US 2001.0053775A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2001/0053775 A1 Seidel et al. 43) Pub. Date: Dec. 20,9 2001 (54) NASAL SOLUTIONS (30) Foreign Application Priority Data (76) Inventors: Matthias Seidel, Ittigen (CH); Jan. 30, 1998 (EP)........................................ 9881OO69-9 Christopher Buckley, Commugny (CH) Publication Classification Correspondence Address: RVNSporation (51) Int. Cl." ......................... A61K 31156; A61K 31/57; ENNINEMARK DEPT (52) U.S. Cl. ........................"I,...s. SUMMIT, NJ 079011027 (21) Appl. No.: 09/880,678 (57) ABSTRACT (22) Filed: Jun. 13, 2001 Related U.S. Application Data The invention relates to liquid pharmaceutical compositions adapted to nasal administration. The liquid nasal formula (63) Continuation of application No. 09/601,123, filed on tions of the invention are characterized inter alia by having Jul. 27, 2000. excellent and prolonged moisturizing properties. US 2001/0053775 A1 Dec. 20, 2001 NASAL SOLUTIONS embodiment of the invention they may also be present in a 0001. The present invention relates to pharmaceutical Slightly Viscous form, e.g. like a Syrup. However, they all compositions intended for nasal administration. More Spe can be clearly discriminated from nasal formulations in gel cifically, it concerns liquid nasal formulations with form in that they-in contrast to gels-are able to form improved moisturizing properties. drops and can be used as SprayS. 0014) Active substances suitable for nasal administration 0002 The nasal administration of active substances is a (a) are e.g. vasoconstrictors, e.g. Xylometazoline, e.g. widely used method of treatment. Active substances which Xylometazoline hydrochloride; indanazoline, metizoline; come into consideration are, for example, vasoconstrictors, naphazoline, e.g. naphazoline hydrochloride; fenoxazoline, Such as Xylometazoline, or antiallergic agents, Such as e.g. fenoxazoline hydrochloride; oxymetazoline, e.g. cromoglycic acid or H receptor antagonists, e.g. dimethin oxymetazoline hydrochloride; tetrahydrozoline, tramaZo dene maleate. Another group of possible active Substances is line, tymazoline; phenylephrine, e.g. phenylephrine hydro e.g. corticosteroids, Such as beclomethasone or fluticasone. chloride; ephedrine, e.g. d-pseudoephedrine hydrochloride; 0003. The indications in which a certain nasally admin or epinephrine; or antiallergic agents, such as (1) cromogly istered drug is to be applied are known in the art. For cic acid (=cromolyn) or a nasally acceptable Salt thereof, e.g. example, vasoconstrictors are e.g. used as nasal deconges the disodium Salt (=disodium cromoglycate), or (2) H tants for alleviating the typical Symptoms of common cold, receptor antagonists, e.g. dimethindene or a nasally accept like running nose, obstructed nose etc., or in rhinitis or able Salt thereof, e.g. dimethindene maleate; acrivastine, Sinusitis. Antiallergic agents and corticosteroids are e.g. brompheniramine, chlorpheniramine, dexchlorpheniramine, used in antiallergic conditions, e.g. hay fever, or in anti triprolidine, bromodiphenhydramine, clemastine, phenyl asthmatic or anti-inflammatory conditions. toloxamine, piprinhydrinate, pyrilamine, tripelennamine, cetirizine, hydroxy Zine, methdilazine, promethazine, trime 0004 Nasal administration of active substances in liquid prazine, azatadine, cyproheptadine, loratadine, astemizole, form, e.g. in the form of drops, a Solution or a Spray diphenhydramine, levocabastine or terfenadine. Examples opposite to nasal administration in gel form-is desirable for corticosteroids are e.g. beclomethasone, e.g. beclometha inter alia because of a much better distribution of the active Sone dipropionate, or fluticaSone, e.g. fluticasone propi Substances within the-partly tiny-nasal cavities and an onate. All active Substances which are capable of Salt easier handling and dosing, e.g. in pediatric or geriatric formation may be present either in free form or in the form patients. of a nasally acceptable Salt. Also mixtures of more than one 0005. However, upon administration of liquid nasal for active Substance come into consideration, e.g. a combination mulations often the patients are Suffering from Side-effects of a vasoconstrictor and an antiallergic agent, Such as like burning, dryness, Stinging of the nasal mucosa or Xylometazoline plus cromoglycic acid or phenylephrine plus Sneezing. One of the reasons for this is that liquids-in dimethindene, or a combination of a vasoconstrictor and a contrast to gels-normally do not remain in the nasal corticosteroid, Such as Xylometazoline plus beclomethasone. cavities for a long period of time but are washed out fast. 0015. In one embodiment of the invention, the active 0006 The present invention addresses these problems Substances used are vasoconstrictors, e.g. Xylometazoline, and provides liquid nasal formulations which do not only naphazoline, fenoxazoline, oxymetazoline, tetrahydrozo moisturize the nasal mucosa but also keep it Sufficiently line, tramazoline, phenylephrine, ephedrine or epinephrine, moisturized for a prolonged period of time. As a result, or any nasally acceptable Salt thereof. In particular preferred liquid nasal pharmaceutical compositions having excellent are Xylometazoline and oxymetazoline and any nasally and prolonged moisturizing properties are obtained. acceptable Salts thereof. 