WO2000041709A1

WO2000041709A1 - Nasal spray based on xylometazoline and camomile extract

Info

Publication number: WO2000041709A1
Application number: PCT/NL2000/000021
Authority: WO
Inventors: Jacqueline Liesbeth Josine Vijgen; Selma Maria Admiraal; Henricus Adrianus Catharina Titulaer
Original assignee: Dagra Pharma B.V.
Priority date: 1999-01-13
Filing date: 2000-01-13
Publication date: 2000-07-20
Also published as: AU2331300A; NL1011016C2

Abstract

The application relates to a preparation for intranasal administration that contains an aqueous solution of a at least one compound having a vasoconstrictive and/or decongestive action and camomile extract. Preferably a water-based camomile extract and/or a camomile extract that is essentially soluble in water, or a mixture of two or more water-soluble constituents of camomile, is used. The compound having a vasoconstrictive action is preferably chosen from xylometazoline, oxymetazoline and/or tramazoline, or pharmaceutical salts thereof. The preparation can also contain one or more preservatives and/or stabilisers and/or known constituents for nasal sprays or nose drops. The preparation is preferably alcohol-free.

Description

Title: Nasal sprav based on xylometazoline and camomile extract

The application relates to a preparation for intranasal administration that contains at least a compound having a vasoconstrictive and/or decongestive action and camomile, in particular in the form of a camomile extract.

In particular the application relates to a nasal spray based on xylometazoline and a camomile extract.

Nasal sprays and nose drops based on xylometazoline are known, for example under the trade name Otrivin . This nasal spray - a solution of 0.5 or 1 mg/ml xylometazoline hydrochloride in water - has a vasoconstrictive and decongestive action on the mucous membrane and the blood vessels in the nose and pharynx. A similar nasal spray based on oxymetazoline is commercially available under the trade name Nasivin .

The disadvantage of the known preparations is. however, that some users, such as children, find them unpleasant. "Rote Liste (Red List) 1995". no. 71031 describes the agent Caltheon®

(Chephasaar), a preparation for nasal administration that contains 5 mg/10 mg tetryzoline per 10 ml; and in addition benzalkonium chloride and aroma substances (fennel, menthol and eucalyptus). However, Caltheon® contains no camomile extract.

The international application WO 88/00473 (ASCHE AKTIENGESELLSCHAFT) relates to a xylometazoline-containing pharmaceutical preparation that, in addition to xylometazoline, can contain one or more ethereal oils, including menthol, eucalyptus, camphor or camomile oil.

However, this is a preparation based on fatty acid triglycerides and not a preparation based on an aqueous solution. Consequently it would also seem improbable that the preparation according to WO 88/00473 contains (predominantly) water-soluble camomile constituents.

The international application WO 95/13810 (SCHERING-PLOUGH) relates to a preparation for nasal administration that contains an aqueous solution of oxymetazoline hydrochloride. This preparation also contains menthol, camphor and eucalyptol: and benzalkonium chloride as stabiliser.

However, the preparations according to WO 95/13810 contain an aromatic alcohol as a mandatory constituent, which appears to be (co-)present in order to guarantee the stability of these preparations (including the antimicrobial stability) (see WO 95/13810, page 1. line 29 - page 2. line 36).

According to the present application alcohol-free preparations are preferably used. Furthermore, WO 95/13810 does not specify the use of camomile constituents.

The international application WO 94/05330 (PROCTER & GAMBLE) describes a nasal spray based on xylometazoline, a polymer constituent and a surfactant. This spray forms a viscous gel on coming into contact with the nasal mucous membranes (see page 15, Claim 1).

Although this spray can contain menthol and eucalyptus, this preparation appears to be completely different from the aqueous solution(s) according to the present application. "Helwig Arzneimittel, Band 2 (Helwig Drugs, Volume 2)" page 47 - 1 1 describes the

Wick (Vick) Sinex® nose drops/nasal spray which contains 4 mg oxymetazoline.HCl, 2.5 mg menthol, 1.5 mg camphor and 0.75 mg cineole per 10 ml solution. The use of camomile extract is not described.

The aim of the invention is, therefore, to provide a preparation for administration to the nose, in particular when suffering from a cold, that is more pleasant for the user than the known preparations. This aim is achieved according to the invention by combining xylometazoline, oxymetazoline or a similar active compound with at least one camomile extract, preferably in or as an aqueous, alcohol-free preparation.

In a first aspect the application therefore relates to a preparation for (intra)nasal administration that contains at least one compound having a vasoconstrictive and/or decongestive action and camomile extract.

The compound having a vasoconstrictive and/or decongestive action can be any compound known per se which is suitable for administration in the nose and which following intranasal administration causes the swelling of the mucous membranes in the nose and/or the pharynx to decrease.

Compounds preferably used are xylometazoline. oxymetazoline. tramazoline or a combination thereof. These compounds can also be used in the form of a pharmaceutically acceptable, water-soluble salt, such as the hydrochloride.

