GB2067403A - Benzodiazepine compositions - Google Patents
Benzodiazepine compositions Download PDFInfo
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- GB2067403A GB2067403A GB8101593A GB8101593A GB2067403A GB 2067403 A GB2067403 A GB 2067403A GB 8101593 A GB8101593 A GB 8101593A GB 8101593 A GB8101593 A GB 8101593A GB 2067403 A GB2067403 A GB 2067403A
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- tranquilliser
- benzodiazepine
- pharmacologically
- butylaminopropiophenone
- pharmaceutically acceptable
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Pharmaceutical compositions comprise (i) a drowsiness - inducing benzodiazepine tranquilliser and (ii) a compound selected from m-chloro- alpha -t- butylaminopropiophenone, m-fluoro- alpha - t-butylaminopropiophenone and the pharmacologically and pharmaceutically acceptable acid addition salts thereof, optionally together with an acceptable carrier therefor.
Description
SPECIFICATION
Combinations of ketones and heterocyclic compounds, formulations thereof, preparation and use in medicine
This invention relates to combinations of an m-halo-a-t-butylaminopropiophenone or a pharmacologically and pharmaceutically acceptable acid addition salt thereof with a benzodiazepine tranquilliser, to pharmaceutical formulations comprising such a combination, to the preparation of such combinations and formulations, and to the concomitant use in human medicine of a said propiophenone or salt thereof and such a benzodiazepine compound.
m-Chloro-a-t-butylaminopropiophenone, m-fluoro-a-t-butylaminopropiophenone and the pharmacologically and pharmaceutically acceptable acid addition salts thereof are known to exhibit antidepressant properties when tested by standard techniques, see for example United Kingdom patent specification no. 1 340 032 which is incorporated herein by reference thereto.
It is also known that a number of compounds of the benzodiazepine type have been proposed for use in human medicine as tranquillisers (anxiolytics) for the treatment interalia of anxiety and have to a varying degree found clinical acceptance. Certain of such compounds however give rise to drowsiness and functional impairment, side effects often unwanted as limiting the performance of the recipient (see for example The Pharmacological Basis of Therapeutics, Goodman L.S. and Gilman A. eds., Macmillan
Publishing Co., Inc., fifth edition (1975) at pages 187 to 193, and Martindale: The Extra Pharmacopoeia, Wade
A. ed., The Pharmaceutical Press, twenty-seventh edition (1977) at pages 1515 to 1570, all of which is incorporated herein by reference thereto).The drowsiness-inducing benzodiazepine tranquillisers include the following: 7-bromo-1 ,3-dihydro-5-(2-pyridinyl)-2H-1 ,4-benzodiazepin-2-one (bromazepam);
7-chloro-N-methyl-5-phenyl-3H-1 ,4-benzodiazepin-2-amine 4-oxide (chlordiazepoxide) and salts thereof; 7-ch loro-2,3-dihydro-2,2-dihydroxy-5-phenyl-1 H-1 ,4-benzodiazepine-3-carboxylic acid (clorazepate) and salts thereof; 7-chloro-1 ,3-dihydro-1 -methyl-5-phenyl-2H-1 ,4-benzodiazepin-2-one (diazepam); 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1 ,4-benzodiazepin-2-one (lorazepam);
7-chloro-2,3-dihydro-1 -methyl-5-phenyl-1 H-1 ,4-benzodiazepine (medazepam) and salts thereof;; 7-chloro-1 ,3-dihydro-3-hydroxy-5-phenyl-2H-1 ,4-benzodiazepin-2-one (oxazepam); and 7-chloro-1 -(cyclopropylmethyl)-1 ,3-dihydro-5-phenyl-2H-1 ,4-benzodiazepin-2-one (prazepam).
It has now been found that the functional impairment and drowsiness in man which follow the administration of a drowsiness-inducing benzodiazepine tranquilliser may be prevented by the concomitant administration of a compound selected from m-chloro-a-t-butylaminopropiophenone, m-fluoro-a-tbutylaminopropiophenone and the pharmacologically and pharmaceutically acceptable acid addition salts thereof. Suitable indications for the administration of the two agents in this manner include
(a) the treatment in man of mixed anxiety and depression, in particular in situations where functional impairment or drowsiness is undesirable, and
(b) the treatment in man of anxiety in situations where functional impairment or drowsiness is undesirable.
