U.S. patent number 3,676,557 [Application Number 05/120,336] was granted by the patent office on 1972-07-11 for long-acting narcotic antagonist formulations.
This patent grant is currently assigned to Endo Laboratories, Inc.. Invention is credited to Leon Lachman, Roy H. Reiner, Elie Shami, Walter Spector.
United States Patent |
3,676,557 |
Lachman , et al. |
July 11, 1972 |
LONG-ACTING NARCOTIC ANTAGONIST FORMULATIONS
Abstract
The pamoate salts of
N-(cyclopropylmethyl)-7,8-dihydro-14-hydroxynormorphinone and
N-allyl-7,8-dihydro-14-hydroxynormorphinone, in oil suspension, are
injectable, long-acting forms of these narcotic antagonists.
Inventors: |
Lachman; Leon (Manhasset,
NY), Reiner; Roy H. (Baldwin Harbor, NY), Shami; Elie
(Hempstead, NY), Spector; Walter (Valley Stream, NY) |
Assignee: |
Endo Laboratories, Inc. (Garden
City, NY)
|
Family
ID: |
22389610 |
Appl.
No.: |
05/120,336 |
Filed: |
March 2, 1971 |
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
56975 |
Jul 21, 1970 |
|
|
|
|
Current U.S.
Class: |
514/282;
546/45 |
Current CPC
Class: |
A61K
9/0019 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61k 027/12 () |
Field of
Search: |
;424/244,260 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
1,461,407 |
|
Dec 1966 |
|
FR |
|
6,706,464 |
|
Jun 1968 |
|
ZA |
|
Other References
Thompson, Am. J. Trop. Med. Hyg. 12, 481 (1963) .
McGregor, Brit. Med. J. 695, Mar. 19, 1966 .
Coatney, Am. J. Trop. Med. Hyg. 12, 504 (1963) .
Waltz, Science, 141, 723, Aug. 1963.
|
Primary Examiner: Rose; Shep K.
Parent Case Text
RELATED APPLICATIONS
This application is a continuation-in-part of application Ser. No.
56,975, filed July 21, 1970 now abandoned.
Claims
What is claimed is:
1. An injectable, long-acting narcotic antagonist formulation,
syringeable through a 20 gauge needle, which comprises:
A. particles of a salt selected from the group consisting of
di-(N-allyl-7,8-dihydro-14-hydroxynormorphinone) pamoate and
di-[N-(cyclopropyl-methyl)-7,8-dihydro-14-hydroxynormorphinone]
pamoate, the average particle size of the salt being between 5 and
50 microns, and essentially all of the particles being less than
100 microns,
thoroughly dispersed and suspended in
B. a gel composed of a vegetable oil which is suitable for
subcutaneous or intramuscular administration, gelled with about 0.1
to 5 percent w/v of aluminum monostearate,
the concentration of the pamoate salt in the gel being equivalent
to a concentration of the corresponding hydrochloride salt in the
range of about 1 to about 500 mg./ml.
2. Formulation of claim 1 wherein the vegetable oil is selected
from the group consisting of peanut oil, corn oil, sesame oil, and
cottonseed oil.
3. Formulation of claim 2 wherein the concentration of the pamoate
salt in the gel is equivalent to a concentration of the
corresponding hydrochloride salt in the range of about 2 to 200
mg./ml., and the concentration of aluminum monostearate in the
vegetable oil is in the range of about 1.0 to 4.0 percent w/v.
Description
BACKGROUND OF THE INVENTION
This invention relates to the known narcotic antagonists,
N-allyl-7,8-dihydro-14-hydroxynormorphinone and
N-(cyclopropylmethyl)-7,8-dihydro-14-hydroxynormorphinone. The
former compound will sometimes be referred to hereinafter by its
generic name, naloxone.
Naloxone and certain of its salts are disclosed in U.S. Pat. No.
3,254,088 as potent narcotic antagonists. A report by Fink et al.,
"Naloxone in Heroin Dependence," Clinical Pharmacology and
Therapeutics, Vol. 9, No. 5, pp. 568-577 (1968) confirms that
naloxone is a highly potent antagonist which is relatively free of
adverse side effects. Fink et al. note however that the antagonist
action of naloxone is quite brief, and conclude:
The short duration of action may be a serious limitation. Further
trials of the narcotic antagonist treatment model are necessary,
and naloxone is the best drug available for such studies, but
pharmaceutical ingenuity may create compounds with longer durations
of action and equal potency and safety.
N-(cyclopropylmethyl)-7,8-dihydro-14-hydroxynormorphinone and
certain of its salts are disclosed in U.S. Pat. No. 3,332,950. This
compound is also a potent narcotic antagonist but, like naloxone it
suffers the disadvantage of relatively short duration of
action.