0007. The invention relates to a liquid nasal pharmaceu 0016. The concentration of the active substances is typi tical composition which comprises cally chosen So that a pharmaceutically, i.e. nasally, effective 0008 (a) one or more active substances suitable for dose thereof can be administered easily, e.g. by a certain nasal administration, number of drops or by Spraying once or twice. 0017 For example, if a vasoconstrictor is used as active 0009 (b) sorbitol; Substance (a), it is e.g. present in an amount of from 0.005 0010) (c) a water-soluble C-C-alkyl-cellulose up to 0.5%, preferably of from 0.01 up to 0.3%, and in derivative; particular of from 0.025 up to 0.2% (m/V) of the total composition. 0011 (d) a vehicle which is present in an amount of at least 90% (m/V) of the total composition, and 0018 Sorbitol (b) can be applied e.g. in solid form or as which is selected from water and mixtures of water acqueous solution, e.g. as a 50-80%-in particular 70%- with propylene glycol, water with glycerol and water non-crystallizing aqueous Solution. with both propylene glycol and glycerol, whereby in 0019 Sorbitol (b) is e.g. present in an amount of from 0.5 all Said mixtures water is present in an amount of at up to 5%, especially of from 0.5 up to 4.5%, more especially least 95% (m/V); and of from 1 up to 3% and in particular of from 1.2 up to 1.6%, 0012 (e) optionally one or more nasally acceptable (m/V) of the total composition. excipients. 0020. A water-soluble C-C-alkyl-cellulose derivative 0013 Liquid nasal pharmaceutical compositions are e.g. (c) is e.g. methyl cellulose or a (hydroxy or carboxy)- drops, Solutions, sprays (nebulizers) or metered-dose sprays. Substituted C-C-alkyl-cellulose, e.g. hydroxypropyl Typically, they are in the form of fluid solutions, but in one methyl cellulose, hydroxyethyl cellulose, hydroxypropyl US 2001/0053775 A1 Dec. 20, 2001 cellulose, ethyl hydroxyethyl cellulose or carboxymethyl 0031) Leuba, D., de Ribaupierre, Y. and Kucera, P. Ion cellulose, e.g. carboxymethyl cellulose Sodium. Preferred transport, ciliary activity and mechanoSensitivity of Sinusal are hydroxypropyl methyl cellulose, methyl cellulose and mucosa: an in vitro study. Amer. J. Physiol. 271, L349-L358, carboxymethyl cellulose, especially hydroxypropyl methyl 1996. cellulose and methyl cellulose, and in particular hydrox 0032 Alberty, J. The effect of antiallergic intranasal ypropyl methyl cellulose. formulations on ciliary beat frequency of human nasal 0021. The water-soluble C-C-alkyl-cellulose derivative epithelium in vitro. Allergy 53,986-989, 1998. (c), especially hydroxypropyl methyl cellulose, is typically 0033 Su, X. Y., Mattern, C., Haecker, R. and Li Wan Po, applied in Solid form with Viscosity grades ranging of from A. Does Sea-water made isotonic affect ciliary beat fre 400 up to 15000 mPats, especially of from 1000 up to 6000 quency? Int. J. of Pharmaceutics 123, 47-51, 1995. mPaS. 0034 Especially, the nasal compositions of the invention 0022. The water-soluble C-C-alkyl-cellulose derivative show unexpected and Superior properties what the transmu (c), especially hydroxypropyl methyl cellulose, is e.g. cosal ion transport is concerned. The latter can be Studied in present in an amount of from 0.1 up to 5%, preferably of Vitro e.g. by the “Voltage clamp technique'. In this method, from 0.2 up to 1.9%, and in particular of from 0.3 up to 1%, the compositions are applied onto the ciliary Surface, and the (m/V) of the total composition. passive ionic flux is measured in the Sense that positive charges flow across the mucosa from ciliary to Submucosal 0023 The amount of (c) must be adjusted so that the side (which contains a Tyrodebicarbonate buffer as a control resulting nasal formulation remains liquid. It Strongly Solution). With the compositions of the invention, a Surpris depends on the Viscosity grade of the cellulose derivative ingly increased passive ionic flux is obtained. Therefrom one used. So while an amount of 0.5% of (c) with a viscosity can conclude that the compositions of the invention will grade of 4000 mPa's may be suitable, the amount of (c) favor the transmucosal