Note: Descriptions are shown in the official language in which they were submitted.
ll~g~73
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LACTATE SALTS OF l-AND d,1-GLAUCINE~
This invention is directed to the lactate salts of l-glau-
cine and d,l-glaucine, to pharmaceutical compositions con-
taining said salts and to methods for using them as anti-
tussive and analgesic agents.
Glaucine which has the following structure:
OCH3
OCH-3 ~
lo H3CO~
H3CO ~H.. CH
.
- -possesses an asymmetric center indicated in the above formu-
la with a star. Thus two optical isomers are possible.
Only one of them, the dextrorotatory form (d-glaucine)
occurs naturally and can be isolated from the yellow poppy.
The racemate, d,l-glaucine, can be synthesized from papave-
rine, following the procedure of Frank and Tietze, Ange-
zO wandte Chemie (1967) pp 815-6, or according to a variety
of other preparative methods such as those described by
Chan and Maitland in J. Chem. Soc. (C) 1966, 753 or by Cava
et al., in J. Org. Chem. 35, 175 (1970). Separation of the
two enantiomers can be carried out by conventional procedu-
res such as using an optically active acid, for instance d-
or l-tartaric acid, to form the diastereoisomeric salts which
can be separated by fractional crystallization.
d-Glaucine hydrobromide and d-glaucine hydrochloride are
known to have antitussive activity (Donev, Farmatsia (Sofia)
1962, 12, (4), p.l7, and Aleshinskaya, Khim. Farm. Zh. 10, ~1),
pp. 144-147 (1976) and Chemical Abstracts 84 : 159725 w).
In addition, Aleshinskaya, supra, stated that glaucine derived
~k
' ' '
::
.
)9~'73
--2--
from the yellow horned poppy (d-glaucine), prolonges
hexenal and chloral hydrate sleep time in mice, and has
analgesic activity at doses of 50--100mg/Kg, as well as
adrenolytic activity.
5 More recent investigations proved that levorotatory and
racemic isomers of glaucine hydrobromide have superior anti-
tussive properties over the prior art dextrorotatory form
(Belgian patent No.866.079).
As it can be ascertained by the above formula,glaucine is
10 structurally related to other plant alkaloids such as codeine.
Codeine and related compounds, such as hydrocodone, are well
known -as antitussive and narcotic analgesic agents. Merck
Index, Ninth Ed., Merck & Co., Rahway, N.J.(1976) monographs
~- Nos. 2420-24 and 4672. Although these compounds are also well
15 known to have a high potential for habituation or addiction,
they remain the most potent and widely used antitussive agents.
Antitussive agents are usually administered orally, most ty-
; pically in the form of a liquid formulation such as an elixir,
suspension or syrup, or in a solid lozenge or cough drop which
is held in the mouth until it dissolves. In both cases the un-
pleasant bitter flavor of the alkaloid is known disadvantage
of such agents. Various formulations have been developed to
mask the unpleasant taste and after taste of codeine with
varying degrees of success. None of these techniques however
25 have been completely successful.
Glaucine, like codeine, has an unpleasant bitter taste. It
has now surprisingly been found that l-and d,l-glaucine lactate,
besides having antitussive properties that are superior to
~he d-glaucine, have analgesic activity uriexpectedly
superior to that of d-glaucine coupled with a very lo w addic-
tive potential, particularly desirable solubility and stabi-
lity properties, and unexpected flavour and palatability pro-
perties which make them particularly useful orally.
1~9473
The novel lactate salts of the invention are crystalline
solids which are prepared by reacting l-glaucine or d,l-
-glaucine (or mixtures thereof) in the form of the bases,
~ith lactate ion under conditions adapted to the formation
of lactate salts of organic bases. The salts can be obtained
in crystalline solid form.
The compounds can be readily prepared by reacting the free
glaucine-base with lactic acid. The reaction proceeds rea-
dily in the presence of an inert organic solvent, such as
- acetone, ethanol, chloroform,methanol, diethyl ether, or
ethyl acetate. The lactate salt typically forms as a precipi-
tate, which can be recovered by conventional techniques such
as filtration or decantation and purified by conventional
steps such as recrystallization and washing.