The propiophenone and benzodiazepine compounds may each be administered to the human recipient by any suitable route but preferably by a route selected from oral and parenteral (inciuding subcutaneous, intradermal, intramuscular and intravenous). Desirably the same route is used for both compounds.
The size of dose required of the propiophenone and benzodiazepine compounds respectively will depend upon a number of factors including the identity of the recipient, the severity and precise nature of the condition to be treated and the route of administration and will ultimately be at the discretion of the attendant physician.
A dose of the propiophenone compound effective in preventing the functional impairment and drowsiness induced by the benzodiazepine compound will generally lie in the range 15 to 600 mg per day and more often in the range 18.75 to 450 mg per day. The desired dose is preferably presented as between two and four sub-doses administered at appropriate intervals throughout the day, thus where three sub-doses are employed each will generally lie in the range 5 to 200 mg and more often in the range 6.25 to 150 mg. For an adult human a suitable daily dose will generally lie in the range 60 to 600 mg and more often in the range 75 to 450 mg; where this is presented as three sub-doses each will thus generally lie in the range 20 to 200 mg and more often in the range 25 to 150 mg.A suitable daily dose for a child will generally be of the order of 25 to 50% of that for an adult and thus will generally lie in the range 15 to 300 mg and more often in the range 18.75 to 225 mg; where this is presented as three sub-doses each will generally lie in the range 5 to 100 mg and more often in the range 6.25 to 75 mg.
Where the propiophenone compound is administered by the oral route an effective dose will generally lie in the range 60 to 600 mg per day conveniently presented as three sub-doses each in the range 20 to 200 mg, and will more often lie in the range 75 to 450 mg per day conveniently presented as three sub-doses each in the range 25 to 150 mg. A daily oral dose for an adult human will generally lie in the range 225 to 600 mg, conveniently three sub-doses each in the range 75 to 200 mg, and more often in the range 300 to 450 mg conveniently as three sub-doses each in the range 100 to 150 mg. For a child a daily oral dose will generally lie in the range 60 to 300 mg, conveniently three sub-doses each in the range 20 to 100 mg, and more often in the range 75 to 225 mg conveniently as three sub-doses each in the range 25 to 75 mg.
Where the propiophenone compound is administered by the parenteral (subcutaneous, intradermal, intramuscular or intravenous) route an effective dose will generally lie in the range 15 to 375 mg per day conveniently presented as three sub-doses each in the range 5 to 125 mg, and will more often lie in the range 18.75 to 300 mg per day conveniently presented as three sub-doses each in the range 6.25 to 100 mg. A daily parenteral dose for an adult human will generally lie in the range 60 to 375 mg, conveniently three sub-doses each in the range 20 to 125 mg, and more often in the range 75 to 300 mg conveniently as three sub-doses each in the range 25 to 100 mg.For a child a daily parenteral dose will generally lie in the range 15 to 180 mg, conveniently three sub-doses each in the range 5 to 60 mg, and more often in the range 18.75 to 150 mg conveniently as three sub-doses each in the range 6.25 to 50 mg.
Antidepressant-effective daily doses and sub-doses of the propiophenone compound will generally lie within the appropriate ranges indicated in the foregoing as "more often" effective in preventing the functional impairment and drowsiness.
Full information as to doses and administration regimes in respect of the benzodiazepine compounds may be found in the literature, for example the ABPI Data Sheet Compendium 1979-80 published by Pharmind
Publications Limited and the Physicians' Desk Reference, 33rd edition (1979) published by Medical
Economics Company all of which is incorporated herein by reference thereto.
The propiophenone and benzodiazepine compounds may be administered separately, either as the raw chemicals or as pharmaceutical formulations, but for general convenience it is desirable that the two compounds be presented together in combination. Preferably the compounds are presented as a combination formulation comprising (i) a compound selected from m-chloro-a-t-butylaminopropiophenone, m-fluoro-a-t-butylaminopropiophenone and the pharmacologically and pharmaceutically acceptable acid addition salts thereof, and (ii) a drowsiness-inducing benzodiazepine tranquilliser, together with one or more
acceptable carriers therefor and optionally other therapeutic ingredients. The carrier(s) must be 'acceptable'
in the sense of being compatible with the other ingredients of the formulation and not deleterious to the
recipient thereof.
