US20050255154A1 - Method and composition for treating rhinitis - Google Patents

Method and composition for treating rhinitis Download PDF

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Publication number
US20050255154A1
US20050255154A1 US10/842,433 US84243304A US2005255154A1 US 20050255154 A1 US20050255154 A1 US 20050255154A1 US 84243304 A US84243304 A US 84243304A US 2005255154 A1 US2005255154 A1 US 2005255154A1
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composition
cetirizine
phospholipid
per
liposome
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US10/842,433
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English (en)
Inventor
Lena Pereswetoff-Morath
Anders Carlsson
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Biolipox AB
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Biolipox AB
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Priority to US10/842,433 priority Critical patent/US20050255154A1/en
Assigned to BIOLIPOX AB reassignment BIOLIPOX AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CARLSSON, ANDERS, PERESWETOFF-MORATH, LENA
Priority to CN201310132640.3A priority patent/CN103271910B/zh
Priority to CNA2005800153171A priority patent/CN1984643A/zh
Priority to MXPA06013121A priority patent/MXPA06013121A/es
Priority to AU2005239866A priority patent/AU2005239866B2/en
Priority to BRPI0510778A priority patent/BRPI0510778B8/pt
Priority to JP2007512327A priority patent/JP4976283B2/ja
Priority to MEP-2012-77A priority patent/ME01436B/me
Priority to HK07106149.0A priority patent/HK1098960B/en
Priority to DK05742190.1T priority patent/DK1771155T3/da
Priority to US10/571,330 priority patent/US20070026058A1/en
Priority to NZ550412A priority patent/NZ550412A/en
Priority to RS20120246A priority patent/RS52311B/sr
Priority to ZA200608407A priority patent/ZA200608407B/xx
Priority to PL05742190T priority patent/PL1771155T3/pl
Priority to SI200531529T priority patent/SI1771155T1/sl
Priority to ES05742190T priority patent/ES2395130T3/es
Priority to HRP20120484TT priority patent/HRP20120484T1/hr
Priority to PT05742190T priority patent/PT1771155E/pt
Priority to CA2536728A priority patent/CA2536728C/en
Priority to AT05742190T priority patent/ATE550015T1/de
Priority to PCT/GB2005/001758 priority patent/WO2005107711A2/en
Priority to EA200602092A priority patent/EA014752B1/ru
Priority to EP05742190A priority patent/EP1771155B1/en
Publication of US20050255154A1 publication Critical patent/US20050255154A1/en
Priority to NO20064521A priority patent/NO335840B1/no
Priority to IL179012A priority patent/IL179012A/en
Priority to US13/444,381 priority patent/US9980959B2/en
Priority to CY20121100541T priority patent/CY1112981T1/el
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00—Nanotechnology
    • Y10S977/902—Specified use of nanostructure
    • Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
    • Y10S977/906—Drug delivery
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00—Nanotechnology
    • Y10S977/902—Specified use of nanostructure
    • Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
    • Y10S977/906—Drug delivery
    • Y10S977/907—Liposome

Definitions

  • the present invention relates to a method for treating rhinitis, and to a corresponding pharmaceutical composition.
  • rhinitis Allergic and non-allergic rhinitis are common disorders affecting about 30% of the population. Rhinitis does have considerable impact on quality of life. In fact, rhinitis is regarded to affect the quality of life, even more so than, e.g., asthma.
  • Hay fever and perennial allergic rhinitis are characterised by sneezing, rhinorrhea, nasal congestion, pruritus, conjunctivitis and pharyngitis.
  • perennial rhinitis chronic nasal obstruction is often prominent and may extend to eustachian tube obstruction.
  • Oral or local antihistamines are first line treatment, and nasal steroids second line treatment for rhinitis.
  • topical corticosteroids and long acting antihistamine agents provide significant relief of symptoms.
  • Antihistamines may also affect non-immunologically (non-IgE) mediated hypersensitivity reactions such as non-allergic rhinitis, exercise induced asthma, cold urticaria, and non-specific bronchial hyperreactivity.
  • Cetirizine dihydrochloride [2- ⁇ 4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl- ⁇ ethoxy]acetic acid is an orally and locally active, potent, long acting peripheral histamine H 1 receptor antagonist.
  • Cetirizine is one of the most widely used second generation antihistamines for the treatment of rhino-conjunctivitis and urticaria. It is effective, well tolerated, and safe when used orally in a dose of 10 mg daily. Sedation and dry mouth do however occur as side effects in orally treated patients. Cetirizine is also approved in children for the treatment of rhinitis.
