FR2537438A1 - STABLE COMPOSITION FOR LOCAL CORTICOTHERAPY CONTAINING THE SOLUBILIZED STATE OF HYDROCORTISONE - Google Patents

Abstract

STABLE COMPOSITION FOR LOCAL CORTICOTHERAPY BASED ON HYDROCORTISONE. THIS COMPOSITION CONTAINS, IN THE SOLUBILIZED STATE, HYDROCORTISONE IN AT LEAST ONE SOLUBILIZING AGENT TAKEN FROM THE GROUP CONSTITUTED BY: I. CAPROLACTAM IN SOLUTION AT LEAST 30 BY WEIGHT IN AN ALIPHATIC ALCOHOL HAVING FROM 2 TO 12 ATOMS OF CARBON; II.CHLORIDE OF 2-ISOSTEARYL 1-HYDROXYETHYL 1-BENZYLIMIDAZOLINIUM IN SOLUTION AT LEAST 25 BY WEIGHT IN WATER; AND III. POLYGLYCEROL ALCOYLPHENOLS CORRESPONDING TO THE FOLLOWING FORMULA: (CF DRAWING IN BOPI) IN WHICH: R REPRESENTS A RADICAL OCTYLPHENYL OR NONYLPHENYL AND N IS A WHOLE NUMBER OF 4 TO 10, OF PREFERENCE 6.

Description

-1 253743 th

  The present invention relates to a novel

  stable position for local corticosteroid therapy likely to

  contain in solubilized state, a high percentage of hydro-

  cortisone, to avoid general contraindications

  encountered by the prolonged use of hydrocortisone compositions. Abuse and especially prolonged use of lotions, ointments, creams or ointments based hydrocortisone is not without some side effects likely to cause, in the long run, a real irreversible atrophy of the skin. Current compositions are generally dosed with hydrocortisone at a percentage of less than about 2% and

preferably of the order of 1%.

  Compositions with a much lower concentration of the order of 0.1% can be used for particular purposes.

  to avoid the disadvantages of compositions with higher con-

  centration, but in this case the duration of treatment is longer and therefore requires medical supervision

followed.

  In order to reduce the duration of treatment and thus avoid side effects, compositions in the form of

  dispersion have also been proposed.

  These compositions, if they make it possible to lead to high concentrations of hydrocortisone, nevertheless have a lower effectiveness because of a lack of penetration on the

skin areas to treat.

  Furthermore, it was also noted that these compositions were poorly stored, hydrocortisone degrading

  in time, which diminishes their activity.

  It has not been possible so far to develop stable compositions for local corticosteroids,

  likely to contain hydrocortisone with a high concentration

  to ensure good penetration and thus

  reduce treatment times and avoid irreversible atrophy

versible of the skin.

  This problem is solved according to the invention by the use

  new hydrocortisone solubilising agents

  capable of solubilizing an amount greater than or equal to 2%.

  Furthermore, the conservation tests of the compositions -2- according to the invention have proved excellent in every respect,

  the rate of degradation after a period of two months at

  The subject of the present invention is a stable composition for hydrocortisone-based local corticosteroids containing, in the solubilized state, hydrocortisone in at least one solubilizing agent selected from the group consisting of: (i) caprolactam in solution at least 30% by weight in an aliphatic alcohol having from 2 to 12 (ii) Isostearyl 1-hydroxyethyl-1-benzylimidazolinium chloride in solution with

at least 25% by weight in water.

  and (iii) the corresponding polyglycerolated alkylphenols

to the following formula:

R-O O C 2 H 3 (CH 2 OH) -O 1 H

  in which: R represents an octylphenyl or nonylphenyl radical and

  is an integer of 4 to 10, preferably 6.

  Among the aliphatic alcohols having from 2 to 12 atoms

  of carbon that may lead to caprolac-

  In particular, ethanol, isopropanol, butanol, heptanol and dodecanol may be mentioned. The solutions are preferably solutions at 40.degree.

  % by weight of caprolactam and the preferred alcohols are the ethanol

nol and dodecanol.

  A 70% by weight solution of caprolactam in

  ethanol makes it possible to solubilize up to 12% by weight of hydro-

  cortisone and ensure good preservation over time, the rate of degradation after two months at room temperature,

  measured by HPLC, being only 2.3%.

  A 40% by weight solution of caprolactam in the

  dodecanol makes it possible to solubilize up to 5.5% by weight of hydro-

  cortisone, the degradation rate after two months at room temperature, measured under the same conditions as above, was

  revealed to be of the order of 5% only.

  Tests using other lactams such as caprylolactam or laurinolactam were significantly lower than those observed with caprolactam, regardless of the nature of the solubilization alcohol used and

  from the point of view of solubilization rate as well as

  servation of hydrocortisone over time.

  2-isostearyl 1-hydroxyethyl-1-benzyl chloride

  imidazolinium is a yellow viscous liquid corresponding to the following formula:

C 2 H 4 OH

2,465 C 1 i

CH 2 CH 2 -C 6 H 5

  CH C C o H (iso) 72 6 18 37 (i he '

CH N

  and having the following characteristics: molecular weight: 478 relative density (25 C): 0.99 p H aqueous solution 5%: 5-7 Aqueous solutions of 2-isostearyl chloride

  1-hydroxyethyl-1-benzylimidazolinium which may be used

  according to the invention are generally not greater than

  % by weight and preferably between 35 and 75%.

  Solutions of between 25% and 90% make it possible to solubilize from 2% to 7% by weight of hydrocortisone, the degradation rate of hydrocortisone after two months at room temperature.

  ambient, measured by HPLC, being less than 5%.