The concentration of the vasoconstrictive compound in the final preparation can be the same as in conventional preparations and for xylometazoline or oxymetazoline, for example, will be in the range of 0.001-5% (m/V), preferably 0.01 -0.5% for children and 0.05-0.5% for adults. For instance, xylometazoline can be used in an amount of 0.5 mg/ml (children) or 1 mg/ml (adults), whilst customary concentrations for oxymetazoline are 2.5 mg/ml (children) or 5 mg/ml (adults).

The camomile extract used can be any camomile extract known per se or any mixture of one or more constituents of camomile known per se. provided said extract/mixture is suitable for use in an aqueous solution, in particular in an aqueous solution of a vasoconstrictive compound as specified above.

Furthermore, the camomile extract is preferably also such that it is suitable for use in preparations for nasal administration, and preferably also such that it is compatible with the other constituents of the preparation.

The camomile extract used in the preparation can also itself exhibit a vasoconstrictive or decongestive action or otherwise contribute to alleviating the symptoms of a cold. In this context a synergistic effect may be obtained with the vasoconstrictive compound used, in which case it may then be possible to use a correspondingly lower concentration of this compound.

The camomile extract is particularly preferentially a water-based camomile extract and/or a water-soluble camomile extract, that is to say an extract that essentially contains only water-soluble constituents of camomile. Furthermore, the camomile extract is highly preferentially an alcohol-free extract.

A non-limiting example of a suitable camomile extract is the extract that is marketed by Flachsmann under the tradename Chamomillae Flor extr.s.sicc. This extract has an excellent aromatic odour/taste in water.

The camomile extract can be incorporated in the preparations according to the invention as such, in the form of a solution or in another suitable form, such as a powder that is added as such to the xylometazoline solution or that is first dissolved in a suitable solvent and is then mixed with the xylometazoline solution. In addition to camomile extracts it is also possible to use other preparations which contain one or more of the constituents of camomile and/or the other extracts mentioned, including constituents such as apiginin, bisabolol, levomenol, kamazolene and the like, constituents soluble in the solvent used once again being preferably used.

In a further aspect the invention therefore comprises a preparation for (intra)nasal administration that contains an aqueous solution of at least one compound having a vasoconstrictive and/or decongestive action and at least one water-soluble constituent of camomile, and preferably a combination of at least two or more water-soluble constituents of camomile. In this context the one or more water-soluble constituents of camomile are preferably present in the preparation - or are added to the preparation - in the form of a camomile extract as described above.

In addition to the camomile extract, eucalyptus, camphor, menthol -containing extracts such as peppermint oil and the like can optionally also be present in the preparation: however, these are preferably used in minor amounts.

The quantity of extract in the preparation can be determined by a person skilled in the art and as a rule is dependent on the strength of the extract used. If. for example, a camomile extract in powder form is used, a solution of 50 gram extract per litre can be mixed with a suitable xylometazoline solution in an extract to xylometazoline solution ratio of 1 : 10 - 1 :200 (V/V), preferably 1 :50 - 1 : 150 (V/V) and more preferentially approximately 1 :100 (V/V). such that the abovementioned xylometazoline concentration is obtained.

In order to obtain stability on storage, preservatives and/or stabilisers can be added to the preparation, such as the agents which are known per se and are suitable for use in a nasal spray or nose drops. These agents are used in quantities known per se and are preferably soluble in the solvent used.

The preservative preferably used is benzalkonium, for example in the form of a water-soluble salt, such as the chloride. This can be used in an amount of 0.01-1 mg/ml, in particular approximately 0.1 mg/ml.

The preparation according to the invention can also contain all constituents for nasal sprays or nose drops which are known per se, such as sodium edetate, sodium phosphate or sodium chloride, in amounts known per se.

The nasal spray according to the invention can be prepared simply by providing an aqueous solution of the xylometazoline or a salt thereof and mixing this with the camomile extract (in the form of a powder or in the form of a solution), the one or more preservatives and any further constituents of the preparation.

In this context, however, it has been found that when the commercially available aqueous camomile extracts are mixed as such with the xylometazoline and the benzalkonium, the clear solution obtained becomes turbid, while at the same time, the benzalkonium concentration decreases. Without being limited to any explanation for this, it is assumed that this incompatibility problem is caused by a reaction between the benzalkonium and constituents of the camomile extract. Although the turbidity can be removed by centrifuging and filtration, turbidity can occur again in combination with the camomile extract, the benzalkonium chloride concentration having decreased dramatically. It is therefore very much preferred to subject the camomile extract to a pretreatment before it is mixed with the other constituents, to improve the compatibility of the extract with the benzalkonium. This pretreatment preferably takes place by a (further) separation step, in which the aqueous/water-soluble constituents are separated off from the other constituents. Specifically, this separation step can be carried out by distillation, and in particular by steam distillation, an aqueous fraction of the camomile extract, which can be used directly, being obtained after/ from condensation of the steam. The incompatible constituents are removed in this step and a clear, alcohol-free, water-based camomile extract is obtained which still has the characteristic pleasant odour and soothing properties of camomile. After mixing the constituents, the preparation is ready for use. The preparation according to the invention is preferably in the form of a clear. alcohol-free aqueous solution. Optionally an oily solution can also be used.

