FR2698545A1 - Syrup containing N-acetyl-cysteine. - Google Patents

Abstract

Syrup containing N-acetyl-cysteine, stable for at least 2 years, having a pleasant odor and taste, consisting of an aqueous solution of NAC, a sweetening agent and a thickening agent, the solution also being able contain a flavoring agent and a preservative, the pH being between 5 and 8.

Description

 The present invention relates to a composition in the form of a syrup containing Nacetyl-cysteine as an active ingredient.

 N-acetyl-cysteine (abbreviated as NAC below) is a compound with several interesting pharmacological properties, making it a widely used drug.

 In the treatment of colds or colds, NAC has proven to be interesting thanks to its mucolytic properties.

 One of the pharmaceutical forms widely used in the therapy of colds or colds is syrup, which is also particularly suitable in pediatric applications.

 NAC is available in several pharmaceutical forms; however the high reactivity of the molecule, the relative instability and the characteristic odor and sulfurous taste make it extremely inconvenient to produce liquid forms for oral use which are stable over time and with good palatability.

 The preparation of a syrup provides, in almost all cases, the use of a disaccharide (sucrose) or a simple sugar as a sweetening and thickening agent in the aqueous solution of the drug.

However, the interaction of NAC with sugars gives the solution an unacceptable brown color and the NAC titer decreases.

 It is thus not possible to leave the NAC in solution for a long period of time in the presence of sucrose.

 Similarly, the reactions giving a brown coloring and causing a bad taste also occur between NAC and the monosaccharides, the use of which is described in French patent application No. 2,631,831 in the name of Calco Anstalt.

 To the best of our knowledge, the only syrup formulation containing NAC on the market consists of a composition to be prepared at the time of use by dissolving an aggregate in a strip.

 After preparation, extemporaneous syrup should be used within 3 weeks.

We have now surprisingly found that it is possible to prepare syrup of
NAC stable over time with a pleasant taste without the use of sugars.

Therefore, the object of the present invention is a composition in the form of a syrup containing (each component relative to 100 ml) - N-acetyl-cysteine 2 -4.2 g / 100 ml - a sweetening agent 0.02-0.3 g / 100 ml - a thickening agent chosen from
sodium carboxymethyl cellulose
and hydroxypropylmethylcellulose or
mixtures thereof 0.1 -4 g / 100 ml and optionally - a flavoring agent 0.1 -0.4 g / 100 ml - a preservative 0.05-0.5 g / 100 ml and more - l sufficient water to make 100 ml, the pH being adjusted in the range of 5-8.

 It follows that the above-mentioned solution is stable in a closed bottle under inert gas for at least two years under ambient conditions.

When the bottle is opened, the solution shows a pleasant taste and is free from bad odors; the NAC maintains the initial titer and the open syrup is stable for at least 5 weeks.

 By sweetening agent, we mean a substance which can give a sweet taste to the solution but which does not contain sugars. Specific examples of sweetening agents are saccharin, sodium saccharin and cyclamates or their mixtures.

 The amount of sweetening agent will be the minimum amount sufficient to give a pleasant taste to the solution.

 The thickening agent is chosen from sodium carboxymethylcellulose, hydroxypropylmethylcellulose and their mixtures. Surprisingly, these substances have been found to be compatible with NAC and can give the solution a thickness suitable for the usual palatability of a syrup.

 To these three basic components (NAC, sweetening agent and thickening agent), water can be added up to the chosen volume, possibly correcting the resulting pH so that it is maintained in the range from 5 to 8. Advantageously, the pH will be 6.5 to 7.

 The syrup could also, but not necessarily, contain a flavoring agent to improve palatability, particularly in the context of pediatric use.

 Since the syrup is generally made in the absence of asepsis, the pharmacopoeia requires the mandatory presence of a preservative.

The preservative is further necessary to ensure microbiological quality during the period of use by the patient.

 In this case, it is advantageous to use preservatives chosen from sodium benzoate, methyl 4-hydroxybenzoate, propyl 4-hydroxybenzoate and mixtures thereof.

 With the dual function of preservative and metallic chelating agent, sodium EDTA could also be used in addition or partially in place of the aforementioned preservatives.

 The preparation of the syrup according to the present invention is carried out under an inert gas by the simple dissolution of the substances in the predetermined quantity of water.

 The resulting solution is shaken in multiple dose bottles or in single dose containers.

 The packaging of multiple dose bottles could constitute the simultaneous contribution of a graduated measure for the correct dosage of single doses for individuals in adulthood (for example 10 ml) or for children (for example 5 ml).

