NO790479L - PROCEDURE FOR PREPARING A PHARMACEUTICAL PREPARATION - Google Patents

Description

Method for the manufacture of a pharmaceutical preparation.

The present invention relates to a method for the production of a pharmaceutical preparation, and the distinctive feature of the method according to the invention is that it combines

a) an active ingredient of formula I

where 1 stands for hydrogen or methyl,

R2' stands for methyl or ethyl, and

n stands for 1 or 2,

with

b) a sedative active substance in the form of a minor tranquilliser.

As active ingredient a) advantageously 10-(2-(dimethylamino)ethyl7-5,10-dihydro-5-methyl-11H-dibenzo[b,07/1]diazepin-11-one is used.

As active ingredient b) chlordiazepoxide, diazepam, prazepam, oxazepam, medazepam, lorazepam or a compound of formula II is advantageously used

"wherein R^, R2 and R^ are the same or different and each stand for hydrogen, fluorine, chlorine, bromine, hydroxy, nitro, cyano, trifluoromethyl, amino, carboxyl, carbamoyl, alkyl (C1_4), alkoxy (C1_4) , alkanoyl (C1_5), alkanoylamino (C]^)' alkanoyloxy ( ci_$) > alkylamino (C1_^), di^alkyl(C1_417amino, alkoxy(c1_4)carbonyl, alkyl(C1_4)carbamoyl, di/alkyl(C^_417carbamoyl , alkylthio(C1_4), alkylsulfinyl(C1_4), alkylsulfonyl(C1_4), aroyl(C^_^1), aroylamino(c7-11) or aroyloxy(c7_-<q>)</>

R4 stands for hydrogen, alkyl(C^_4), aryl(C6_1Q), <cyclo>alkyl(C3_6), aralkyl (C7_1;L) or f enacyl (C7_11),

R5 and R& are the same or different and mean hydrogen or alkyl(C1_4),

A stands for polymethylene (C2_5), which may be substituted with alkyl (C1_4) or hydroxyalkyl (c2_4) or phenyl, and X means oxygen or sulphur.

Advantageously used as active ingredient b) 10-chloro-11b-(2-chlorophenyl)-2,3,7,11b-tetrahydrooxazolo/3,2-d7/1,47benzo-diazepin-6(5H)-one or 10- chloro-2,3,7,11b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-d]1,47benzodiazepine-6(5H)-one.

These and other features of the method according to the invention appear in the patent claims.

R1 and R4 are preferably hydrogen, R2 is preferably chlorine, bromine or nitro, R^ is preferably hydrogen, chlorine, fluorine or methyl, R^ is preferably hydrogen, R& is preferably hydrogen or methyl, A is preferably dimethylene, which is optionally substituted with alkyl, and X preferably stands for oxygen. R2 is preferably located in the position marked "a" in the ring.

Preferred compounds of this group are

10-bromo-11b-(2-fluorophenyl)-2,3,7r11b-tetrahydrooxazolo-/3,2-d7/1,4/benzodiazepine-6(5H)-one and more preferably

10-chloro-11b-(2-chlorophenyl)-2,3,7,11b-tetrahydrooxazolo-[3,2-d7/1,4]benzodiazepine-6(5H)-one known as "Cloxazolam"

and

10-chloro-2,3,7,11b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-b7]/i,47benzodiazepine-6(5H)-one known as "Oxazolam".

The above-mentioned compounds can be used in the form of the free bases or in the form of pharmaceutically acceptable acid addition salts which have the same degree of action as the free bases. Such salts include salts with organic acids in particular, e.g. maleic acid or methanesulfonic acid, or salts with inorganic acids such as e.g. hydrochloric acid or perchloric acid, in consideration.

The compounds of formula I are known and have an antidepressant effect.

The recognition that underlies the present invention is that a combination of a compound of formula I with a tranquilizer in the form of a so-called "Minor tranquilliser'} especially with a compound of formula II, in addition to a central effect in the brain, which surprisingly, the sum of the effects of the individual components exceeds the sum of the effects of the individual components and that the maximum effect is further achieved faster than one would expect from the effects of the individual components. This was determined using quantitative standard electroencephalography (EEG) in clinical trials. In one trial, 10 young healthy subjects received a placebo, 80 mg of a compound of formula I, such as dibenzepine, 1 or 2 mg of the aforementioned minor tranquilliser, such as "Cloxazolam", and a combination of 80 mg of a compound of formula I with 1 or 2 mg of a "minor tranquillizer" in a random (randomized) double-blind trial in single doses with a one-week interval between oral administrations . After feeding, the EEG (Alpha, Beta, Delta and Theta waves) was measured every 2 hours for 15 min. over a period of 8 hours. The intensity of the Alpha, Beta, Delta and Theta waves was determined according to Mat§j£ek, Quantitative

Analytic Studies in Epilepsy, Raven Press, New York 1976, 183-205. The combination exhibits a dose-dependent significant increase in Delta activity and a decreasing Alpha activity, which is stronger than the sum of the individual Delta and Alpha activities of the individual components.

In addition, the maximum values for the Alpha and Delta activities were achieved earlier than one would expect based on the sum of the individual Alpha and Delta activities of the individual components.

The combination is therefore suitable for use as an anti-depressant preparation.

The doses used obviously vary according to the relationship

between the active substances a) and b) in the combination, the method of administration as well as the method of treatment. Usually, daily doses of the active ingredient a) amount to 40 to 720 mg.

For treatment of e.g. psychogenic depressions, depressive states of despondency and somatic depressions constitute the daily added dose of the active ingredient a) preferably 40 to 240 mg. The one for treatment of e.g. endogenous depressions daily added dose of the active ingredient a) should amount to 120 to 720 mg, preferably 240 to 600 mg. The weight ratio between active ingredient a) and active ingredient b) is between 240:1 and 10:1, preferably between 200:1 and 20:1, preferably between 80:1 and 40:1. Appropriately, the dose of the active ingredient b) is 50 to 100% of that indicated for the minor tranquilliser added to the normal daily dose.

The daily administered dose can preferably be administered 2 to 4 times a day in partial amounts or 1 to 2 times a day in slow-release form.

The active substances a) and b) can be present together in a form of supply or separated until the simultaneous supply.

Methods for the production of pharmaceutical preparations of this type are known, and pharmaceutical preparations containing active ingredients a) or b) are also known, but pharmaceutical preparations containing the active ingredients a) and b) together are new but can be produced in the usual way.

The new pharmaceutical preparations can be administered enterally in the form of

tablets, capsules, dragees, suppositories, suspensions and syrups or parenterally in the form of injection solutions or suspensions. The foæbrukket is supplied with both the active ingredient

a) as the active ingredient b) orally in the form of a single dose. This single dose can, if desired, contain the active ingredients a) and b) in separate form, e.g. in separate layers in a layered tablet or in an almond tablet.. The pharmaceutical preparations can contain, next to the active ingredients, pharmacosytically resistant organic or inorganic excipients, possibly granulation aids, binders, lubricants, suspending agents, wetting agents and preservatives. Furthermore, the preparations may further contain colourings, flavorings, bulking agents etc. Calcium carbonate, lactose, microcrystalline cellulose, mannitol or talc can be used as excipients for the production of tablets and as a granulating and distributing agent starch, alginic acid or microcrystalline cellulose, as a binder starch, gelatin or polyvinyl pyrrolidone, and as a lubricant magnesium stearate, stearic acid, colloidal silicon dioxide or talc. The tablets may optionally be coated, in order to delay distribution and adsorption in the digestive tract and thus to maintain a delayed effect over a longer period of time. As suspending agents for the production of liquid dosage forms, in particular methyl cellulose, tragacanth and sodium alginate and as wetting agents polyoxyethylene stearate and polyoxyethylene sorbitan monooleate come into consideration. In addition to this, preservatives such as p-hydroxybenzoic acid alkyl esters can also be used. Capsules can contain the active ingredients a) and b) alone or in a mixture with an inert solid diluent, e.g. calcium phosphate, starch, lactose, mannitol, colloidal silicon dioxide and microcrystalline cellulose.

Due to easy preparation and favorable supply, solid preparations are preferred, especially for the active ingredient a), e.g. hard gelatin capsules and tablets.

"Cloxazolam" is used because of its poor solubility, preferably in the form of solid preparations.

Example 1: Layered tablet

Layered tablets, which contain the following ingredients, can be prepared in a manner known per se and can be used for the treatment of depression in a dose of 1 to 2 tablets daily:

Composition of the second layer

Example 2: Coated tablet

Coated tablets containing the following ingredients were prepared in a manner known per se and are suitable for the treatment of depression in a dose of 1 to 2 tablets 2 to 4 times a day:

Cloak

Claims (8)

1. Procedure for the production of a pharmaceutical preparation, characterized by combining) an active substance with formula I where 1 stands for hydrogen or methyl, R2 1 stands for methyl or ethyl, and n stands for 1.or 2, with b) a sedative active substance in the form of a minor tranquillisec 2. Method as stated in claim 1, characterized in that as active ingredient a) 10-β-(dimethylamino)ethyl 7-5,10-dihydro-5-methyl-11H-dibenzo/b,e_7/1,4/diazepin-11-one is used. 3. Method as stated in claim 1, characterized in that chlordiazepoxide, diazepam, prazepam, oxazepam, medazepam, lorazepam or a compound of formula II is used as active ingredient b) wherein Ri > R2°9 R3 are identical or different and separate stands for hydrogen, fluorine, chlorine, bromine, hydroxide, nitro, cyano, trifluoromethyl, amino, carboxyl, carbamoyl, alkyl(C1 _4 ), alkoxy(C1 _4 ), alkanoyl(c1_5)/ alkanoylamino (C^_j-), alkanoyloxy (C^ _^ ), alkylamino(C^ _4 ), di/alkyl (C^_4)w7amino, alkoxy(C^ _4 )carbonyl, alkyl(C^ _4 )-carbamoyl, di/alkyl(C^ _4 ^/carbamoyl, alkylthio(C^ 4 ), alkylsulfinyl(C1 _4 ) , alkylsulfonyl(C1 _4 ), aroyl(c7 _11 )/ aroylamino(c7 _11 ) or aroyloxy(c7 _1 1) </> R4 stands for hydrogen, alkyl(C^4), aryl(C6_10), cycloalkyl(C2_6), aralkyl(C7_11) or phenacyl(C7_11)' R,- and Rg are the same or different and mean hydrogen or alkyl(C1 _4 ), A stands for polymethylene (C2_j-) which is optionally substituted with alkyl(C^_4 ) or hydroxyalkyl(C2_4 ) or phenyl, and X means oxygen or sulphur. 4. Method as stated in claim 1, characterized in that 10-chloro-11b-(2-chlorophenyl)-2,3,7,11b)-tetrahydro-oxazolo/3,2-df/ is used as active ingredient b) 1,4w7benzodiazepine-6 (5H )-one. 5. Method as stated in claim 1, characterized in that 10-chloro-2,3,7,11b-tetrahydro-2-methyl-11b-phenyl-oxazolo/3,2-d// is used as active ingredient b) 1,4/benzodiazepine-6(5H)-one. 6. Method as stated in claim 1, characterized in that a weight ratio between active ingredient a) and active ingredient b) of between 240:1 and 10:1 is used. 7. Method as stated in claim 1, characterized in that a weight ratio between active ingredient a) and active ingredient b) of between 200:1 and 20:1 is used. 8. Method as stated in claim 1, characterized in that a weight ratio between active ingredient a) and active ingredient b) of between 80:1 and 40:1 is used.