The formulations include those suitable for oral or parenteral (including subcutaneous, intradermal,
intramuscular and intravenous) administration although the most suitable route may depend upon for
example the condition of the recipient. The formulations may conveniently be presented in unit dosage form
and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step
of bringing into association the propiophenone and benzodiazepine compounds (the active ingredients) with
the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by
uniformly and intimately bringing into association the active ingredients with liquid carriers our finely divided
solid carriers or both, and then, if necessary, shaping the product into the desired formulation.
Formulations of the present invention suitable for oral administration may be presented as discrete units
such as capsules, cachets or tablets each containing a predetermined amount of each active ingredient; as a
power or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an
oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredients 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 ingredients in a
free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent,
lubricating, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable
machine a mixture of the powdered compounds moistened with an inert liquid diluent. The tablets may
optionally be coated or scored and may be formulated so as to provide slow or controlled release of the
active ingredients therein.
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions
which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic
with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may
include suspending agents and thickening agents. The formulations may be presented in unit-dose or
multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried
(lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for
injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared
from sterile powders, granules and tablets of the kind previously described.
It should be understood that in addition to the ingredients particularly mentioned above the formulations
of this invention may include other agents conventional in the art having regard to the type of formulation in
question, for example those suitable for oral administration may include flavouring agents.
Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose of each of the
two active ingredients, or an appropriate fraction thereof.
As regards the propiophenone ingredient, suitable amounts for presentation as unit dosage formulations
include the following:
(a) for oral administration: 25 mg, 50 mg, 75 mg, 100 mg and 150 mg;
(b) for parenteral administration: 6.25 mg, 12.5 mg, 25 mg, 50 mg and 100 mg.
As regards the benzodiazepine ingredient, suitable amounts for presentation as unit dosage formulations include the following:
(a) for oral administration: chlordiazepoxide and salts thereof: 5 mg, 10 mg and 25 mg; chlorazepate and salts thereof: 3.75 mg, 7.5 mg, 11.25 mg, 15 mg and 22.5 mg; diazepam: 2 mg, 5 mg and 10 mg; lorazepam: 0.5 mg, 1 mg and 2 mg; medazepam and salts thereof: 5 mg and 10 mg; oxazepam: 10 mg, 15 mg and 30 mg; and prazepam: 10 mg;
(b) for parenteral administration: chlordiazepoxide and salts thereof: 100 mg; diazepam: 10 mg and 20 mg; and lorazepam: 4 mg.
It will be appreciated that where the benzodiazepine compound is administered or formulated in the form of a salt the said salt should be pharmacologically and pharmaceutically acceptable.
The propiophenone compound is preferably selected from m-chloro-a-t-butylaminopropiophenone and the pharmacologically and pharmaceutically acceptable acid addition salts thereof and is more preferably one of the said salts thereof.
Especially preferred amongst the propiophenone compounds is m-chloro-a-t-butylaminopropiophenone hydrochloride.
The benzodiazepine compound is preferably selected from 7-chloro-N-methyl-5-phenyl-3H-1,4benzodiazepin-2-amine 4-oxide (chlordiazepoxide) and salts thereof, in particular the hydrochloride salt, and 7-chloro-1 ,3-dihydro-1 -methyl-5-phenyl-2H-1 ,4-benzodiazepin-2-one (diazepam).