The preparation has a pH of between 5.0 and 7.0, preferably of approximately 6.0. and preferably has an osmotic value of 0.01-2 osmol, in particular approximately 0.3 osmol/kg. The preparation is furthermore preferably in the form of a galenic preparation or a galenic combination. The preparation according to the invention can be used in the treatment and/or alleviation of the symptoms of a (nasal) cold and similar disorders of the nose, mouth and pharynx, in particular by reducing the swelling of the mucous membranes in the nose and pharynx, and/or as a decongestive. To this end the preparation can be administered to the nose one or several times a day in a manner known per se, for example in the form of a spray or drops.

The preparations according to the invention are preferably marketed in a suitable container, such as a bottle, tube, spray, atomiser or dropper bottle, atomiser and the like, which as a rule will contain 1-100 ml, usually 5-20 ml, of the preparation and which also contains means for - preferably metered - administration of the preparation to the nose. such as a dropper, atomiser nozzle or a metering pump.

For instance, it is possible to use a container which has a metering pump which delivers a unit dose, for example of between 10-500. preferably 100-200 and more preferentially approximately 140-150 microlitres solution per dose. It is also possible to use a dropper bottle which has a spray nozzle or atomiser, or a bottle with a dropper in the cap.

Compared with conventional xylometazoline or oxymetazoline preparations, the preparation according to the invention is more pleasant for the user. For instance, it has a caring/soothing action and a pleasant odour. Furthermore, the preparation preferably does not contain any alcohol.

The invention will now be explained on the basis of the following non-limiting example.

Example

Preparation based on xylometazoline and camomile distillate.

A preparation for adults (0.1 % xylometazoline) and a preparation for children (0.05% xylometazoline) of the following compositions were made up:

0.1% 0.05% (adults) (junior)

Xylometazoline hydrochloride 10 mg 5 mg

Camomile distillate (50 mg/ml 0.1 ml 0.1 ml camomile extract per distillate)

Sodium edetate 10 mg 10 mg

Sodium biphosphate 15 mg 15 mg

Sodium chloride 80 mg 80 mg

Disodium phosphate 5 mg 5 mg

Benzalkonium chloride solution 2 mg 2 mg (50% m V)

Aqua purificata to make up to 10 ml to make up to 10 ml

This preparation can, for example, be marketed in a glass bottle provided with a metering pump, which dispenses approximately 140-150 microlitres solution per dose.

Claims

1. Preparation for (intra)nasal administration that contains an aqueous solution of at least one compound having a vasoconstrictive and/or decongestive action and camomile extract.

2. Preparation according to Claim 1, wherein the camomile extract is a water-based extract and/or an essentially water-soluble camomile extract.

3. Preparation for (intra)nasal administration that contains an aqueous solution of at least one compound having a vasoconstrictive and/or decongestive action and at least one water- soluble constituent of camomile, and preferably a combination of at least two or more water-soluble constituents of camomile.

4. Preparation according to one of the preceding claims, wherein the compound having a vasoconstrictive and/or decongestive action is chosen from xylometazoline, oxymetazoline and/or tramazoline, optionally in the form of a pharmaceutically acceptable, water-soluble salt; or a combination thereof.

5. Preparation according to one of the preceding claims that also contains one or more preservatives and/or stabilisers and optionally one or more further constituents known per se for nasal sprays or nose drops.

6. Preparation according to Claim 5, wherein the preservative is benzalkonium, optionally in the form of a water-soluble salt, such as the chloride.

7. Preparation according to one of the preceding claims, wherein the camomile extract has been subjected to a pretreatment to render it compatible with the preservative used and/or with the other constituents of the preparation, in particular to steam distillation.

8. Preparation according to one of the preceding claims that is essentially alcohol-free.

9. Preparation according to one of the preceding claims, comprising an aqueous, alcohol- free solution of: xylometazoline or oxymetazoline in an amount of 0.001 -5% (m/V), preferably

0.01-0.5% (V/V) for children and 0.05-0.5% (V/V) for adults, a water-soluble camomile extract in an amount of 1 : 10 - 1 :200 (V/V), benzalkonium chloride in an amount of 0.01 mg/ml - 1 mg/ml.

10. Preparation according to one of the preceding claims, in a suitable container, such as a bottle, can. spray, atomiser or dropper bottle or atomiser, wherein the container also contains means for. preferably metered. administration of the preparation to the nose, such as a dropper, spray nozzle or a metering pump.