  Among the polyglycerolated alkylphenols,

  According to the invention, the octylphenyl ether of poly-

  glycerol with 6 moles of glycerol (n = 6) (viscous liquid, soluble in water and having a cloud point of 0.5% in 5% salt water at 63 ° C), ie polyglyceryl nonylphenyl ether at 6 moles of glycerol (n = 6) (viscous liquid, soluble in water and having a cloud point of 0.5% in water at 64 ° C) o

  These polyglycerolated alkylphenols make it possible to

  biliserize up to 2% by weight of hydrocortisone and ensure excellent preservation over time, the degradation rate after two months at room temperature being less than 5%,

measured by HPLC.

  The hydrocortisone concentration of the compositions according to the invention for local steroids is generally not greater than 12%, depending on the solubilizing agent used, but is preferably between 0.01 and 5% and more particularly

  between 0.5 and 4% by weight relative to the total weight of the composition

sition. -3-

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  According to the invention, the solubilising agent of hydro-

  cortisone as defined above represents from 8 to 98%

  weight of the total weight of the composition.

  The compositions according to the invention can be in various forms, especially in the form of lotions, shampoos, ointments or gels and are intended to treat all

  diseases related to local corticosteroid therapy.

  Lotions are essentially made up of

  the solubilising agent, which may be supplemented with additives

  for this type of preparation.

  The gels are obtained using gelling agents such as silica, cellulose derivatives, carboxyvinyl polymers (Carbopols), gums of natural or synthetic origin, etc. used at a concentration that may vary between 0.5 and

  15% relative to the total weight of the composition.

  Ointments are anhydrous compositions based on

  example of petrolatum, paraffin oil and / or waxes.

  The compositions according to the invention are particularly

  indicated in the treatment of eczema, erythrocyte

  eczematous or psoriatic dermatitis, pruriginous lesions of chronic lupus erythematosus, psoriasis and parapsoriaris in plaque, hypertherrophic scars, solar erythema

or radiotherapy.

  These treatments require an average application twice a day by massaging possibly to facilitate

penetration.

  Several examples of the compositions will now be given by way of illustration and without any limiting character.

according to the invention.

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EXAMPLE A

  Local corticosteroid gel -caprolactam in 50% solution in ethanol 95 g hydrocortisone 3 g Hydroxypropylcellulose acetate 2 g

EXAMPLE B

  Local corticosteroid lotion - 2-isostearyl 1hydroxyethyl 1-benzylimidazolinium chloride 45 g (active ingredient) hydrocortisone 3 g water q s p 100 g

EXAMPLE C

  Hydrocortisone local corticosteroid ointment 2.5 g caprolactam 50% solution in ethanol 50.5 g polyoxyethylenated C 12 C 18 fatty acid glycerides 30 g miglyol 17 g

EXAMPLE D

  Lotion for local corticosteroids caprolactam in 50% solution in ethanol 92 g hydrocortisone 3.5 g glycerin 4.5 g

EXAMPLE E

  Alkylphenol polyglycerol scalp corticosteroid shampoo of formula:

R O C 2 H 3 (CH 2 OH) O 3 H

  R = nonylphenyl 50 g propylene glycol * 20 g absolute ethanol 20 g hydrocortisone 1.5 g water q s p O100 g

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  In this example, the polyglycerolated alkylphenol may be replaced by the same compound in which

R = octylphenyl.

  The compositions A to E above are stable in storage. Good penetration and good tolerance have been observed.

  Compared to the usual hydrocor-

  tisone treatment times could be reduced significantly, thus avoiding prolonged use and risks

cutaneous atrophy.

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Claims (6)

  A stable composition for local corticosteroid treatment based on hydrocortisone, characterized in that it contains, in the solubilized state, hydrocortisone in at least one solubilizing agent selected from the group consisting of: (i) caprolactam at least 30% by weight solution in an aliphatic alcohol having 2 to 12 carbon atoms, (ii) 2-isostearyl 1-hydroxyethyl-1-benzylimidazolinium chloride in solution at least% by weight in water, and (iii) polyglycerolated alkylphenols corresponding to the following formula: R O E C 2 H 3 (CH 2 H) O N H   in which: R represents an octylphenyl or nonylphenyl radical and   n is an integer of 4 to 10, preferably 6.   2 composition according to claim 1, characterized in that the concentration of hydrocortisone is not greater than 12% and is preferably between 0.01 and% and more particularly between 0.5 and 4% by weight relative to to the total weight of the composition.   3 Composition according to any one of the claims   preceding, characterized in that the solubilizing agent of hydrocortisone represents from 8 to 98% by weight of the weight total of the composition.   4 Composition according to Claim 1, characterized in that the caprolactam is in solution in an alcohol selected from the group consisting of ethanol, isopropanol,   butanol, heptanol and dodecanol.   Composition according to Claim 4, characterized in that the caprolactam solution is a solution between 40 and 70% by weight.   6 Composition according to Claim 1, characterized in that the aqueous solution of 2-isostearyl 1-hydroxyethylbenzylimidazolinium chloride is a solution comprising between 25 and 90% by weight.   -7- Composition according to Claim 1, characterized in that the polyglycerolated alkylphenols are either polyglycerol octylphenyl ether with 6 moles of glycerol or polyglyceryl nonylphenyl ether with 6 moles of glycerol.   8 Composition according to any one of the claims   previous ones, characterized by the fact that it is   form of an alcohol, a shampoo, an ointment or a gel.