 In order to better illustrate the present invention, the following examples are now given.

Example i
10 liters of a syrup containing (each component compared to 100 ml)
NAC 2.1 g
Saccharin 0.04 g
0.2 g sodium carboxymethylcellulose
Sodium benzoate 0.15 g
Sodium edetate 0.1 g
0.25 g raspberry flavoring
Water, sufficient to make 100 ml, was prepared by simply dissolving the substances in purified and deaerated water under a nitrogen atmosphere.

 The pH of the resulting solution was corrected to the correct value of 6.5 by the addition of sodium hydroxide.

 The solution was distributed at the rate of 150 ml / bottle.

 The bottles were kept for 2 years at room temperature.

 After this period, the NAC title was found to be greater than 95% of the original title.

 This title was found to be greater than 90% of the original title also 5 weeks after the opening of the bottle.

 The syrup, also after 2 years of storage, showed a pleasant smell and taste and a good general palatability.

Example 2
10 liters of a syrup with the following composition (each component relative to 100 ml)
NAC 2.1 g
Sodium saccharin 0.04 g Hydroxypropyl methylcel lulose 0.2 g Methyl 4-hydroxybenzoate 0.1 g
Sodium edetate 0.1 g
Apricot flavoring 0.1 g
Water, sufficient to make 100 ml, was prepared by dispersing hydroxypropylmethylcellulose in a portion of boiling water which was cooled to room temperature. After hydration of the hydroxypropylmethylcellulose, it was poured into a solution obtained by dissolving all the remaining substances in purified and deaerated water, under a nitrogen atmosphere.

 The pH of the solution was adjusted to pH 6.5 with sodium hydroxide.

 The solution was distributed into single-dose 10 ml sachets each containing about 200 mg of NAC.

Example 3
10 liters of a syrup with the following composition (each component relative to 100 ml)
NAC 2.1 g
Sodium saccharin 0.04 g Hydroxypropyl methylcellulose 0.2 g
Sodium edetate 0.1 g
Apricot flavoring 0.1 g
Water, sufficient to make 100 ml, was prepared by dispersing hydroxypropylmethylcellulose in a portion of boiling water which was cooled to room temperature. After hydration of the hydroxypropylmethylcellulose, it was poured into a solution obtained by dissolving all the remaining substances in purified and deaerated water, under a nitrogen atmosphere.

 The pH of the solution was adjusted to pH 6.5 with sodium hydroxide.

 The solution was dispensed into single-dose 10 ml glass vials with a rubber stopper each containing about 200 mg of NAC.

Example 4
By operating as described in Example 1, 10 liters of syrup having the following composition were prepared (each component relative to 100 ml)
NAC 4.2 g
Sodium saccharin 0.08 g
Sodium carboxymethylcellulose 0.20 g
Sodium benzoate 0.15 g
Sodium edetate 0.10 g
Raspberry flavoring 0.4 g
Water, enough to make 100 ml.

 The pH of the solution was adjusted to pH 6.5 with sodium hydroxide.

 The solution was distributed in bottles at the rate of 150 ml per bottle.

Example 5
By operating as described in Example 2, 10 liters of syrup having the following composition were prepared (each component relative to 100 ml)
NAC 2.10 g
Saccharin 0.04 g
Hydroxypropylmethylcellulose 0.40 g 4-Methyl hydroxybenzoate 0.10 g
0.4 g banana flavoring
Water, enough to make 100 ml
The pH of the solution was corrected to pH 7 with sodium hydroxide.

 The solution was distributed in bottles at the rate of 450 ml per bottle.

Claims (4)

 1. Composition in the form of a syrup containing (each component relative to 100 ml) - N-acetyl-cysteine 2 -4.2 g / 100 ml - a sweetening agent 0.02-0.3 g / 100 ml - a thickening agent chosen from  sodium carboxymethylcellulose,  hydroxypropylmethylcellulose and  their mixtures 0.1 -4 g / 100 ml and optionally - a flavoring agent 0.1 -0.4 g / 100 ml - a preservative 0.05-0.5 g / 100 ml and more - from sufficient water to make 100 ml, the pH being adjusted in the range 5-8.  2. Composition according to Claim 1, characterized in that the sweetening agent is chosen from saccharin, sodium saccharin, cyclamates and their mixtures.  3. Composition according to claim 1, characterized in that the preservative is chosen from sodium edetate, sodium benzoate, methyl 4-hydroxybenzoate, propyl 4-hydroxybenzoate and their mixtures.  4. Composition according to claim 1, characterized in that the pH is between 6.5 and 7.