  • antihistamines include reduced sneezing and rhinorrhea, while nasal blockage is less responsive.
  • Local administration of antihistamines (azelastine and levocabastine) has advantages, such as rapid onset of action and fewer side effects.
  • cetirizine dihydrochloride is not an approved medicine for local administration, although it has been administered in that manner in clinical trials.
  • cetirizine presumably as di-hydrochloride
  • Concentrations of 0.625, 1.25, and 2.5 mg/mL of cetirizine were sprayed three times a day for two weeks (Clement P, Roovers M H, Francillon C, Dodion P. Dose - ranging, placebo - controlled study of cetirizine nasal spray in adults with perennial allergic rhinitis. Allergy September 1994; 49(8):668-72).
  • the most common side effects were related to nasal events, though no difference in incidence between the placebo and the cetirizine-treated groups were seen. However, the authors speculate that local irritation had an adverse effect on treatment efficacy.
  • cetirizine nasal spray was found to reduce symptoms and increase nasal peak flow after an allergen challenge.
  • cetirizine mist was administered to the lung with a nebulizer.
  • Ghosh S K De Vos C, McIlroy I, Patel K R. Effect of cetirizine on exercise induced asthma. Thorax April 1991; 46(4):242-4).
  • cetirizine Due to the irritation of the nasal mucosa by cetirizine it is necessary to decrease its immediate exposure of the drug in nasal administration. It has been reported that this can be achieved by providing cetirizine in form of a composition containing cyclodextrin (EP 0 605 203 B1).
  • Still another object of the present invention is to provide a process for the manufacture of this composition.
  • An additional object of the invention is to provide a method for the treatment of rhinitis by nasal administration of cetirizine which lacks at least some of the drawbacks of known methods.
  • the present invention is based on the finding that the presence of liposomes in an aqueous cetirizine solution of a pH at which its zwitterionic form predominates, such as a pH from about pH 4 or pH 5 to about pH 7 and even pH 8, reduces or even eliminates irritation of the nasal mucosa or the ocular mucosa caused by the drug.
  • a pH at which its zwitterionic form predominates such as a pH from about pH 4 or pH 5 to about pH 7 and even pH 8
  • a pharmaceutical composition for the treatment of rhinitis by nasal or ocular administration comprising zwitterionic cetirizine, polar lipid liposome, a pharmaceutical acceptable aqueous carrier and, optionally, a pharmaceutically acceptable buffer capable of providing a pH of from pH 4 to pH 8, preferably from pH 5.0 to pH 7.0, with the proviso that, if the polar lipid comprises phospholipid, the amount of phospholipid in the composition from is from 10 or 17 mg to 120 mg per mL, more preferred from 35 mg to 70 mg per mL.
  • any pharmaceutically acceptable salt of cetirizine as well as the zwitterionic form thereof can be used in the invention. Particularly preferred is the use of nitrate salts of cetirizine, most preferred of cetirizine dinitrate.
  • composition of the invention comprises cetirizine or a salt of cetirizine in an amount of from 1 mg/mL to 23 mg/mL calculated on the zwitterionic form, preferably in an amount of from 5.5 mg/mL to 22 mg/mL.
  • composition of the invention can be administered as a nasal spray, nasal drops, and eye drops. It is also possible to administer it as a fine mist to the lungs by nebulization. Irrespective of administration route the irritating properties of cetirizine are reduced by the composition of the invention.
  • Liposomes are well known in the art.
  • a liposome is a structure consisting of one or more concentric spheres of lipid bilayers separated by water or aqueous buffer compartments.
  • Liposomes can be prepared by various methods using solvents, reduced pressure, two-phase systems, freeze drying, sonication etc. described, for instance, in Liposome Drug Delivery Systems, Betageri G V et al., Technomic Publishing AG, Basel, Switzerland, 1993, which is incorporated herein by reference.
  • Liposomes may be based on phospholipids, in particular phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidic acid (PA), phosphatidylserine (PS), or mixtures thereof.
  • PC phosphatidylcholine
  • PG phosphatidylglycerol
  • PI phosphatidylinositol
  • PA phosphatidic acid
  • PS phosphatidylserine
  • the phospholipids of the invention comprise polar and non-polar groups linked to a backbone entity carrying hydroxyl groups, such as glycerol.
