DE4396086B3 - Syrup with N-acetylcysteine - Google Patents

Abstract

Composition in the form of a syrup containing (per 100 ml): - N-acetylcysteine 2-4.2 g / 100 ml - a sweetener from the group consisting of saccharin, sodium saccharin, cyclamate or mixtures thereof 0.02-0.3 g / 100 ml - a thickening agent selected from sodium carboxymethylcellulose and hydroxypropylmethylcellulose or mixtures thereof 0.1-4 g / 100 ml - a preservative 0.05-0.5 g / 100 ml and also water q. s. to 100 ml with the pH in the range of 5-8.

Description

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

N-acetylcysteine (hereinafter referred to as NAC for short) is a compound which has several useful pharmacological properties making it a widely used drug.

In the treatment of colds NAC proved to be useful because of its mucolytic properties.

One of the pharmaceutical forms widely used in the treatment of common cold is syrup, which is particularly suitable for use in pediatrics.

NAC is available in several pharmaceutical forms, but the high reactivity of the molecule, its relative instability, and the characteristic sulfuric odor and taste make it extremely difficult to obtain liquid forms for internal use that are stable and tasty over a long period of time.

The preparation of a syrup in virtually all cases provides for the use of a disaccharide (sucrose) or a simple sugar as a sweetener and thickener for the aqueous solution of the drug. However, the interaction of NAC with sugars gives the solution an undesirable brown color and the NAC titer decreases.

Therefore, it is not possible to keep NAC in solution in the presence of sucrose for a long time.

Similarly, the reactions which result in a brownish coloration and result in a malodor also occur between NAC and the monosaccharides, their use in the French patent application FR 26 31 831 A1 (Calco Anstalt) is described.

GB 2 192 789 A and GB 2 192 790 A describe solid granules and effervescent tablets that contain NAC and bicarbonate and must be drunk immediately after dissolution.

WO 89/03210 A1 describes liquid sucrose-containing preparations which, in addition to methylcellulose and ibuprofen, also contain bicarbonate in order to bring the ibuprofen into solution. In cases where patients do not tolerate sucrose, it is replaced with artificial sweeteners.

EP 0 138 540 B1 and EP 0 373 103 A1 describe liquid drugs in which the active ingredient is to be kept in suspension and which contain sugar alcohols or saccharides as sweeteners.

GB 905 197 A describes a syrup containing an antiviral drug as well as large amounts of sugar, p-hydroxymethyl benzoate, citric acid, sodium citrate, gum tragacanth and polyethylene glycol monostearate.

EP 0 465 921 A1 describes against dental plaques effective chewing gums containing NAC as an active ingredient.

EP 0 340 662 A1 describes solid water-soluble pharmaceutical compositions containing, in addition to the active ingredient NAC, large amounts of xylitol.

As far as is known, the only syrup formulation available on the market containing NAC consists of a composition to be prepared at the time of use by dissolving a granulate in water.

After preparation, the untreated syrup must be consumed within 3 weeks.

It has now surprisingly been found that it is possible to produce, without the use of sugars, a NAC syrup which is stable for a long time and has a pleasant taste.

The subject of the present invention is therefore a composition in the form of a syrup containing (per 100 ml): - N-acetylcysteine 2-4.2 g / 100 ml A sweetener from the group of saccharin, sodium saccharin, cyclamate or mixtures thereof 0.02-0.3 g / 100 ml A thickening agent selected from sodium carboxymethylcellulose and hydroxypropylmethylcellulose or mixtures thereof 0.1-4 g / 100 ml - a preservative 0.05-0.5 g / 100 ml and also - water qs to 100 ml, the pH being in the range of 5-8.

The above solution is stable in a sealed bottle under inert gas under ambient conditions for at least 2 years. When the bottle is opened, the solution shows a pleasant taste and no bad smell; NAC maintains its initial titer and the open syrup is stable for at least 5 weeks.

Sweeteners in the composition according to the invention are saccharin, sodium saccharin, cyclamate or mixtures thereof, which can give the solution a sweet taste but which contain no sugar.

The amount of sweetener is the minimum amount sufficient to give the solution a pleasant taste.

The thickener is selected from sodium carboxymethylcellulose and hydroxypropylmethylcellulose or mixtures thereof. Surprisingly, these substances proved to be compatible with NAC and able to impart a viscosity to the solution, as is common for the general character of a syrup.

These four basic components (NAC, sweetener, thickener and preservative) may be added to the chosen volume of water, optionally adjusting the resulting pH to remain within the range of 5-8. Preferably, the pH is 6.5 to 7.

The syrup may also, but need not, contain a flavoring to enhance the palatability, especially for use in pediatrics.

