Hydrophilic pharmaceutical composition containing ketoprofen lysine salt for topical use

A hydrophile pharmaceutical composition in the form of foam is described which contains as active ingredient Ketoprofen lysine salt having a concentration between 10 and 20% p/volume of solution which allows, for topic treatment, the maximum absorption of the active principle. The foam is applied for the local treatment in painful and phlogistic conditions, of rheumatic or traumatic nature, of the articulations, of the musles, of the tendons and of the ligaments.

The object of the present invention relates to a topical pharmaceutical 
composition in the form of foam containing as active ingredient a compound 
having anti inflammatory activity which belongs to the class of the 
arylpropionic acids. 
More particularly the arylpropionic acid contained in the composition which 
is the object of the invention is represented by the lysine salt of 
2-(8-benzoylphenyl) propionic acid, known also as ketoprofen lysine salt, 
a compound which forms the object of Italian Patent n.degree.1.104.556, in 
the name of the instant Applicant, issued on 21st Oct. 1986. 
The 2-(3-benzoylphenyl) propionic acid or ketoprofen, as which the majority 
of the non-steroid antiinflammatories or FANS, derives its mechanism of 
action essentially from the inhibition of the biosynthesis of 
prostaglandins, prostacyclines and tromboxane. Compared to the ketoprofen, 
the ketoprofen lysine salt, even presenting a parallel pharmaceutical 
profile and a similar antiinflammatory-analgesic potency, offers the 
advantage of a considerably higher solubility in water and a greater 
gastric tolerability. The muscle-skeleton apparatus is particularly 
subject to possible physical trauma with a consequent formation of local 
inflammatory processes and therefore it is convenient to have at disposal 
compositions containing topical non-steroid antiinflammtory (FANS) drugs. 
The topical administration route is certainly the elective one for 
non-steroids antiinflammatory drugs, in case of local inflammatory 
processes because it minimizes the appearance of collateral effects, 
especially the gastric and renal ones, which appear during the therapy 
with the majority of such drugs. 
With the exception of the drugs used for their surface topical effects, 
those which are applied on the skin have to penetrate the appropriate 
cutaneous layer to produce the therapeutical desired effect. The FANS, to 
work their action, therefore have to go through corneous layer and the 
vital part of the epidermis. The corneous layer, being a keratinized 
tissue, behaves like an artificial semipermeable membrane and the 
molecules of the drug penetrate by passive diffusion therethrough 
according to the gradient of concentration. Therefore the speed of 
penetration through this cutaneous layer depends on the concentration of 
the drug in the carrier, on its solubility in water and its coefficient of 
distribution between the corneous layer and the carrier. 
Therefrom it derives that in order that an antiinflammatory drug may have 
the desired effect it has to be administrated in elevated concentrations, 
thus it has to be contained in high concentrations in the pharmaceutical 
form for topical administration. 
The topical pharmaceutical composition in the form of foam which is one of 
the objects of the present invention, allows to concentrations between 10 
and 20%, of the ketoprofen lysine salt, to be obtained concentrations. 
Such are concentrations not otherwise obtainable with other formulations, 
for example with a gel. A further advantage provided by the topical 
pharmaceutical composition of the invention is represented by the very low 
quantity of excipients contained therein which may, to some extent, 
interact with the skin. In particular said excipients, in the 
pharmaceutical composition in the form of a foam, totally amount to a 
percentage ranging from 5% to 10% p/volume of solution, with a very low 
con Lent of alcoholic excipients, i.e. lower than 5%, while in the 
traditional pharmaceutical forms for topical use, such as gel or cream 
containing FANS, the percentages of alcoholic excipients are much higher 
and they may even reach 40% p/volume of solution. 
The pharmaceutical composition in the form of foam contains 10-20% of a 
ketoprofen lysine salt solution, preferably 15% of ketoprofen lysine salt 
solution, and is emulsified, when delivered, by means of a suitable gas, 
for example, a mixture of butane, propane and isobutane gases, commonly 
denominated butane-propane, preferably mixed in the ratio of butane: 
propane: isobutane=4: 4: 2, in a quantity from 3 up to 7% by weight of the 
solution. 
The quantity of a gaseous mixture corresponding to 5% by weight the 
solution is particularly preferred. In the pharmaceutical composition in 
the form of foam other components, such as a surfactant or an ionic or 
non-ionic emulsifier, an emollient substance, a thickener and optionally 
small quantities of a scent and of a bacteriostatic substance are also 
included. As ionic emulsifier potassium laurylsulphate may be used and as 
non-ionic emulsifier non-ethoxylated derivatives such as sorbitan esters 
or ethers (SPAN) or ethoxylated derivatives such as, for example, 
polyoxyethylenesorbitan ethers or esters and polyoxymethylene ethers and 
esters (Cremophor, myrj) may be used. The quantity of the emulsifier is 
between 2 and 8% by volume of solution. The quantity particularly 
preferred for ionic emulsifiers is between 2 and 3% by volume of solution 
while for the non-ionic emulsifiers said quantity is between 3 and 5% by 
volume of solution. 
