U.S. patent application number 13/444381 was filed with the patent office on 2018-04-19 for method and composition for treating rhinitis.
This patent application is currently assigned to Biolipox AB. The applicant listed for this patent is Anders Carlsson, Lena Pereswetoff-Morath. Invention is credited to Anders Carlsson, Lena Pereswetoff-Morath.
Application Number | 20180104238 13/444381 |
Document ID | / |
Family ID | 34968224 |
Filed Date | 2018-04-19 |
United States Patent
Application |
20180104238 |
Kind Code |
A9 |
Pereswetoff-Morath; Lena ;
et al. |
April 19, 2018 |
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.
Inventors: |
Pereswetoff-Morath; Lena;
(Stockholm, SE) ; Carlsson; Anders; (Stockholm,
SE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Pereswetoff-Morath; Lena
Carlsson; Anders |
Stockholm
Stockholm |
|
SE
SE |
|
|
Assignee: |
Biolipox AB
Stockholm
SE
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20130039969 A1 |
February 14, 2013 |
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|
Family ID: |
34968224 |
Appl. No.: |
13/444381 |
Filed: |
April 11, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10571330 |
May 4, 2006 |
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PCT/GB2005/001758 |
May 6, 2005 |
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13444381 |
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10842433 |
May 11, 2004 |
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10571330 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 37/08 20180101;
Y10S 977/907 20130101; A61K 9/127 20130101; A61P 43/00 20180101;
A61K 9/0048 20130101; Y10S 977/906 20130101; A61P 11/02 20180101;
A61K 31/495 20130101; A61P 37/00 20180101; A61K 9/0043
20130101 |
International
Class: |
A61K 31/495 20060101
A61K031/495; A61K 9/127 20060101 A61K009/127; A61K 9/00 20060101
A61K009/00 |
Claims
1. A pharmaceutical composition for the treatment of rhinitis by
nasal or ocular administration comprising zwitterionic cetirizine,
a polar lipid liposome and a pharmaceutically-acceptable aqueous
carrier, wherein the concentration of zwitterionic cetirizine is
substantially similar in the aqueous carrier both within and
surrounding the liposomes, and the diameter of the liposomes is
less than about 200 nm.
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,
##STR00003## wherein R.sub.1 and R.sub.2 independently represent a
saturated or unsaturated, branched or straight chain alkyl group
having between 7 and 23 carbon atoms and R.sub.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.sub.2--CH(OH)--CH.sub.2OH,
--CH.sub.2--CH.sub.2--N(CH.sub.3).sub.3--CH.sub.2--CH.sub.2--NH.sub.2,
--H or --CH.sub.2--CH(NH.sub.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 phospholipid
comprises Lipoid S75, Lipoid S100 and/or Lipoid S75-3N.
19. A composition as claimed in claim 13, wherein the phospholipid
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, ##STR00004## wherein R.sub.1 and R.sub.2
independently represent a saturated or unsaturated, branched or
straight chain alkyl group having between 7 and 23 carbon atoms and
R.sub.3 represents an amide or ester bonding group.
24. A composition as claimed in claim 20, wherein the glycolipid
comprises a glycosphingolipid.
25. A composition as claimed in claim 24, 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.
26. A composition as claimed in claim 25, wherein the
glycosphingolipid comprises sphingomyelin or a product derived
therefrom.
27. A composition as claimed in claim 20, wherein the glycolipid
comprises a glycophosphatidylinositol.
28. 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.
29. 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.
30. A composition as claimed in claim 29, wherein the amount is
from about 20 mg/mL to about 40 mg/mL.
31. A composition as claimed in claim 1, which further comprises an
antioxidant.
32. A composition as claimed in claim 31, wherein the antioxidant
is .alpha.-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.
33. A composition as claimed in claim 1, which further comprises a
chelating agent.
34. A composition as claimed in claim 33, wherein the chelating
agent is ethylenediaminetetraacetic acid, ethylenediaminetriacetric
acid and/or diethylenetriaminepentaacetic acid.
35. A composition as claimed in claim 1, which further comprises a
preservative.