Since the syrup is generally not prepared under aseptic conditions, the drug requires the unconditional presence of a preservative. The preservative is also needed to ensure the microbiological quality during the period of use by the patient.

Suitable preservatives may be selected from sodium benzoate, methyl 4-hydroxybenzoate, propyl 4-hydroxybenzoate and mixtures thereof.

With its dual function as a preservative and as a metal chelator, sodium EDTA may also be employed in addition to the above preservatives or as a partial replacement for the above preservatives.

The preparation of the syrup according to the invention is carried out under inert gas by simply dissolving the substances in the predetermined amount of water.

The resulting solution is dispensed on multidose bottles or on single-dose containers.

The packaging of the multi-dose bottles may provide for the simultaneous provision of a graduated measuring device for the correct dosage of the single doses for adults (for example 10 ml) or for children (for example 5 ml).

The following examples are intended to better explain the present invention.

example 1

10 liters of a syrup (100 ml each) NAC 2.1 g saccharin 0.04 g sodium 0.2 g sodium benzoate 0.15 g Sodium EDTA 0.1 g raspberry flavor 0.25 g Water qs to 100 ml were prepared by simply dissolving the substances in pure degassed water under a nitrogen atmosphere. The pH of the resulting solution was adjusted to the correct value of 6.5 by addition of sodium hydroxide.

The solution was divided into volumes of 150 ml / bottle.

The bottles were stored for 2 years at room temperature.

After this period, the NAC titer was greater than 95% of the starting titer.

Even 5 weeks after opening the bottle, such a titer was more than 90% of the initial titer.

The syrup had a pleasant taste and smell and a general taste even after 2 years of storage.

Example 2

10 l of a syrup of the following composition (per 100 ml): NAC 2.1 g sodium 0.04 g hydroxypropyl methylcellulose 0.2 g Methyl 4-hydroxybenzoate 0.1 g Sodium EDTA 0.1 g apricot flavor 0.1 g Water qs to 100 ml were prepared by dispersing hydroxypropyl methylcellulose in a portion of boiling water which was cooled to room temperature. After hydration of the hydroxypropyl methylcellulose, it was poured into a solution obtained by dissolving all the other substances in pure degassed water under a nitrogen atmosphere.

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

The solution was divided into sachets for single doses of 10 ml each containing approximately 200 mg NAC.

Example 3

10 l of a syrup of the following composition (per 100 ml): NAC 2.1 g sodium 0.04 g hydroxypropyl methylcellulose 0.2 g Sodium EDTA 0.1 g apricot flavor 0.1 g Water qs to 100 ml were prepared by dispersing hydroxypropyl methylcellulose in a portion of boiling water which was cooled to room temperature. After hydration of the hydroxypropyl methylcellulose, it was poured into a solution obtained by dissolving all the other substances in pure degassed water under a nitrogen atmosphere.

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

The solution was divided into 10 ml single-dose glass ampoules with rubber plugs, each containing approximately 200 mg NAC.

Example 4

Following the procedure described in Example 1, 10 liters of syrup having the following composition (per 100 ml) were prepared: NAC 4.2 g sodium 0.08 g sodium 0.20 g sodium benzoate 0.15 g Sodium EDTA 0.10 g raspberry flavor 0.4 g Water qs to 100 ml.

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

The solution was dispensed in bottles of 150 ml per bottle.

Example 5

Following the procedure described in Example 2, 10 liters of syrup having the following composition (per 100 ml) were prepared: NAC 2.10 g saccharin 0.04 g hydroxypropyl methylcellulose 0.40 g Methyl 4-hydroxybenzoate 0.10 g banana flavor 0.4 g Water qs to 100 ml.

The pH of the solution was adjusted to pH 7 with sodium hydroxide.

The solution was dispensed in bottles at 450 ml per bottle.

Claims (4)

Composition in the form of a syrup containing (per 100 ml): - N-acetylcysteine 2-4.2 g / 100 ml A sweetener from the group of saccharin, sodium saccharin, cyclamate or mixtures thereof 0.02-0.3 g / 100 ml A thickening agent selected from sodium carboxymethylcellulose and hydroxypropylmethylcellulose or mixtures thereof 0.1-4 g / 100 ml - a preservative 0.05-0.5 g / 100 ml and also - water qs to 100 ml, the pH being in the range of 5-8. A composition according to claim 1, wherein the preservative is selected from sodium EDTA, sodium benzoate, methyl 4-hydroxybenzoate, propyl 4-hydroxybenzoate and mixtures thereof. A composition according to claim 1 wherein the pH is between 6.5 and 7. A composition according to any one of claims 1 to 3, further comprising a flavor in the amount of 0.1 to 0.4 g per 100 ml of syrup.