It will be understood from the foregoing description that this invention may comprise any novel feature described herein, principally but not exclusively for example:
(a) a combination comprising (i) a drowsiness-inducing amount of a drowsiness-inducing benzodiazepine tranquilliser and (ii) a compound selected from m-chloro-a-t-butylaminopropiophenone, m-fluoro-a-t- butylaminopropiophenone and the pharmacologically and pharmaceutically acceptable acid addition salts thereof in an amount effective to prevent the drowsiness induced by the said tranquilliser;;
(b) a pharmaceutical formulation comprising (i) a drowsiness-inducing amount of a drowsiness-inducing benzodiazepine tranquilliser and (ii) a compound selected from m-chloro-a-t-butylaminopropiophenone, rn4luoro-ct-t-butylaminopropiophenone and the pharmacologically and pharmaceutically acceptable acid addition salts thereof in an amount effective to prevent the drowsiness induced by the said tranquilliser, together with an acceptable carrier therefor;
(c) a formulation according to (b) wherein the propiophenone is selected from m-chlorn-t- butylaminopropiophenone and the pharmacologically and pharmaceutically acceptable acid addition salts thereof;
(d) a formulation according to (b) wherein the propiophenone is a pharmacologically and pharmaceutically acceptable acid addition salt of m-chloro-a-t-butylaminopropiophenone;;
(e) a formulation according to (b) wherein the propiophenone is m-chloro-a-t-butylaminopropiophenone hydrochloride;
(f) a formulation according to any of (b) to (e) wherein the tranquilliser is selected from
bromazepam;
chlordiazepoxide and the pharmacologically and pharmaceutically acceptable salts thereof;
chlorazepate and the pharmacologically and pharmaceutically acceptable salts thereof;
diazepam;
lorazepam;
medazepam and the pharmacologically and pharmaceutically acceptable salts thereof;
oxazepam; and
prazepam;
(g) a formulation according to any of (b) to (e) wherein the tranquilliser is selected from chlordiazepoxide and the pharmacologically and pharmaceutically acceptable salts thereof;
(h) a formulation according to any of (b) to (e) wherein the tranquilliser is chlordiazepoxide;
(i) a formulation according to any of (b) to (e) wherein the transquilliser is chlordiazepoxide hydrochloride;
(j) a formulation according to any of (b) to (e) wherein the tranquilliser is diazepam;
(k) a formulation according to any of (b) to (j) suitable for oral administration;
(I) a formulation according to any of (b) to (j) suitable for parenteral administration;
(m) a combination or formulation respectively according to (a) and any of (b) to (I) wherein the propiophenone is present in an antidepressant-effective amount;;
(n) a formulation according to any of (b) to (m) in unit dosage form comprising the propiophenone and the tranquilliser each in a non-toxic amount;
(o) a method for the preparation of a combination or formulation, as appropriate, according to any of (a) to (n) comprising admixture of the ingredients thereof and, if appropriate, shaping of the product;;
(p) a method for preventing the functional impairment and drowsiness in man which follow the administration of a drowsiness-inducing, non-toxic amount of a drowsiness-inducing benzodiazepine tranquilliser, comprising the concomitant administration of a compound selected from m-chloro-a-tbutylaminopropiophenone, m-fluoro-a-t-butylaminopropiophenone and the pharmacologically and pharmaceutically acceptable acid addition salts thereof in a non-toxic amount effective to prevent the functional impairment and drowsiness induced by the said tranquilliser; and
(q) a method for the treatment in man of mixed anxiety and depression comprising the concomitant administration of (i) an anxiolytic-effective, non-toxic amount of a drowsiness-inducing benzodiazepine tranquilliser and (ii) an antidepressant-effective, non-toxic amount of a compound selected from m-chloro-a-t-butylaminopropiophenone, m-fluoro-a-t-butylaminopropiophenone and the pharmacologically and pharmaceutically acceptable acid addition salts thereof.
The following Examples are provided in illustration of the present invention and should not be construed as in any way constituting a limitation thereof.
EXAMPLE 1
Administration to man of m-chloro-a-t-butylaminopropiophenone hydrochloride and diazepam
(1) The effects of single oral doses of
(a) m-chloro-a-t-butylaminopropiophenone hydrochloride (100 mg),
(b) diazepam (2.5 mg or 5 mg),
(c) the propiophenone compound of (a) (100 mg) plus diazepam (2.5 mg or 5 mg), and
(d) lactose dummy were separately examined in twelve healthy volunteers using a balanced cross over design and double blind conditions. Results were analysed by analysis of variance and values of p < 0.05 taken as significant.
(2) A significant reduction in signals detected in the Wilkinson vigilance test (Prog. Clin. Psychol., 8, 28-43 (1968)) occurred one to two hours after diazepam 5 mg and a similar trend occurred after diazepam 2.5 mg compared with dummy. Performance after the propiophenone compound 100 mg and after the propiophenone compound 100 mg plus diazepam 5mg did not differ from that after dummy.
Calculations indicated that diazepam reduced the subjects' ability to discriminate between signals and noise, rather than theirwillingnessto report.
