NZ258544A

NZ258544A - Time-stable aqueous syrup containing n-acetyl cysteine

Info

Publication number: NZ258544A
Application number: NZ258544A
Authority: NZ
Inventors: Federico Stroppolo; Daniele Bonadeo; Alessandro Saudino
Original assignee: Zambon Spa
Priority date: 1992-12-02
Filing date: 1993-11-23
Publication date: 1996-11-26
Also published as: BE1006799A3; CA2150462A1; ES2070806A1; SE9502001D0; HUT72668A; HU211912A9; MD1714G2; DK61495A; CZ136795A3; JPH08503703A; CZ282550B6; CA2150462C; NO314018B1; HU9501586D0; NL9320052A; ES2070806B1; AU667611B2; GB2288977B; LU88618A1; HU221484B

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £58544 New Zealand No. 258544 International No. PCT/EP93/03280 Priority Date(s): Complete Specification F.Ted; TMss: (6) B Publication Date:.. Z.OM.B9S. P.O. Journal No: NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of Invention: Syrup containing N-acetyl-cysteine Name, address and nationality of applicant(s) as in international application form: a*. HpUo* (cm/fry ZAMBON GROUP SpA,^Via della Chimica, 9, 1-36100 Vicenza, Italy WO 94/12168 PCT/EP93/03280 i<> 25854 4 SYRUP CONTAINING N-ACETYL-CYSTEINE The present invention relates to a composition in the form of a syrup containing N-acetyl-cysteine as active ingredient. N-acetyl-cysteine (hereinafter briefly referred to as NAC) is a 5 compound endowed with several useful pharmacological properties, making it a widely used drug. In the treatment of cold diseases, NAC showed to be useful thanks to its mucolytic properties. One of the pharmaceutical forms largely used in the therapy of cola 10 diseases is syrup, particularly suitable also for pediatric use. NAC is available in several pharmaceutical forms, however the high reactivity of the molecule, the relative instability ana the characteristic sulphureous smell and taste make extremely troublesome the achievement of liquid forms for oral use which are 15 time-stable and with a good palatability. The preparation of a syrup provides, practically in all the cases, the use of a disaccharide (sucrose) or of a simple sugar as a sweetening and thickening agent of the aqueous solution of the drug. However, the interaction of NAC with sugars gives to the solution an 20 unacceptable brown colouring and the titre of NAC decreases. Thus, it is not possible to leave NAC in solution for a long time in the presence of sucrose. Similarly, the reactions giving brown colour and causing baa smell take place also between NAC and the monosaccharides whose use is 25 described in the French patent application No. 2631831 in the name of Calco Anstalt. As far as we know, the only syrup formulation containing NAC on the market consists in a composition to be prepared at the moment of use by dissolution in water of a granulate. After preparation, the extemporaneous syrup must be used within 3 WO 94/12168 - 2 - PCT/EP93/03280 weeks. We have now surprisingly found that it is possible to prepare a time-stable NAC syrup having a pleasant taste without using sugars. 5 Therefore, object of the present invention is a composition in the form of a syrup containing (each 100 ml): - N-acetyl-cysteine 2 -4.2 - a sweetening agent 0.02-0.3 - a thickening agent selected among: 10 sodium carboxymethylcellulose and hydroxypropylmethylcellulose or mixtures thereof 0.1 -A and optionally: - a flavouring agent 0.1 -0.4 15 - a preservative 0.05-0.5 and further - water q.s. to 100 ml pH being settled within the interval 5-8. The above solution results to be stable in a closed bottle under • 20 inert gas for at least 2 years under environmental conditions. When the bottle is opened, the solution shows to have a pleasant taste and to be free from bad smells; NAC maintains the initial titre and the open syrup results to be stable for at least 5 weeks. For sweetening agent we mean a substance able to give a sweet taste 25 to the solution but wich does not contain sugars. Specific examples of sweetening agents are saccharin, sodium saccharin and cyclamates or mixtures thereof. The amount of sweetening agent will be the minimum amount sufficient to give a pleasant taste to the solution. 2Q The thickening agent is selected among sodium carboxymethylcellulose g/100 mi g/100 ml g/100 ml g/100 ml g/100 ml 94/12168 PCT/EP93/03280 methylcellulose and hydroxypropylmethylcellulose or mixtures thereof. Surprisingly, these substances showed to be compatible with NAC and to be able to give to the solution a thickness suitable for 5 the usual palatability of a syrup. To these three base components (NAC, sweetening agent and thickening agent) water can be added up to the selected volume, by optionally rectifying the resultant pH so that it is maintained within the interval from 5 to 8. Preferably, pH will be from 6.5 to 7. 10 The syrup could also, but not necessarily, contain a flavouring agent in order to improve the palatability, especially for pediatric use. Since the syrup is generally manufactured in absence of asepsis, pharmacopoeiae require the compulsory presence of a preservative. 