  • the phospholipid is of natural origin, preferably membrane phospholipid.
  • the phospholipid is of synthetic or semi-synthetic origin.
  • Phospholipids can be represented by the general formula I wherein R 1 and R 2 independently represent a saturated or unsaturated, branched or straight chain alkyl or alkylene group having 7-23 carbon atoms, preferably 11-19 carbon atoms; and R 3 represents an amide or ester bonding group, such as —CH 2 —CHOH—CH 2 OH (phosphatidylglycerol), —CH 2 —CH 2 —CH 2 —N(CH 3 ) 3 (phosphatidylcholine), —CH 2 —CH 2 —NH 2 (phosphatidylethanolamine), H (phosphatidic acid), —CH 2 —CH(NH 2 )—COOH (phosphatidylserine).
  • R 1 and R 2 independently represent a saturated or unsaturated, branched or straight chain alkyl or alkylene group having 7-23 carbon atoms, preferably 11-19 carbon atoms
  • R 3 represents an amide or ester bonding group, such as —CH 2
  • Particularly preferred phospholipids are those swelling in water, which are capable of spontaneous liposome formation.
  • a phospholipid to form a liposome in excess of water it is necessary that a lamellar liquid crystalline phase is formed, as with phosphatidylcholine (PC).
  • Phosphatidylethanolamine (PE) on the other hand normally favours the reversed hexagonal phase.
  • the phospholipid of the invention does not swell spontaneously in water, it is nevertheless possible to obtain liposomes from it by adding a more polar, swellable phospholipid, such as an anionic phospholipid, preferably phosphatidylglycerol.
  • a more polar, swellable phospholipid such as an anionic phospholipid, preferably phosphatidylglycerol.
  • the liposome formation can be performed at room temperature or any other temperature above 0° C. if the phase transition temperature of the acyl chains (chain melting; gel-to-liquid crystals) is below the freezing point of water, which is the case for natural phospholipids.
  • the polar lipid comprises or, more preferred, consists of glycolipid.
  • glycolipid designates a compound containing one or more monosaccharide residues bound by a glycosidic linkage to a hydrophobic moiety such as an acylglycerol, a sphingoid or a ceramide (N-acylsphingoid).
  • glycolipid is a glycoglycerolipid.
  • glycoglycerolipid designates a glycolipid containing one or more glycerol residues.
  • glycoglycerolipid comprises or consists of galactoglycerolipid, preferably digalactosyldiacylglycerol of the general formula (II) R 1 and R 2 having the same meaning as in general formula (I).
  • glycolipid is a glycosphingolipid.
  • glycosphingolipid designates lipids containing at least one monosaccharide residue and either a sphingoid or a ceramide.
  • Glycosphingolipid comprises neutral glycophingolipids such as mono- and oligoglycosylsphingoids as well as mono- and oligoglycosylceramides. Most preferred are the respective mono forms.
  • Glycosphingolipid additionally comprises acidic glycosphingolipids such as sialoglycosphingolipids, uronoglycosphingolipids, sulfoglycosphingolipids, phosphoglycosphingolipids, and phosphonoglycosphingolipids.
  • the glycosphingolipid can be ceramide, monohexosylceramide, dihexosylceramide, sphingomyelin, lysosphingomyelin, sphingosine, or mixtures thereof.
  • the glycosphingolipid is sphingomyelin or products derived from sphingomyelin.
  • the sphingomyelin content is preferably established by chromatographic methods.
  • Sphingomyelin can be extracted from milk, preferably bovine milk, brain, egg yolk or erythrocytes from animal blood, preferably sheep.
  • Synthetic and semi-synthetic sphingolipids are comprised by the invention.
  • glycolipid is a glycophosphatidylinositol.
  • glycophosphatidylinositol designates glycolipid which contains saccharides glycosidically linked to the inositol moiety of phosphatidylinositols.
  • composition of the invention may also comprise antioxidant.
  • Antioxidants of the invention comprise alpha tocopherol, ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, citric acid, fumaric acid, malic acid, monothioglycerol, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, sodium sulfite, tartaric acid, and vitamin E.
  • the buffer of the invention is a pharmaceutically acceptable buffer of any kind that does not interfere with the formation of liposomes, such as a phosphate, citrate, or acetate buffer, and which is capable of maintaining a pH of from about pH 4 to about pH 8 or from about pH 5.0 to about pH 7.0.