The reaction is typically carried out by dissolving the free
base glaucine in the inert organic solvent at a temperature
from ambient temperature to the boiling point of the mixture,
and adding an equimolar amount or an excess of lactic acid.
Lactic acid can be employed in from about 0.5 to about 1 to
2 to 3 fold molar excess or more. Use of equimolar amounts is
preferred.
When using excess lactic acid,the excess lactic acid preci-
pitating with the product can be removed by recrystallization.
Mixture of the 1- and d,l-glaucine lactate, l-glaucine lac-
tate salts, and the racemic salt are all useful as antitussiveagents and analgesic agents, with similar desirab~e proper-
ties. For convenience it is generally preferred to use a
single lactate salt, such as the d,l-glaucine lactate or 1-
-glaucine lactate, the preferred salt being d,l-glaucine lactate.
The glaucine lactate salts are highly effective, orally active
antitussive agents and also have analgesic activity when admi-
nistered orally, combined with surprising palatability and
-
.
~1~9a~73
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des.irable stabili.ty and solubility, and a useful free-
dom from undesired side effects, such as addictive proper-
ties. They can be administered at dosages of from about 0.1
to about 40 milligrams or more per kilograms (mg/Kg) for anti-
tussive effect, and from a~out 0.1 to about 60 mg/Kg for anal-
gesic use, preferabily by oral administration. They are also
active parenterally as a-ntitussives and analgesics, by intra-
peritoneal injection, for example.
In practicing the method of the invention, an antitussive
amount of-one or more of the glaucine lactates is administered
- - internally to an animal, typically a mammal in need thereof~ -
Administration can be carried out either by a parenteral
route, such as by intravenous, intraperitoneal, or intramus-
cular injection, or by introduction into the gastrointestinal
tract via oral or rectal administration, for example, or by
oral administration of a glaucine lactate solution in the
form of a throat spray, for example.
. The antitussive amount of the compound, that is, the amount
- of the glaucine lactate sufficient to inhibit or alleviate
coughing depends on various factors such as the size, type
: and age of the animal to be treated, the particular salt or.
mixture of salts employed, the route and frequency of adminis-
tration, the severity of cough (if any) and the causative agent
involved, and the time of administration. Similar considera-
tions apply to selection of the analgesic amount of the com-
pound, that is the amount of the glaucine lactate sufficient
to allevia~e pain symptoms. The glaucine lactate salts are
generally effective when administered orally as well as in
parenteral dosages. For example, in antitussive evaluations
3 in wh.ich codeine phosphate has an ED50 of 10.9 mg/Kg by
intraperitoneal injection and an oral ED50 of 86.6 mg/Kg, the
llV9~73
--5--
oral and intraperitoneal ED50' 5 obtained with d,l-glau-
cine lactate are 63.4 and 7.9 mg~Kg. In particular cases,
the dosage to be admini.stered can ~e ascertained by con-
ventional- range finding techniques, for example, by obser-
- ving the antitussive activity produced at different dosage
rates.
Good antitussive results can be obtained when the salts
are administered orally at dosage rates from about 0.1 to
about 0.2, to about 0.5-to about 1 to about 10 to about 20
to 25 to 30 to 40 to about 80 milligrams of glaucine salt
compound per kilogram of animal body weight and at rates of
0.1 to 40 mg/Xg by intraperitoneal injection. It is general-
ly desirable to administer individual dosages at the lowest
- amount which provides the desired cough suppression conso-
nant with a convenient dosing schedule. Oral administration
is the route generally preferred for administration of anti-
tussive agents. The glaucine lactates of the invention thus
combine high oral antitussive potency with palatability,
making them particularly useful orally.
Dosage units adaptable to oral administration such as tablets,
capsules, lozenges, elixirs, syrups and the like are prefer-
red and the active glaucine lactate compound can be formula-
ted in conventional timed release capsule. or tablet formu-
lations.
In using the compounds of the invention, the active glaucinelactate ingredient is preferably incorporated in a composi-
tion comprising a pharmaceutical carrier and from about 0.001
: to about 95 percent by weight of the glaucine lactate salt
compounds. The term "pharmaceutical carrier" refers to known
pharmaceutical excipients useful in formulating pharmacologi-
cally-active compounds for internal administration to animals,
~ .
