GB2052982A

GB2052982A - Therapeutic combinations

Info

Publication number: GB2052982A
Application number: GB8021231A
Authority: GB
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1979-07-02
Filing date: 1980-06-27
Publication date: 1981-02-04
Also published as: ZA803988B; FR2460671A1; IT8049133A0; NL8003740A; BE884082A; PT71473B; SE8004872L; AU5977880A; IL60455A0; JPS5610167A; PT71473A; DE2926653A1

Abstract

Compositions having enhanced anxiolytic activity comprising as active agents a) an indole adrenergic beta -blocker e.g. pindolol and b) a benzodiazepine minor tranquilizer e.g. cloxazolam and oxazolam.

Description

SPECIFICATION Novel therapeutic combinations The present invention relates to novel pharmaceutical compositions having anxiolytic activity, as well as to methods of treating anxiety.

It has already been proposed to combine adrenergic ss-blockers of various types with various classes of minor tranquilizer (see e.g.

U.K. Patent Specifications Nos. 1,305,644 and 1,315,450). Such combinations are said to be of use in the treatment of heart conditions as well as neuropathic cardio-vascular disorders.

In accordance with the present invention it has now surprisingly been found that coadministration of specifically, as active agent a), an indole adrenergic ssblocker and specifically, as active agent b), a benzodiazepine minor tranquilizer, results in an enhanced and advantageous anxiolytic activity.

Combinations of an active agent a) and b) as aforesaid have been found to exhibit anxiolytic characteristics attributable to both a central as well as a peripheral mode of action.

In addition, clinical trials, e.g. as hereinafter described, have shown that such combinations of active agents are particularly effective in the treatment of exogenous anxiety conditions (i.e. anxiety conditions induced by external stimuli), for example, as are observed in stress situations. In this latter connection the effectiveness of such combinations in treating specific aspects of the overall anxiety syndrome, e.g. tension and nervous agitation, is especially worthy of mention.

For such specific aspects, combinations of an agent a) and an agent b) have been found to exhibit synergistic anxiolytic activity.

It has furthermore been found that coadministration of an active agent a) and an active agent b) as aforesaid results in beneficial action upon disturbances in both pulserate and systolic blood-pressure caused by, or associated with, anxiety. By alleviating such disturbances, progressive escalation of anxiety via feed-back from the peripheral system is reduced.

It will be appreciated that in view of the particular anxiolytic profile exhibited by active agents a) and b) in combination, in particular their combined effectiveness in relieving tension and nervous agitation, and having regard to the inherent adrenergic ss-blocking activity of agent a), the use of such combinations will find especial applicability in the treatment of patients suffering from e.g. hypertension or functional cardiovascular disturbances, particularly where these are associated with symptoms of anxiety.

Accordingly in one aspect the present invention provides a pharmaceutical composition comprising as active agents, a) an indole adrenergic ss-blocker and b) a benzodiazepine minor tranquilizer.

Suitable indole adrenergic ssblockers for use in the compositions of the invention are those of the formula I,

wherein R1 is H, CH3, -COOalkyl(C, 4), -CON H2 or CN; R2 is H, Cl or CH3; R3 is alkyl having 3 to 7 carbon atoms or a group of formula

wherein A is alkylene having 2 to 5 carbon atoms, X is a direct bond, oxygen or sulphur and R5 and R6 independently of each other are H, alkoxy having 1 to 4 carbon atoms, F, Cl or Br; and Y is H, alkanoyl having 2 to 5 carbon atoms or benzoyl optionally substituted by F, Cl or Br or by alkyl or alkoxy each having 1 to 4 carbon atoms; with the proviso that: 1) when R1 is -COOalkyl, -CONH2 or CN, R2 is H or CH 2) when R2 is Cl, R1 is H or CH3 and R3 is a group of formula

and that 3) when Y is alkanoyl or optionally substitured benzoyl, R3 is alkyl.

The compounds of the formula I are in general known, e.g. from U.K. Patent Specifications Nos. 1,138,968; 1,138,969; 1,260,907 and 1,268,960, DOS 26 35 209 and DOS 28 30 211.