(3) Subjective effects, measured using visual analogue scales, showed that the subjects rated themselves significantly more drowsy, muzzy and dreamy after both diazepam 2.5 mg and diazepam 5 mg than after dummy. Afterthe propiophenone compound 100 mg plus either diazepam 2.5 mg or diazepam 5 mg the ratings never differed from dummy on any dimension.
The subjective effects had largely disappeared by six hours after dosing.
(4) It was concluded that the propiophenone compound prevented the functional impairment and drowsiness seen after diazepam.
EXAMPLE 2
Pharmaceutical formulations
Throughout the following the material referred to as Propiophenone Hydrochloride is m-chloro-a-tbutylaminopropiophenone hydrochloride.
(A) TABLETS a) Propiophenone hydrochloride plus diazepam
mg pertablet
Propiophenone Hydrochloride 100
Diazepam 5
Lactose 200
Starch 60
Methyl cellulose 6
Microcrystalline Cellulose 100
Magnesium Stearate 4
475
Mix the Propiophenone Hydrochloride, Diazepam, Lactose, Starch and half of the Microcrystalline
Cellulose. Granulate with a solution of the Methyl cellulose in water. Dry the granules. Mix in the rest of the
Microcrystalline Cellulose and the Magnesium Stearate. Compress.
b) Propiophen one Hydrochloride plus Chlordiazepoxide Hydrochloride
mg per tablet
Propiophenone Hydrochloride 100
Chlordiazepoxide Hydrochloride 10
Lactose 200
Sodium Starch Glycollate 20 Polyvinylpyrrolidone 6
Microcrystalline Cellulose 100
Stearic Acid 4
440
Mix the Propiophenone Hydrochloride, Chlordiazepoxide Hydrochloride, Lactose, Sodium Starch
Glycollate and half the Microcrystalline Cellulose. Granulate with a solution of the Polyvinylpyrrolidone in 50% aqueous alcohol. Dry the granules. Mix in the rest of the Microcrystalline Cellulose and the Stearic Acid.
Compress.
(B) CAPSULES a) Propiophenone Hydrochloride plus Diazepam
mg per capsule
Propiophenone Hydrochloride 50
Diazepam 2
Starch 200
Talc 2
254
Mix the Propiophenone Hydrochloride, Diazepam, Starch and Talc. Fill into gelatin capsules.
b) Propiophen one hydrochloride plus chlordiazepoxide hydrochloride
mg per capsule
Propiophenone Hydrochloride 50
Chlordiazepoxide Hydrochloride 5
Lactose 150
Starch 30
Gelatin 2
Magnesium Stearate 2
239
Mix the Propiophenone Hydrochloride, Chlordiazepoxide Hydrochloride, Lactose and Starch. Granulate with a solution of Gelatin in 50% aqueous alcohol. Dry the granules. Mix in the Magnesium Stearate. Fill into gelatin capsules.
(C) SYRUP
Propiophenone Hydrochloride 12.5 mg
Diazepam 0.5 mg
Sucrose 3 500 mg
Citric Acid 25 mg
Sodium Benzoate 5 mg
Methylhydroxybenzoate 5 mg
Glycerol 500 mg
Colour 1.5 mg
Flavour 0.005 ml
Purified waterto 5 ml
Dissolve the Methyl Hydroxybenzoate, Sodium Benzoate and Citric Acid in Purified Water. Add and dissolve the Sucrose and the Colour. Add and dissolve the Propiophenone Hydrochloride and Diazepam.
Add the Glycerol and the flavour and make up to volume with Purified Water and mix. Filter to give a clear bright syrup.
(D) INJECTIONS a) Propiophenone hydrochloride plus diazepam
Propiophenone Hydrochloride 25 mg
Diazepam 10 mg
Propylene Glycol 0.8 ml
Alcohol 0.2 ml
Sodium Benzoate 100 mg
Benzoic Acid 100 mg
Benzyl Alcohol 0.03 ml
Water for Injection to 2 ml
Dissolve the Propiophenone Hydrochloride and Diazepam in the Propylene Glycol and the Alcohol. Add the Benzyl Alcohol. Add and dissolve the Benzoic Acid and Sodium Benzoate. Make to volume with Water for
Injection. Sterilise by filtration and fill under aseptic conditions into sterile vials or ampoules.
b) Propiophenone hydrochloride plus chlordiazepoxide hydrochloride
Vial 1
Propiophenone Hydrochloride, Sterile 100 mg
Chlordiazepoxide Hydrochloride, Sterile 100 mg
equivalent to base
Mix the Propiophenone Hydrochloride, Sterile, and Chlordiazepoxide Hydrochloride, Sterile and fill into
vials under aseptic conditions.