SUMMARY OF THE INVENTION
This invention provides injectable, long-acting narcotic antagonist
formulations which comprise a salt selected from the group
consisting of di-(N-allyl-7,8-dihydro-14-hydroxynormorphinone)
pamoate (sometimes hereinafter referred to as di-naloxone pamoate)
and di[N-(cyclopropylmethyl)-7,8-dihydro-14-hydroxynormorphinone]
pamoate, suspended in an oil which is suitable for parenteral
administration.
It has been discovered that the suspensions of this invention
exhibit surprisingly prolonged duration of action. At the same
time, the suspensions exhibit the desirable qualities of potency,
quick onset of action, low toxicity, and absence of disturbing side
effects.
DESCRIPTION OF THE INVENTION
Di-naloxone pamoate is an odorless, light yellowish-tan powder with
the empirical formula (C.sub.19 H.sub.21 NO.sub.4).sub.2.sup..
C.sub.23 H.sub.16 O.sub.6 and the structural formula: ##SPC1##
Di-naloxone pamoate is prepared by mixing naloxone hydrochloride
with disodium pamoate in a 2:1 molar ratio in aqueous solution. The
relatively insoluble di-naloxone pamoate precipitates, is removed
by filtration, purified by recrystallization from ethanol or other
suitable solvent, and dried. The product need not be anhydrous. It
will ordinarily contain at least 1 mole of water and may contain up
to about 10 percent by weight of combined or uncombined water
and/or combined or uncombined solvent. A specific procedure which
can be used to produce di-naloxone pamoate is as follows:
To a solution of 9.6 g. (0.024 mol) of naloxone hydrochloride
monohydrate in approximately 100 ml. water a solution of 5.4 g.
(0.012 mol) of disodium pamoate monohydrate in a similar volume of
water is slowly added, with stirring. The precipitate, which forms
almost instantaneously, is stirred for about 1 hour, the solvent is
filtered off, and the residue washed with water and then dried.
Yield: 12 g.
Recrystallization from 300 ml. of boiling ethanol yields 8 g. of
product, which, after drying for 3 hours at 80.degree. in a vacuum
oven, decomposes at 198.degree.-225.degree. C.
Di-[N-(cyclopropylmethyl)-7,8-dihydro-14-hydroxynormorphinone]
pamoate is an odorless, buff-colored powder with the empirical
formula (C.sub.20 H.sub.23 NO.sub.4).sub.2.sup.. C.sub.23 H.sub.16
O.sub.6 and the structural formula: ##SPC2##
Di-[N-(cyclopropylmethyl)-7,8-dihydro-14-hydroxynormorphinone]
pamoate is prepared in a manner similar to that used for preparing
di-naloxone pamoate, and like di-naloxone pamoate it may contain up
to about 10 percent by weight of combined or uncombined water
and/or solvent. A specific procedure which can be used to produce
this salt is as follows:
To a solution of 5.7 g. (0.015 mol) of
N-(cyclopropylmethyl)-7,8-dihydro-14-hydroxynormorphinone
hydrochloride in approximately 100 ml. water a solution of 3.4 g.
(0.0075 mol) of disodium pamoate monohydrate in a similar volume of
water is slowly added, with stirring. The precipitate which forms
is stirred for about an hour, filtered, and the residue washed with
water and dried. Yield: 7.2 g.
Recrystallization from ethanol yields 6.1 g. in two crops, which
are combined and dried for 3 hours at 100.degree. C. in a vacuum
oven to give material which decomposes at 200.degree.-207.degree.
C.
The oil medium for suspensions of this invention can be any
vegetable oil which is suitable for parenteral use. The vegetable
oil, for example, may be peanut oil, corn oil, sesame oil, or
cottonseed oil.
In order to provide stable suspensions, a viscosity-increasing
agent is incorporated into the vegetable oil. Suitable
viscosity-increasing agents are the fatty acid salts of aluminum,
especially those containing about seven to 25 carbon atoms.
Aluminum monostearate is particularly preferred. The aluminum
monostearate or other viscosity-increasing agent will ordinarily be
used in an amount in the range of from 0.1-5.0 percent (w/v), based
on the oil. The preferred range is 1.0-4.0 percent (w/v).