Suitable benzodiazepine minor tranquilizers for use in the compositions of the invention are those of the formula II.

wherein R4, R5 and R6 independently of each other are H, alkyl or alkoxy each having 1 to 4 carbon atoms, halogen, hydroxy, NO2, CN, acyl, CF3, amino, acylamino, N-mono-(C1 4- alkyl)-amino, N, N-di-(C14-alkyl)-amino, acyloxy, carboxyl, (C14-alkoxy)-carbonyl, carbamoyl, N-mono-(C1 4-alkyí)-carbamoyl, N, N-di (C14-alkyl)-carbamoyl, or alkylthio, alkylsulfinyl or alkylsulfonyl each having 1 to 4 carbon atoms, R7 is H, alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, aralkyl having 7 to 9 carbon atoms, aryl or phenacyl, R8 and R9 independently of each other are H or alkyl having 1 to 4 carbon atoms, B is polymethylene, optionally substituted by one or more alkyl groups having 1 to 4 carbon atoms, hydroxy-substituted alkyl groups having 1 to 4 carbon atoms and/or phenyl groups, and X is oxygen or sulphur.

The compounds of the formula Il are also known, e.g. from U.K. Patent Specifications Nos. 1,254,736 and 1,276,909.

Alkyl groups in the compounds of the formulae I and II may be branched- or straightchain and may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl and tert.-butyl as well as, in the case of R3, n-pentyl, n-hexyl and n-heptyl and the iso-isomers thereof. Halogen stands for fluorine, chlorine, bromine or iodine. Acyl groups may be an aliphatic or an atomatic acyl group, and examples include formyl, acetyl, propionyl, butyryl, benzoyl, toluoyl and naphthoyl; and these groups may suitably form the acyl portion of an acylamino group. Examples of suitable acyloxy groups are acetoxy, propionyloxy, butyryloxy and benzoyloxy. Examples of suitable cycloalkyl groups are cyclopropyl, cyclopentyl and cyclohexyl. Aryl represents phenyl or naphthyl and examples of aralkyl groups are benzyl and phenethyl.The polymethylene group may be, for example, ethylene, propylene, trimethylene, 1 ,2-butylene, 1,3-butylene, 2,3-butylene, tetramethylene, 1 -hydroxymethylethylene or 1-phenylethylene. A is preferably ethylene or propylene.

Especially preferred compounds of the formula I for use in the compositions of the invention are: i) 1 -(I ndol-4-yloxy)-2-hydrnxy-3-isopropyl- aminopropane (also known as Pindolol); ii) 1 -(2-Methyl-indol-4-yloxy)-2-hydroxy-3- isopropyl-aminopropane (also known as Mepindolol); iii) 1 -(2-Carboisopropoxy-indol-4-yloxy)-2-hyd roxy-3-tert.-butyl-aminopropane; and iv) 1 -(2-Methyl-indol-4-yloxy)-2-benzyloxy-3- tert.-butyl-aminopropane.

Especially preferred compounds of the formula II are: i) 1 O-Chloro-1 1 b-(2-chlorophenyl)- 2,3,7,11 b-tetrnhydrnoxawIo3,2-dJ[1 ,4lben- zodiazepin-6(5H)-one (also known as Cloxazolam); and ii) 1 0-Chloro-1 1 b-phenyl-2,3,7, 11 b-tetrahy- drnoxazolo[3,2-d][1 ,4]benzodiazepin-6(5H)one (also known as Oxazolam).

The combination of Pindolol as indole adrenergic ss-blocker and Cloxazolam as benzodiazepine minor tranquilizer is the most preferred.

The active agents a) and b), in particular the compounds of formulae I and II above, may be employed in the form of individual isomers, e.g. in the form of individual optical antipodes.

Equally, they may be employed in free base form or in pharmaceutically acceptable acid addition salt form. Such acid addition salt forms are known and include salts with both organic and inorganic acids, e.g. the halides, sulphates, phosphoric acid salts, maleates, methane sulphonates, succinates and sulphonates.

The activity of such pharmaceutically acceptabie salt forms will generally be of the same order as that of the respective free base form.

As used herein all amounts of such compounds recited, refer to the amount of the free base form. This also applies to weight ratios.

The compositions according to the invention may be prepared in conventional manner, using conventional galenical techniques. For example, compositions may be prepared by mixing together of the active agents a) and b).

