manufacture of a granulate containing triamterene and hydrochlorothiazide: Ingredients 46.30% by weight triamterene 23.15% by weight hydrochlorothiazide 15.84% by weight lactose 6.90% by weight calcium carbonate 5.80% by weight maize starch 1.4û% by weight polyvinylpyrrolidone 0.16% by weight copolymer of dimethylaminoethyl methacrylate-butyl methacrylate methyl methacrylate (50:30:20) 0.45% by weight Aerosil (the word "Aerosil" being a registered Trade Mark) The ingredients are pulverised and granulated together.

c) Manufacture of a lactose granulate: A granulate is made in a fluidised bed mixer from 98 kg lactose (DIN 2()) with 24 kg of isopropanol and 16 kg of a copolymer of dimethylaminoethyl-methacryalte-butyl methacrylate-methyl methacrylate (50: 30: 20), which granulate consists of 98% by weight of lactose and 2% by weight of lacquer from the above-mentioned copolymers.

d) Manufacture of the tablet composition: The granulate containing propranolol hydrochloride according a) and the granulate containing triamterene and hydrochlorothiazide according to b) are mixed together with the lactose granulate according to c) in a tumbler mixer along with 5.00% by weight talc, 5.00% by weight calcium carboxy-methyl cellulose, 1.72% by weight maize starch, 0.50% by weight magnesium stearate and 0.20% by weight Aerosil. The mass is then pressed into tablets.

The finished tablet contains 80 parts of propranolol hydrochloride, 50 parts of triamterene and 25 parts of hydrochlorothiazide.

e) Manufacture of coated tablets.

Coated tablets are made by coating with a conventional finishing composition in a coating basin with a spray gun.

WHAT WE CLAIM IS: 1. Pharmaceutical compositions having an antihypertensive action and comprising: (a) at least one ss-receptor blocking agent of general formula I

[wherein n is O or 1: Ar represents, in the case where n is 1, a homo - or heterocyclic radical which contains at least one optionally substituted six-membered aromatic ring connected directly to the rest of the molecule, and, in the case where n is o, represents a phenyl, napthyl, tetrahydronapthyl or indanyl groups optionally substituted by a lipophilic substituent; and R represents a lower alkyl or hydroxyalkyl group or non-toxic acid addition salt thereof; (b) at least one potassium - retaining diuretic agent; and (c) at least one pharmaceutical carrier or excipient, components (a) and (b) being present in sufficient amounts to provide the said antihypertensive action.

2. Compositions as claimed in claim 1 which contain an amount of component (a) sufficient for the maintenance of a ss-receptor blocking effect and an amount of component (b) which is less than that necessary to provide an effective antihypertensive action in the absence of component (a).

3. Compositions as claimed in claim 1 or claim 2 comprising a ss-receptor blocking agent of general formula 1 (as defined in claim 1) wherein n is I and Ar represents a homo - or heterocyclic radical containing at least one phenyl. napthyl. tetrahydronapthyln indolyl or indanyl group either unsubstituted or substituted by one or more lower (as herein defined) alkyl. alkoxy. alkenyl, alkenoxy, alkynyl, alkynoxy. alkylmercapto. alkylsulphonyl. hydroxya(lkyl. aminoalkyl. alkylamino, dialkylamino, alkanoyl. alkanoyloxy, benzamido. alkanoylamino, aryl, aryloxy. arylamino, arylmercapto, arylsulfonyl, arvlsulfonvlamino, arylamino, arylalkoxy. haloalkyl. alkoxyal kyl, monoalkylaminoalkyl. dialkylaminoalkyl, nitro, hydoxy. amino and/or cyano groups and/or halogen atoms.

4. Compositions as claimed in claim I or claim 2 comprising a ss-receptor blocking agent of general formula I (as defined in claim 1) wherein n is O and the said lipophilic substituent is a halogen atom, a nitro group or a lower (as herein defined) alkyl or alkoxy group.