The viscosity-increasing agent is incorporated into the vegetable
oil with agitation and heating as necessary to produce a stable
vegetable oil gel. For example, an aluminum monostearate gel can be
prepared by suspending an amount of aluminum monostearate in a
suitable vegetable oil. Under constant agitation, heat is applied
until a temperature of 85.degree.-90.degree. C. is attained. A
heating rate of 5.degree. C. per minute is applied until this
temperature is reached. This temperature is maintained for 30-45
minutes to eliminate water from the system. Heating is continued,
but retarded to 2.degree.-3.degree. C. per minute until a
temperature of 125.degree. C. is attained. 15 minutes' stirring at
this temperature will stabilize the gel that is formed. Using this
technique, vegetable oil gels can be made at temperatures between
125.degree. C. and 150.degree. C.
A preservative can be added to the vegetable oil gel, if desired,
in an amount ordinarily used in injectable dosage forms, i.e. about
0.05 percent to 0.5 percent (w/v) based on oil. The parabens, in
combinations ordinarily used in parenterals, are preferred, but
other preservatives recognized for use in parenterals (e.g. phenol,
cresol, chlorobutanol) can also be used.
Antioxidants commonly used in pharmaceutical products may also be
incorporated. These include, for example, ascorbyl palmitate,
hydroquinone, propyl gallate, nordihydroguaiaretic acid, butylated
hydroxy toluene, butylated hydroxy anisole, .alpha.-tocopherol and
its esters, phenyl .alpha.-naphthylamine, lecithin, and mixtures of
these. The amount of antioxidant, when used, will ordinarily be in
the range from about 0.005 to 0.2 percent (w/v) based on the
oil.
The suspensions of the invention can also contain other
therapeutically active compounds, in amounts sufficient to enhance
the utility of the formulation for its intended purpose. These
adjuvants can be formulated so as to be released immediately or
over an extended period of time. Examples of other types of
therapeutically active ingredients which can be included in the
suspensions, either as the compounds themselves or their
pharmaceutically acceptable salts, are:
a. major tranquilizers, such as chlorpromazine or molindone, or
minor tranquilizers, such as chlordiazepoxide, glutethimide or
pentobarbital, for the symptomatic relief of narcotic withdrawal
symptoms;
b. analeptics, such as picrotoxin or pentamethylenetetrazole, or
central nervous system stimulants such as methylphenidate, for
antagonism of acute respiratory depression caused by agents other
than narcotics; and
c. various narcotics or other narcotic antagonists such as
methadone, meperidine or cyclazocine, in dosage ratios which
provide retention of analgesia or appropriate withdrawal therapy,
while simultaneously minimizing side effects.
In preparing the suspensions of the invention the di-naloxone
pamoate or
di-[N-(cyclopropylmethyl)-7,8-dihydro-14-hydroxynormorphinone]
pamoate is added to the vegetable oil gel in amounts equivalent to
naloxone hydrochloride or
N-cycloproylmethyl-7,8-dihydro-14-hydroxynormorphinone
hydrochloride (anhydrous basis) in the range from about 1 to about
500 mg./ml. of suspension, preferably 2 to 200 mg./ml., more
preferably 5 to 100 mg./ml. The mixture is then mechanically worked
to reduce the particle size of the suspended materials and
thoroughly disperse them in the gel. The average particle size of
the suspended materials should be sufficiently small that the
suspension is syringeable through a 20 gauge needle. It is
preferred that the average particle size be between 5 and 50
microns, and that essentially all of the particles be less than
about 100 microns. Particle size reduction and dispersion of the
suspended materials can be accomplished with the use of a
laboratory blender, colloid mill, sonic mill, or other comparable
equipment.
Aseptic techniques may be used throughout the preparation, or other
suitable techniques for making sterile parenterals can be used.
A suspension of the invention, containing an amount of di-naloxone
pamoate equivalent to 10 mg. of naloxone hydrochloride per ml. in 2
percent aluminum monostearate in peanut oil, was tested for
duration of Numorphan-antagonist effect in mice. The test used was
the subcutaneous counteraction of the Numorphan HCl induced Straub
tail in mice. Two tests, each using three mice, were made. Each
mouse received one injection of the above formulation (5 cc./kg.)
and was challenged with a Numorphan HCl injection (2 mg./kg.) at
various time intervals thereafter. Results, expressed as the number
of mice protected out of three, were as follows:
Time of Challenge Test 1 Test 2 15 minutes 3/3 3/3 24 minutes 3/3
3/3 48 hours 2/3 2/3 72 hours - 0/3
The fact that all of the mice were protected at 15 minutes shows
that the suspension of the invention provides quick onset of
action. At the same time the suspension provided protection to all
of the mice for 24 hours and for two-thirds of the mice for 48
hours. In contrast, an aqueous solution of naloxone hydrochloride
protects mice for only about 5 hours.