  • a chelating agent may be used to reduce the metal ion catalysed oxidation of phospholipid and/or cetirizine.
  • useful chelating agents are ethylenediaminetetraacetic acid (EDTA), ethylenediaminetriacetic acid and diethylenetriaminepentaacetic acid (DTPA). It is also possible to use other agents that protect the composition of the invention and, in particular, possible unsaturated fatty acid residues therein, from oxidation.
  • composition of the invention can comprise one or more preservatives.
  • preservatives for liquid pharmaceutical compositions are benzalkonium chloride, benzoic acid, butylated hydroxyanisole, butylparaben, chlorbutanol, ethylparaben, methylparaben, phenoxyethanol, and phenylethyl alcohol.
  • composition of the invention can also comprise viscosity-increasing agent such as, for instance, hydrophilic polymers like polyethyleneglycol, cellulose derivatives such as hydroxypropylmethyl cellulose.
  • viscosity-increasing agent such as, for instance, hydrophilic polymers like polyethyleneglycol, cellulose derivatives such as hydroxypropylmethyl cellulose.
  • Buffering agents preservatives, viscosity-increasing agents, anti-oxidants, chelating agents and other optional additives will be selected keeping in mind that their detrimental effect on liposome stability should be kept at a minimum. For a given agent this can be ascertained by simple experiments, which are within the reach of a person skilled in the art.
  • the liposome of the invention is prepared by direct swelling of the compound in an aqueous medium without adding any other substances such as stabilizers etc. which are normally required.
  • a process for preparing a pharmaceutical composition for the treatment of rhinitis by nasal or ocular administration comprising zwitterionic cetirizine, polar lipid liposome, a pharmaceutical acceptable aqueous carrier and, optionally, a pharmaceutically acceptable buffer capable of providing a pH of from about pH 4 to about pH 8, preferably from about pH 5.0 to about pH 7.0, with the proviso that, if the polar lipid comprises phospholipid, the amount of phospholipid in the composition is from 10 or 17 mg to 120 mg per mL, more preferred from 35 mg to 70 mg per mL, comprising
  • a preferred aqueous medium is a buffered aqueous solution of cetirizine.
  • Useful buffers are those capable of buffering at a pH within the range from pH 4 to pH 8, more preferred from about pH 5.0 to about pH 7.0, and comprise phosphate buffer, citrate buffer, acetate buffer. The person skilled in the art is aware of the inherent buffering effect of zwitterionic cetirizine.
  • the formation of the liposomes of the invention is facilitated by the spontaneous swelling the polar lipid in water forming a lamellar liquid crystalline phase having a maximum water content of about 35% by weight.
  • a spontaneous formation of liposomes can be obtained when water is added to this lamellar phase. If spontaneous formation is not obtained, the formation of liposomes can be accomplished by mechanical dispersion of the lamellar liquid-crystalline phase in excess water.
  • a preferred dispersion method is vigorous mechanical mixing by, for instance, high speed homogenisation, such as by means of an Ultra Turrax® (Jankel & Kühnke, Germany) homogeniser, but shaking, vortexing and rolling can also be performed.
  • high speed homogenisation such as by means of an Ultra Turrax® (Jankel & Kühnke, Germany) homogeniser, but shaking, vortexing and rolling can also be performed.
  • a homogeneous size distribution of the liposomes of the invention is desirable. It can be obtained by extrusion through a membrane filter, such as one made of polycarbonate, with a pore size of 100 nm. Membrane filters for use in the invention can be procured from Avestin Inc., Canada. A reduced average liposome size and narrowed liposome size distribution is also obtained when the liposomal dispersion is subjected to high-pressure homogenisation with a suitable homogeniser (Rannie A P V, type 7.30 VH, Rannie A S, Denmark) at 500 bar for 4-6 cycles.
  • a suitable homogeniser Rannie A P V, type 7.30 VH, Rannie A S, Denmark
  • composition according to the invention does not normally require conventional treatment with organic solvents such as chloroform or dichloromethane. However, if two or more membrane lipids are used it may be necessary to treat them with organic solvent prior to the addition of the aqueous solvent.
  • a method for treating rhinitis comprising the nasal administration of a pharmacologically effective amount of the composition of the invention to a person suffering from rhinitis.
  • a pharmacologically effective amount of the composition of the invention for nasal administration any state-of-the-art devices suitable for producing sprays of aqueous liposomal dispersions can be used.
  • a corresponding method of treatment according to the invention by ocular administration is also dislosed.
  • the composition of ocular administration is in the form of eye drops.
  • a pharmaceutical composition for the treatment of rhinitis by nasal or ocular administration comprising cetirizine and a pharmacologically acceptable liposomal carrier comprising polar lipid dispersed in an aqueous medium with the proviso that, if the polar lipid comprises phospholipid, the amount of phospholipid in the composition is from 10 mg or 17 mg per mL to 120 mg per mL, more preferred from 35 mg per mL to 70 mg per mL.
  • a buffer solution is prepared by dissolving the buffering agents disodium phosphate dihydrate (Na 2 HPO 4 .2H 2 O) and potassium dihydrogen phosphate (KH 2 PO 4 ) in 1600 ml water (80% of the total batch volume) in a 2000 mL volumetric flask.
  • the weighed amount of active agent is added to the buffer solution and dissolved by stirring with a magnetic stirrer, followed by addition of 100 ml aqueous 1 M sodium hydroxide.
  • the phospholipid is separately weighed and added to the cetirizine solution.
  • Ultrasonication further reduces mean particle size.
  • the vials with the homogenised composition of the invention are placed in an ultrasonication bath and sonicated for 2 ⁇ 10 minutes, whereupon the samples have an almost clear appearance in comparison with the opaque composition afforded by Ultra-Turrax® homogenisation.
  • a buffer solution is prepared by dissolving anhydrous citric acid and solid sodium hydroxide in 160 mL water (80% of the total batch volume) in a 200 mL volumetric flask. The weighed amount of active agent is added and dissolved by stirring with a magnetic stirrer. The phospholipid is separately weighed and added to the cetirizine solution. Stirring is continued until a well dispersed suspension has been formed, the pH of which is adjusted to pH 5.0 ⁇ 0.1 with 1.0 M NaOH and/or 1.0 M HCl. The volume of the preparation is then brought to the final batch volume of 200 mL.
  • the preparation is transferred to a high pressure homogeniser (Rannie A P V, type 7.30 VH, Rannie A S, Denmark) and homogenised at 500-800 bar for 5 cycles. Aliquots of the thus obtained composition of the invention are removed from the collecting vessel and transferred to glass vials.
  • a high pressure homogeniser Rannie A P V, type 7.30 VH, Rannie A S, Denmark
  • Example 4 the particle size reduction method is compared with high speed homogenisation (Ultra Turrax® T25 homogeniser (Jankel & kuhnke, Germany), as described in Example 1.
  • the composition described in this example has been used in both homogenisation methods.
  • Particle size distribution was determined by dynamic light scattering (Zetasizer 4, Malvern Instruments, UK) at an angle of 90° and at room temperature, using a ZET5104 sizing cell and auto:CONTIN analysis mode.
  • Cetirizine dinitrate 11.2 mg Phospholipid (soybean; Lipoid S75; Lipoid GrnbH, 70.0 mg Germany) Disodium phosphate dihydrate; Na 2 HPO 4 .2H 2 O 10.7 mg Potassium dihydrogen phosphate; KH 2 PO 4 5.5 mg 1 M HCl and/or 1 M NaOH To pH 7.0 Water for injection To 1 mL
  • Cetirizin dinitrate 11.1 mg Phospholipid (dioleoylphosphatidylglycerol; DOPG, 35.0 mg Avanti Polar Lipids, AL, USA) Disodium phosphate dihydrate; Na 2 HPO 4 .2H 2 O 10.7 mg Potassium dihydrogen phosphate; KH 2 PO 4 5.5 mg 1 M HCl and/or 1 M sodium hydroxide To pH 7.0 Water for injection To 1 mL
  • Nasal irritation test in a dog model Cetirizine dinitrate (5.6, 11.1 and 22.2 mg/mL, respectively, in the composition of EXAMPLES 1-3; not homogenised) was administered twice daily for 14 days to four male beagle dogs per group (5-6 months old, weighing 10.1-14.2 kg). Clinical signs and body weights were monitored throughout the study. A necropsy was performed, and the nasal cavity was collected and processed (fixated, decalcified and stained with haematoxylin and eosin). Four sections from the nasal cavity were evaluated microscopically, covering squamous, ciliated respiratory, and olfactory epithelium. No treatment-related clinical signs were observed during the administration period. The mean body weight gain over the administration period was unremarkable. The macroscopic and microscopic examination of the nasal cavity and the nasal mucosa preparations did not reveal any signs of mucosal irritation or other change.