As an emollient substance propylene glycol, glycerin or polyethyleneglycols 
having a molecular weight between 300 and 3.000 (Carbowax of Polywax 
300-1.500-3.000) may be used. The quantity of emollient varies from 2 to 
6% by volume of solution; quantities between 3 and 4% by volume of 
solution are particularly preferred. 
As a thickening substance, substituted amides of saturated or unsaturated 
fatty acids of vegetable origin (Comprelan Henkel); substituted and/or 
salified celluloses such as, for example, methylethylcellulose, sodium 
carhoxymethylcellulose, methylcellulose, isopropylmethylcellulose; 
substituted vinyl pyrrolidone polymers having different molecular weights 
such as, for example, polyvinylpyrrolidone K 30; carboxypolymethylene 
(Carbopol) may be used. The quantity of the thickener varies from 0.2 to 
3% by volume of solution. The scent optionally present may be constituted 
by netolin lavender in a quantity from 0.05% to 0.2% by volume of 
solution. 
The bacteriostatic substance which, although not strictly necessary, can be 
present to assure the microbiological purity as time passes, may be 
constituted by benzoic acid and by its esters (Nipagin-Nipasol) or by 
benzilic alcohol and is added in a quantity from 0.1 to 0.5% by volume of 
solution. The topical antiinflammatory pharmaceutical composition in the 
form of foam, the object of the present invention, is of simple 
application and it is suitable for the local treatment of painful and 
phlogistic conditions, of rheumatic or traumatic nature, of the 
articulations of the muscles, of the tendons and of the ligaments. A 
suitable posology foresees that, according to the area that has to be 
treated and of the entity of the inflammation, the foam can be applied 2-3 
times a day on the effected parts and made to penetrate by lightly rubbing 
.

The examples which follow are given only to illistrate, without limiting, 
the object of the invention. 
EXAMPLE 1 
Ketoprofen lysine salt (1.5 kg) is dissolved under stirring in depurated 
water (6.5 1). 
In another container are placed: 
Polysorbate 80 (0.4 kg); propylene glycol (0.4 kg); PVP K25 
(polyvinylpyrrolidone) (0.3 kg); nerolin lavender (0.02 kg); 
benzilic alcohol (0.03 kg) and water q.s. to 1 liter. 
The second solution is added, under stirring, to the first one and then, it 
is brought to volume (10/1) with water. 
is controlled (range limits: 7-8.0). It is filtered under pressure and it 
is divided in small bottles. The valve is installed and secured to the 
small bottle. It is pressurized by loading butane-propane gas (5% by 
weight). 
The final composition of tile solution for 100 ml is the following: 
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Ketoprofen lysine salt 15.0 g 
Polysorbate 80 4.0 g 
Propylene glycol 4.0 g 
Polyvinylpyrrolidone (PVP K25) 
3.0 g 
Nerolin lavender 0.2 g 
Benzilic alcohol 0.3 g 
Depurated water q.s. to 100 ml 
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EXAMPLE 2 
Operation is carried out similarly to what was described in Example 1 
suitably varying the excipients and the following final composition is 
obtained: 
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Ketoprofen lysine salt 15.00 g 
Sodium Laurylsulphate 2.00 g 
Polyethyleneglycole (Carbowax 300) 
5.00 g 
Sodium Carboxymethylcellulose l.v. 
0.25 g 
Nerolin lavender 0.20 g 
Nipagin 0.10 g 
Nipasol 0.02 g 
Depurated water q.s. to 100 ml 
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EXAMPLE 3 
Operation is carried out similarly to what was described in Example 1 
suitably varying the excipients and the following final composition is 
obtained: 
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Ketoprofen lysine salt 15.00 g 
Span 20 5.50 g 
Glycerin 3.00 g 
Hydroxypropylmethylcellulose E 3 
0.35 g 
Nerolin lavender 0.20 g 
Benzoic acid 0.12 g 
Depurated water q.s. to 100 ml 
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EXAMPLE 4 
Operation is carried out similarly to what was described in Example 1 
suitably varying the excipients and the following final composition is 
obtained: 
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Ketoprofen lysine salt 15.00 g 
Cremophor EL 4.00 g 
Propylene glycol 4.00 g 
Methylethylcellulose 0.30 g 
Nerolin lavender 0.20 g 
Nipagin 0.12 g 
Depurated water q.s. to 
100 ml 
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EXAMPLE 5 
Operation is carried out similarly to what was described in Example 1 
suitably varying the excipients and the following final composition is 
obtained: 
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Ketoprofen lysine salt 15.00 g 
Myrj 52 5.00 g 
Glycerin 3.00 g 
Polyvinylpyrrolidone K 30 
4.00 g 
Nerolin lavender 0.15 g 
Benzilic alcohol 0.30 g 
Depurated water q.s. to 100 ml 
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The absorption of the hydrophilic solution of ketoprofen lysine salt was 
studied on Female rabbits (New Zealand, 9-11 weeks) after topical 
administration of the composition in the form of foam at different 
concentrations (5%, 10%, 15% and 20%) which all had the excipient 
composition as described in Example 1. The foam was applied to 4 groups of 
rabbits (n=3) on the back, previously depilated (24 hours before the 
treatment), in an area of 100 cm.sup.2 (10 cm .times.10 cm), at a dose 
role of 10 mg/kg (average weight of animals 2000 g .+-.200 g). 