5. Compositions is claimed in any of preceding claims comprising a ss-receptor blocking

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. b) Manufacture of a granulate containing triamterene and hydrochlorothiazide: Ingredients 46.30% by weight triamterene 23.15% by weight hydrochlorothiazide 15.84% by weight lactose 6.90% by weight calcium carbonate 5.80% by weight maize starch 1.4û% by weight polyvinylpyrrolidone 0.16% by weight copolymer of dimethylaminoethyl methacrylate-butyl methacrylate methyl methacrylate (50:30:20) 0.45% by weight Aerosil (the word "Aerosil" being a registered Trade Mark) The ingredients are pulverised and granulated together. c) Manufacture of a lactose granulate: A granulate is made in a fluidised bed mixer from 98 kg lactose (DIN 2()) with 24 kg of isopropanol and 16 kg of a copolymer of dimethylaminoethyl-methacryalte-butyl methacrylate-methyl methacrylate (50: 30: 20), which granulate consists of 98% by weight of lactose and 2% by weight of lacquer from the above-mentioned copolymers. d) Manufacture of the tablet composition: The granulate containing propranolol hydrochloride according a) and the granulate containing triamterene and hydrochlorothiazide according to b) are mixed together with the lactose granulate according to c) in a tumbler mixer along with 5.00% by weight talc, 5.00% by weight calcium carboxy-methyl cellulose, 1.72% by weight maize starch, 0.50% by weight magnesium stearate and 0.20% by weight Aerosil. The mass is then pressed into tablets. The finished tablet contains 80 parts of propranolol hydrochloride, 50 parts of triamterene and 25 parts of hydrochlorothiazide. e) Manufacture of coated tablets. Coated tablets are made by coating with a conventional finishing composition in a coating basin with a spray gun. WHAT WE CLAIM IS:

1. Pharmaceutical compositions having an antihypertensive action and comprising: (a) at least one ss-receptor blocking agent of general formula I

agent of general formula I (as defined in claim 1) wherein R represents a branched lower alkyl or hydroxyalkyl group.

6. Compositions as claimed in claim 5 wherein the said branched lower alkyl group is an iso - propyl, tert - butyl or sec - butyl group.

7. Compositions as claimed in claim 1 wherein the said ss-receptor blocking agent comprises propranolol or a non-toxic acid addition salt thereof.

8. Compositions as claimed in claim 1 wherein the said (3-receptor blocking agent comprises dichloro-isoproterenol or alprenolol, or a physiologically compatible acid addition salt thereof.

9. Compositions as claimed in any one of claims 1 to 7 wherein the said ss-receptor blocking agent is in the form of the hydrochloride.

10. Compositions as claimed in any of the preceding claims wherein the said diuretic agent comprises an anti-kaliuretic agent.

I I. Compositions as claimed in claim 10 wherein the said anti-kaliuretic agent comprises triamterene.

12. Compositions as claimed in claim 10 wherein the said anti-kaliuretic agent comprises amiloride or spironolactone.

13. Compositions as claimed in claim 1 wherein the said B-receptor blocking agent comprises propranolol or the hydrochloride thereof and the said potassium-retaining diuretic agent comprises triamterene.

14. Compositions as claimed in any of the preceding claims wherein the said ss-receptor blocking agent and the said diuretic agent are present in a weight ratio of 1.2:1 to 2:1.

15. Compositions as claimed in claim 14 wherein the said ss-receptor blocking agent and the said diuretic agent are present in a weight ratio of 1.6:1.

16. Compositions as claimed in any of the preceding claims further containing a saluretic agent.

17. Compositions as claimed in claim 16 wherein the said saluretic agent comprises hydrochlorothiazide or chlorothiazide.

18. Compositions as claimed in claim 17 containing propranolol hydrochloride, triamterene and hydrochlorothiazide in a weight ratio of 1:0.2:0.1 to 1:0.8:0.4.

19. Compositions as claimed in claim 18 containing propranolol hydrochloride, triamterene and hydrochlorothiazide in a weight ratio of about 1:0.3:0.15.

20. Compositions as claimed in claim 18 containing propranolol hydrochloride, triamterene and hydrochlorothiazide in a weight ratio of about 1.6:1:0.5.

21. Compositions as claimed in any of the preceding claims in dosage unit form.

22. Compositions as claimed in claim 21 containing about 80 mg of propranolol hydrochloride and 25-50 mg of triamterene per dosage unit.

23. Compositions as claimed in claim 22 wherein each dosage unit further contains 12.5-25 mg of hydrochlorothiazide.

24. Compositions as claimed in any of the preceding claims adapted for oral administration.

25. Compositions as claimed in claim 24 in the form of tablets, capsules or dragees.

26. Compositions as claimed in any of claims 1 to 23 adapted for parenteral administration.

27. Compositions as claimed in claim 1 substantially as herein described.

28. Pharmaceutical compositions as claimed in claim 1 substantially as herein described in the Example.