36. A composition as claimed in claim 35, wherein the preservative
is benzalkonium chloride, benzoic acid, butylated hydroxyanisole,
butylparaben, chlorbutanol, ethylparaben, methylparaben,
propylparaben, phenoxyethanol and/or phenylethyl alcohol.
37. A composition as claimed in claim 1, which further comprises a
viscosity-increasing agent.
38. A composition as claimed in claim 37, wherein the
viscosity-increasing agent is polyethyleneglycol, crosslinked
polyvinylpyrrolidone and/or hydroxypropylmethyl cellulose.
39. A composition as claimed in claim 1, wherein the diameter is
between about 40 nm and about 100 nm.
40. 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.
41. A process as claimed in claim 40, wherein, prior to the
homogenisation step, the pH is adjusted to the desired value by
adding an acid or a base.
42. A process as claimed in claim 41, wherein, prior to the
homogenisation step, water, saline or buffer solution is added to
the preparation to obtain a desired final batch volume.
43. A process as claimed in claim 42, wherein the addition of
water, saline or buffer takes place after the pH adjusting
step.
44. A process as claimed in claim 40, wherein at least one of the
solutions/liquids is/are purged with nitrogen and/or argon.
45. A process as claimed in claim 40, 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.
46. A process as claimed in claim 40, wherein, if a mixture of
polar lipids is used, it is pre-treated with organic solvent.
47. A process as claimed in claim 40, wherein the homogenisation
step (b) comprises vigorous mechanical mixing, high speed
homogenisation, shaking, vortexing and/or rolling.
48. A process as claimed in claim 40, which comprises an additional
liposome size-reduction step.
49. A process as claimed in claim 48, wherein the size-reduction
step comprises extrusion through a membrane filter.
50. A process as claimed in claim 40, wherein the homogenisation
step and/or size-reduction step comprises high-pressure
homogenisation.
51. A pharmaceutical composition obtained 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 to obtain a preparation; and (b) homogenising the
preparation to obtain the pharmaceutical composition; wherein the
composition comprises zwitterionic cetirizine, a polar liposome and
a pharmaceutically acceptable aqueous carrier; the concentration of
zwitterionic cetirizine is substantially similar in the aqueous
carrier both within and surrounding the liposomes, and the diameter
of the liposomes is less than about 200 nm.
52. A composition as claimed in claim 51, wherein, in the process,
prior to the homogenisation step, the pH is adjusted to the desired
value by adding an acid or a base.
53. A composition as claimed in claim 52, 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.
54. A composition as claimed in claim 53, wherein the addition of
water, saline or buffer takes place after the pH adjusting
step.
55. A composition as claimed in claim 51, wherein, in the process,
at least one of the solutions/lipids is/are purged with nitrogen
and/or argon.
56. A composition as claimed in claim 51, 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.
57. A composition as claimed in claim 51, wherein, in the process,
if a mixture of polar lipids is used, it is pre-treated with
organic solvent.
58. A composition as claimed in claim 51, wherein, in the process,
the homogenisation step (b) comprises vigorous mechanical mixing,
high speed homogenisation, shaking, vortexing and/or rolling.
59. A composition as claimed in claim 51, which comprises, in the
process, an additional liposome size-reduction step.
60. A composition as claimed in claim 59, wherein the
size-reduction step comprises extrusion through a membrane
filler.
61. A composition as claimed in claim 51, wherein, in the process,
the homogenisation step and/or size-reduction step comprises
high-pressure homogenisation.
62. 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.
63. A method as claimed in claim 62, wherein the administration is
intranasal.
64. A method as claimed in claim 62, wherein the administration is
intraocular.
65. A method as claimed in claim 62, wherein the administration is
to the lung.
66. The composition of claim 8 wherein the salt is a hydrochloride
salt.
67. The composition of claim 66 wherein the salt is cetirizine
dihydrochloride.
68. A composition as claimed in claim 1 wherein the concentration
of cetirizine varies by about .+-.50% when comparing concentrations
inside and outside of the liposomal structures.