The animals, immediately after the treatment, were put in metab obolic 
cages. 2 ml of blood were taken at the following times: 0 (pre-dose), 15, 
30, 60, 120, 240 and 360 minutes and urines were collected during the 
periods; 0-6 h, 6-12 h and 12-24 h after administration. 
The determination of ketoprofen acid level in the plasma and urine was made 
by the HPLC method using as internal standard (IS) the Suprofen acid. 
The samples of plasma, after adding IS adding were acidified with 1M 
potassium phosphate, pH=2.0 and extracted with ethyl ether. The urines, 
after adding IS underwent alkaline hydrolysis by 1N NaOH for 30 minutes, 
were then neutralized by adding 1N HCl, finally acidified to pH=2.0 with 
1M potassium phosphate, and then extracted with ethyl ether. The ether 
phases of plasma and urine were evaporated to dryness under nitrogen. The 
residues of the plasma and urine extracts were taken up in 0.2M NH.sub.4 
-formiate (pH=6.5) and injected in HPLC (volume of injection 20 .mu.l ). 
The chromatography conditions are as follows: 
Column: Merck Lichrospher 10RP-18 5 .mu.m 125.times.4 mm with mobile phase 
pre-column: NH.sub.4 -formiate 0.2M pH (35% CH.sub.3 CN) 
Flow rate: 1 ml/min 
Detection: UV to 258 nm 
The applied method is linear within the tested range 0.020-2 .mu.g/ml 
(r.sup.2 0.99 ) for plasma and of 0.05-25 .mu.g/ml (r.sup.2 0.99) for 
urines. The limit of the method is 0.01 .mu.g/ml and the minimum 
concentration detectable is 0.05 .mu.g/ml for both plasma and urine. 
The administration in the rabbit of the hydrophilic solution of ketoprofen 
lysine salt in the form of foam at 5%, 10%, 15% and 20% at a dose rate of 
10 mg/kg does not result levels higher in the plasma than the detectable 
limit of the method, while dosable levels of ketoprofen have been found in 
urines. 
In Table 1 are shown the values of total excretion in each animal and the 
relative average (.+-.DS). The FIG. 1 shows how after the application of 
the 5%, 10%, 15%, and 20% solutions there is an increase of the levels of 
ketoprofen in the urines which is proportional to the concentration of the 
active principle present in the composition. 
The direct comparison between the concentrations of ketoprofen found in 
each period of urine collection and the concentrations of the active 
principle in the compositions was made with the Duncan test. The obtained 
results show that the formulations containing 5%, 10% and 15% of 
ketoprofen lysine salt are statistically different (p 0.05) from each 
other, while a statistical difference did not exist between the 15% 
formulation and the 20% one. 
TABLE 1 
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Cumulative levels of ketoprofen acid after the 
application on the skin of a rabbit of 10 mg/kg of ketoprofen 
lysine salt foam at 5%, 10%, 15% and 20%. 
Ketoprofen lysine salt foam at 5% 
Collecting 
Cumulative urine excretion (.mu.g) 
time 1 2 3 Average .+-. SD 
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0-6 h 50 48 43 47 .+-. 4 
6-12 h 130 123 113 122 .+-. 9 
12-24 h 153 146 143 147 .+-. 5 
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Ketoprofen lysine salt foam 10% 
Collecting 
Cumulative urine excretion (.mu.g) 
time 4 5 6 Average .+-. SD 
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0-6 h 126 122 121 123 .+-. 13 
6-12 h 261 268 256 262 .+-. 6 
12-24 h 286 296 275 286 .+-. 11 
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Ketoprofen lysine salt foam 15% 
Collecting 
Cumulative urine excretion (.mu.g) 
time 7 8 9 Average .+-. SD 
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0-6 h 195 205 196 199 .+-. 6 
6-12 h 387 359 386 377 .+-. 16 
12-24 h 473 473 456 467 .+-. 10 
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Ketoprofen lysine salt foam 20% 
Collecting 
Cumulative urine excretion (.mu.g) 
time 10 11 12 Average .+-. SD 
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0-6 h 198 205 208 204 .+-. 5 
6-12 h 381 390 406 392 .+-. 13 
12-24 h 471 490 487 483 .+-. 10 
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