Vial2 (diluent)
Polysorbate 80 80 mg
Benzyl Alcohol 0.03 ml
Propylene Glycol 0.4 ml
Maleic Acid 32 mg
Sodium Hydroxide qs to pH 3
Waterfor Injection to 2 ml
Mix the Polysorbate 80 and Propylene Glycol. Add the Benzyl Alcohol. Dissolve the Maleic Acid in 70% of
the Water. Add this solution to the Polysorbate 80 solution. Adjust to pH 3 with the Sodium Hydroxide, make
to volume with Water for Injection. Sterilise by filtration and fill under aseptic conditions into sterile vials or
ampoules.
Claims (34)
1. A combination comprising (i) a drowsiness-inducing amount of a drowsiness-inducing benzodiaze
pine tranquilliser and (ii) a propiophenone compound selected from m-chloro-a-t
butylaminopropiophenone, m-fluoro-a-t-butylaminopropiophenone and pharmacologically and phar
maceutically acceptable acid addition salts thereof in an amount effective to prevent the drowsiness induced
by the said tranquilliser.
2. A pharmaceutical formulation comprising (i) a drowsiness-inducing amount of a drowsiness-inducing
benzodiazepine tranquilliser and (ii) a propiophenone compound selected from m-chloro-a-t
butylaminopropiophenone, m-fluoro-a-t-butylaminopropiophenone and pharmacologically and phar
maceutically acceptable acid addition salts thereof in an amount effective to prevent the drowsiness induced
by the said tranquilliser, together with an acceptable carriertherefor.
3. Aformulation according to claim 2 wherein the propiophenone compound is selected from
m-chloro-a-t-butylaminopropiophenone and pharmacologically and pharmaceutically acceptable acid
addition salts thereof.
4. A formulation according to claim 2 wherein the propiophenone compound is a pharmacologically and pharmaceutically acceptable acid addition salt of m-chloro-a-t-butylaminopropiophenone.
5. A formulation according to claim 2 wherein the propiophenone compound is m-chloro-a-tbutylaminopropiophenone hydrochloride.
6. A formulation according to any of claims 2 to 5 wherein the benzodiazepine tranquilliser is selected from
bromazepam;
chlordiazepoxide and pharmacologically and pharmaceutically acceptable salts thereof;
chlorazepate and pharmacologically and pharmaceutically acceptable salts thereof;
diazepam;
lorazepam;
medazepam and pharmacologically and pharmaceutically acceptable salts thereof;
oxazepam; and
prazepam.
7. A formulation according to any of claims 2 to 5 wherein the benzodiazepine tranquilliser is selected from chlordiazepoxide and pharmacologically and pharmaceutically acceptable salts thereof.
8. A formulation according to any of claims 2 to 5 wherein the benzodiazepine tranquilliser is chlordiazepoxide.
9. A formulation according to any of claims 2 to 5 wherein the benzodiazepine tranquilliser is chlordiazepoxide hydrochloride.
10. A formulation according to any of claims 2 to 5 wherein the benzodiazepine tranquilliser is diazepam.
11. A formulation according to any of claims 2 to 10 in unit dosage form wherein the propiophenone compound and the benzodiazepine tranquilliser are each present in a non-toxic amount.
12. Aformulation according to any of claims 2 to 11, suitable for oral administration.
13. A formulation according to claim 11, suitable for oral administration, wherein the propiophenone compound is present in an amount in the range 25 to 150 mg.
14. A formulation according to claim 13 wherein the benzodiazepine tranquilliser is chlordiazepoxide or a pharmacologically and pharmaceutically acceptable salt thereof present in an amount selected from 5 mg, 10 mg and 25 mg.
15. A formulation according to claim 13 wherein the benzodiazepine tranquilliser is diazepam present in an amount selected from 2 mg, 5 mg and 10 mg.