15 The preservative is further required to assure the microbiological quality during the time of use by the patient. In this case, preservatives selected among sodium benzoate, methyl 4-hydroxybenzoate, propyl 4-hydroxybenzoate and mixtures thereof will be preferably used. 20 With the double function of preservative and of metal chelating agent also sodium EDTA could be used in addition to or in partial substitution of the above preservatives. The preparation of the syrup according to the present invention is carried out under inert gas by simple dissolution of the substances 25 in the predetermined amount of water. The resultant solution is shared into multidose bottles or in single-dose containers. The packaging of multi-dose bottles could provide the contemporaneous supplying of a graduated measure for the correct dosage of the single doses for grown-up people (for example 10 ml) or for children WO 94/12168 PCT/EP93/03280 - A - (for example 5 tnl). In order to better illustrate the present invention the following examples are now given. Example 1 10 liters of a syrup containing (each 100 ml): NAC 2.1 g Saccharin 0.04 g Sodium carboxymethylcellulose 0.2 g 10 Sodium benzoate 0.15 g Sodium edetate 0.1 g Raspberry flavour 0.25 g Water q.s. to 100 ml were prepared by simple dissolution of the substances in purified 15 and de-aerated water under nitrogen atmosphere. The pH of the resultant solution was rectified to the correct value o.5 by addition of sodium hydroxide. The solution was shared at the rate of 150 ml/bottle. The bottles were stored for 2 years at room temperature. 20 After this period, the titre of NAC resulted to be higher than 95% of the initial one. Such a titre resulted to be higher than 90% of the initial one also after 5 weeks from the opening of the bottle. The syrup, also after 2 years of storage, showed to have a pleasant 25 taste and smell and a good general palatability. Example 2 10 1 of a syrup having the following composition (each 100 mi): NAC 2.1 g Sodium saccharin 0.04 g Hydroxypropylmethylcellulose 0.2 g WO 94/12168 PCT/EP93/03280 5 Methyl 4-hydroxybenzoate 0.1 g Sodium edetate 0.1 g Apricot flavour 0.1 g 5 Water q.s. to 100 ml were prepared by dispersion of hydroxypropylmethylcellulose in a part of boiling water which was cooled to room temperature. After hydration of hydroxypropylmethylcellulose, it was poured into a solution obtained by dissolving all the remaining substances in 10 purified and de-aerated water, under nitrogen atmosphere. The pH of the solution was rectified to pH 6.5 with sodium hydroxide. The solution was shared into single-dose sachets of 10 ml each containing about 200 mg of NAC. 15 Example 3 10 1 of a syrup having the following composition (each 100 ml): NAC 2.1 g Sodium saccharin 0.04 g Hydroxypropylmethylcellulose 0.2 g 20 Sodium edetate 0.1 g Apricot flavour 0.1 g Water q.s. to 100 ml were prepared by dispersion of hydroxypropylmethylcellulose in a part of boiling water which was cooled to room temperature. After 25 hydration of hydroxypropylmethylcellulose, it was poured into a solution obtained by dissolving all the remaining substances in purified and de-aerated water, under nitrogen atmosphere. The pH of the solution was rectified to pH 6.5 with sodium hydroxide. The solution was shared into single-dose glass vials of 10 mi with </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 94/12168 - 6 - PCT/EP93/03280 rubber stopper each containing about 200 tng of NAC. Example 4 By working as described in Example 1,10 1 of syrup having the following composition (each 100 ml) were prepared: NAC A.2 g Sodium saccharin 0.08 g Sodium carboxymethylcellulose 0.20 g Sodium benzoate 0.15 g Sodium edetate 0.10 g Raspberry flavour 0.4 g Water q.s. to 100 ml The pH of the solution was rectified to pH 6.5 with sodium hydroxide. The solution was shared into bottles at the rate of 150 ml each bottle. Example 5 By working as described in Example 2, 10 1 of syrup having the following composition (each 100 ml) were prepared: 20 NAC 2.10 g Saccharin 0.04 g Hydroxypropylmethylcellulose 0.40 g Methyl 4-hydroxybenzoate 0.10 g Banana flavour 0.4 g 25 Water q.s. to 100 ml The pH of the solution was rectified to pH 7 with sodium hydroxide. The solution was shared into bottles at the rate of 450 ml each bottle. 30 WO 94/12168 PCT /EP93/03280 25 q 5 4 4 - 7 - WHAT WE CLAIM IS:

1. A time-stable composition in the form of a syrup containing (each 100 ml): 2 -4.2 g/100 ml, 0.02-0.3 g/100 ml, and 0.1 -4 g/100 ml; 0.1 -0.4 g/100 ml, and/or 0.05-0.5 g/100 ml; N-acetyl-cysteine a sweetening agent a thickening agent selected among: sodium carboxymethylcellulose and hydroxypropylmethylcellulose and mixtures thereof and optionally: a flavouring agent a preservative and further water q.s. to 100 ml; said composition having a pH settled within the interval 5-8.

2. A composition according to claim 1 wherein the sweetening agent is selected among saccharin, sodium saccharin, cyclamates and mixtures thereof.

3. A composition according to claim 1 wherein the preservative is selected among sodium edetate, sodium benzoate, methyl 4-hydroxybenzoate, propyl 4-hydroxybenzoate and mixtures thereof.

4. A composition according to claim 1 wherein the pH is between 6.5 and 7.

5. A time-stable composition in the form of a syrup containing N-acetyl-cysteine, substantially as herein described with reference to the Examples. £AMfe?r4.. by mo uutnoriaed A J PARK & p® / </div>