ANALGESIC COMPOSITIONS COMPRISING LAEVO- OR DEXTRO-PROPOXYPHENE AND BENZODIAZEPINES AND PROCESS

SUBSTANCES ANALGESIQUES COMPRENANT DES LEVO- OU DEXTRO-PROPOXYPHENES ET DES BENZODIAZEPINES

English Abstract

ANALGESIC COMPOSITIONS COMPRISING
LAEVO-OR DEXTRO-PROPOXYPHENE AND
BENZODIAZEPINES AND PROCESS
ABSTRACT OF THE DISCLOSURE
Analgesic compositions having a remarkably high analgesic activity
and a process for obtaining an analgesic effect are provided, in which the
active components are laevo or dextro-propoxyphene and at least one of certain
benzodiazepines. The analgesic activity of these combinations is remarkable,
inasmuch as the laevo-propoxyphene and the benzodiazepines when administered
separately do not display appreciable analgesic activity, and moreover benzo-
diazepines that are pharmacologically inert may also be effective in these
combinations.

Claims

1. An analgesic composition having a remarkably high analgesic
activity, comprising as analgesically active components .alpha., d-propoxyphene
and/or .alpha., 1-propoxyphene,or a pharmaceutically acceptable salt thereof,
and at least one benzodiazepine or a pharmaceutically acceptable salt
thereof, each in an amount within the weight ratio range propoxyphene:
benzodiazepine from 100:0.5 to 2:1 imparting or enhancing analgesic
activity, compared to the propoxyphene and the benzodiazepine when
administered separately, the benzodiazepine having the formula:
<IMG>
wherein:
R1 is selected from the group consisting of hydrogen, alkyl,
<IMG> ,amino or alkylamino <IMG>, where R and R' are selected
from the group consisting of hydrogen, lower alkyl having from
one to three carbon atoms, and bivalent alkylene having from one
27

to four carbon atoms; and linked the nitrogen at two positions to form
a heterocyclic ring; provided when the propoxyphene is the .alpha.,d isomer,
the alkyl is n-butyl or methyl;
R2 is selected from the group consisting of hydrogen, oxo oxygen =
O, hydroxyl OH, alkyl, and amino or alkylamino.<IMG>, where R and R' are
as defined above; provided, when the propoxyphene is the .alpha.,d isomer,
R2 is = O or OH;
R3 is selected from the group consisting of hydrogen, hydroxyl
OH and carboxyl COOH:
R4 is selected from the group consisting of <IMG>, <IMG>,
where X is halogen,<IMG>, and amino or alkylamino <IMG> where
R and R' are as defined above, provided, when the propoxyphene is the
.alpha.,d isomer, R4 is <IMG> or <IMG>, where X is Cl or F; and
R5 is selected from the group consisting of hydrogen, halogen and
nitro NO2; provided, when the propoxyphene is the .alpha.,d-isomer, R5 is
H, NO2, Br or Cl.
2. An analgesic composition in accordance with
claim 1 in which the propoxyphene is .alpha.,1 propoxyphene, and
the benzodiazepine is selected from the group consisting of
chlordiazepoxide, diazepam, oxazepam, clorazepate, flurazepam,
lorazepam, nitrazepam, medazepam, bromazepam, prazepam, and
DDD-azepam.
3. An analgesic composition in accordance with
claim 1 in which R1 is CH3, and the propoxyphene is .alpha.,1-
-propoxyphene.
4. An analgesic composition in accordance with
claim 1 in which R1 is <IMG> , and the propoxyphene is
.alpha.,1-propvxyphene.
28

5. An analgesic composition in accordance with
claim 1 in which R1 is hydrogen, and the propoxyphene is
.alpha.,1-propoxyphene.
6. An analgesic composition in accordance with
claim 1 in which R1 is
<IMG>
and the propoxyphene is .alpha.,1-propoxyphene.
29

7. An analgesic composition in accordance with
claim 1 in which R2 is NHCH3, and the propoxyphene is
.alpha.,1-propoxyphene.
8. An analgesic composition in accordance with
claim 1 in which R2 is = O, and the propoxyphene is
.alpha.,1-propoxyphene.
9. An analgesic composition in accordance with
claim 1 in which R2 is OH, and the propoxyphene is
.alpha.,1-propoxyphene.
10. An analgesic composition in accordance with
claim 1 in which R3 is OH, and the propoxyphene is
.alpha.,1-propoxyphene.
11. An analgesic composition in accordance with
claim 1 in which R3 is COOH, and the propoxyphene is
.alpha.,1-propoxyphene.
12. An analgesic composition in accordance with
claim 1 in which R5 is C1, and the propoxyphene is
.alpha.,1-propoxyphene.
13. An analgesic composition in accordance with
claim 1 in which R5 is Br, and the propoxyphene is
.alpha.,1-propoxyphene.
14. An analgesic composition in accordance with
claim I in which R4 is <IMG>, and the propoxyphene is
.alpha.,1-propoxyphene.
15. An analgesic composition in accordance with
claim 1 in which R4 is <IMG>, and the propoxyphene is
.alpha.,1-propoxyphene.
16. An analgesic composition in accordance with
claim 1 in which the propoxyphene is .alpha..1-propoxyphene, and
the benzodiazepine is selected from the group consisting of
oxazepam, clorazepate, flurazepam, lorazepam, nitrazepam,
medazepam, bromazepam, prazepam, and DDD-azepam.

17. An analgesic composition in accordance with claim 1 in which
R1 is hydrogen, and the propoxyphene is .alpha.,d-propoxyphene.
18. An analgesic composition in accordance with claim 1 in which
R1 is <IMG>, and the propoxyphene is .alpha.,d-propoxyphene.
19. An analgesic composition in accordance with claim 1 in which
R1 is <IMG> and the propoxyphene is .alpha..d-propoxyphene.
20. An analgesic composition in accordance with claim 1 in which
R2 is = O, and the propoxyphene is .alpha.,d-propoxyphene.
21. An analgesic composition in accordance with claim 1 in which
R2 is OH, and the propoxyphene is .alpha.,d-propoxyphene.
22. An analgesic composition in accordance with claim 1 in which
R3 is OH, and the propoxyphene is .alpha.,d-propoxyphene.
23. An analgesic composition in accordance with claim 1 in which
R3 is COOH, and the propoxyphene is .alpha.,d-propoxyphene.
24. An analgesic composition in accordance with claim 1 in which
R3 is hydrogen, and the propoxyphene is .alpha.,d-propoxyphene.
25. An analgesic composition in accordance with claim 1 in which
R4 is <IMG>, and the propoxyphene is .alpha.,d-propoxyphene.
26. An analgesic composition in accordance with claim 1 in which
R4 is <IMG>, and the propoxyphene is .alpha.,d-propoxyphene.
27. An analgesic composition in accordance with claim 1 in which
R4 is <IMG>, and the propoxyphene is .alpha.,d-propoxyphene.
28. An analgesic composition in accordance with claim 1 in which
R5 is Cl, and the propoxyphene is .alpha.,d-propoxyphene.
31

29. An analgesic composition in accordance with claim 1 in which
R5 is H, and the propoxyphene is .alpha.,d-propoxyphene.
30. A pharmaceutical composition in dosage unit form comprising
an analgesic composition in accordance with claim 1 and a pharmaceutically
acceptable carrier.
31. A pharmaceutical composition in accordance with claim 30
in which the propoxyphene is .alpha.,1-propoxyphene, and the benzodizepine
is selected from the group consisting of chlordiazepoxide, diazepam,
bromazepam, prazepam, and DDD-azepam.
32. A pharmaceutical composition in accordance with claim 30
in which R1 is CH3, and the propoxyphene is .alpha.,1-propoxyphene.
33. A pharmaceutical composition in accordance with claim 30
in which R1 is <IMG>, and the propoxyphene is .alpha.,1-propoxyphene.
34. A pharmaceutical composition in accordance with claim 30
in which R1 is hydrogen, and the propoxyphene is .alpha.,1-propoxyphene.
35. A pharmaceutical composition in accordance with claim 30
in which R1 is
<IMG>
and the propoxyphene is .alpha., 1-propoxyphene.
36. A pharmaceutical compostion in accordance with claim 30
in which R2 is NHCH3, and the propoxyphene is .alpha.,1-propoxyphene.
37. A pharmaceutical composition in accordance with claim 30
in which R2 is = O, and the propoxyphene is .alpha.,1-propoxyphene.
38. A pharmaceutical composition in accordance with claim 30
in which R2 is OH, and the propoxyphene is .alpha.,1-propoxyphene.
32

39. A pharmaceutical composition in accordance with claim 30
in which R3 is OH, and the propoxyphene is .alpha.,1-propoxyphene.
40. A pharmaceutical composition in accordance with claim 30
in which R3 is COOH, and the propoxyphene is .alpha.,1-propoxyphene.
41. A pharmaceutical composition in accordance with claim 30
in which R3 is Cl, and the propoxyphene is a .alpha.,1-propoxyphene.
42. A pharmaceutical composition in accordance with claim 30
in which R5 is Br, and the propoxyphene is .alpha.,1-propoxyphene.
43. A pharmaceutical composition in accordance with claim 30
in which R4 is <IMG>, and the propoxyphene is .alpha.,1-propoxyphene.
44. A pharmaceutical composition in accordance with claim 30
in which R4 is <IMG>, and the peopoxyphne is .alpha.,1-propoxyphene.
45. A pharmaceutical composition in accordance with claim 30
in which the propoxyphene is a .alpha.,1-propoxyphene, and the benzodiazepine
is selected from the group consisting of oxazepam, clorazepate, flurazepam,
lorazepam, nitrazepam, medazepam, bromazepam, prazepam, and
DDD-azepam.
46. A pharmaceutical composition in accordance with claim 30
in which R1 is hydrogen, and the propoxyphene is .alpha.,d-propoxyphene.
47. A pharmaceutical composition in accordance with claim 30
in which R is <IMG>, and the propoxyphene is .alpha.,d-propoxyphene.
48. A pharmaceutical composition in accordance with claim 30
in which R1 is <IMG> and the propoxyphene is .alpha.,d-propoxyphene.
33

49. A pharmaceutical composition in accordance with claim 30
in which R2 is = O, and the propoxyphene is .alpha.,d-propoxyphene.
50. A pharmaceutical composition in accordance with claim 30
in which R2 is OH, and the propoxyphene is .alpha.,d-propoxyphene.
51. A pharmaceutical composition in accordance with claim 30
in which R3 is OH, and the propoxyphene is .alpha.,d-propoxyphene.
52. A pharmaceutical composition in accordance with claim 30
in which R3 is COOH, and the propoxyphene is .alpha.,d-propoxyphene.
53. A pharmaceutical composition in accordance with claim 30
which R3 is hydrogen, and the propoxyphene is .alpha.,d-propoxyphene.
54. A pharmaceutical composition in accordance with claim 30
in which R4 is <IMG>, and the propoxyphene is .alpha.,d-propoxyphene.
55. A pharmaceutical composition is accordance with claim 30
in which R4 <IMG>, and the propoxyphene is .alpha.,d-propoxyphene.
56. A pharmaceutical composition in accordance with claim 30
in which R4 is C-Cl, and the propoxyphene is .alpha.,d-propoxyphene.
57. A pharmaceutical composition in accordance with claim 30
in which R5 is Cl, and the propoxyphene is .alpha.,d-propoxyphene.
58. A pharmaceutical composition in accordance with claim 30
in which R5 is H, and the propoxyphene is .alpha.,d-propoxyphene.
34

59. An analgesic composition having a remarkably high analgesic
activity comprising as analgesically active compounds .alpha.,d-propoxyphene
or a pharmaceutically acceptable salt thereof and at least one benzodiazepine
or a pharmaceutically acceptable salt thereof, each in an amount within
the weight ratio range propoxyphene:benzodiazepine from 100: 0.5 to
2.1 imparting or enhancing analgesic activity, compared to the propoxy-
phene and the benzodiazepine when administered separately, the benzo-
diazepine having the formula:
<IMG>
wherein:
R1 is selected from the group consisting of hydrogen and methyl;
R2 is selected from the group consisting of hydrogen and?O;
R3 is hydrogen;
R4 is selected from the group consisting of?CH, and?N; and
R5 is selected from the group consisting of NO2, Cl and Br.

60. An analgesic composition in accordance with claim 59 in
which the benzodiazepine is selected from the group consisting of
nitrazepam, medazepam and bromazepam.
61. An analgesic composition in accordance with claim 59 in
which R1 is hydrogen.
62. An analgesic composition in accordance with claim 59 in
which R1 is CH3.
63. An analgesic composition in accordance with claim 59 in
which R2 is?O.
64. An analgesic composition in accordance with claim 59 in
which R2 is H.
65. An analgesic composition in accordance with claim 59 in
which R1 is hydrogen and R2 is O.
36

66. An analgesic composition in accordance with claim 59 in
which R4 is?N.
67. An analgesic composition in accordance with claim 59 in
which R4 is?C-H.
68. An analgesic composition in accordance with claim 59 in
which R5 is Cl.
69. An analgesic composition in accordance with claim 59 in
which R5 is NO2.
70. An analgesic composition in accordance with claim 59 in
which R5 is Br.
37

Description

377~34~
;~ SI~I3C I F IC~ ~ ION
Propoxyphene, 4-dimethylamin~-3-methyl-1, 2-diphellyl-
propi~n~oxybutan~, is related structurally to meth~done, and has the
formula
~' f H3 /CH3
C H3CH2l --O--~ C HCH2--N\
O I H2 CH3
Propoxyphene
The compound exists as four stereoisomers
The less soluble diastereoisomer is designated as the ~-
isomer, and the more soluble as the ~-isomer. The o~ andcY, -d-
-- diastereoisomers have marked analgesic activity. Theo~, -l-diastere~-is~mer has no analgesic action, but it has antitussive activity. The ,B-
diastereoisomers are substantially inactive~ The United States Dispen-
sator~2 26th Edition, page 963, indicates that the o~, dextro isomer,
d-propoxyphene hydrochloride, is as effective in humans as codeine
phosphate in relieving pain. On the other hand, the cY,-d. 1- race~nate
has about one-half the analgesic potency of codeine, due no doubt to the
presence in an amount of 50% by weight ~f the anal{~esically-inactive ~ laevo
is~mer. Regarding -the~, laev~ isomer, The 7Jnited States ~-
satory states that, in contrast to propoxyphene, 1 propoxyphene has
therapeutically useful antitussive activity but no analgesic action.
d-prop~phene has little, if any, addicting liability,
and is used t~ pruvide relief in mild to rnoderate pain, whether acute,
--1--
~'

- 1~37~B4L7
chronic, or recurrent. It tends to produce fewer ~stroilltcstillal sicle
effects tllan codeine, but it is not s~lfficiently potent to relieve severe pain~
and it is of little lltility as an antitussive. Several forn~ulations ~ , d-
propo.~yphene hydrochloride are available commercially.
;~ Goodman and Gilman, The Pharmaceutical Basis of Thera-
peutics, 3rd Edition, indicate that ~, d-propoxyphene produces analgesia
by acting on the central nervou~ system. Oral doses of the order of 65 t~
100 mg. are about as ef~ective as oral doses of 65 mg. of codeine. Lower
doses, 32 mg. j for example, are sometimes no m~re ef~ective than a
10 placebo, h~wever. -
Because of its relatlvely low activily, except at rather highdoses, cY, d-propo~yphene has been the subJect of investigation, with the-
- view of improving its effectiveness.
Miller, U. S. patent No. 3,845,192, patented October 29,
15 1974, reported that the addition of one or both of the tranquilizers chlor-
diazepoxide and diazepam to a, d-propo~yphene even at doses below those
at which these benæodiazepines exhibit tranquilizing effects results in
improved analgesia, notably a higher pain threshhold. No other benzo-
dia2epines are referred to.
- Miller, U. S. patent No. 3, 749, 797, patented July 31,
1973 suggested combinatîons oî al~ d-pr~po~yphene and namoxyrate, and
No. 3, 800, 041 suggested combinations of a, d-propo~yphene and indome~
thacin, each of which give an ephanced analgesic effect.
In all o~ these combinati~ns, at least one component, and in
the case of the last two mentioned patents, both of the
components, are analgesic~.

~ ~37~ 7
-~ Certain benzoclia~pines have tlle ability to d~pr ess the central
ne~ ous system (~hich can nlanifest itself as tranquilizing or hypnotic action).
L. de Angelis, U. Traversa and ~. Yertua in a paper entitled"3tructure-
activity relationships within the class of 1,4-benzodia~epines: presence oE
- ~ chlorine and central nervous system activities ' published in Current
Therapeutic Research, 16 No. 4, 324 to 337 (1~74) reported that the presence
of 7-CI substituents (as in chlord~nethyl-diazepam) imparts the highest
potency to the molecule. On the other hand~ the absence of such a radical
(as in dechloro-demethyl diazepam) virtually induces a complete loss of
10 activity. Thus, DDI:~ Azepam is pharmacologically inert. ThLs benzodiazepine
has the formula:
~ [
.-'' ' ' ~
However, the presence of a 7-Cl substituent does not guarantee
.: 20 pharmacological activlty. Sternbach, the discoverer of chlordiazepoxide
(~ibr~un~ diazepam (~aliun~ ~nd many other benzodiazepines3 reported
in The Journal of Or~anic Cherl~istry 26 I111 (1961) that 2-aminoethylamino-5-
phenyl-7-chloroben~odiazepine-4-o~;ide, called "Compound 3" for short, is :
pharmacologically inactiYe, lacking tranquilizing and hypnotic properties,
25 and ls not used medicinally. It has the following stl; uc~ural formula:
* Tradernark
~* Trademark
f~

77~ 7
~N~ICl-12CH2NH2
Cl~ ~CHz
In accordance with the instant invention, it has now been determined
that combinations of or, d-propoxyphene and/or o~ propoxyphene with one or .
more of selected benzodiazepines display an enhanced a.nalgesic activi~,
10 greater than that of c~, d-propoxyphene or o~ propoxyphene or the benzo-
diazepine aloneO Combinations of ~,1 levopropoxyphene; the non-analgesic
stereoisomer of a, d-propoxyphene, in comblnation with one or more benzo-
diazepines dlsplay an analgesic activity no less great than that of similar
combinations of ~, d-propoxyphene with chlordiazepoxide or diazepam, the
combinatiorls of U. S. patent No. 3, 845, 192 . That such comblnatiorls have an
enhanced analge~ic activity is quite remarka~le, in view o~ the lack of
appreciable analgesic activity of the cY, l_propoxyphene and benzodiazepine
components. Whi]e it might be expected that com~inations containing a, d-
propoxyphene would have at leas~ the analgesic activity of 0!7 d-prOpOxyphene7
20 it would not be expected that combinations containing both the ~, d-propoxyphene
and benzodiazepine would have an enhanced analgesic actiYity, inasmuch as
the benzodiazepines are not analg~sics. Some o~ the benzodiazepines
effective in the combinations of the invention are in fact pharmacologically
inert, and are not even tranquilizers. Moreover, while it might be expected
25 that combinationY containing ol,d propoxyphene would have at lea~;t the analge~ic
activity of ~, d-propoxyphene, ~t would not b~ expected that combinations
".

7~
containin~ the laevopropoxypher~ woulcl have any analgesic ~ctivity wh~tsoever,
inasmuch as laevopropoxyphene i~ not ~n analgesic, and the benzodiazepine~
are not analgesics, either, but tranquilizers.
The benzodiazepines OI which at least one and option~lly two,
S three or more can be employed in combinations with cY, d-propoxyphene are
defined by the formula:
R
0 ~ 9
¢~4
In the abo~ e formula, the R substituents are defined as follvws: ¦
Rl is selected from the group consisting of hydrogen, methyl~
n-butyl, -C~2- ~ , and alkylamino o~ the type R , in which R and R' are
-N-R' .
selected from the group consisting of hydrogen, lower alkyl having from one
to three carbon atoms, and bivalent alkylene having from two to four carbon
a~oms, and linked to the nitrogen at two positions to form a heterocyclic .
ring; .
R2 i~ selected from the group consis~ing o~ hydrogen, oxo
oxygen -O and hydroxyl OH;
R3 is selectedfrom the group conslsting ofhydrogen, hydroxyl O~ .
and c~ boxyl COOH;
~"~ . .

R~ is sel~cted frc)m the group con~ tirl~ o~CH allcl ~C-~7
where X is F or Cl; and
~5 iS selected from the ~roup consisting of H~ N02, Br and Cl.
Representative benzodiazepines falling within the above ~ormula
- 5 which can be employed include
,, , . ..
;. . Rl R2 R3 R~, R5
. Oxaz epam H --O OH ~ CH Cl
Clorazepate . : H (OH) 2 COOH ~CH Cl
u :~ !
Flurazepa~ /CzH5 =O H ~C-F Cl
~CH2CH2 _ N
. --- ....................... - ~2H5
Lorazepam. H =O OH ~,C-Cl . Cl '
Nitr~zepam H =O H 1 3CH I NC~2 ¦
Medazep~ C~{3 ~I H . ~EI Cl
Brom~zep~m H . .--O ~-I ~N ~3r
Prazepam CH2 a --0 H ~CH Cl j
DDD Azepam H e O H CH H
The benzodiazepines of Which at least one and optionally two,
three or more can be employed in combinations with a, l_~?%opoxyphene are
:. de~ined by the ~ormula:
~s

77~L7
In the above formula, the R substituents are clefined as ~ollows:
~ Rl is selected from the group consisting of hydrogen, alkyl7
-CH2~, amino or a~kylamino of the type R , in which R and R'
N-R'
are selected from the group consisting of hydrogen, lower al~yl having
from one to three carbon atoms, and bivalent alkylene ha~ing from two
i to four carbon atoms; and linked to the nitrogen at two positions to form
: a heterocyclic ring;
. R2 is selected from the group eonsisting of hydrogen, oxo
., .
oxygen ., O, hydroxyl OH, alkyl, and amino or alkylamino of the type
R where R and R ' are as defined above;
-N-R'
R3 is selected from the group consisting of hydrogen, hydroxyl,
15 OH alld carboxyl COOH;
.!
R4 is selected from the group consisting of ~CH, ~C-X, where
X IS halogen, ~N, alld amino or alkylamino R , where R alld
~C-N-R'
R' are as defined above; and
R5 is selected ~rom the group consisting oE hydrogen, halogen
and nitro NO2, the halogen being, for example, chlorine, or bromine.
Representative benzodiazepines falling within the ~ove -Eormula
which can be employed include:
~ '
- .
'' .

I ~77B~27
Chlordiazepoxide H NHCH3 H ~CH C1
Diazepam CH[3 = H " CH Cl
: Oxazepam H = O O~ ~CH Cl
- 5 Clorazepate H (OEi) 2 COOH ~CH Cl
: ~ Flurazepam /C2H5 -O H ~C-F Cl
2CH N
- 2
v ~2H5
Lorazepam ~ - : H - O OH ~C-Cl Cl
Nitrazepam ~ H = O H ~CH N()2
- Medazepam CH3 H H ~CEI Cl
Bromazepam H = O H ~J Br
l?razepam . -cH2~ o H ~CH Cl
- DDD Azepam H = O H . ~CÉ H
The a, d and a, l-propoxyphene and benzodiazepine can be employed
as the free base or as their pharmaceutically acceptable salts. A
pharmaceutically acceptable salt is a salt whose toxicity is not significantly
greater than that o~ the free base. Pharn:laceutically acceptable salts are
. .
readily prepared by reacti~n of the free amine w-lih an or~;anic or inor~
- . ~o ganie acid providing a pharmaceutically acceptable anion. Any pharma-
.
- ceutically acceptable salt can be used including, for example, the hydro-
. - ' .
chloride, hydrobromide, sulphate, bisulphate, acetate, salicylate, val-
erate3 oleate, phenate, laurate, b~rate benzoate, lactate, phosphate,
tosylate, citrate, maleate, fumarate, succinate, tartrate, and napsylate.
2~ Usually, the levopropo~yphene is employed as the hydrochlo~ide ~r
napsylate salt, and the benzodiazepine is normally employed as the hydro~
- chloride.
...
' '~-"``''',i`l I

In the combinatiolls o~ the invention, th~ oe,d-and ~,1 propo7~yph~ne
give an effectivc an~lgesic effect in a single oral tlo~e provicling an amount
within the-range from about 0. 5 to abo.lt 30 mg.- propoxyphene per kg. of
animal body wei~ht The doses can, of course, be varied according to the
species of animal being treated, the particular state which is treated, the
route of administration, and other factors, as is well knownL If the species
,
is a s~nsitive one, a lesser oral dose will suffice, such as, for a single oral
dose, an amount of propoxyphene within the range from aboul; O. 5 to about 5 mg.per kg. of animal body weight. In parenteral administration, the doses are
lower by a factor of one-third to one-fifth of the amount of the oral doses. For.~ - medical applications, it is suggested that reference be made to The Physician's
Desk Reference To Pharmaceutical Specialties and Biologicals, 27th Edition
: .
(19~3) Medical Economics, Inc., page 875.
;~ The benzodiazepine is used in an amount to impart analgesic activity
to the non~nalgesic ~ propoxyphene, and an enhanced analgesic activity to
the analgesic ~, d-propoxyphene, which amount accordingly constitutes a
potentiating dose. The potentiating dose varies with the benzodiazepine,
and also varies with the species of animal, the veterinary or medical state
being treated, the route of administration, and other known factors.
` 20 Generally, an analgesic effect is obtained by employing any of the
benzodiazepines in the normal dosage amounts for the particular bellzodiazepine
employed when used as a tranquilizer. The tranquilizing dosage amounts
`~ for benzodiazepines are set ~orth in The Ph~sician's Desk Reference of
Pharmaceutical Specialties and Biolo~icals, 27th Edition, (1973), Medical
,i , ............. .
` 25 Economics, Inc., pages 537, 1169, 1178, 1192 and 1567 or in similar
publications such as Martindale, The E_tra Pharma_p a, The Pharm_ceutical
Press London, 26th Edition, (1972). I,esser doses can, however, be used
''',' ," . '

~77B~7
provided only that the relative proportions of benzodiazePine and propoxyphene
in the combin~tions of the invention are selected to give an analgesic effec~.
The relative proportions depend, of course, upon the particular benzodiazepine
employed, the animal, the veterinary or medical state being treated, the route
of administration, and other known factors. In general, however, the weight
ratio of propo~yphene:benzodiazepine is within the range from 100: O. 5 to 2.1.
The compositions in accordance with the invention are nonaddictive,
and consequently administration of the compositions can be repeated inter-
mittently or recurringly, on a regular or irregular basis, as required.
.
The process in accordance with the invention accordingly comprises
administering to a warm-blooded animal both 0~7 d-propoxyphene and/or
propoxyphene and abenzodiazepine, separately, i.e., in succession, or
together, in amount~ to give an analgesic e~ect when present together in the
animal. In general, the compositions are convenientl~r administered and
accordingly are usually formulated in combination with inert adjuvants
appropriate for the particular combination and route of administration that is
selected.
The preferred route of administration-is orally. The com-
positions for ~ral adrninistration can assume any ~ the ns~rmal ~rms, such
as tablets, capsules, suspensi~ns, elixirs, p~wders and jellies. T~e com-
positions can also be administered parenterally, such as by intramuscular,
intraven~us or subcutane~us administration, using conventional pr~cedures,
or in the form of rectal suppositories~
In combinations with adjuvants and inert diluents, the com~
positions of the invention can have any desire~ concentration of the active
,
;: .

~ L~77~7
in~reclients, i. e., the propoxyphene clncl the b~n~odi~zepine. A rnOre
concentrated cormposition c~n be formulated Eor dilution with water or other
inert liquid before use. Usually, however, it is con ~nient to have the corn-
position available in unit dose form, i. e., a unit dosage amount such that
one portion o~ the composition provides the normally desired dose. Larger
doses can be obtained by combining units, and lesser doses by subdividing
units, facilitated by score lines or demarcations of some conventional sort.
The compositions of the invention can also include additional
active in~redients to bolster or supplement the analgesic effect, including,
for example, aspirin, acetysalicylic acid, acetylphenetadine, acetylamino-
phene, codeine, and similar components.
In accord with usual medical practice, the combinati~ns in
- accordance with the invention can be supplied in unit dose compositions
comprising from about 25 to about 200 mg. of the p~opoxyphene (calcu-
1~ lated as the free base) and from about 0. 5 to about 25 mg. of the benzodiaze-
i~ pine or benzoclia~epines (calculated as the free base).
In the following Examples, the compositions in accordancewith the invention were evaluated using a standardized "hot plate" test for
analgresia as described by Nathan B. Eddy and Dorothy Lineback, The Journal
2~ of Pharmacological and Experimental Therapy 107 385 ~1953). It is generall~
. . .
accepted that this test measures analgesic action and that the results obtained
- in this test are applicable to all kinds o~ warm-blooded animals including rnan.
The results of the test can be extrapolated to humans in a relative or qualitative
but not in a cluantitative manner.
.. ~ 11
'
.....
'
. .
. .
' ' . ' ' .

'7
-- The test is carl L~d out ~y placin~r mice onto a hot pl~Lte, th~
temperature of which is maintclined between 55 and 55. 5"C~ and determining
the reaction time of the test animal io the sensation of heat, evidenced by
lif~in~ the front feet and kickintr the hind feet. Normal average reaction
time f~r mice pri~r to administration of the analgesic composition in
accordance with the invention is 9. 51 + 1. 02 seconds, with more than g~c of
the mice falling within the range from 6 to 13 seconds. The lengthening of the
reaction time at a ~,iven interval following the administration of a substance
is a measure of the analgesic effect. No mouse is left on ~he hot plate for
1~ lon~er than 30 seconds, since injury might result; failure to react in 30
.~econds is thus reported as complete analgesia.
In the standardized test, the reaction tim0 of the mice is noted
at 10 minute intexvals for one hour following administration of the analgesic
composition being evaluated. However, in the present Examples, the
15 tabulated data in Table I gives only the results at 30 minutes ~d at 60
minutes following administration. Administration in each case was intra-
peritoneally. The test dosage is shown in the Table.
Group A: ~,d-propoxyphene compositions:
. ~ . , . _
EXAMlPLES 1 to 15
A number of combinations were made up composed of ~, d-propox~y-
phene and the benzodiazepine named in Table I. In some cases, a number of
dosages were used, while in others, only one dosage was used.
; The results of the test were as follows:
12
.

~7~
.~
. , ~ o o o C~ CO o o o o o o o o
.. , ~
~ ~ 0~
~ o ~ O
O C~ 0 0 ~ O
.
.
.' ~
. C~ .C
u~ o u~ ~ ~ ~ ~ u~ ~ r- ~ a~
C: -- o ~ C~ N ~ C~ C~
o ~ O ~ U~ ~ I O CD tD C'~
~ ~ CO ~, ~ W _ C,~
: E~
~ CD ~ c~ c~ ~J It~ C~;l 11~ etl ~> c~;~ ~
~ g g g ~ g g
.. h ~ h ^ ~1
;' ' ' '~ ~X a~ X ,~
h C: X
a ~ a~~S S~E ~a
. ~ 'Z ,1 ~ ~d ~
¢ m ~
. ~ a a 8 ~ bc
.. .
.

-
~778~7
-I
o o o o o o o o o o o
.,. C)
_. ,.
!
~ .- I ~ I
~ o ~, ~ ~ ~ o ~ ~ o ~ ~ ~ ~
. . . ~ , I
~; 0~, ~ .~ o r~ ~ ,t
C~ ~
~ .~ .o
~3 C~ ~ 0 5~ O~ N C~
O .U~ ~ D O ~ o
` C .-cS
c~ cc o ~ c~ o o~ ~D
1'- ~ ~ '~ ~ C~ ~ c~
.. ~ ~ .
O O
E-l
,''
3 o ~ o o o o u~ o o o ~ u~ o o o u~
.~. o
Q
~r ~ O ~ ,_ O O O O
_ o ~ ~ ~ ` ,~ o ~
a) h ~ h h h
a ~
x: x - x x - ~ - x - ~ ~
h ~ h ~: h ~ h C t: a
E ,, i. ~ ~ ~o o , 5 ~ N a N '~J ~ N ~
5.) U ~ U ~ C) ~ p ~ h S ~ ~
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. ~ ~
a ~a a ~a
l I
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78a~
. ~ o o o oo o o o C7
:
a~
a
~, o
O ~ O ~ C~ O O O
,, ~ hO ~
~ ¢ ~ h O L~ CQ ~ co O O O O
' z 0~
~ c~ O a~ r-. . .
.: a) ~ ~ ,, e~ ~I c~ a~ CD a~
~ :~
'' O ~ ~ ~ CD ~ a~ a~ O~ ~ ~ c~
~ ~ ,~ ~ oo ~ o~ ~
.~ o ~
.", ~ ~
C~ o
.. ~
: E~
~
.' ~
'` '^ a) ~ Lt~ oo o~ C) Q O 1~ o O
. ~
?
k
Q
o~ ~ o ~ ~ ~ o ~ O
~ c~ o~ ~ o~ ~ o4
.~. O ~h 0~ g ~
~ ~ h;~
o o o.~ o _ ~ :1 - O O o ^ o `
~',, O ~qO
" a1 O ~ ~
. ~ ~ ~ L~ h
O ~ ~
, ~:1 C) V ~ )
.
: ~ 15
.

1~77~8~
.,
Oxazepam (Serax) ~ en testecl alone ~t Z5 n-g/kg (Contl ol , 1)
~ra~e no increase in the reaction tinle. Howe~rer, ~vhen it was combined with
~, d-pr~L)o~;yphene (Darvon) at 25 mg/~ xamule 1) the re~Lction time
increase~l to 16. 3 seconds for the 30-minute te~t and 14. 5 seconds for the
- ~ 60-minute test. As is evident, Ser.~ at the 25 mg/kg level is ineffective by
itself but w ith 25 mg/kg of Darvon shows a synergistic efIect over Darvon
alone at this level (compare with Control B 1).
Oxazepam (Ser~:) at the 50 mg/kg level when used alone (Control C2)
gives a definite increase In the reaction time, both at 30 minutes and at 60
minutes. When combined with 25 mg/~g of o~, d-propox~phene ( Darvon~ at
this level of Oxazepam (Serax) ~Example 2), a substantial improvement in the
reaction time is noted. However, to achie~e best results the a!, d-propoxyphene
(Darvon) must be increased to 40 mg/kg (Example 3).Twelve of the sixteen
mice show complete analgesia on the 30-minute test and ten show complete
analgesia on the 60-minute test. However, the ~0 mg/kg level for c~, d-propoxy-
!~ ' )~
phene (Darvon) rnay be considered dangerously high since deaths are observed
at the 60 ma/kg level (Control B 3).
~lurazepam ~Dalmane) when tested alone at ~0 mg/kg (Control D)
gave a definite increase in the reaction time to 15. 4 and 13. 7 seconds. When
it was combined with ~, d-propoxyphene (Darvon) at 25 mg/kg (Example 4),
` `~ the reaction time increased to 25. 6 seconds for the 30-minute te~t and 21. 7
" seconds for the 60-minute test. As is evident7 Dalmane with ~5 mg/kg of
Darvon shows a synergistic effect over Darvon alone at this level (compare
~ith Control B 1). However, to achieve best results the o~, d-propoxyphene
2~ (Darvon) must be increased to ~0 mg/kg, (Fxample 5). Seven of the eight
mice show complete analgesia on the 30~minute test, ~nd three show complete
analgesia on the 60-minute test.
16

~77~
- Clor~elr.lte ~rIl lr~e~ 50 nlg/kg (Cc)nl~ oL ~ also ~r Lve a
clefinite inc~ ease in tlle r e~tioll tim~, both in til~ 30-rr~ ute al-ld in the 60-
minut~ tests. Furthel, complet~ alg~si~ was obtaired with one mouse in
both the 30-and the 60-minute te~;ts. ~dding 25 mg/lcg of Da:rvon (Example 6)
;, pl oduced a substantially greater increase in the reaction time and complete
anakresia in more than half the animals in the 30-minute tests and in half
the animals in the 60-minute tests. Increasing the Darvon dosage to 40 mg/kg
(Example 7) produced a decrease in the reaction time, though the number of
mice showLng complete analgesia was unchanged. This decrease may be
attributed to e~perimental error, probably due to variations in the specific
reactions of the individual mice.
Increase in the Tranxene level to 100 mg/kg (Control E 2) showed
no increase in the reaction time when the Tranxene ;~7as used alone. However,
when Darvon was added to the extent of 25 mg/kg (Example 8~, ~ll of the mice
sho~Yed complete analgesia. Increase in the Darvon leYel to 40 mg/kg with
- Tranxene at 100 mg/kg (Example 9) showed a slight decrease in the reaction
time .
Prazepam when tested alone at 25 mg/kg (Control F 1) gave no
significant increase in the reaction time. However, when it was combined with
c~, d-propoxyphene (Darvon) at 25 mg/kg (E2~ample 10) the reaction time increased
to 23 seconds for the 30-minute test and 20.g seconds ~or the 60-minute test. Asis evident, Prazepam at the 25 mg/kg level with 25 mg/kg of Darvon shows a
synergistic effect over I)arvon alone, at this level (compare with Control B 1).Prazepam clt the 50 mg/kg level when used alone (Control F2) gives a .
`` 25 definite increase in the reaction time both at 30 minutes and at 60 minutes. When
17
.

~77~3~7
.. .. ..
inec~ with 25 mv/kg of ~, cl-propoxyp~ ne ~D~arvon) ~t l;his l~Yel (Fxample 12) a
substanti~l improvell~ent ill t~le l eactioll tinle to ~5. 6 allcl 28. 2 second~ i~ not~d.
~Iowev~r, as Example 11 shows, to achiev~ best results, the
- ~, d-propoxyphelle (r)arVon) must be increas~d to 40 mg/kg. All of the
eight mice show conlplete analgesia on the 3~-minute test and five show
complete analgesia on the 60-minute test.
Lorazepam when tested alone at 25 mg/kg (Control G) gave no
significant increa~e in the reaction time. However, when it was combined with
o~, d-pr~poxyphene (Darvon) at 25 mg/kg (Example 13), the reaction time increas-
ed to 25. 4 seconds for the 30-second test but receded to 12~ 5 seconds for the
60^minute test. As is evident, Lorazepam with 25 mg/l~ o~ Darvon shows
a synergistîc effect over Darvon alone at this level (compare with Control 3 1~.
However, to achieve best results the cY, d-propoxyphene (Darvon) must be
increased to 40 m~/kg (Example 14~. Six out of eight rnice show complete
`~5 analgesia on the 30-minute test, and three show complete analgesia on the
F
60-minute test.
The results for Example 15 indicate that DI)D Azepam markedly
increases the analgesic action of ~, d-propoxyphene. This is of interest
because this compound is known to lack tranquilizing or hypnotlc properties,
;~Q and is not medicinally used.
Controls I A, B, C and D show that Compound 3, also
pharmaceutically inert, given by itself in doses as high as lO0 mg/kD,does
not by itself extend the reaction time of mice on the hot plate,
.~
nor does it potentiate the analgesic action of o~, d-propoxyphene (~Sarvon).
2~ This compound is closely related in structure to the benzodiazepines of this inven-
tion, but diffeI s from them in not increasillD and in not potentiating the
;` analgesic action of o~, d-propoxyphene.
18
;.''
.

77~
Th~;e results for l)rjn l~Y,er~lrrl alld Co~ )o~ d 3 shc)~/ that the
p~tenti~ltino effect of a benzodi.l~,epit~c on the an~l~esic activity of Dc~voll
is not correl~ted ~I,it'l other pharmacc)logical activity or inactivi'y. Even
benzo~iazepines that are not clinically used because they have no tranquilizing,
an~iol~ tic or hypnotic action, can be ~ffective in this invention. Such an
inacti~Te compouncl may, such as DDD A~epam, or may not, ~uch as
Compoulld 3, potentiate the analgesic acti~n of o~, d-propox~rphene (Darvon).
One cannot make predictions from what has been known about the benzo-
diazepines whether a benzodiazepine will or will not synergistically enhance
,
10 the anal~esic action of o~ d-propoxyphene (~arvon).
:; The following are E~amples of compositions for dosage units or
other application forms in accordance with the invention:
-i Tablet formulation
Parts/ tablet
-~ 15 Active compounds 15
~ Lactose 86
. .
Corn starch (dried) 45. 5
~,` Gelatin ~. 5
Magnesium stearate 1. 0
,:.
The compound was powdered and passed through a sie~e, and
well mixed with the lactose and 30 mg of the corn starch.
- The mixed powders weI e combined with a warm gelatin solution
" prepared by stirring the gelatin in water and heating to ~orm a 10~C w/w
solution, granulated by passing through a B.S. No. 12 sie~e, and the moist
~5 granules dried 'dt 40C.
The dried granules were re-granulated and the balance of the
starch and the magnesium stearate were add~d and thoroughly mi~ed.
The granules were compresi-ied to produce tablets each weighing
, ~ 150 mg.
,.
'' 19

~78~L7
le~ r()rn~ L~ioll
Par ts/tablet
~ct i~ e conlpoullcls 100
-~ Lactose 39
Cornstarch (driecl) 80
Gelatin 4 0
~iagnesium stearate ~.0
The method of preparation is identical with tha~ of the preceeding7
except that 60 parts of starch is used in the granulation process and 20 parts
10 during tableting.
Capsule formulation
.
,. Parts/capsule
. .
Active compounds 250
Lactose 150
The compounds and lactose were passed through a sieve and the
_. powders well mixed to,gether before filling into hard gelatin capsules of
, ..
suitable size, so that each capsule contained 400 mg.
Suppositories
:~ Parts!suppository
Active compounds 50
Cocoa butter g50
The compounds were powdered and passed through a sieve and
triturated with molten cocoa butter at 45 C to form a smooth suspension.
The mixture was well stirred and poured into moulds, each of
25 nominal 1 g capacity, to produce supposltories.
. .
~. 20
.
. . ~
... : ... ... .. ~ .. , . . :
.. . . . .

~.~77847
C~ ct~; '
Parts/ca let
- ~cti~e colllpounc~s 100
Lactose 400
- ~ 5 The compounds were passed through a sieve, mixecl with lactose
pre~ iously sieved and filled into cachets of suitable size so that each contained
. 500 nlg.
-:. Intramuscular injection (suspension in aqueous vehicle)
.
`~ Parts
`. 10 Compounds 10
` ~ Sodium citrate 5.~
... Sodium carbo~methylcellulose (low viscosity grade) 2. 0
Mlethyl para-hydroxybenzoate 1. 5
. ` Propyl para-hydroxybenzoate 0. 2
.: ~
~, Water for injection to 1. 0 ml.
; r The sodium citrate and sodium carboxymethylcellulose were
, .
mixed with sufficient water for injection at 90C. The mixture was cooled to
50-C and the methyl and propyl para-hydroxybenzoates added followed by the
medicament previously milled and sieved 300 rnesh. When cooled the
.~ 20 injection was made up to volume and sterilized by heating in an autoclave.
C-roup B~ propoxyphene compositions:
.
; E~MPLES 1 to 1~
A number of combinations were made up composed of laevo-
~ ` propoxyphene and the benzodiazepine namecl in Table I. In som~ cases,
`~ ~` 25 a number of dosages were used, while in others, only one dosage was used.
~` The results of the test were ~s follows:
:,:
. ~
21
'``'''`
~`
: .
. . ,

