FR2660553A1 - Syrup based on carbocisteine having improved stability - Google Patents

Abstract

The invention relates to a syrup based on carbocisteine whose stability has been improved by adjustment of the pH to around 7.

Description

 The present invention relates to a carbocistein-based syrup. It relates more particularly to a syrup with improved stability over time, especially when stored at a temperature slightly above room temperature.

The syrups containing carbocistein or S- (carboxymethyl) -L-cysteine or 3 - [(carboxymethyl) thio] alanine are sold in particular under the following brand names: Rhinathiol,
Mucoplexil, Muciclar. They have the disadvantage after relatively short storage times and particularly when the temperature is slightly higher than the ambient temperature to reveal non-toxic secondary degradation products. These by-products adversely affect the activity of the syrup by the fact that they reduce the level of active ingredient present.

 For non-regulated products for the general public, it is annoying to see the title in active ingredients fall over time when storage conditions are too severe. Thus a bottle of adult Mucoplexil syrup stored at 350C for two years sees its title drop by about 10 to 30% while the same syrup but in pediatric form sees its title fall by about 50%.

 We have sought to improve the stability of carbocistein solutions in order to allow an improved preservation, especially as regards the duration, of the pharmaceutical forms containing said solutions.

 We have found that the stability of the solutions of S- (carboxymethyl) -L-cysteine was improved by maintaining the pH of said solutions between 6.5 and 7.5 and preferably around 7.

 The amount of degradation product which is predominantly a lactam is divided by 3 when the pH at manufacture is set at 7 relative to the same solution where the pH is fixed at around 6.

 This effect of pH on stability is even more pronounced when the carbocistein is in solution even more diluted for example in pediatric liquid pharmaceutical forms.

In the context of the present invention, it is preferred to prepare liquid formulations containing by weight about 5% of
S- (carboxymethyl) -L cysteine, 40% sugar and 0.15% of a stabilizer selected from methyl and ethyl parahydroxybenzoates and whose PH is fixed at 7 with sodium hydroxide.

 Of the pediatric formulations, it is preferred to use solutions containing, by weight, approximately 2% of S- (carboxymethyl) -L-cysteine, 70% of sugar and 0.15% of preserving agent, the pH of which is fixed at 7 by sodium hydroxide. .

 The invention will be more fully described with the aid of the following examples which should not be considered as limiting.

 These examples prove the significant improvement in stability with respect to the duration and / or the heat of the carbocistein syrups whose pH is fixed at around 7 by soda compared to the commercial syrup.

The commercial syrup has the following composition:
- 750 kg carbocistein
- caramel fragrance 30 kg
- sucrose syrup 8923 kg
- methyl parahydroxybenzoate 22.5 kg
- sodium hydroxide 163.8 kg
- purified water qs 15,000 liters
Methyl parahydroxybenzoate is dissolved in water at about 800 ° C and then this solution is transferred to a vat containing the mixture of sugar syrup and perfume. The carbocistein is gradually dissolved with stirring at room temperature in the water containing sodium hydroxide. The preceding syrup is mixed with this solution. Homogenize by stirring. The pH of the syrup obtained is between 6 and 6.4.

TABLE I
CURRENT MUCOPLEXIL SYRUP (5.5 <PH <6.5)

<tb><SEP> TA <SEP> 350C
<tb><SEP> TO
<Tb>

<SEP> 1 <SEP> year <SEP> variation <SEP> 6 <SEP> months <SEP> variation
<tb> PH <SEP> 6.20 <SEP> 6.0 <SEP> 5.80
<tb> Title <SEP> (HPLC) <SEP> 5,10 <SEP> 4,82 <SEP> 5,5 <SEP>% <SEP> 4,69 <SEP> 8 <SEP>%
<Tb>
New syrup with a composition equivalent to commercial syrup but in which soda has been added

<tb><SEP> TA <SEP> 350C
<tb><SEP> TO <SEP>
<Tb>

<SEP> 1 <SEP> year <SEP> variation <SEP> 6 <SEP> months <SEP> variation
<tb> PH <SEP> 7 <SEP> 6.6 <SEP> 6.7
<tb> Title <SEP> (HPLC) <SEP> 4.99 <SEP> 4.90 <SEP> 1.8 <SEP>% <SEP><SEP> 4.80 <SEP> 3.8 <SEP> %
<tb> TABLE 2
COMPARISON WITH COMPETITION AT 45 C, 45 DAYS