.
llV9473
and which are substantially non-toxic and non-sensitizing
under conditions of use. The compositions can be prepared
by known techniques for the preparation of tablets, cap-
sules, cough drops, lozenges, troches, suppositories,
solutions, elixirs, syrups, emulsions, dispersions, wetta-
ble and effervescent powders, sterile injectable compositions,
and can contain suitable excipients known to be useful in
the preparation of the particular type of composition de-
sired.
The compounds may be administered in conjunction with other
active ingredients or other antitussive or analgesic agents.
Otner active ingredients can include, for example, anti-
histamines, decongestants, expectorants, mucolytic agents,
bronchodilator and antibacteria; agents or local anesthe-
tics. Combinations of this type are generally useful fortreating coughing or pain in combination with other symp-
toms.
Particularly desirable compositions are those prepared in
the form of dosage units, such as solid forms, including
troches, lozenges,,tablets, capsules, or measured volumes
of liquid compositions, containing from about 0.1 milli-
gram to about 20 to 30 milligrams of the glaucine salt per
unit! for antitussive use and from about 0.1 milligram to
about 30 to about 60 milligrams for analgesic use.
Example 1 - Preparation of d,l-glaucine lactate.
A. Two grams of d,l-glaucine was dissolved in 40 millili-
ters absolute alcohol (ethanol) at a temperature of 50C,
and the solution was added, with stirring, to a solution
of 0.57 grams of 85 percent lactic acid diluted with 5 mil-
- liliters of ethanol.
73~
--7--
The resulting mixture was concentrated under vacuum,
cooled; and diethyl ether was added to the concentrated
solution until a precipitate formed. The white crystal-
line solid precipitate was collected ~y filtration and
washed with diethyl ether. The d,l-glaucine lactate product
(1.5 gram yield) was found to melt at 148.6-151C. After
recrystallization from ethanol-diethyl ether, the purified
salt was found to melt a~ 153.3C. The product evidenced no
optical rotation. (/ ~D = in water-100 mg/20 ml).
-. , , , _.
B. 5.6 Grams (0.02 mole) of d,l-glaucine was dissolved in
30 ml of alcohol USP (95 percent ethanol, 5 percent water).
A solution of ~.5 grams (0.02 mole) of 85 percent d,l-lactic
acid (~ D=0) in 50 ~1 of alcohol USP was added to the giau-
cine solution with stirring. The solution was concentrated
under reduced pressure, cooled in a refrigerator, and dry
diethyl ether was added until crystal formation was complete.
The crystalline product was separated by filtration, washed
with diethyl ether, and found to melt at 14? -151C.
~Yield 7;3 grams, 100 percent) The d,l-glaucine-d,l-lactate
product was dissolved in 130 ml alcohol USP at about 60C,
filtered, and cooled. Diethyl ether was added to precipita-
te the product, and the purified d,l-glaucine-d,l-lactate was
found to melt at 153C. (Yield 96 percent; assay 99.8 percent
pure)-
C. Elemental analysis of d,l-glaucine lactate:
C,H,N-calculated 64.70, 7.01, 3.14; C,~H,N-found 62.19,
7.17, 3.02.
1~ 7~
Example 2 - ~eparate groups of guinea pigs were orally
administered various doses of a test compound, or distil-
led water for a control group. One hour after oral dosing,
th.e guinea pigs were exposed to a 5 percent aerosol of ci-
tric acid for a 10 minute test period. The number of cough
responses produced during the last five minutes of exposure
. . . to the citric acid aerosol was recorded and the dosage ef-
fected to suppress coughing in 50 percent of the guinea
1 pigs (ED50) was caIculated. An antitussive effec.t was recor-
.: . ded for a guinea pig when its total number of coughs during
' the 5 minute. test period were at least two standard devia-'
tion units below the mean number of coughs per guinea pig
: ' in the control group. In these operations, codeine phos-
phate was found to have an oral ED50 of 86.6; d-glaucine
hydrobromide an ED50 of 89.0; and d,l-glaucine lactate an
ED50 of 63.4 milligrams per kilogram.
Example 3 - In an operation similar to that of Example 2,
test compounds were administered to guinea pigs by intra-
peritoneal injection, with one group of guinea pigs-^recei-
ving distiiled water as a control. ED50':s were calculated
for a-ntitussive activity in the citric acid aerosol test
. as described in Example 2. Codeine phosphate was found to
2 have an ED50 of 10.9 mg/Kg; d-glaucine hydrobromide an ED50
of 10.0 mg/Kg; and d,l-glaucine lactate an ED50 of 7.9 mg/Kg.
Example 4 - A,cough.syrup vehicle formulation was prepared
containi.ng the following pharmaceutically-acceptable excipients:
~ 7 3
Excipient Amount
5ugar (cane) 1600 grams
50rbitol solution USP 600 grams
Et~anol (Alcohol USP) 21 ~rams
Water q. 5 . to 4 liters total
The solubility of d,l-glaucine hydrobromide in this cough
syrup vehicle was found to be 0.3 percent, or about 15
milligrams in a 5 milliliter dosage unit. The solubility
of d,l-glaucine lactate was found to be 2 percent, or about
100 milligrams per 5 milliliter dosage unit.
.
Example 5 - Stability of d,l-glaucine lactate was examined
in the syrup vehicle of Example 4. After one month at ambient
temperature, 40C and 55C, respectively, syrup formulated
to contain 0.6 percent d,l-glaucine lactate was found to
retain 98.8, 100.6, and 96.7 percent, respectively, of the
original glaucine concentration.
Syrups containing codeine phosphatej 0.2 percent, contained
97.5, 104.5 or 100 percent, respectively, after one month at
~- ambient temperature, 40C or 55C. Syrups containing d,l-gla~-
cine hydrobromide, 0.2 percent, resulted in assays of 99,96
and 89.5 percent, respectively, after one month at ambient
temperature, 40C and 55C.
After three months, the percentage amount of antitussive
agent remaining was as shown below.
- .
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~1~)9473
--10--
Percentage Remaining
after 3 ~onths at
CompoundAm~ient 40~C 55C
5 d,l-Glaucine Lactate104.1 97.0 97.4
Codeine Phosphate101.3 101.1 88.4
d,l-Glaucine HBr100.8 93.3 91.4
Example 6 - In a procedure similar to that 'of Example 5,
syrup formulations were prepared, placed in amber glass
bottles and transparent (flint) glass bottles, and held
under conditions of ambient temperature with continuous
exposure to light. tAbout 21.520 lux'of combined fluorescen't
and incandescent light, for 24 hours/day~.
- After one month, the d,l-glaucine hydrobromide assay of
amber bottles was 84 percent, that of flint glass bottles
was 74.5 percent. d,l-Glaucine lactate in amber glass had
- an assay of 94 percent, in flint glass 80.6 percent. Codeine
phosphate appeared stable in both types of container, with
assays of 100 percent.
' In other operations, crystalline d,l-glaucine lactate was
found to retain over 99 percent o-its original assay after
2 months s'torage at 40C.
Example 7 - Physical dependency liability was evaluated in
2~ mice by the procedure of Saelens, et al., Arch. Int. Pharma-
codynam, 190:213-218, 1971. In this procedure, mice are ad-
ministered increasing doses of a test compound at intervals
on two consecutive days. The last dosage on the second day
is followed by intraperitoneal injection of the morphine
antagonist, naloxone, at a dosage of 100 mg/Kg, and the
mice are observed for characteristic -jumping behaviour in-
dicative of opiate withdrawals or morphine antagonism. In
7;3
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these operations, morphine sulfate produced stimulation
and Straub tail in mice, followed by jumping in 5 of 9
mice (g6 jumps total) after naloxone treatment. Codeine
phosphate produced Straub tail and stimulation, and nalo-
xone-induced jumping in 2 of 6 mice (23 jumps total).
d,l-Glaucine lactate produced no Straub tail at the high-
est dose (100 mg/Kg) and no jumping behaviour in any of
the ten mice tested.
.
' ' ~ '
Example 8 - Several d,l-glaucine salts were prepared as
0.2~percent (weight by volume) solutions in distilled water.
The various salt solutions were evaluated for palatability
by touching a few drops to the tongue. In these operations,
which included blind sampling by a trained flavor formula-
tor experienced in flavoring of formulations containing
agents such as codeine and dextromethorphan, the hydrobro-
~; mide was characterized as objectionable with a bitter, sharp
and metallic initial taste which increased with tlme. The
sulfate, maleate, citrate, acetate, pamoate and p-toluene-
sulfonate salts were similar to the hydrobromide and similar-
ly objectionable. The salicylate and succinate salts were
ranked as more objectionable thanthe hydrobromide. d,l-Glau-
cine lactate was found to lack the sharp, metalIic flavor
and to be unobjectionable.
Example 9 -
A. A flavored cough syrup formulation is prepared to contain
the following-
1~9~73
Ingredient Amount
Sucrose (100% invert sugar-
-dry Basis) 26.4 grams
5 Sorbitol syrup USP 10 milliliters (mI)
Glycerine 5 ml
Alcohol USP 5.4 ml
Piperonal 10.0 milligrams (mg)
Vanillin 7.5 mg
10 Ethyl vanillin 10.0 mg
Ethyl maltol - 7.5 mg
l-menthol 7.5 mg
d,l-glaucine lactate 600 mg
Purified water USP q.s. to 100 ml total
The syrup contain-s 0.6 percent (weight by volume) d,l-
- -glaucine lactate and a 5 ml dosage unit (1 teaspoon)
; contains 30 mg of active lactate salt. The syrup can be
sealed into 5 ml plastic lined foil pouches, or filled
into conventional glass bottles. Dosage uni~s of 15 mg
and 20 mg per 5 ml dose can be made by using 300 or 400 mg
of d,l-glaucine lactate or l-glaucine lactate or mixtures -
. . .
thereof in the above formula.
B. Tablets are prepared as follows: 40 grams l-glaucine
lactate; 150 grams of modified starch (Sta-Rex 1500) are
mixed and granulated with sufficient aqueous alcohol (75
percent water, 25 percent ethanol) to prepare a granulation.
The granulation is dried and mixed ~ith 15 grams starch USP;
1.5 grams stearic acid (40 mesh); 0.5 grams hydrogenated
vegetable oil (40 mesh),3 grams colloidal silicon dioxide
and microcrystalline cellulose q.s. to 300 grams. The ingre-
dients are mixed and compressed into 300 milligram tablets
~1~9473
using 11/32 inch (=8,7 mm) tablet dies. The tablets
contain 40 m111igrams of l-glaucine lactate each.
C. Capsules are prepared by blending 10 grams d,l-glau-
cine lactate, 3 grams colloidal silica; 2 grams stearic
acid and 285 grams lactose; and filling the ~lend into
No. 2 gelatin capsules, 300 milligra~s per capsule. This
provides 10 milligrams of glaucine lactate per capsule.
Larger unit dosages, such as 15, 20 or 25 mg, can be pre-
pared by using 15, 20 or 25 grams glaucine lactate and
lactose q.s. to 300 grams. Smaller dosages are similarly -
- prepared.
.
D. Troches are prepared by mlxing 30 grams d,l-glaucine
lactate~435-grams powdered sugar and 35 grams powdered
acacia; adding sufficient water to form a pliable mass;
rolling the mass into a cylindrical shape and dividing the
mass into 0.5 gram segments.
Example 10 - In other operations, various dosages of d,l-
,,
-glaucine lactate were administered to groups of mice by
the oral route or by intraperitoneal inj-ection, and the
dosage which is lethal to 50 percent of the mice (LD50)
was calculated from the mortality observations within 72
hours adter administration. The LD50 for intraperitoneal
injection was found to be 178 mg~Kg. The oral LD50 in these
operations was found to be 383 mg/Kg.
Example 11 - Test compounds were evaluated for analgesic
activity in the phenyl-p-quinone mouse writhing test of
-14-
Hendershot & Forsaith, J. ~harmacol. Exptl~ Therap.
125(3)~ 237 (1~7~). The test compounds were administered
orally 30 minutes prior to the phenyl-p-quinone challenge.
In these operations, the oral ED50's for d-glaucine hydro-
bromide, codeine phosphate, and dtl-glaucine lactate were
found to be 34.0, 21.1 and 25.5 mg~Kg respectiVely.
:
