Method and composition for treating rhinitis

Abstract

There is provided pharmaceutical compositions for the treatment of rhinitis by, for example, nasal or ocular administration comprising zwitterionic cetirizine, a polar lipid liposome and a pharmaceutical-acceptable aqueous carrier. The compositions are preferably homogeneous in their nature.

1 . A homogeneous pharmaceutical composition for the treatment of rhinitis by nasal or ocular administration comprising zwitterionic cetirizine, a polar lipid liposome and a pharmaceutical-acceptable aqueous carrier.  
   
   
       2 . A composition as claimed in  claim 1 , which further includes a pharmaceutically-acceptable buffer capable of providing a pH of from about pH 4 to about pH 8.  
   
   
       3 . A composition as claimed in  claim 2 , wherein the pH range is about pH 5 to about pH 7.  
   
   
       4 . A composition as claimed in  claim 2 , wherein the buffer is a phosphate, citrate or acetate buffer.  
   
   
       5 . A composition as claimed in  claim 4 , wherein the buffer is disodium phosphate, dipotassium phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, phosphonic acid plus base, sodium citrate, citric acid plus base, sodium acetate or acetic acid plus base.  
   
   
       6 . A composition as claimed in  claim 2 , wherein the quantity of buffer is in the range of about 1 mg/mL to about 30 mg/mL.  
   
   
       7 . A composition as claimed in  claim 1 , wherein cetirizine is provided in the form of a salt.  
   
   
       8 . A composition as claimed in  claim 7 , wherein the salt is a chloride salt, a hydrochloride salt or a nitrate salt.  
   
   
       9 . A composition as claimed in  claim 8 , wherein the salt is cetirizine dinitrate.  
   
   
       10 . A composition as claimed in  claim 1 , wherein the amount of cetirizine or salt employed in preparation of the composition is from about 1 mg/mL to about 30 mg/mL calculated on the zwitterionic form.  
   
   
       11 . A composition as claimed in  claim 10 , wherein the amount is from about 5.5 mg/mL to about 22 mg/mL.  
   
   
       12 . A composition as claimed in  claim 1 , wherein the polar lipid is of a natural origin, is of a synthetic/semi-synthetic origin, or comprises a mixture of the two.  
   
   
       13 . A composition as claimed in  claim 1 , wherein the polar lipid comprises or consists of a phospholipid or a mixture of phospholipids.  
   
   
       14 . A composition as claimed in  claim 13 , wherein the phospholipid comprises one that is based on phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidic acid, phosphatidylserine or a mixture thereof.  
   
   
       15 . A composition as claimed in  claim 13 , wherein the phospholipid comprises one that is represented by the general formula I,  
     
       
         
         
             
             
         
       
     
     wherein R 1  and R 2  independently represent a saturated or unsaturated, branched or straight chain alkyl group having between 7 and 23 carbon atoms and R 3  represents an amide or ester bonding group.  
   
   
       16 . A composition as claimed in  claim 15 , wherein the amide or ester bonding group is —CH 2 —CH(OH)—CH 2 OH, —CH 2 —CH 2 —N(CH 3 ) 3 —CH 2 —CH 2 —NH 2 , —H or —CH 2 —CH(NH 2 )—COOH.  
   
   
       17 . A composition as claimed  claim 13 , wherein the phospholipid comprises a membrane lipid derived from soybean.  
   
   
       18 . A composition as claimed in  claim 17 , wherein the phospolipid comprises Lipoid S75, Lipoid S100 and/or Lipoid S75-3N.  
   
   
       19 . A composition as claimed in  claim 13 , wherein the phospolipid comprises dilaurylphosphatidylcholine, dimyristolphosphatidyl-choline, dipalmitoylphosphatidylcholine, dilaurylphosphatidylglycerol, dimyristolphosphatidylglycerol, dioleoylphosphatidylcholine or dioleoylphosphatidylglycerol.  
   
   
       20 . A composition as claimed in  claim 1 , wherein the polar lipid comprises or consists of a glycolipid or a mixture of glycolipids.  
   
   
       21 . A composition as claimed in  claim 20 , wherein the glycolipid comprises a glycoglycerolipid.  
   
   
       22 . A composition as claimed in  claim 21 , wherein the glycoglycerolipid comprises a galactoglycerolipid.  
   
   
       23 . A composition as claimed in  claim 21 , wherein the glycoglycerolipid comprises a digalactosyldiacylglycerol of the general formula II,  
     
       
         
         
             
             
         
       
     
     wherein R 1  and R 2  independently represent a saturated or unsaturated, branched or straight chain alkyl group having between 7 and 23 carbon atoms and R 3  represents an amide or ester bonding group.  
   
   
       24 . A composition as claimed in  claim 20 , wherein the glycolipid comprises a digalactosyldiacylglycerol.  
   
   
       25 . A composition as claimed in  claim 20 , wherein the glycolipid comprises a glycosphingolipid.  
   
   
       26 . A composition as claimed in  claim 25 , wherein the glycosphingolipid comprises a monoglycosylsphingoid, an oligoglycosylsphingoid, an oligoglycosylceramide, a monoglycosylceramide, a sialoglycosphingolipid, a uronoglycosphingolipid, a sulfoglycosphingolipid, a phosphoglycosphingolipid, a phosphonoglycosphingolipid, a ceramide, a monohexosylceramide, a dihexosylceramide, a sphingomyelin, a lysosphingomyelin, a sphingosine or a mixture thereof.  
   
   
       27 . A composition as claimed in  claim 26 , wherein the glycosphingolipid comprises sphingomyelin or a product derived therefrom.  
   
   
       28 . A composition as claimed in  claim 20 , wherein the glycolipid comprises a glycophosphatidylinositol.  
   
   
       29 . A composition as claimed in  claim 1 , wherein the amount of polar lipid substance that is used is in the range of about 10 mg/mL to about 120 mg/mL.  
   
   
       30 . A composition as claimed in  claim 1 , wherein the amount of phospholipid in the composition is from about 17 mg/mL to about 70 mg/mL.  
   
   
       31 . A composition as claimed in  claim 30 , wherein the amount is from about 20 mg/mL to about 40 mg/mL.  
   
   
       32 . A composition as claimed in  claim 1 , which further comprises an antioxidant.  
   
   
       33 . A composition as claimed in  claim 32 , wherein the antioxidant is α-tocopherol, ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, citric acid, fumaric acid, malic acid, monothioglycerol, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium metabisulfate, potassium metabisulfate, sodium sulfite, tartaric acid and/or vitamin E.  
   
   
       34 . A composition as claimed in  claim 1 , which further comprises a chelating agent.  
   
   
       35 . A composition as claimed in  claim 34 , wherein the chelating agent is ethylenediaminetetraacetic acid, ethylenediaminetriacetric acid and/or diethylenetriaminepentaacetic acid.  
   
   
       36 . A composition as claimed in  claim 1 , which further comprises a preservative.  
   
   
       37 . A composition as claimed in  claim 36 , wherein the preservative is benzalkonium chloride, benzoic acid, butylated hydroxyanisole, butylparaben, chlorbutanol, ethylparaben, methylparaben, propylparaben, phenoxyethanol and/or phenylethyl alcohol.  
   
   
       38 . A composition as claimed in  claim 1 , which further comprises a viscosity-increasing agent.  
   
   
       39 . A composition as claimed in  claim 38 , wherein the viscosity-increasing agent is polyethyleneglycol, crosslinked polyvinylpyrrolidone and/or hydroxypropylmethyl cellulose.  
   
   
       40 . A composition as claimed in  claim 1 , wherein the diameter of the liposomes is less than about 200 nm.  
   
   
       41 . A composition as claimed in  claim 40 , wherein the diameter is between about 40 nm and about 100 nm.  
   
   
       42 . A process for the preparation of a composition as claimed in  claim 1 , which process comprises: 
 (a) adding a polar lipid or a mixture of polar lipids that is/are swellable in aqueous media to an aqueous solution of cetirizine with stirring; and    (b) homogenising the preparation.    
   
   
       43 . A process as claimed in  claim 42 , wherein, prior to the homogenisation step, the pH is adjusted to the desired value by adding an acid or a base.  
   
   
       44 . A process as claimed in  claim 43 , wherein, prior to the homogenisation step, water, saline or buffer solution is added to the preparation to obtain a desired final batch volume.  
   
   
       45 . A process as claimed in  claim 44 , wherein the addition of water, saline or buffer takes place after the pH adjusting step.  
   
   
       46 . A process as claimed in  claim 42 , wherein at least one of the solutions/liquids is/are purged with nitrogen and/or argon.  
   
   
       47 . A process as claimed in  claim 42 , wherein the aqueous solution of cetirizine is formed either by adding buffer to an aqueous solution of cetirizine or salt thereof, or adding cetirizine or salt thereof to an aqueous buffer solution, prior to the addition of lipid.  
   
   
       48 . A process as claimed in  claim 42 , wherein, if a mixture of polar lipids is used, it is pre-treated with organic solvent.  
   
   
       49 . A process as claimed in  claim 42 , wherein the homogenisation step (b) comprises vigorous mechanical mixing, high speed homogenisation, shaking, vortexing and/or rolling.  
   
   
       50 . A process as claimed in  claim 42 , which comprises an additional liposome size-reduction step.  
   
   
       51 . A process as claimed in  claim 50 , wherein the size-reduction step comprises extrusion through a membrane filter.  
   
   
       52 . A process as claimed in  claim 42 , wherein the homogenisation step and/or size-reduction step comprises high-pressure homogenisation.  
   
   
       53 . A homogeneous pharmaceutical composition obtainable by a process comprising: 
 (a) adding a polar lipid or a mixture of polar lipids that is/are swellable in aqueous media to an aqueous solution of cetirizine with stirring; and    (b) homogenising the preparation.    
   
   
       54 . A composition as claimed in  claim 53 , wherein, in the process, prior to the homogenisation step, the pH is adjusted to the desired value by adding an acid or a base.  
   
   
       55 . A composition as claimed in  claim 54 , wherein, in the process, prior to the homogenisation step, water, saline or buffer solution is added to the preparation to obtain a desired final batch volume.  
   
   
       56 . A composition as claimed in  claim 55 , wherein the addition of water, saline or buffer takes place after the pH adjusting step.  
   
   
       57 . A composition as claimed in  claim 53 , wherein, in the process, at least one of the solutions/lipids is/are purged with nitrogen and/or argon.  
   
   
       58 . A composition as claimed in  claim 53 , wherein, in the process, the aqueous solution of cetirizine is formed either by adding buffer to an aqueous solution of cetirizine or salt thereof, or adding cetirizine or salt thereof to an aqueous buffer solution, prior to the addition of lipid.  
   
   
       59 . A composition as claimed in  claim 53 , wherein, in the process, if a mixture of polar lipids is used, it is pre-treated with organic solvent.  
   
   
       60 . A composition as claimed in  claim 53 , wherein, in the process, the homogenisation step (b) comprises vigorous mechanical mixing, high speed homogenisation, shaking, vortexing and/or rolling.  
   
   
       61 . A composition as claimed in  claim 53 , which comprises, in the process, an additional liposome size-reduction step.  
   
   
       62 . A composition as claimed in  claim 61 , wherein the size-reduction step comprises extrusion through a membrane filler.  
   
   
       63 . A composition as claimed in  claim 53 , wherein, in the process, the homogenisation step and/or size-reduction step comprises high-pressure homogenisation.  
   
   
       64 . (canceled)  
   
   
       65 . A method for the treatment of rhinitis comprising the administration of a composition as claimed in  claim 1  to a person suffering from or susceptible to that disorder.  
   
   
       66 . (canceled)  
   
   
       67 . A method as claimed in  claim 65 , wherein the administration is intranasal.  
   
   
       68 . A method as claimed in  claim 65 , wherein the administration is intraocular.  
   
   
       69 . A method as claimed in  claim 65 , wherein the administration is to the lung.  
   
   
       70 . The composition of  claim 8  wherein the salt is a hydrochloride salt.  
   
   
       71 . The composition of  claim 70  wherein the salt is certirizine dihydrochloride.