7'7
~lo
o ~ ~ o o,~ o o o ~ L~ ~ o ~ co o
~, ~ o C~
Ul
~ ~1~ ''
EE¦o o o~oc~ o u~ co ~ o e~ er o ~
,.
, O CO ~ ~ 00 ~ e~ C~J h
~ C~
. p; o ~ o o~ ~ o ~ r~ i O r~
o
a) :
I _ ~ .
¢ ~ C~ ~
~q Ln O O O O O O ~ O O O O O U~ ~ ~ O U~ ' ~ ~ ~ o
' ~ ~ S~
) I ,1 L~ ,~ ~ rl h h h ~ h u~
,~ O h ~ o
O .q o rl ~,q o ~11` o z o ~,c
æ ~ ~z ^ ^ ~z
~ R ~ C D ~, U~
o a o~ C2'
o ~,~ o ~ 0~ o~ E ~ E a
..
a
a) ¢ ~ ~ m ~ a~ r1
;~ L C ~ ~ E ~ O '
22
:
:. .

& C~ ~ CD C~ ~ ~ V ~ ~ O C~
,~d .tn
E
~ fi s~ ~ ~ ~ o
.~ ~Z o
~ C~
,. ,
.~ h 1:-- C`;l tD ~ 00 d~
c a ,, ~
6) o ~ co ~ r~
~~
~ o
;~;
E-' 0 o ~ o o o o ~ o c~ u~ o o o c:~ o o o o o o o
Lq 1-~ N ~ t~ t~ ~ C~ O L~ O t~ L~ m
O . ~
a
: td td ~ td td td~ ~
_ rd ~ ~ h ~- h D (d
; O O= ~: 0: 0: tV O tl) tD ~ ~ t h
`: Z z tl) O tl) !i~ tl) Z tl~ t~ O t~
tD: tD tD ,Z. X ~ ^ -~
= _ = _ = rd: tb ~ rd ~ ~ X ~ X X: ~: h z = bO
X X X ~ C sc--td O = S~ -~
h ~ h S h ~C~ cl l~i rd ~ ~d h 5~ h td ID h r~d ti,~ ~ O
O 0 tD 0 tl) !:~ tl~ ~ ~D a ".~ C E~ ~ rd o
cn.~ cn ~ c~
E ~; E =, ~, f a i~ E ~ G 3 ~ ~ ~ e O
c~ O~o~o ~ ~ ,~v
~q
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. ~:L ~ ~ O O ~J t~ r~
:. ~ h 00 g a~ O ,~ a ~ ~
, .
-. 23
.. ~ .
~.-
:. ~3

Itis a~l)are~ olll C~rltl~ls B5 alld BG tilcltat dosag~s in
e~cess ~ ~0 nlg. per kg. ttl~ t~xicity lin~it of ~ levo~)r~poxy~ ene i~
exceeclecl. Collseql..ently, the m~imulll do~e used in these tests witl mice
was ~0 mg. per kg.
It is als~ apparent from the untreated Control A and the
C~ntrols B1-B4 that levopr~poxyphene is not effective as an analgesic
by itself. S~)me of the benz~diazepines in Cvntr~ls C to H evidence a
minimal effect, but in n~ way as great an analgesic efeect as for the
combinati~ns of Examples 1 to 14. The data show true synergism, which
is all the more remarkable because neither of these components, taken
separately, displays analgesic properties.
The following are Examples of comp~sitions for d~sage
units or other application f~rms in ac~ordance with the invention:
. .: .
Tablet formulati~n
Active comp~unds 15
Lactose 8 6
n Corn starch (dried) 45-5
Gelatin 2. 5
Magnesium stearate 1. 0
The compound was powdered ancl passed thr~ugh a sie~e,
and well mixed with the lactose and 30 mg. of the corn starch.
`-` The mi~ed powders were combined with a warm gelatin
solutîon prepared by stirring the gelatin in water and heating to form a
25 10~- w./w. s~lution, granulated by passing through a B. S. No. 12 sieve,
; ` and the ~m~ist granules dried at 40C.
The dried granules were re-granulated and the balance ~f
the starch and the magnesium stearate were adclecl ancl thorou~hly mix~cl.
. ` .
...
2~
'

~7~7
Ttle ~r~nules were compr~ssed tr~ proclu~ t~b1ets e~ch
~eighitlg 150 Illg.
Tablet fvrmul_tion_
Part3/tablet
Active compounds 100
Lactose 39
: Cornstarch (dried) 80
Gelatin 4- o
Magnesium stearate 2. 0
The meth~d ~f preparati~n is identical with that of the
precedingg except that 60 parts of starch is used in the granulation
process and 20 parts during tableting.
Capsule form latio~
Parts/capsule
Active comp~unds 250
Lactose 150
The comp~unds and lact~se were passed thrs:ugh a sieve
and the powders well mixed together before filling into hard gelatin
. ~ . .
capsules of suitable size, so that each capsule contained 400 mg;
2 0 Suppositories
Parts/supp~sitory
Active compounds 50
Cocoa butter 950
The compounds were p~wdered and passed thr~gh a sieve
and triturated with molten cocoa butter at 45C to form a smooth sus-
'~ pension.
The mixture was well stirred and poured ints~ moulds,
each of nominal 1 g. capacity, to produce suppositories.
Cachets
~achet
Active compounds 100
Lactose a~oo
~'

Tlle cvlnp~ul~d.s were pas~;ed tllrc:u~ll a gieve, mi~.ed with
lactose previol1sly sieved ancl filled illtv cacllets ~f suitable siY,e s~
that each contained 500 mg~
Intranluscular injection (suspensivn in aqueous vehicle)
_ _ . _ _ _ _ _
Parts
Comp~unds 10
Sodium citrate 5 7
Sodium carbnxymethylcellul~se (low
viscosity grade) 2 . 0
Methyl para-hydroxybenzoate 1. 5
Propy 1 para - hydroxybellzs)ate o .
Water for injection to 1. 0 ml.
The sodium citrate and sodium carboxymethylcellulose
were mixed with sufficient w~ter for injection at ~0C. The mixture
was cooled to 50C and the methyl and pr~pyl para-hydr~xybenzoates~
added f~ wed by the rnedicament previously milled and sieved 300
mesh. When cooled the injection was made up to volume and sterilized
by heating in an autoclave.
.
... .
'
.
.
,
2 6
.~
.~
' ~ '