The same formulation was also tested for duration of effect in
rats. The test was subcutaneous injection for prevention of
Numorphan induced loss of righting reflex. Two tests, each using
four rats, were made. Each rat received one subcutaneous injection
of the above formulation (1 cc./kg.) and was challenged with a
subcutaneous Numorphan injection (1 mg./kg.) at various time
intervals thereafter. The rats were considered protected if they
did not lose their righting reflex in 30 minutes after the
Numorphan subcutaneous challenge. Results, expressed as the number
of rats protected out of four, were as follows:
Time of Challenge Test 1 Test 2 15 minutes 4/4 4/4 24 hours 3/4 3/4
48 hours 2/4 3/4 72 hours 1/4 2/4
Another suspension of the invention, containing an amount of
di-naloxone pamoate equivalent to 50 mg. of naloxone hydrochloride
per ml. in 2 percent aluminum monostearate in peanut oil, was
tested for duration of effect in dogs. Six dogs were used. Each dog
received one I.M. injection of the di-naloxone pamoate suspension.
The dosage was 0.1 cc./kg. for two dogs and 0.2 cc./kg. for the
other four. Numorphan HCl was given at various time intervals
thereafter; the dosage was 0.5 mg./kg. I.V., a prostrating dose.
The following is the score system used:
0 - Prostration, head drop - no protection
1 - Head weakness - slight protection
2 - Hind and front leg weakness - moderate protection
3 - Hind leg weakness only - almost complete protection
4 - Normal, no effect - complete protection.
Results were as follows:
Antagonist Time Intervals Dog Dosage 24 48 72 96 7 10 14 21 No./Sex
(cc./kg.) hrs. hrs. hrs. hrs. days days days days
__________________________________________________________________________
1/M 0.1 4 3 0 2/M 0.1 3 10 3/M 0.2 4 4 3 22 0 4/F 0.2 4 4 2 0 5/F
0.2 3 2 0 6/M 0.2 3 1 0
__________________________________________________________________________
in a similar test on two dogs, using a suspension of the invention
containing an amount of di-naloxone pamoate equivalent to 50 mg. of
naloxone hydrochloride per ml. of 2 percent aluminum monostearate
in sesame oil, results showed that a dosage of 0.2 cc./kg. gives
almost complete protection against Numorphan after 17 days.
A suspension of the invention, containing an amount of
di-[N-(cyclopropylmethyl)-7,8-dihydro-14-hydroxynormorphinone]
pamoate equivalent to 10 mg. of
N-cyclopropylmethyl-7,8-dihydro-14-hydroxynormorphinone
hydrochloride per ml., in a peanut oil gel containing 2 percent
aluminum monostearate, was compared with an aqueous control
solution containing 10 mg./ml. of the
N-(cyclopropylmethyl)-7,8-dihydro-14-hydroxynormorphinone
hydrochloride for duration of Numorphan antagonist effect in mice.
The same formulations, as well as the di-naloxone pamoate
formulation described above in the rat test, were also compared for
duration of Numorphan antagonist effect in rats.
In the mouse: The protocol was the same as that described above for
the test of the di-naloxone pamoate suspension in mice, except that
each individual animal was challenged only once with a subcutaneous
injection of Numorphan (different groups of mice being challenged
at the various time intervals), and groups of 10 animals were used
for each point. Results, expressed as the number of mice protected
out of 10, are shown in the following table; column D shows the
results for mice injected with the suspension of the invention, and
column C shows the results for the mice injected with the control
solution.
Time of Challenge C D 15 minutes 10/10 10/10 2 hours 10/10 - 6
hours 6/10 - 24 hours 0/10 9/10 48 hours - 2/10 72 hours - 0/10
In the rat: The protocol was the same as that described above for
the test of the di-naloxone pamoate suspension in rats, except that
each individual animal was challenged only once with a subcutaneous
injection of Numorphan (different groups of rats being challenged
at the various time intervals), the dosage of the test or control
solution was 10 mg./kg., and groups of 10 animals were used for
each point, except that a group of only five animals was used for
the 92 hour period. Results, expressed as the number of rats
protected out of 10 (or five) are shown in the following table;
column D shows the results for rats injected with the
di-[N-(cyclopropylmethyl)-7,8-dihydro-14-hydroxynormorphinone]
pamoate suspension, column C shows the results for rats injected
with the control solution and column E shows the results for rats
injected with the di-naloxone pamoate suspension.
Time of Challenge C D E 30 minutes 10/10 10/10 10/10 1 hour 10/10 -
- 6 hours 8/10 - - 24 hours 0/10 10/10 10/10 41 hours - 9/10 4/10
48 hours - 6/10 2/10 65 hours - 1/10 0/10 72 hours - 1/10 0/10 92
hours - 0/5 -
* * * * *