  • Ocular irritation test in a rabbit model The potential irritating properties of the phospholipid composition of the invention (EXAMPLE 1-3) was also assessed in an eye irritation test in three white (albino), female New Zealand rabbits per treatment weighing between 2.8 to 3.4 kg. The concentrations investigated were 5.6, 11.1 and 22.2 mg/mL in the composition of EXAMPLE 1. 0.1 mL of the composition was placed in the left eye of each rabbit. The right eye served as untreated control. The eyes were examined prior to treatment and at 1, 24, 48, and 72 h after treatment. The ocular reaction to treatment was graded according to a subjective numerical scoring system.
  • Nasal irritation test A single dose (110 ⁇ L in each nostril) of cetirizine dinitrate (11.1 mg/mL) was administered to five healthy volunteers at four sessions in one of four formulations (I-IV) in each session.
  • Formulations I, II, and III are formulations of the invention whereas reference formulation IV is not a formulation of the invention.
  • the test was performed to investigate the reduction of irritation by liposome formulation as compared to plain buffer solution. Also the influence of particle size and the ratio phospholipid to cetirizine was studied.
  • Nasal symptom score were assessed at 1, 10, 30 minutes post administration.
  • the nasal symptom score included the following variables: nasal congestion, rhinorrhea, itching/sneezing, burning/pain, and taste. These symptoms were qualified by the subjects according to a no—mild—moderate—severe symptom scale (0-3). The results are reported as total score, adding all five subjects scores (maximum score of 15).
  • Nasal irritation test A single dose (110 ⁇ L in each nostril) of cetirizine dinitrate (11.1 mg/mL) was administered to four healthy volunteers at four sessions in one of four formulations (I-IV) in each session. The test was performed to investigate the irritative properties of formulations with different membrane lipids of natural and synthetic origin.
  • Nasal symptom score were assessed at 1, 10, 30 minutes post administration.
  • the nasal symptom score included the following variables: nasal congestion, rhinorrhea, itching/sneezing, burning/pain, and taste. These symptoms were qualified by the subjects according to a no—mild—moderate—severe symptom scale (0-3). The results are reported as total score, adding all four subjects scores (maximum score of 12).

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US10/842,433 2004-05-11 2004-05-11 Method and composition for treating rhinitis Abandoned US20050255154A1 (en)

Priority Applications (28)

Application Number Priority Date Filing Date Title
US10/842,433 US20050255154A1 (en) 2004-05-11 2004-05-11 Method and composition for treating rhinitis
EP05742190A EP1771155B1 (en) 2004-05-11 2005-05-06 Method and composition for treating rhinitis
PL05742190T PL1771155T3 (pl) 2004-05-11 2005-05-06 Sposób i kompozycja do leczenia nieżytu nosa
SI200531529T SI1771155T1 (sl) 2004-05-11 2005-05-06 Postopek in sestavek za zdravljenje rinitisa
MXPA06013121A MXPA06013121A (es) 2004-05-11 2005-05-06 Metodo y composicion para el tratamiento de rinitis.
AU2005239866A AU2005239866B2 (en) 2004-05-11 2005-05-06 Method and composition for treating rhinitis
BRPI0510778A BRPI0510778B8 (pt) 2004-05-11 2005-05-06 composição farmacêutica, processo para preparação da :mesma, e, uso de uma composição
JP2007512327A JP4976283B2 (ja) 2004-05-11 2005-05-06 鼻炎の治療方法及び組成物
MEP-2012-77A ME01436B (me) 2004-05-11 2005-05-06 Postupak i kompozicija za lečenje rinitisa
HK07106149.0A HK1098960B (en) 2004-05-11 2005-05-06 Method and composition for treating rhinitis
DK05742190.1T DK1771155T3 (da) 2004-05-11 2005-05-06 Fremgangsmåde og sammensætning til behandling af rhinitis
US10/571,330 US20070026058A1 (en) 2004-05-11 2005-05-06 Method and composition for treating rhinitis
NZ550412A NZ550412A (en) 2004-05-11 2005-05-06 Method and composition for treating rhinitis
RS20120246A RS52311B (sr) 2004-05-11 2005-05-06 Postupak i kompozicija za lečenje rinitisa
ZA200608407A ZA200608407B (en) 2004-05-11 2005-05-06 Method and composition for treating rhinitis
CN201310132640.3A CN103271910B (zh) 2004-05-11 2005-05-06 治疗鼻炎的方法和组合物
HRP20120484TT HRP20120484T1 (hr) 2004-05-11 2005-05-06 Postupak i kompozicija za liječenje rinitisa
AT05742190T ATE550015T1 (de) 2004-05-11 2005-05-06 Verfahren und zusammensetzung zur behandlung von rhinitis
ES05742190T ES2395130T3 (es) 2004-05-11 2005-05-06 Método y composición para el tratamiento de rinitis
PT05742190T PT1771155E (pt) 2004-05-11 2005-05-06 Método e composição para o tratamento da rinite
CA2536728A CA2536728C (en) 2004-05-11 2005-05-06 Method and composition for treating rhinitis
CNA2005800153171A CN1984643A (zh) 2004-05-11 2005-05-06 治疗鼻炎的方法和组合物
PCT/GB2005/001758 WO2005107711A2 (en) 2004-05-11 2005-05-06 Method and composition for treating rhinitis
EA200602092A EA014752B1 (ru) 2004-05-11 2005-05-06 Способ и композиция для лечения ринита
NO20064521A NO335840B1 (no) 2004-05-11 2006-10-05 Blanding for behandling av rhinitt og anvendelse av og framgangsmåte for framstilling av samme
IL179012A IL179012A (en) 2004-05-11 2006-11-02 A drug containing cetirizine for the treatment of nasal inflammation, a process for its preparation and use
US13/444,381 US9980959B2 (en) 2004-05-11 2012-04-11 Method and composition for treating rhinitis
CY20121100541T CY1112981T1 (el) 2004-05-11 2012-06-13 Μεθοδος και συνθεση για την αγωγη της ρινιτιδας

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US10/571,330 Continuation-In-Part US20070026058A1 (en) 2004-05-11 2005-05-06 Method and composition for treating rhinitis
US11/571,330 Continuation-In-Part US7385214B2 (en) 2004-07-06 2005-07-04 System and method for correcting systematic error of, and calibrating for, tilt angle of surface topology sensor head having plurality of distance sensors

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AT (1) ATE550015T1 (enExample)
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CY (1) CY1112981T1 (enExample)
DK (1) DK1771155T3 (enExample)
EA (1) EA014752B1 (enExample)
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HR (1) HRP20120484T1 (enExample)
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ME (1) ME01436B (enExample)
MX (1) MXPA06013121A (enExample)
NO (1) NO335840B1 (enExample)
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PL (1) PL1771155T3 (enExample)
PT (1) PT1771155E (enExample)
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WO2005107711A3 (en) 2006-03-16
US20180104238A9 (en) 2018-04-19
EP1771155A2 (en) 2007-04-11
RS52311B (sr) 2012-12-31
HK1098960A1 (en) 2007-08-03
PT1771155E (pt) 2012-05-15
US20070026058A1 (en) 2007-02-01
ME01436B (me) 2012-12-31
JP4976283B2 (ja) 2012-07-18
US9980959B2 (en) 2018-05-29
IL179012A (en) 2014-11-30
ATE550015T1 (de) 2012-04-15
CN103271910A (zh) 2013-09-04
SI1771155T1 (sl) 2012-09-28
CY1112981T1 (el) 2016-04-13
BRPI0510778B8 (pt) 2021-05-25
NZ550412A (en) 2010-08-27
PL1771155T3 (pl) 2012-08-31
AU2005239866A1 (en) 2005-11-17
NO20064521L (no) 2007-02-06
EA200602092A1 (ru) 2007-06-29
MXPA06013121A (es) 2007-05-16
WO2005107711A2 (en) 2005-11-17
CN1984643A (zh) 2007-06-20
ES2395130T3 (es) 2013-02-08
HRP20120484T1 (hr) 2012-07-31
CA2536728A1 (en) 2005-11-17
ZA200608407B (en) 2007-12-27
AU2005239866B2 (en) 2010-03-04
US20130039969A1 (en) 2013-02-14
JP2007537220A (ja) 2007-12-20
BRPI0510778B1 (pt) 2020-03-10
IL179012A0 (en) 2007-03-08
EP1771155B1 (en) 2012-03-21
CA2536728C (en) 2011-02-01
CN103271910B (zh) 2018-11-06
EA014752B1 (ru) 2011-02-28
NO335840B1 (no) 2015-03-02
DK1771155T3 (da) 2012-07-09

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