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Патент USA US3085942

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United States Patent 0
iC€
3,085,932
, Patented Apr. 16, 1963
1
2
3,085,932
The compositions of this invention are prepared simply
by intimately mixing the two active components. The
THERAPEUTIC COMPOSITION COMPRISING 3,3
mixture is then embodied into a suitable dosage form.
DIETHYL - 5 - METHYL - 2,4 - PEPERIDINEDIONE
AND
1
Suitable dosage forms include capsules, pressed or coated
tablets, syrups, oily suspensions, etc. The methods by
7-CHLORO-2-lviETHYLAM[N0-5-PHENYL
3H-1,4-BENZODIAZEPINE-4-OXIDE
Saul Howard Rubin, Nutley, and Gerhard Zbinden, Essex
which such dosage forms are obtained are well known in
Foils, N.J., assignors to Hoifmann-La Roche Inc., Nut
the art.
ley, N.J., a corporation of New Jersey
In addition to the active ingredients, the compositions
No Drawing. Filed Dec. 21, 1961, Ser. No. 161,270
of this invention may contain the various adjuvants con
7 Claims. (Cl. 167—52)
10 ventionally used in the formulation of pharmaceutical
preparation. Exemplary of the adjuvants'that may be em
This invention relates to novel therapeutic composi
ployed in producing the compositions in encapsulated or
tions. More particularly, the invention relates to therapeu
tablet form are ?llers, such as coprecipitated aluminum
tic compositions comprising a mixture of 3,3-diethyl-5
hydroxide-calcium carbonate, dicalcium phosphate or lac
methyl-2,4-piperidinedione with 7-chloro-2-methylamino
5-phenyl-3H-l,4-benzodiazepine 4-oxide or one of its 15 tose in the presence of disintegrating agents, such as maize
medicinally acceptable acid addition salts.
The compositions of the present invention have been
starch; and lubricating agents, such as talc, calcium stear
ate, etc. The compositions may, moreover, be produced
in the form of suspensions in oil, for example, in a vege
found to be useful in the inducement of sound sleep.
They are especially well suited for use, however, in the
table oil, such as arachis oil. Such suspensions may con
treatment of patients with sleep problems associated with 20 tain sweetening agents and preservatives of the type nor
mally employed in the art.
anxiety, tension or other common emotional disturbances.
The ratio of the active components comprising the
These compositions, therefore, fill a long existing need
products of this invention can be varied within rather
in the treatment of patients with heart disease or other
Wide limits. For example, the products may contain from‘
chronic ailments, in the treatment of neuropsychiatric
patients and in the treatment of patients in pre- and post 25 about 4 to about 120 parts by weight of 3,3-diethyl-5
methyl-2,4-piperidinedione for each part by Weight of 7
operative states.
_
chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine 4
3,3~diethyl-S-methyl-2,4-piperidinedione is a non-nar
oxide or for each part by weight of a salt thereof. The
cotic, sedative-hypnotic which possesses high therapeutic
preferred products of the invention, however, contain
activity and, at the same time, manifests low toxicity. It
has been found that 7-chloro-2-m'ethylamino-S-phenyl 30 from about 15 parts by weight to about 25 parts by weight
of 3,3-diethyl-5-methyl-2,4-piperidinedione for each part
3H-1,4-benzodiazepine 4-oxide, and medicinally accept
by weight of 7-chloro-2-methylamino-5-phenyl-3H-1,4
able salts thereof, compounds ‘which, in therapeutic doses,
do not have hypnotic properties, cause sleep potentiation
of 3,3-diethyl-5-methyl-2,4-piperidinedione.
Moreover, in some animal species, particularly in the
'
35
dog, administration of 3,3-diethyl-5-methyl-2,4-piperi
benzodiazepine 4-oxide, or salt thereof.
A typical adult dosage of the active ingredients com
prising the present compositions may vary within the range
of from about 175 mg. to 225 mg. of 3,3-diethyl-5-methyl
2,4-piperidinedione with from about 8 mg. to about 12
dinedione appears to induce an initial phase of excitation
which phase is followed by a sedation phase and a hyp
mg. of 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzo
notic phase. It has been found that 7-chloro-2-methyl—
diazepine 4-oxide, or salt thereof. For example, a hard
methyl-2,4-piperidinedione. On the contrary, it appears
to suppress this initial excitation. Such effect, while high
ly advantageous, was entirely unexpected.
amino-5-phenyl~3H-1,4-benzodiazepine 4-oxide, or salt
thereof, may be administered to the patient at bedtime.
amino-5-phenyl-3H-1,4-benzodiazepine 4-oxide does not 40 shell capsule containing 200 mg. of 3,3-diethyl-5amethyl—
2,4-piperidinedione and 10 mg. of 7-chloro-2-methyl
potentiate the excitation phase induced by 3,3-diethyl-5
Thus, the present invention comprises therapeutically
In cases of severe insomnia, a second capsule may be
45 prescribed. Smaller doses may, of course, be recom
active compositions comprising a mixture of 3,3-diethyl-5
mended in particular cases, for example, in the treatment
methyl-2,4-piperidinedione with 7-chloro-2-methylamino
of children and debilitated patients. It should 1be fully
5-phenyl-3H-1,4-benzodiazepine 4-oxide. A medicinally
understood, however, that the dosages set forth herein are
exemplary only and that they do not, to any extent, limit
the scope of this invention.
For a fuller understanding of the nature and objects of
this invention, reference may be had to the following
examples which are given merely as illustrative of the in
acceptable acid addition salt of 7-chloro-2-methylamino-5
phenyl-3H-1,4-benzodiazepine 4-oxide can be used, if de
sired.