16. A tablet according to any of claims 12 to 15.
17. A capsule according to any of claims 12 to 15.
18. Aformulation according to any of claims 2 to 11, suitable for parenteral administration.
19. A formulation according to claim 11, suitable for parenteral administration, wherein the propiophenone compound is present in an amount in the range 6.25 to 100 mg.
20. A formulation according to claim 19 wherein the benzodiazepine tranquilliser is diazepam present in an amount selected from 10 mg and 20 mg.
21. A sterile aqueous solution according to any of claims 18 to 20.
22. A method for the preparation of a combination according to claim 1 which comprises admixture of the benzodiazepine tranquilliser and propiophenone compound ingredients thereof.
23. A method for the preparation of a pharmaceutical formulation according to any of claims 2 to 21 which comprises admixture of the benzodiazepine tranquilliser and propiophenone compound with the carrier therefor and, if necessary, shaping of the product.
24. A combination according to claim 1 whenever prepared by a method according to claim 22.
25. A pharmaceutical formulation according to any of claims 2 to 21 whenever prepared by a method according to claim 23.
26. A pharmaceutical formulation substantially as hereinbefore described with particular reference to
Example 2.
27. A method substantially as herein before described, with particular reference to Example 2, for the preparation of a pharmaceutical formulation according to claim 26.
28. A method for preventing the functional impairment and drowsiness in man which follow the administration of a drowsiness-inducing, non-toxic amount of a drowsiness-inducing benzodiazepine tranquilliser, comprising the concomitant administration with the said tranquilliser of a propiophenone compound selected from m-chloro-a-t-butylaminopropiophenone, m-fluoro-a-t-butylaminopropiophenone and pharmacologically and pharmaceutically acceptable acid addition salts thereof in a non-toxic amount effective in preventing the functional impairment and drowsiness induced by the said tranquilliser.
29. A method according to claim 28 wherein the propiophenone compound is selected from m-chloro-a-t-butylaminopropiophenone and pharmacologically and pharmaceutically acceptable acid addition salts thereof.
30. A method according to claim 28 wherein the propiophenone compound is a pharmacologically and pharmaceutically acceptable acid addition salt of m-chloro-a-t-butylaminopropiophenone.
31. A method according to claim 28 wherein the propiophenone compound is m-chloro-a-t- butylaminopropiophenone hydrochloride.
32. A method according to any of claims 28 to 31 wherein the benzodiazepine tranquilliser is selected from chlordiazepoxide and pharmacologically and pharmaceutically acceptable salts thereof.
33. A method according to any of claims 28 to 31 wherein the benzodiazepine tranquilliser is diazepam.
34. A method according to any of claims 28 to 33, substantially as hereinbefore described with particular reference to Example 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8101593A GB2067403B (en) | 1980-01-21 | 1981-01-20 | Bezodiazepine compositions |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8001910 | 1980-01-21 | ||
| GB8101593A GB2067403B (en) | 1980-01-21 | 1981-01-20 | Bezodiazepine compositions |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2067403A true GB2067403A (en) | 1981-07-30 |
| GB2067403B GB2067403B (en) | 1984-07-04 |
Family
ID=26274218
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8101593A Expired GB2067403B (en) | 1980-01-21 | 1981-01-20 | Bezodiazepine compositions |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2067403B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5030632A (en) * | 1986-09-23 | 1991-07-09 | Sandoz Pharm. Corp. | Low dose temazepam |
| US5211954A (en) * | 1986-09-23 | 1993-05-18 | Sandoz Ltd. | Low dose temazepam |
| US5629310A (en) * | 1986-09-23 | 1997-05-13 | Sterling; William R. | Low dose temazepam |
-
1981
- 1981-01-20 GB GB8101593A patent/GB2067403B/en not_active Expired
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5030632A (en) * | 1986-09-23 | 1991-07-09 | Sandoz Pharm. Corp. | Low dose temazepam |
| US5211954A (en) * | 1986-09-23 | 1993-05-18 | Sandoz Ltd. | Low dose temazepam |
| US5326758A (en) * | 1986-09-23 | 1994-07-05 | Sandoz Pharm. Corp. | Low dose temazepam |
| US5629310A (en) * | 1986-09-23 | 1997-05-13 | Sterling; William R. | Low dose temazepam |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2067403B (en) | 1984-07-04 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |