Note: Descriptions are shown in the official language in which they were submitted.
ROEMMERS S.A.I.C.F.
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Pharmaceutical preparation for topical application
The invention relate~ to pharmaceutical preparations for
to~ical application which are preferably in the form of
cream~ or gel~ and contain as active substance the L-ly~ine
salt of the 2-[(3-chloro-2-methylphenyl~amino]-3-pyridine
carboxylic acid of the formula ~I), hereinafter designated
lysine clonixinate.
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The pharmaceutical preparations are useful as topical
analgesics and anti-inflammatory agents.
Drugs for oral and rectal administration and injectable
solutions containing lysine clonixinate as active substance
are known from the literature, for example from DE-PS
2,253,134 and US-PS 3,973,027 and/or are available on the
marXet. These drug~ develop a good analge~ic and anti-
inflammatory actlvity. ~owever, there are cases in which
they are no~t suitable or appli~able. Thus, when a person
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suffers from pain in a limited area of the body, for
example after a blow or knock or due to a minor accident,
in the case of contusions, di~tortions, luxations or
arthritis, arthroRis, tenalgia, bursitis, myalgia and sport
injuries, a localized topical application of a substance is
generally regarded as the mos1; suitable way or the most
suitable method for healing. It is also important not to
apply an active substance more strongly or more weakly than
i9 necessary to relieve or eliminate the pain or
inflammation, and thus to avoid unnecessary secondary
reactions or habituation to the active substances, ox
dependence thereon, or obtaining only slight relief.
Finally, topical Eormulations such as creams or gel~ are
less dangerous than tab]ets, in particular for self-
medication, as is made possible by freely purchasable
remedies. Thus, the making availahle of remedie~ for
topical application which develop a mean analgesic and
anti-inflammatory activity i8 an important problem in
therapeutics~
Topical formulations containing the analgesic/anti-
inflammatory agent as active substances are generally known
from the literature. For example, NL-OS 8,100,917 (1982),
CH-PS 651,4~4 (1985) and US-PS 9,407,824 (1983) relate to
the amine salts of diclofenac. In DE-OS 2,935,776 (1981)
as well various organic salts of anti-inflammatory
medicaments are named which are suitable for topical
application.
It has now been found that the L-lysine salt of 2-[(3-
chloro-2-methylphenyl)aminol-3-pyridine carboxylic acid is
very well suited to the preparation of pharmaceutical
compositions for topical application and develops a very
good effect on such an application.
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The ~ubject of the invention is therefore pharmaceutical
preparations for topical application, preferably in the
form of cream~ or gels, which with re~pect to the weight
contain as active sub~tance 1 to 10 % by weight L-ly~ine
salt of the 2- E ( 3-chloro-2-methylphenyl)amino]-3-pyridi.ne
carboxylic acid and 2 to 15 % by weight pharmaceutically
acceptable emulsifiers, 2 to 20 % by weight
pharmaceutically acceptable emollients or ~oftening agents,
0.01 to 0.2 % by weight pharmaceutically acceptable
preservation substance~ and water to make up 100 % by
weight. Possibly, these agen~s may also contain 0.2 to 5 %
by weight ruhefacients and in the ca~e of creams 3 to 18 %
by weight pharmaceutically acceptable lubricant~ or in the
case of gels a . 5 to 5 % by weight pH-value modifiers, the
accompanying water always being adjusted to make up 100 %
by weight.
The pharmaceutical preparations according to the invention
are distinguished by the following advantages:
-- local action,
- rapid response~reaction due to rapid absorption,
- low toxicity in uninjured or undama~ed tissues or
organs.
According to an preferred embodiment the pharmaceutical
preparations according to the invention for topical
application contain 3 to 7 % by weight L-lysine salt of the
2-[(3-chloro-2-methylphenyl)amino]-3-pyridine carboxylic
acid as active substance, 3 to 13 ~ by weight
pharmaceutically accep~able emulsifiers, 3 to 10 ~ by
weight pharmaceutically acceptable emollients, 0.02 to 0.1
% by weight pharmaceu~ically acceptable preservation
substance~ and water as remainder up to 100 %. Possibly,
0.5 to 2 ~ by weight rubefacients may al~o be contained
therein ~nd in the ca~e of crea~s 8 to 12 % by weight
pharmaceutically acceptable lubricants and in the ca~e of
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gels 1 to 3 % by weight modifiers of the pH-value, the
accompan~ing water always being made up to a total of
100 %.
Advantageously, the emul~ifiers are selected from the group
of the following substances: Glyceryl monostearate,
glyceryl monostearate/polyoxyethylene stearate, ketostearyl
alcohol/potassium lauryl sulfate ~emulsifier wax) and
carbomer.
The softening agent or emollient is preferably selected
from propylene glycol, glycerol, sorbite and isopropyl
myristate.
As preservative agents or substance, methyl parabene, ethyl
parabene and propyl parabene have proved expedient.
Menthol is advantageously used as rubefacient.
As already mentioned, the pharmaceutical preparations
according to the invention are preferably brought into the
galenic form of a cream or a gel.
If the pharmaceutical preparation according to the
invention i5 to be formulated as cream, a~ emulsifier
advantageously ketostearyl alcohol/lauryl sulfate
("emul~ifier wax") is used and the lubricants are selected
from the group consisting of mineral oil, vaseline and
fatty acids.
If the pharmaceutical preparations according to the
invention are formulated as gel, advantageously carbomer is
used as emulsifier and propylene glycol as softening agent,
and the modifiers for the pH-value or buffer are selected
from the group consisting of ~odium hydroxide, triethanol
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amine, trlmethamine, (tris~hy~roxymethyl)amino methane) and
lysine.
For both creams and gels, isopropyl myristate is very well
suited as ~oftening agent or emollient.
Of the preservation agents r methyl parabene and propyl
parabene are preferred.
According to the invention, the L-lysine salt of the 2-1(3-
chloro-2-methylphenyl)amino~-3-pyridine carboxylic acid can
be used for the preparation of a pharmaceutical composition
for topical application in order to relieve or at least
alleviate pain and/or inflammations in humans and animals.
The following examples serve for more detailed explanation
of the invention.
Example 1: Topical pharmaceutical preparation in the
form of a cream without rubefacient.
A cream was made having the following composition:
- lysine clonixinate5.0 % by weight
- isopropyl myristate9.0 % by weight
- methyl parabene0.1 % by weight
- emulsifier wax13.0 % by weight
- mineral oil 10.0 % by wei~ht
- water up to 100.0 % by weight
The lubricant, emulsifier and the emollient are melted
together at 65 to 70C. The active substance and the
preservation agent are di3solved in water. The oily phase
is added under constant stirring to the aqueous solution
and after cooling to room temperature the desired cream is
obtained.
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Example 2: Topical pharmaceutical preparation in the
form of a cream with a rubefacient.
A cream of the following composition was prepared:
- lysine clonixinate5.0 % by weight
- isopropyl myristate10.0 % by weight
- methyl parabene0.1 % by weight
- propyl parabene0.02 % by weight
-"emulsifier wax"10.0 % by weight
- vaseline10.0 ~ by weight
- menthol 1.0 ~ by weight
- water up to100.0 % by weight
The lubricant and the emulsifier were melted together at
65-70C. The active substance and the preservation agent
were dissolved in water. The oil pha~e is added under
constant stirring to the aqueous solution.
Menthol was dissolved up to complete solution in the
emollient.
After cooling to 40C the menthol solution in the emollient
was added to the emulsion with constant stirring. After
cooling to room temperature the desired cream was obtained.
Example 3: I'opical pharmaceutical preparation in the
form of a gel without rubefacient.
A gel of the following composition was prepared:
- lysine clonixinate5.0 ~ by weight
- carbomer 3.0 % by weight
- propylene glycol5.0 ~ by weight
- isopropyl myristate3.0 % by weight
:
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- glycerol 3.0 % by weight
- methyl parabene 0.1 % by weight
- propyl paraben0 0.02 % by weight
- - sodium hydroxide 1.5 % by weight
- water up to 100.0 % by weight
The active substance was diissolved in the mixture of
propylene glycol and glycerol (solution A). The
preserYation substances were dii~olved in water, the
emulsifier wai~ dispersed in the aqueous solution and the
buffer (pH-modifier) was added (dispersion B). The
solution A was poured over the diispersion B and finally
isopropyl myristate was added.
Example 4: Topical pharmaceutical preparation in the
form of a gel wi~h rubefacient.
A gel of the following composition was prepared:
- lysine clonixinate 5.0 % by weight
~ carbomer 3.0 ~ by weight
- propylene glycol 6.0 ~ by weight
- isopropyl myristate 3.5 % by weight
: - methyl parabene 0.1 % by weight
- sodium hydroxide 2.0 % by weight
- menthol 1.0 % by weight
water up to 100.0 % by weight
The active siubstance was dissolved in the propylene glycol
and a third of the total amount of water (solution A). The
: preservation substance was dis~olved in the r~maining water
and the em~lsifier disperised in isaid aqueoui~ solution;
: thereupon, the buffer IpH-modifier~ was added (dispersion
B). Th~ solution A was then poured into the diispersion B
whilst stirring and finally the menthol dissolved in
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isopropyl myri~tate added. The p~l-value was checked and
adjusted to ~.2-8.g.
The following examples 5 and 6 will explain the
advantageous use of the topical agent according to the
invention compared with a conventional analge~ic/anti-
inflammatory agent (diclofenac) both as regard~ the
alleviation of inflammation~ and the absorption or takeup
(through the ~kin).
Example 5
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Anti-inflammatory effect. Paw edema induced by
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Carragheenin in 1 % dosage was administered to Wistar rats
of both sexes, body weight 175 200 g, that is 0.1 ml into
the paw, corresponding to the procedure adopted by Winter
et al. ~. Pharmacol. and Exp. Therap. 1949, 96; 99). 30
minutes previously, in each case one of the three groups of
six test animals had been treated with the following
compositions: lysine clonixinate cream corresponding to
example 1, 5 %; 20 mg/kg; sodium diclofenac 5 %, 20 mg/kg;
excipient; in each case on an area of 20 cm3 on the back of
the previously shaved animals. The inflammatory edema of
the paw was measured with'a Ugo Basile plethysmometer 3 and
5 h after the carragheenin administration. The percentage
alleviation or reduction of the inflammation wa~ determined
with respect to the control group. The results are
eum~arized in tùe following rable l.
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Percentage alleviation of the inflammation
by the various compounds tested
Pharmaceutical
preparation % alleviation
3 h 5 h
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lysine clonixi:nate 50 48
~qodium diclofenac 35 30
Exa,m~,le 6
'rran~dermal ab~orption. Com~arative tes$q between a,cre"am
a,n,d, ",a""",g"e,,l" ",ea,c"h",",c",o",n"t,,a, i,n",i",n~,",,,ly"si,n,e"""c",l"on,i,xi,n,a,"te,l",,"",w"i,th,
corres~ondln~ commercially avail,able productq
As teqt animals, Flemish giant rabbits having a body weight
of about 3.5 kg were used which had been shaved on their
backs over an area of 10 cm3.
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Each group contained three animals which had been treated
;~ with the following formulations and the~following doses:
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a~ Iysine clonixlnate, 5 % cream, 20 mg/kg, prepared
according to examp]e l.
b) Lysine clonixinate, 5 % gel, 20 mg/kg, prepared
according to example 3.
c) Sodium diclofenac, 5 % cream, 20 mg/kg.
d) Diclofenac diethyl ammonium salt, 5 % gel, 20 mg/kg.
Blood 3amples were taken from the central artery of the ear
and the concentration~ of the various active ~ubstance~
determined.
The result~ are ~hown in the following Table 2 and in the
diagram attached a~ Fig. l.
T a b 1 ~ 2
Concentration of lysine clonixinate and diclofenac
in mg/ml in the various formulations and at various
times
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Pharmaceuticai time h
prep~ation _ _ ______ _ ~ ~ , _
1 2 3 4 6 2~ 2~
~_..,. ,,., . _. _ .__ _ ~ __ _ ~ . - _
cloni- cream0 56 ~ l2 0 61 ~ 13 ~ 0 14 0 19 ~ 0 ~2
xina~e .- _ ~ _ _ ~ ~ . ~_
0,54 0,6~ ~ 0,68 0,fiO 0,17 0,~
~l+ 0,I~ ~,1l 0,12 ~ ~,14 ~ 0,1Z + 0,03 ~ 2
__ ~ . . ___--_- _ _~ . ............ , _.
Dicl0,30 0,35 ~o42 0,50 0,30 0,1a 0,10
~_ cream ~ 0~07 -~,08 ~ 0,Q8 ~ 0010 ~ 0,07 ~ 0,04 + 0,02
~n~c _ ~ _ _ _ _ ~ _
Cel 0,36 0,40 0,45 V,4B 0,3t 0,16 0,09
~ ~,a6 ~,08 0,0~ 0,~ ~ Q,0~ ~ 0,03 ~ 0,02
~ _ ........... , ,- . __ _ _ ~ . ~ __ '. ,
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