<SEP> BRONCHOKOD # <SEP> NUCLICLAR # <SEP> RHIMATHIOL #
<tb><SEP> to <SEP> 45 <SEP> yrs <SEP> to <SEP> 45 <SEP> yrs <SEP> to <SEP> 45 <SEP> days
<tb> PH <SEP> 5.75 <SEP> 5.70 <SEP> 6.15 <SEP> 5.12 <SEP> 5.02 <SEP> 5.66
<tb> Title <SEP> (CLMP) <SEP> 4.86 <SEP> 4.62 <SEP> 5.04 <SEP> 4.81 <SEP> 4.99 <SEP> 4.73
<tb> Impurities <SEP> (CCM) <SEP> Small <SEP> Task <SEP> Small <SEP> Task <SEP> Small <SEP> Task
<tb><SEP> task <SEP> diffuse <SEP> task <SEP> more <SEP> task <SEP> more
<tb><SEP> broadcasts <SEP> more <SEP> im <SEP> broadcasts <SEP> important- <SEP> diffuse <SEP> important
<SEP> pregnant <SEP> aunt <SEP> aunt
<tb> TO: Zero point on the day of purchase TABLE 3
COMPARISON OF THE STABILITY OF RHINATHIOLR AND "MUCOPLEXILR STABILIZED"

DURATION <SEP> to <SEP> 3 <SEP> months <SEP> 6 <SEP> months <SEP> 1 <SEP> in
<tb> TEMPERATURE <SEP> TA <SEP> 35 C <SEP> 45 C <SEP> 35 C <SEP> 45 C <SEP> TA
<tb><SEP> MUCOPLEXIL <SEP> RHINATHIOL <SEP> MUCOPLEXIL <SEP> RHINATHIOL <SEP> MUCOPLEXIL <SEP> RHINATHIOL <SEP> MUCOPLEXIL <SEP> RHINATHIOL <SEP> MUCOPLEXIL <SEP> RHINATHIOL <SEP> MUCOPLEXIL <SEP> Rhinathiol
<tb> CARBO- <SEP> 4.99 <SEP> 4.88 <SEP> 4.86 <SEP> 4.73 <SEP> 4.70 <SEP> 4.28 <SE> 4.85 <SEP> 4.68 <SEP> 4.4 <SEP> 3.40 <SEP> 4.85 <SEP> 4.24
<tb> CISTEINE
<tb> LACTAME
<tb> (as <SEP>% / carbo <SEP> - <SEP> 0.89 <SEP> 1.53 <SEP> 3.53 <SEP> 4.96 <SEP> 16.1 <SEP> 2, 65 <SEP> 7.15 <SEP> 11 <SEP> 44 <SEP> 1.16 <SEP> 2.5
<tb> cisteine
<Tb>
From Table 1, it can be seen that the stability of the carbocistein syrup adjusted to PH7 at zero time is significantly improved when the syrup is stored at a reduced heat (350C), the title difference reaches 0.19 for the syrup stabilized against 0.41 for unstabilized syrup for a shelf life of 6 months at 350C.

 From Table 2, it can be noted that among the commercial syrups all having a PH between 5.5 and 6.2 all lose at least 0.23% and up to 0.26% in title when they are stored 45 days at 450C.

 Carbocistein syrups are particularly sensitive to heat storage.

From Table 3, it can be noted that at room temperature even after one year of storage the stabilized carbocisteine syrup lost only 0.14% against 0.64 for the syrup of
RhinathiolR, at 350C for 6 months the loss is 0.14% for carbocistein syrup stabilized against 0.20% for syrup of
RhinathiolR and at 450C for 6 months the loss is 0.59 for the syrup stabilized against 1.48 for the syrup of Rhinathiol.

 These stability tests prove the clear improvement of the new composition as to its stability over time and heat compared to the currently marketed syrups.

Claims (2)

 1 - Syrup containing an aqueous solution of S- (carboxymethyl) -L cysteine with improved stability, characterized in that the pH of the solution is adjusted to a value of approximately 7.  2 - Syrup according to claim 1 characterized in that it contains 5% of S- (carboxymethyl) -L cysteine, 40% of sugar and 0.15% of preservative and that its pH is stabilized at 7 by addition of hydroxide sodium.