The compositions of the invention may be put up in accordance with standard tech- niques and with the optional addition of conventional pharmaceutical excipients e.g. as tablets, dragees, solutions, emulsions, powder, capsules or depot-forms. Preferably, the compositions of the invention are put up in unit dosage form, particularly in unit dosage form suitable for oral administration. Such unit dosage forms may contain active agents a) and b) separately, e.g. in separate layers in a layer or mantle tablet.

Tablets in accordance with the invention may be prepared for example by mixing of the active agents with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrating agents such as corn-starch or alginic acid, binding agents such as starch or gelatine, lubricants such as magnesium stearate or talc and/or preservatives such as polymethylene carboxylate, carboxymethyl cellulose or polyvinylacetate. Such tablets may comprise several layers, as in a mantle tablet. Such mantle tablets may be formulated, such that one of the active agents a) and b) is present in the core and other partially or wholly in the mantle.

In a similar fashion, dragees may be obtained by coating dragee cores, obtained analogously to tablets, with conventional coating agents, such as kolloidon, shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depot-effect or to avoid incompatability of individual ingredients the dragee may comprise more than one layer. Similarly the dragee coating may comprise several layers.

Liquid formulations for oral administration may additionally contain e.g. sweetening agents such as saccharin, cyclamates, glycerine or sugar as well as taste improving agents e.g. aromatic agents such as vanillin or orange extract. In addition they may contain suspending agents or thickeners such as sodium carboxy-methyl-cellulose, wetting agents such as condensation products of fatty acid alcohols with ethylene-dioxide, or preserving agents such as p-hydroxy-benzoate.

Injectable solutions may be prepared in conventional manner, e.g. with the addition of preserving agents such as p-hydroxy-benzoate or stabilizers such as komplexon, and filled into ampoules.

In accordance with the foregoing the present invention provides, in a further aspect, a process for the production of a pharmaceutical composition, which comprises formulating an active agent a) as stated above with an active agent b) as stated above. The composition is preferably formulated in unit dosage form.

In yet a further aspect the present invention provides a pack or dispenser-device containing separately an active agent a) and an active agent b) as stated above and adapted for the concomitant administration of said active agents a) and b). Such packs and dispenserdevices may be constructed or devised in accordance with methods known in the art.

Preferably the pack or dispenser-device bears directions for the concomitant administration of a pre-determined amount of active agents a) and b). The directions may for example be printed directly on the pack or device.

As already stated co-administration of an active agent a) an indole adrenergic ssblocker and an active agent b) a benzodiazepine minor tranquilizer, provides an enhanced and advantageous anxiolytic activity.

This effect may be demonstrated in standard animal tests as well as in clinical trials.

In one such series of trials involving 56 test subjects (all d: average age 23.3 years), the anxiolytic effectiveness of unit doses comprising a) 4 mg of an indole adrenergir ssblocker, such as Pindolol, together with b) 1.5 mg of a benzodiazepine minor tranquilizer, such as Cloxazolam, was compared with that of the individual components a) and b) at the same dosages and administered independently.

The overall investigation consisted of a series of 1 6 individual trials, conducted on separate days and involving 7 to 9 subjects per trial.

At the start of each trial, each subject received a questionnaire, with the aid of which he provided a subjective scaling from 1 to 50 for each of the anxiety criteria "tension", "claustrophobia", "nervous agitation", "mood" and "tiredness". The scale for each subject was individually standardised in advance of the trial by his plotting values for subjective response to situations experienced.

Blood-pressure and pulse-rate were measured.

Each subject then received, as test dose, (i) a placebo, or a unit dosage comprising (ii) 4 and 1.5 mg of agents a) and b) as above, in combination; (iii) 4 mg of agent a) as above; or (iv) 1.5 mg of agent b) as above, the individual test doses being administered in randomised, double-blind fashion.

A further questionnaire was issued for the scaling of anxiety criteria as before.

Approximately 100 minutes after medication the subjects were exposed to induced stress, involving mental addition (addition of two-figure numbers: oral reply) and repetition of 3 to 9 figure numbers (forwards and backwards).

Blood-pressure and pulse-rate were measured during the stress-situation and immediately afterwards a further questionnaire was issued.

Approximately 1 30 minutes after medication, a tape-recording of the stress-procedure was played back to the subjects. A further questionnaire was issued and blood-presure and pulse-rate measured.

A final questionnaire was issued approximately 1 80 minutes after medication and blood-pressure and pulse-rate measured again approximately 1 95 minutes after medication.

The full test procedure was repeated as before, after regular treatment of the subjects with the test-dose over a three week period.

Estimation of anxiolytic effectiveness based on analysis of the returns from the trial in accordance with standard techniques indicate that dose (ii) comprising the combination of agents a) and b) was a far more effective medication than doses (iii) and (iv) containing the agents individually.

Favourable results were achieved with dose (ii) for each of the anxiety criteria "tension", "claustrophobia", "nervous agitation", "mood" and "tiredness", and in particular in respect of the criteria "tension" and "nervous agitation".

In addition the results indicated superior efficacy for the dose (ii) in reducing the rate of rise of systolic blood-pressure under stress as well as reducing increase in pulse-rate.

All medications were well tolerated.

The co-administration of active agents a) and b) is accordingly indicated for use in the treatment of anxiety, in particular exogenous anxiety, e.g. in alleviating stress, and in parti cular for the treatment of tension and nervous agitation.

Accordingly in yet a further aspect the present invention provides a method of treating anxiety in a subject in need of such treatment which method comprises concomitantly administering to said subject an active agent a) and an active agent b) as stated above in an anxiolytically effective amount. Preferably agents a) and b) are administered simultaneously, e.g. in admixture. Most preferably they are administered orally.

The exact daily dosages of active agents a) and b) for use in the method of the invention will of course depend upon the particular indole adrenergic blocker and benzodiazepine minor tranquilizer employed, as well as the mode of administration and the condition to be treated.

A suitable indicated daily dosage is in the range of from about 4 to about 24 mg, preferably from about 8 to about 1 6 mg and most preferably about 1 2 mg of active agent a), e.g. Pindolol. For active agent b), e.g.

Cloxazolam, an indicated daily dosage is in the range of from about 1.5 to about 9 mg, preferably about 3 to about 6 mg and most preferably about 4.5 mg.

Conveniently the active agents are administered in sustained release form or alternatively in divided doses e.g. suitable for oral administration and containing e.g. from about 2 to about 6 mg, preferably about 4 mg of active agent a).

An indicated weight ratio of active agent a) to active agent b) is from about 10:1 to about 1 :20 preferably from about 5:1 to about 1:3 and most preferably about 4:1.5.

The following examples are illustrative of the preparation of compositions for use in the invention: EXAMPLE 1: Process for the production of 1000 tablets 4 g Pindolol, 1.5 g Cloxazolam, 100.4 g lactose, 0.04 g pigment and 10 g corn-starch are mixed thoroughly to produce a homogeneous composition. The powder mixture is moistened with a solution comprising 2 g of gelatine dissolved in aqueous alcohol, granulated through a sieve and then dried. 289 of magnesium stearate and 0.06 g of colloidal silicic acid and are added to the dried granulate, to produce 1 20 g of tablet composition.

The tablet composition is subsequently processed by conventional pressing techniques to produce 1000 tablets each of 1 20 mg.

EXAMPLE 2: Process for the production of 1000 capsules 49 Pindolol, 1.5 g Cloxazolam, 104.44 g lactose, 10 g corn-starch and 0.06 g colloidal silica are mixed in a conventional mixer. The initially obtained mixture is passed through a sieve and then further mixed until homogeneous. The obtained powder mixture is then filled into 1000 hard gelatine capsules, each containing 1 20 mg of powder.

Claims

1. A pharmaceutical composition comprising as active agents, a) an indole adrenergic ss-blocker and b) a benzodiazepine minor tranquilizer.

2. A composition according to claim 1, wherein active agent a) is a compound of formula I

wherein R1 is H, CH3, -C0Oalkyl(C14), -CON H2 or CN; R2 is H, CI or CH3; R3 is alkyl having 3 to 7 carbon atoms or a group of formula

wherein A is alkylene having 2 to 5 carbon atoms, X is a direct bond, oxygen or sulphur and R5 and R6 independently of each other are H, alkoxy having 1 to 4 carbon atoms, F, Cl or Br; and Y is H, alkanoyl having 2 to 5 carbon atoms or benzoyl optionally substituted by F, Cl or Br or by alkyl or alkoxy each having 1 to 4 carbon atoms; with the proviso that: 1) when R is -COOalkyl, -CONH2 or CN, R2 is H or CH3; 2) when R2 is Cl, R, is H or CH3 and R3 is a group of formula

and that 3) when Y is alkanoyl or optionally substituted benzoyl, R3 is alkyl.

3. A composition according to claim 2, wherein active agent a) is a compound selected from the group consisting of i) 1 -(indol-4-yloxy)-2-hydroxy-3-isopropyl- aminopropane, ii) 1 -(2-methyl-indol-4-yloxy)-2-hydroxy-3- isopropyl-aminopropane, iii) 1 -(2-carboisopropoxy-indol-4-yloxy)-2-hy- droxy-3-tert.-butyl-aminopropane, and iv) 1 -(2-methyl-indol-4-yloxy)-2-benzyloxy-3- tert.-butyl-aminopropane.

4. A composition according to claim 1, wherein active agent b) is a compound of formula

wherein R4, R5 and R6 independently of each other are H, alkyl or alkoxy each having 1 to 4 carbon atoms, halogen, hydroxy, NO2, CN, acyl, CF3, amino, acylamino, N-mono-(Cl 4- alkyl)-amino, N, N-di-(C, 4-alkyl)-amino, acyloxy, carboxyl, (C1 4-a lkoxy)-carbonyl, carbamoyl, N-mono-(C, 4-alkyl)-carbamoyl, N,N-di (C, 4-aíkyl)-carbamoyl, or alkylthio, alkylsulfinyl or alkylsulfonyl each having 1 to 4 carbon atoms, R7 is H, alkyl having 1 to 4 carbon atoms, cyclo-alkyl having 3 to 6 carbon atoms, aralkyl having 7 to 9 carbon atoms, aryl or phenacyl, R8 and R9 independently of each other are H or alkyl having 1 to 4 carbon atoms, B is polymethylene optionally substituted by one or more alkyl groups having 1 to 4 carbon atoms, hydroxy-substituted alkyl groups having 1 to 4 carbon atoms and/or phenyl groups, and X is oxygen or sulphur.

5. A composition according to claim 4, wherein active agent b) is a compound selected from the group consisting of i) 1 0-chloro-1 1 b-(2-chlorophenyl) 2,3,7,11 b-tetrahydrooxazolo[3, 2-d] 1 ,4]ben- zodiazepin-6(5H)-one, and ii) 1 O-chloro-1 1 b-phenyl-2,3,7, 11 b-tetrahy- drooxazolo-[3,2-d][1 ,4]benzodiazepin-6(5H)- one.

6. A composition according to claim 2 or 3, wherein active agent b) is a compound as defined in claim 4 or 5.

7. A composition according to claim 1, wherein active agent a) is 1-(indol-4-yloxy)-2hydroxy-3-isopropyl-aminopropane and active agent b) is 1 0-chloro-1 1 b-(2-chlorophenyl)2,3,7,11 b-tetrahydrooxazolo[3, 2-d)[1 ,4jben- zodiazepin-6(5H)-one.

8. A composition according to any one of claims 1 to 7 wherein the ratio of active agent a) to active agent b) is from about 10:1 to about 1 :20 parts by weight.

9. A composition according to claim 8 wherein the ratio is from about 5:1 to about 1:3 parts by weight.

10. A composition according to claim 9 wherein the ratio is about 4:1.5 parts by weight.

11. A composition according to any one of claims 1 to 10 in unit dosage form.

1 2. A composition according to claim 11 containing from about 2 to about 6 mg of active agent a).

1 3. A composition according to claim 1 2 containing about 4 mg of active agent a).

1 4. A composition according to claim 1 substantially as hereinbefore described with reference to the accompanying examples.

1 5. A composition according to any one of claims 1 to 14 for use in the treatment of anxiety.

16. A pack or dispenser-device containing separately an active agent a) and an active agent b) according to any one of claims 1 to 7 and adapted for the concomitant presentation or administration of said active agents a) and b).

1 7. A pack or dispenser-device according to claim 1 6 bearing directions for the concomitant administration of a predetermined amount of said active agents a) and b).