Since, however, 3,3-diethyl-5-methyl-2,4-piperi
dinedione is somewhat unstable in an 'acid environment,
when that compound is used in admixture with an acid
addition salt of 7-chloro-2-methylamino-5-phenyl-3I-I-1,4
benzodiazepine 4-oxide, there should be present also a
su?icient quantity of alkali, for example, an alkaline filler,
such as coprecipitated aluminum hydroxide-calcium car
vention and are not to‘ be construed in a limiting sense.
Example 1
The following ingredients, in the quantities indicated,
were intimately mixed in a suitable container.
bonate, to render the ?nished product basic, or at least
neutral, in reaction. In general, any one of many medic 60
7-chloro-2-m'ethylamino-5-phenyl-3H-1,4~
Grams
inally acceptable acid addition salts of 7-chloro-2-methyl
amino-5-phenyl-3H-1,4-benzodiazepine 4-oxide can be
used in the practice of this invention. These include salts
benzodiazepine 4-oxide __________________ __
1,020 '
3,3-diethyl-5-methyl-2,4-piperidinedione _____ __ 20,400‘
of 7 - chloro-Z-methylamino-S-phenyl-BH-1,4-benzodiaze—
Coprecipitated aluminum hydroxide-calcium
pine 4-oxide with conventional mineral acids, such as 65
hydrochloric acid, hydrobromic acid, nitric acid, phos
carbonate _____________________________ __
400
Starch __________________________________ __
5,400
T alc ___________________________________ __ 1,5 00'
phoric acid; and with conventional organic acids, such as
Lactose ________________________________ __
1,280
benzoic acid, toluene sulfonic acid, acetic acid, citric acid,’
maleic acid, tartaric acid, lactic acid, etc. In producing
The mixture was then passed through a Fitzpatrick com
the preferred products of the invention, however, 7-chloro 70 minuting machine, following which the milled powder
2-methy1amino-S-phenyl-SH-1,4-benzodiazepine 4 - oxide,
was mixed and re-blended.
or the hydrochloric acid salt thereof, is used.
then passed into hard-shell capsules.
The powdery mixture Was
3,085,982
3
In this example, 200 parts by weight of 3,3-diethyl-5
methyl-2,4-piperidinedione and 20 parts by weight of
comprising a mixture of 3,3-diethyl-5-methyl-2,4-piperi
dinedione and 7~chloro-2-methy1amino-5-phenyl-3H-1,4~
7 - chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine
benzodiazepine 4-oxide with a solid pharmaceutical ad~
4-oxide were ?rst intimately admixed. To this mixture,
juvant, there being present in said composition, for each
part by weight of said 1,4-benzodiazepine-4-oxide com
ponent, from about 4 to about 120 parts by weight of
said 2,4-piperidinedione component.
5. A therapeutic composition for internal administra
tion in shaped unit dosage form for oral administration
65.0 parts by weight of coprecipitated aluminum hydrox
ide-calcium carbonate were added.
This mixture was
granulated with a mixture of 5 parts by weight of gelatin
and 5 parts by weight of cornstarch.
Thereafter, the granulate, thus obtained, was mixed
with 3.6 parts by weight of cornstarch, 4.0 parts by weight
of talc and 0.4 parts by weight of magnesium stearate.
comprising a mixture of 3,3-diethyl-5-methyl-2,4-piperi
dinedione and a medicinally acceptable acid addition salt
The product was then compressed into tablets by con
ventional means.
4
4. A therapeutic composition for internal administra
tion in shaped unit dosage form for oral administration
Example 2
of 7 - chloro-2-methylamino-5-phenyl-3H-1,4-benzodiaze
15 pine 4-oxide with a solid pharmaceutical adjuvant, there
We claim:
being present in said composition, for each part by weight
1. A therapeutic composition comprising 3,3-diethyl-5
of said 1,4-benzodiazepine-4-oxide component, from
methyl-2,4-piperidinedione and a compound selected from
about 4 to about 120 parts by weight of said 2,4-piperi
the group consisting of 7-chloro-Z-methylamino-S-phenyl
dinedione component.
3H-1,4-benzodiazepine 4-oxide and a medicinally accept 20
6. The composition of claim 5 wherein the hydro
able acid addition salt thereof, there being present in said
chloride salt of 7-chloro-2-methylamino-5-phenyl-3H-1,4
composition, for each part by weight of said 1,4-benzo
diazepine-4-oxide component, from about 4 to about 120
parts by weight of said 2,4-piperidinedione component.
benzodiazepine 4-oxide is employed.
7. A process for treating insomnia which comprises
internally administering a therapeutic composition com‘
2. The composition of claim 1 which contains pharma 25 prising from about 175 mg. to about 225 mg. of 3,3-di—
ceutical adjuvant material.
ethyl-5-methyl-2,4-piperidinedi0ne and from about 8 mg.
3. A therapeutic composition for internal administra
to about 12 mg. of a compound selected from the group
tion in unit dosage form comprising a mixture of 3,3
consisting of 7-chloro-2-methylamino-5-phenyl-3H-1,4
diethyl-S-methyl-2,4-piperidinedione and a compound
benzodiazepine 4-oxide and a medicinally acceptable acid
selected from‘ the group consisting of 7-ch1oro-2-methyl 30 addition salt thereof.
amino-5-phenyl-3H-1,4-benzodiazepine 4-oxide
and a
medicinally acceptable acid addition salt thereof with a
pharmaceutical adjuvant, there being present in said com
position, for each part by weight of said 1,4-benzodiaze
pine-4-oxide component, from about 4 to about 120 parts 35
by weight of said 2,4-piperidinedione component.
References Cited in the ?le of this patent
Physicians’ Desk Reference, page 798 (Hyptran), page
710 (Noludar), January 1961.
The New England J. of Med, Apr. 27, 1961, pages
870-873, vol. 264, No. 17.
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