EP0232254A1

EP0232254A1 - Oxazepam containing pharmaceutical composition

Info

Publication number: EP0232254A1
Application number: EP85903997A
Authority: EP
Inventors: Pawan Seth; Pyare Seth
Original assignee: Individual
Current assignee: Individual
Priority date: 1985-07-24
Filing date: 1985-07-24
Publication date: 1987-08-19
Also published as: WO1987000428A1; NO871229L; NO871229D0; DK149787A; DK149787D0

Abstract

Composition pharmaceutique ayant une solubilité améliorée et une vitesse de dissolution accrue et destinée au traitement des troubles du sommeil, et utilisée comme tranquillisant, contenant en tant qu'ingrédient actif 7-chloro-1,3-dihydro-3-hydroxy-5-phényl-2H-1,4-benzodiazépine-2-one associé à une substance porteuse, et procédé pour la préparation de l'ingrédient actif de la composition pharmaceutique et son utilisation.Pharmaceutical composition having improved solubility and increased dissolution rate and intended for the treatment of sleep disorders, and used as a tranquilizer, containing as active ingredient 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl -2H-1,4-benzodiazepine-2-one associated with a carrier substance, and process for the preparation of the active ingredient of the pharmaceutical composition and its use.

Description

Oxazepam containing pharmaceutical composition.

Technical Field of the Invention

The present invention relates to a pharmaceutical composition having improved solubility and improved rate of dissolution for the treatment of sleep disorders and as a tranquiliser containing as an active ingredient 7- chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiaze- pin-2-one associated with a carrier, as well as a process for the preparation of the active ingredient of the pharmaceutical composition and the use thereof.

Background of the Invention

Pharmaceutical compositions for the treatment of sleep disorders should display the following properties:-

(a) a rapid onset of activity following administration, for example within one to two hours;

(b) the activity of the medicament should last for a period corresponding to that of the normal period of sleep (8 to 10 hours);

(c) there should be minimal residual sedating effects after 10 to 12 hours, so that after awakening, the subject can attend to his/her normal daily routine.

From the foregoing it is apparent that for a medicament which is to be used as a hypnotic, it is a prerequisite that there be a relatively rapid onset of action and that over the desired period of sleep a regulated con centration of active ingredient in the therapeutic range should be maintained.

Up to now there have been many attempts to develop active ingredients and indeed new classes of drugs which fulfil the above criteria for a hypnotic drug. The benzodiazepines have been widely studied in this connection. Up to now, however, it has not proved possible to optimise a suitable active ingredient such as 7-chloro- 1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2- one so that it can meet the aforesaid requirements as a hypnotic.

It is known (D. Breimer et al. Drug Research 30(1) No. 5a (1980) pp 875 et seq) that, among the various benzodiazepines large diferences exist with regard to their pharmacokinetic properties and metabolism in man. Some, like diazepam, are eliminated from the body at a relatively slow rate. Oxazepam on the other hand is rather rapidly metabolised without the .formation of active metabolites. These differences are clinically very important since pharmacokinetic factors determine the duration of action of the medicament and hence also the amount of the dose. For the various clinical indications of the benzodiazepines the required duration of action of the medicament differs quite fundamentally. In anti- convulsant and anti-anxiety therapy continuous treatment is pursued, so that compounds where the parent medicament or active metabolites thereof have a long elimination half-life are preferred. If on the other hand the benzodiazepine is used as a hypnotic, the duration of action should be restricted to the night so that on the following day no tiredness or other side effects are felt. For the alleviation of sleep disorders a relatively short duration of action is necessary especially when the medicament is taken every night.

The compound 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl- 2H- 1,4-benzodiazepin-2-one which has been accorded the international short name oxazepam is a known compound. 7-Chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzo- diazepin-2-one is used mainly as the active ingredient in tranquilisers for the alleviation of anxiety states for calming the patient and sometimes for alleviation of sleep disorders. It is administered orally in the form of tablets or capsules which may for example contain from 15 to 50 mg of 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H- 1,4-benzodiazepin-2-one (Swiss Drug Index 1982).

Although 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4- benzodiazepin-2-one has pharmacokinetic properties which would indicate its suitability for use as a hypnotic, such a high dose has to be used as a result of the relatively low solubility that side effects appear. Thus, following administration of 45-50 mg oxazepam patients display severe side effects the following morning (Brit. J. Clin. Pharmacology 1978, 6, 325-333).

A further disadvantage arising out of the low solubility of 7-chloro-1,3-dihydro-3-hydrσxy-5-phenyl-2H-1,4-benzo- diazepin-2-one is that it is very slowly absorbed in the gastrointestinal tract which results in delayed appearance of hypnotic activity in the body.

It has not previously proved possible to formulate a hypnotic having 7-chloro-1,3-d-ihydro-3-hydroxy-5-phenyl- 2H-1,4-benzodiazepin-2-one as the active ingredient which showed sufficient hypnotic activity (for example to induce rapid sleep onset) at a dosage of less than 45 mg.

It is clear that the use of 7-chloro-1,3-dihydro-3-hy- droxy-5-phenyl-2H-1,4-benzodiazepin-2-one in the treatment of sleep disorders would be more advantageous if it would be possible to decrease the dosage to such an extent that the desired activity was achieved without any accompanying side effects. There are also situations where rapid onset of action is required for a tranquiliser, e.g. when rapid treatment of an anxiety state is required and parenteral administration should be avoided.

Known processes for increasing the solubility and dissolution rate of 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl- 2H-1,4-benzodiazepin-2-one such as diminution of particle size by milling in pin mills or air-jet micronisation have not been successful. Oxazepam, due to its extreme hydrophobic surface shows a very high tendency of agglomeration which often nullifies the very purpose of particle size reduction. As such, the use of micronised 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-ben- zodiazepin-2-one has not resulted in any appreciable improvement in the dissolution rate or rate of absorption in the body, as reflected in most of- the presently available 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H- 1,4-benzodiazepin-2-one dosage forms.

It is an object of the present invention to provide an orally administrable pharmaceutical composition based on the active ingredient 7-chloro-1,3-dihydro-3-hydroxy-5- phenyl-2H-1,4-benzodiazepin-2-one for the effective treatment of sleep disorders, which is quickly absorbed and displays the minimum of side effects.

It is a further object of the present invention to provide a formulation effective against sleep disorders containing a difficultly soluble agent.

It is a further object of the present invention to provide a method of inducing or sustaining sleep in subjects by administration of a pharmaceutical composition.

Disclosure of the Invention

These and other objects are achieved by the present invention by adsorbing 7-chloro-1,3-dihydro-3-hydroxy- 5-phenyl-2H-1,4-benzodiazepin-2-one onto a suitable pharmaceutical carrier or excipient in order to increase its ability to be absorbed on ingestion.

According to one preferred embodiment of the invention there is provided a pharmaceutical composition for the treatment of sleep disorders or for use as a tranquiliser containing as an active ingredient the substance 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzo- diazepin-2-one adsorbed in fine particle form on a pharmaceutial carrier or excipient as a substrate, wherein, the 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl- 2H-1,4-benzodiazepin-2-one has improved solubility and rate of dissolution following administration of the pharmaceutical composition. The pharmaceutical carrier or excipient may be one having a large specific surface area on which 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl- 2H-1,4-benzodiazepin-2-one can be deposited from solution in fine particle form, such as a starch or a micro- crystalline cellulose. However, other pharmaceutical carriers may be used such as calcium diphosphate montmorillonite and silicates such as aerosil.

The composition of the present invention is primarily suited to the treatment of sleep disorders since the release pattern of the oxazepam is ideally suited to this indication. However, should the medical picture so dictate, the composition may also be used for other indications calling for oxazepam therapy, including treatment of tension, agitation and anxiety and associated autonomic disorders, i.e. use as a general tranquiliser.

In the pharmaceutical composition of the invention the said carrier or excipient and also the 7-chloro-1,3-di- hydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one conveniently has a particle size of less than 40 microns, preferably less than 20 microns. The particle size will usually lie in the range of from 10 to 40 microns The fine particle size of the 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one is critical to the present invention. The 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one should preferably all have a particle size of less than 5 microns and even better solubility and rate of dissolution and hence rapid sleep onset will be achieved if the particle size is less than 1 micron.

The 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-ben- zodiazepin-2-one and pharmaceutical carrier or excipient may be present in the composition in any desired ratio e.g. 1:1 or 1:2 or more. Larger or smaller ratios may of course be used, eg up to 1:10, but this will simply increase the bulk and expense of the composition. Ratios down to 1:0.5 can also be used, but the problems start to occur with the adsorption of the 7-chloro-1,3-dihy- dro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one.

The present invention also provides a process for the preparation of the pharmaceutical composition of the instant invention. The process according to the invention comprises mixing a solution of 7-chloro-1,3-dihy- dro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one in an organic solvent in which the pharmaceutical carrier or excipient is suspended and which preferably also contains a surfactant, with a non-solvent for 7-chloro- 1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin- 2-one the said organic solvent and the non solvent being mutually miscible under the conditions of mixing so as to precipiate the 7-chloro-1,3-dihydro-3-hydroxy-5-phe- nyl-2H-1,4-benzodiazepin-2-one in fine particle form on the substrate.

Best results are achieved in the process according to the invention if the organic solution is poured into a large quantity of the non-solvent rather than simply mixing non-solvent into the organic solution. The non- solvent most conveniently employed for many reasons is water although other convenient non-solvents may of course be used.

Also according to the present invention there is provided a process for the preparation of a pharmaceutical composition using the compound oxazepam adsorbed onto a carrier in accordance with the invention.

This product serves as the active ingredient component in the pharmaceutical formulation of hypnotics.

Detailed description of the Invention

Any suitable organic solvent which is capable of dissolving 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-ben- zodiazepin-2-one at a mildly elevated temeprature can be used in the process of the present invention. It is, however, preferred to use ethanol or acetone as the organic solvent. Other organic solvents such as dioxan which are miscible with water in all proportions and conventionally employed in the preparation of pharmaceutical compositions can also be employed.

The pharmaceutical carrier or diluent may be any pharmaceutically acceptable material which displays the necessary large specific surface area. The two materials of choice from the po.ints of view of availability and price are starch and micro crystalline cellulose. Direct suspension of the pharmaceutical carrier or excipient in the heated organic solution modifies the pharmaceutical carrier or excipient to such an extent that it results in the association with the active ingredient according to the invention and gives the desired rapid dissolution rate of 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one. Suspension of the starch in the organic solution may be effected at any convenient temperature. Such a temperature may conveniently be from 60 to 80°C, preferably about 75°C.

Starches which may be used include finally milted starches from maize, rice and other cereals as well as potato starch and cassava starch.

The surfactant or wetting agent which can be used may be any such agent which is convenient. One example of such an agent is polyethyleneglycol-sorbitan-monooleate. Other surfactants which can be used include polyethyl- eneglycol-sorbitan-monostearate as well as polyhydroxy- ethylene stearate.

The normal procedure is to first prepare the pharmaceutical composition of the invention (adsorbate) and then to add other conventional pharmaceutical carriers and excipients thereto. However, the other conventional pharmaceutical carriers and excipients can also already be present during the actual precipitation step.

According to one theory of the mechanism of the invention, to which we do not wish to be limited, the oxazepam can be absorbed in fine particle size form by virtue of the use of a pharmaceutical carrier or excipient having a large surface area. It should be noted that in the present invention the pharmaceutical carriers or excipients have no pharmacplogical activity of their own.

The dosage unit forms of the invention for the treatment of sleep disorders conveniently contain from 10 to 40 mg of 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzo- diazepin-2-one, preferably from 25 to 35 mg. Other dosages such as 20 or 30 mg may of course be used.

The dosage unit forms for use as a tranquiliser may vary widely e.g. from 5 to 50 mg. Other dosages which may be similar to those mentioned above for sleep disorders may also be used.

The formulations may conveniently be presented in unit dosage and may be prepared by any of the methods well known in the art of pharmacy.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the pharmaceutical composition of the invention; as a powder or granules; or a suspension in an aqueous liquid or non-aqueous liquid such as a syrup, an elixir, an emulsion or a draught. The pharmaceutical composition may also be presented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active compound being in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine, comprising a mixture of the powdered active compound with any suitable carrier.

A syrup may be made by adding the active compound to a concentrated, aqueous solution of a sugar, for example, sucrose, to which may also be added any accessory ingredient. Such accessory ingredient (s) may include flavourings, an agent to retard crystallization of the sugar or an agent to increase the solubility of any other ingredient, such as polyhydric alcohol for example glycerol or sorbitol.

Formulations for rectal administration may be presented as a suppository with a conventional carrier such as cocoa butter.

In addition to the aforementioned ingredients, the formulations of this invention may further include one or more accessory ingredient (s) selected from diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.

Best mode of carrying out the invention

The invention will now be illustrated in more detail with particular reference to the following examples.

Example 1

(Preparation of active ingredient)

100 g of oxazepam was suspended in 5 litres of ethanol (ca 96%) with stirring. 10 g of polyethyleneglycol-sorbitan-monooleate were then added with continued stirring and the mixture warmed to ca 75°C with continued stirring until a clear solution was obtained. To this solution was added 200 g corn starch with stirring until a uniform suspension was obtained. The suspension was then decanted in a thin slow stream into 20 litres of water with continuous rapid stirring. Stirring was continued for a further half hour until a milky white suspension was formed. The ethanol was removed from the suspension by distillation on a rotary evaporator. The aqueous suspension was then passed through a spray-dryer to give a fine flowing white powder which contains 33 to 35% by weight of oxazepam adsorbed on the starch as carrier particles.

Example 2 The procedure of Example 1 was repeated with the sole difference that acetone was used as the solvent in place of ethanol.

Example 3

The procedure of Example 1 was followed with the sole difference that microcrystalline cellulose or Montmorillonite was used in place of starch.

In the following Example a pharmaceutical tablet formulation is given.

Example 4

The fine powder material obtained in Example 1 was used to prepare a tablet containing 25 or 35 mg oxazepam using the following "direct compression" formula:-

Oxazepam-starch-adsorbate 100.00 mg

(i.e. oxazepam = 35 mg)

Lactose 87.00 mg

Microcrystalline cellulose 60.00 mg

(AVICEL 102)

Colloidal silica (Aerosil) 1.00 mg

Magnesium stearate 2.00 mg

Tablet Weight 250.00 mg

The above ingredients are mixed together, sieved and directly compressed on a tablet machine into tablets containing 35 mg oxazepam.

Example 5

The oxazepam-starch adsorbate prepared according to Example 1 was formulated as follows to be filled into hard. gelatine capsules Oxazepam-s tarch-adsorbate 100 .00 mg

( oxazepam = 35 mg ) Lactose 100 . 00 mg

Colloidal silica ( Aeros il ) 1 . 00 mg S tarch 47 . 00 mg Magnesium s tearate 2 . 00 mg

250 . 00 mg

The above mixture was f illed into capsules in which 35 mg ox azepam was contained per capsule .

Example 6

A comparative in vivo pharmacokinetic study was made in 12 healthy human volunteers using a commercially available oxazepam tablet containing 50 mg oxazepam (Tablet A) and an experimental tablet containing 25 mg oxazepam made according to Example 4 (Tablet B). The in vivo study was planned as a cross-over experimental design and blood samples were drawn at various time intervals after the administration of the tablets. The blood samples were then analysed for the oxazepam content, using a gas chromatography method with an electron capture detector.

The results of this comparative study are shown in the following Tables I - V.

Table I shows the time course of average blood concentration of oxazepam for the 12 volunteers, using the two types of tablets for a total period of 48 hours.

Table II shows a comparison of t_max values (the time to reach the maximum blood concentration) in the volunteers individually. It was found that, whereas the commercial tablet A took an average period of about five hours (range 1 - 9 hours), the experimental tablet B reached peak blood concentration within 1 1/2 hours (range 3/4 - 3 hours). Table III shows a comparison of C_max values (the maximum blood concentration) for the two types of oxazepam tablets. It was rather surprising to observe that almost identical peak blood concentrations (average 516 - 535 ng/ml) were reached in both the cases, although tablet B contained only half the dose (= 25 mg oxazepam) as that contained in commercial tablet A ( = 50 mg oxazepam).

Table IV shows a comparison of oxazepam blood concentrations reached after 10 minutes and 20 minutes respectively after the administration. It can be observed that after twenty minutes, the blood concentrations of oxazepam reached with tablet B were almost four times higher than those achieved with the commercial tablet A. Evidently it is desirable for the induction of sleep and onset of hypnotic activity that a certain minimum level of drug concentration in the blood is achieved rapidly, which is possible with the tablet B, but not with commercial tablet A.

Table V shows the comparative oxazepam blood concentrations present after 9 hours and 24 hours respectively. In case of tablet B, the drug concentration level after 9 hours fell back to a very low level, comparable to those reached with tablet A after 24 hours only. This can have an important influence for causing the side effects observed with commercial tablet A.

This pharmacokinetic study, could show that an optimally formulated product containing half the dose (such as esprim tablet B) was able to show a desirable hypnotic activity with reasonably rapid onset of activity and minimal side effects, whereas a typical sample of commer cial tablet A containing twice the dose (= 50 mg ) of oxazepam, but in a slow-absorption formulation was unsuitable as a hypnotic agent. This series of pharmacodynamic and clinical studies made on healthy volun teers thus showed the rapid onset of sleep achieved using the pharmaceutical composition of the invention (eg well inside 2 hours) and that no daytime sedation or hampering of daytime activity was observed.

ND = not detectable ( ≤ 2 ug/ml)

_x

Claims

C L A I M S

1. A pharmaceutical composition containing, as an active ingredient, the substance 7-chloro-1,3-dihydro- 3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one, characterised in that in order to improve its solubility and rate of dissolution the 7-chloro-1,3-dihydro-3-hydroxy- 5-phenyl-2H-1,4-benzodiazepin-2-one is adsorbed on a pharmaceutical carrier or excipient in fine particle form.

2. A pharmaceutical composition as claimed in claim 1, characterised in that the 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one is present after adsorption in a particle size of less than 5 microns.

3. A pharmaceutical composition as claimed in claim 1, characterised in that the 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one is present after adsorption in a particle size of less than 1 micron.

4. A pharmaceutical composition as claimed in any one of claims 1 to 3 , characterised in that said pharmaceutical carrier or excipient has an average particle size of less than 40 microns.

5. A pharmaceutical composition as claimed in claim 4, characterised in that said pharmaceutical carrier or excipient has an average particle size of less than 20 microns.

6. A pharmaceutical composition as claimed in any one of claims 1 to 5, characterised in that the pharmaceutical carrier or excipient is starch.

7. A pharmaceutical composition as claimed in any one of claims 1 to 6, characterised in that the pharmaceutical carrier or excipient is microcrystalline cellulose.

8. A pharmaceutical composition as claimed in any one of the preceding claims characterised in that the ratio of 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzo- diazepin-2-one to pharmaceutical carrier or diluent is from 1:1 to 1:10.

9. A pharmaceutical composition as claimed in claim 8 characterised in that the ratio of 7-chloro-1,3-dihydro- 3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one to pharmaceutical carrier or diluent is from 1:1 to 1:2.

10. A pharmaceutical composition as claimed in any one of the preceding claims for the treatment of sleep disorders.

11. A pharmaceutical composition as claimed in any one of claims 1 to 9 for use as a tranquiliser.

12. A process for the preparation of a pharmaceutical composition containing 7-chloro-1,3-dihydro-3-hydroxy- 5-phenyl-2H-1,4-benzodiazepin-2-one characterised in that one mixes a solution of 7-chloro-1,3-dihydro-3- hydroxy-5-phenyl-2H-1,4-benzodiazepiπ-2-one in an organic solvent in which a pharmaceutical carrier or excipient is suspended with a non-solvent for the 7-chloro- 1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2- one, the said organic solvent and non-solvent being mutually miscible under the conditions of mixing so as to precipitate the 7-chloro-1,3-dihydro-3-hydroxy-5- phenyl-2H-1,4-benzodiazepin-2-one in fine particle form onto the pharmaceutical carrier or diluent.

13. A process according to claim 12, characterised in that the solution also contains a surfactant.

14. A process according to claim 13, characterised in that the surfactant is polyethyleneglycol sorbitan monooleate.

15. A process according to any one of claims 12 to

14, characterised in that the non-solvent is water.

16. The use of a pharmaceutical composition as claimed in any one of claims 1 to 11 or when produced by a process as claimed in any one of claims 12 to 15 in dosage unit medicament form containing from 10 to 40 mg 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzo- diazepin-2-one per dosage unit for the treatment of sleep disorders.

17. The use of a pharmaceutical composition as claimed in any one of claims 1 to 11 or when produced by a process as claimed in any one of claims 12 to 15 in dosage unit medicament form containing from 5 to 50 mg 7-chloro-1.3-dihydro-3-hydroxy-5-phenyl-2H-1.4-benzo- diazepin-2-one per dosage unit as a tranquiliser.

18. The use as claimed in claim 16, wherein the dosage unit contains from 25 to 35 mg 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one.

19. The use of 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one having improved solubility and rate of dissolution, for the treatment of sleep disorders characterised in that the 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one is adsorbed on a pharmaceutical carrier or diluent in fine particle form.

20. The use of 7-chloro-1.3-dihydro-3-hydroxy-5- phenyl-2H-1.4-benzodiazepin-2-one having improved solubility and rate of dissolution as a tranquiliser char acterised in that the 7-chloro-1.3-dihydro-3-hydroxy- 5-phenyl-2H-1.4-benzodiazepin-2-one is adsorbed on a pharmaceutical carrier or diluent in fine particle form.

21 The use as claimed in claim 19 or claim 20 characterised in that the particle size of the 7-chloro- 1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin- 2-one is less than 5 microns.

22. The use as claimed in claim 20 characterised in that the particle size of the 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one is less than one micron.

23. The use of 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one for the preparation of means for the treatment of sleep disorders.

24. The use of 7-chloro-1.3-dihydro-3-hydroxy-5- phenyl-2H-1.4-benzodiazepin-2-one for the preparation of means for the treatment of anxiety and tension disorders.

25. Each and every novel feature of the invention hereinbefore described.