69. A composition as claimed in claim 1 wherein the concentration
of cetirizine varies by about .+-.40% when comparing concentrations
inside and outside of the liposomal structures.
70. A composition as claimed in claim 1 wherein the concentration
of cetirizine varies by about .+-.30% when comparing concentrations
inside and outside of the liposomal structures.
71. A composition as claimed in claim 1 wherein the concentration
of cetirizine varies by about .+-.20% when comparing concentrations
inside and outside of the liposomal structures.
72. A composition as claimed in claim 1 wherein the concentration
of cetirizine varies by about .+-.10% when comparing concentrations
inside and outside of the liposomal structures.
Description
FIELD OF THE INVENTION
[0001] This invention relates to a method for treating rhinitis,
and to a corresponding pharmaceutical composition.
BACKGROUND AND PRIOR ART
[0002] Allergic and non-allergic rhinitis are common disorders
affecting about 30% of the population. Rhinitis has a considerable
impact on quality of life. In fact, rhinitis is regarded to affect
the quality of life more so than, e.g., asthma.
[0003] Hay fever and perennial allergic rhinitis are characterised
by sneezing, rhinorrhea, nasal congestion, pruritus, conjunctivitis
and pharyngitis. In perennial rhinitis, chronic nasal obstruction
is often prominent and may extend to eustachian tube
obstruction.
[0004] Oral or local antihistamines are first line treatments, and
nasal steroids second line treatments for rhinitis. For most
patients, 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.
[0005] Cetirizine dihydrochloride,
[2-{4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl}ethoxy]acetic
acid is an orally and locally active, potent, long acting
peripheral histamine H.sub.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.
[0006] The main clinical affects of antihistamines include reduced
sneezing and rbinorrhea. However, reduction of nasal blockage
appears to be less responsive.
[0007] Local administration of antihistamines (such as azelastine
and levocabastine) has advantages, including rapid onset of action
and fewer side effects. At present, however, cetirizine
dihydrochloride is not an approved medicine for local
administration, although it has been administered in that manner in
clinical trials.
[0008] In one trial (Francillon C, Pecoud A. Effect of nasal spray
of cetirizine in a nasal provocation test with allergen. J Allergy
Clin. Immunol. 1993:91, Suppl. 2:258 (abstract)), cetirizine nasal
spray was found to reduce symptoms and increase nasal peak flow
after an allergen challenge. Further, in exercise-induced asthma, a
good protective effect was seen when 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 1991 April; 46 (4), 242-4).
[0009] Some effect was seen on symptoms when cetirizine (presumably
as the dihydrochloride) was given as a nasal spray in patients with
perennial allergic rhinitis. 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 1994 September; 49 (8),
668-72). The most common side effects were related to nasal events,
although no difference in incidence between the placebo and the
cetirizine-treated groups was seen. However, the authors of this
article speculated therein that local irritation had an adverse
effect on treatment efficacy.
[0010] Indeed, due to the irritation of the nasal mucosa by
cetirizine, it has been found to be necessary to decrease its
immediate exposure in nasal administration. In European Patent No.
EP 605 203 B1, it has been reported that this can be achieved by
providing cetirizine in form of a composition containing
cyclodextrin.
[0011] Liposomes (also known as lipid vesicles) are colloidal
particles that are prepared from polar lipid molecules derived
either from natural sources or chemical synthesis. Such spherical,
closed structures composed of curved lipid bilayers, are typically
used to entrap drugs, which are often cytotoxic, in order to reduce
toxicity and/or increase efficacy. Liposome-entrapped drug
preparations are often provided in a dry (e.g. freeze-dried) form,
which is subsequently reconstituted with an aqueous solution
immediately prior to administration. This is done in order to
minimise the possibility of leakage of e.g. cytotoxic drug into
aqueous solution and thereby reducing the entrapping effect of the
liposome.
[0012] Liposomes have also been employed to encapsulate various
drug compounds for delivery via the nasal route, in order to
improve bioavailability or as an adjuvant. Drugs that may be
mentioned include tetanus toxoid vaccine, insulin, desmopressin and
diphenhydramine hydrochloride (see Turker et al, Review Article:
Nasal Route and Drug Delivery Systems, Pharm, World Sci., 2004; 26,
137-142 and the references cited therein), as well as
ciprofloxacin, CM3 and salbutamol (see Desai et al, A Facile Method
of Delivery of Liposomes by Nebulization, J. Control. Release,
2002; 84, 69-78).
[0013] Liposome-entrapped cetirizine has also been administered
topically to evaluate peripheral antihistaminic activity and
systemic absorption in a rabbit model (Elzainy et al, Cetirizine
from Topical Phosphatidylcholine-Hydrogenated Liposomes, The AAPS
Journal, 2004; 6, 1-7. See also Drug Development and Industrial
Pharmacy, 2005; 31, 281-291).
[0014] The lipophilic behaviour of the cationic (wherein the anion
is chloride), zwitterionic, and anionic forms of cetirizine in
buffered aqueous phosphatidylcholine liposome systems containing
from about 1 to 33.5 mg/mL of phospholipid has also been studied
(Plemper van Balen G at al., Lipophilicity behaviour of the
zwitterionic antihistamine cetirizine in phosphatidylcholine
liposomes/water systems, Pharm. Res. 2001; 18, 694-701). The aim
with the study, in which separate solutions of PBS-diluted egg
phosphatidylcholine liposomes were poured into separate
compartments of dialysis cells, was to gain insight into the
mechanism of interaction of the various electrical species of
cetirizine and other drugs with liposomal membranes. The
zwitterionic form of cetirizine, which dominates in the pH range of
from about pH 4 to about pH 7, and even from about pH 3 to about pH
8, was considered by the authors of this article to be prevented
from entry into the liposomal membrane by rendering the formation
of lipophilic folded conformers of cetirizine more difficult. In
this respect, cetirizine was not entrapped in liposomal membranes
for delivery of drug to patients.
[0015] To the applicant's knowledge there is no prior disclosure or
suggestion in the art of a homogeneous pharmaceutical composition
comprising zwitterionic cetirizine, a polar lipid liposome and a
pharmaceutical acceptable aqueous carrier.
[0016] Surprisingly, we have found that the irritation normally
associated with (e.g. nasal) administration of cetirizine may be
reduced by way of use of just such a composition.
[0017] According to the invention, there is provided pharmaceutical
compositions suitable 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, which compositions are referred to hereinafter as
"the compositions of the invention".
[0018] The skilled person will appreciate that zwitterionic
cetirizine is employed in compositions of the invention in a
pharmacologically-effective amount (vide infra). The term
"pharmacologically-effective amount" refers to an amount of
cetirizine, which is capable of conferring the desired therapeutic
effect on a treated patient, whether administered alone or in
combination with another active ingredient. Such an effect may be
objective (i.e. measurable by some test or marker) or subjective
(i.e. the subject gives an indication of, or feels, an effect).
[0019] By "pharmaceutical compositions" we include compositions
that are suitable for use in direct administration to mammals, and
especially humans. In this respect, the term is intended to
encompass formulations that include only components that are
regarded in the art as suitable for administration to mammalian,
and especially human, patients. In the context of the present
invention, the term may also mean that the compositions of the
invention are in a form of a liquid that is ready-to-use, directly
from the shelf, and not a formulation in which drug is encapsulated
inside liposomes requiring reconstitution shortly prior to
administration in order to avoid leakage of drug from liposomes
into an aqueous carrier.
[0020] The compositions of the invention are preferably
homogeneous. By "homogenous" we include not only that the
compositions of the invention comprise liposomes dispersed evenly
throughout the aqueous carrier, but further that the active
ingredient is distributed throughout the whole composition in a
substantially similar concentration in the relevant aqueous medium,
whether that medium is located inside or outside of the liposomal
structures. By "substantially similar", we include that the
concentration may vary by about .+-.50%, such as about .+-.40%,
preferably about .+-.30%, more preferably about .+-.20% and
particularly about .+-.10% (when comparing concentrations inside
and outside of the liposomal structures) at room temperature and
atmospheric pressure. Drug concentration profiles may be measured
by standard techniques known to the skilled person, such as
.sup.31P-NMR. For example, a standard in situ probing technique, or
a technique that involves separation of the liposomal fraction from
the free aqueous carrier and measurement of the
amount/concentration of drug associated with each fraction may be
employed. Separation may be accomplished by centrifugation,
dialysis, ultrafiltration, or gel filtration.
[0021] It is preferred that the compositions of the invention
further include a pharmaceutically-acceptable buffer capable of
providing a pH of from about pH 4 (e.g. 4.0) to about pH 8 (e.g.
8.0), preferably from about pH 5 (e.g. 5.0) to about pH 7 (e.g.
7.0). Appropriate buffers include those that will not interfere
with the formation of liposomes, such as a phosphate (e.g. disodium
phosphate, dipotassium phosphate, sodium dihydrogen phosphate,
potassium dihydrogen phosphate or phosphoric acid plus base),
citrate (e.g. sodium citrate or citric acid plus base), or acetate
buffer (e.g. sodium acetate or acetic acid plus base), which is
capable of maintaining a pH within the above-specified ranges.
Buffers may be employed in an amount that is suitable to provide
for the above-mentioned effects and such will be appreciated by the
skilled person without recourse to inventive input. Appropriate
quantities are for example in the range of about 1 mg/mL to about
30 mg/mL.
[0022] Any pharmaceutically-acceptable salt of cetirizine as well
as the free base form thereof may be used in the manufacture of
compositions of the invention. Preferred salts include chloride
salts, hydrochloride (e.g. dihydrochloride) salts and, more
particularly, nitrate salts of cetirizine, most preferably
cetirizine dinitrate.
[0023] The amount of cetirizine or salt thereof that may be
employed in preparation of compositions of the invention may be
determined by the physician, or the skilled person, in relation to
what will be most suitable for an individual patient. This is
likely to vary with the severity of the condition that is to be
treated, as well as the species, age, weight, sex, renal function,
hepatic function and response of the particular patient to be
treated. It is preferred however that the compositions of the
invention comprise cetirizine or a salt thereof in an amount of
from about 1 mg/mL to about 30 (e.g. about 25, such as about 23)
mg/mL calculated on the zwitterionic form, preferably in an amount
of from about 5.5 mg/mL to about 22 mg/mL. A further preferred
range is between about 6 mg/mL and about 15 mg/mL, such as about 8
mg/mL to about 12 mg/mL.
[0024] In such a case, the total amount of active ingredient that
may be present may be sufficient to provide a daily dose of drug
per unit dosage that is in the range about 4 mg to about 20 mg,
such as about 5 mg to about 15 mg, more preferably about 7 mg to
about 12 mg and most preferably about 8 mg to about 10 mg. The
skilled person will appreciate that compositions of the invention
may be dosed once or more times daily in one or more
administrations in order to provide the aforementioned daily
dose.
[0025] The above-mentioned dosages are exemplary of the average
case; there can, of course, be individual instances where higher or
lower dosage ranges are merited, and such are within the scope of
this invention.
[0026] The term "liposome" will be well understood by those skilled
in the art to include a structure consisting of one or more
concentric spheres of polar lipid bilayers separated by water or
aqueous buffer compartments.
[0027] Liposomes may 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, the relevant disclosures in which document are hereby
incorporated by reference.
[0028] The term "polar lipid" will be well understood by the
skilled person to include any lipid with a polar head-group and two
fatty acid residues, which is capable of forming liposomes.
[0029] Polar lipids, such as those described hereinafter, may be of
a natural and/or a synthetic/semi-synthetic origin. Mixtures of
natural and synthetic/semi-synthetic polar lipids may also be
employed in compositions of the invention.
[0030] Polar lipids that may be employed in compositions of the
invention may thus be based on, for example, phospholipids, and in
particular phosphatidylcholine (PC), phosphatidylglycerol (PG),
phosphatidylinositol (PI), phosphatidic acid (PA),
phosphatidylserine (PS), or mixtures thereof.
[0031] Phospholipids that may be employed in compositions of the
invention comprise polar and non-polar groups linked to a backbone
entity carrying hydroxyl groups, such as glycerol.
[0032] Phospholipids may also be represented by the general formula
I
##STR00001##
wherein R.sub.1 and R.sub.2 independently represent a saturated or
unsaturated (e.g. alkenyl), branched or straight chain alkyl group
having between 7 and 23 carbon atoms, preferably between 11 and 19
carbon atoms; and R.sub.3 represents an amide or ester bonding
group, such as [0033] --CH.sub.2--CH(OH)--CH.sub.2OH
(phosphatidylglycerol), [0034]
--CH.sub.2--CH.sub.2--N(CH.sub.3).sub.3 (phosphatidylcholine),
[0035] --CH.sub.2--CH.sub.2--NH.sub.2 (phosphatidylethanolamine),
[0036] --H (phosphatidic acid), or [0037]
--CH.sub.2--CH(NH.sub.2)--COOH (phosphatidylserine).
[0038] The phospholipid may be of natural origin. Natural
phospholipids are preferably membrane lipids derived from various
sources of both vegetable (e.g. rapeseed, sunflower, etc., or,
preferably, soybean) and animal origin (e.g. egg yolk, bovine milk,
etc.). Phospholipids from soybean, a major source of vegetable
phospholipids, are normally obtained from the by-products (i.e.
lecithins) in the refining of crude soybean oil by the degumming
process. The lecithins are further processed and purified using
other physical unit operations, such as fractionation and/or
chromatography. Other phospholipids may be obtained, for example,
by pressing various suitable seeds and grains, followed by solvent
extraction and then further processing as described above,
Phospholipids of natural origin that may be mentioned include for
example those that are available under the tradenames Lipoid S75,
Lipoid S100 and Lipoid S75-3N (Lipoid GmbH, Germany), which are all
blends of several different phospholipids that are found in
soybean.
[0039] The phospholipid may alternatively be of synthetic or
semi-synthetic origin (i.e. prepared by chemical synthesis). For
example, a multi-step chemical synthetic approach may be used in
order to obtain the key phospholipid intermediates,
1,2-diacylglycerol, from (S)-1,2-isopropylideneglycerol, the latter
providing the glycerol backbone that is characteristic of
phospholipids. 1,2-Diacetylated phospholipids may then be obtained
when the corresponding polar head group is attached via chemical
synthesis to the 1,2-diacylglycerol intermediate. Generally,
however, the origin of glycerol and the fatty acids used in the
various steps may be of both natural and synthetic origin.
Synthetic and/or semi-synthetic phospholipids that may be mentioned
include dilaurylphosphatidylcholine (DLPC),
dimyristolphosphatidylcholine (DMPC),
dipalmitoylphosphatidylcholine (DPPC), dilaurylphosphatidylglycerol
(DLPG), dimyristolphosphatidylglycerol (DMPG),
dioleoylphosphatidylcholine (DOPC) and dioleoylphosphatidylglycerol
(DOPG).
[0040] The polar lipid may alternatively comprise or, more
preferably, consist of a glycolipid. In the context of the present
invention, the term "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).
[0041] A glycolipid may be a glycoglycerolipid. In the context of
the present invention, the term "glycoglycerolipid" designates a
glycolipid containing one or more glycerol residues. According to a
preferred aspect of the invention, the glycoglycerolipid comprises,
or consists of, galactoglycerolipid, more preferably a
digalactosyldiacylglycerol of the general formula II,
##STR00002##
wherein R.sub.1 and R.sub.2 are as hereinbefore defined.
[0042] The glycolipid may alternatively be a glycosphingolipid. In
the context of the present invention, the term "glycosphingolipid"
designates a lipid containing at least one monosaccharide residue
and either a sphingoid or a ceramide. The term may thus comprise
neutral glycophingolipids, such as mono- and
oligoglycosylsphingoids as well as oligo- and, more preferably,
monoglycosylceramides. The teen additionally comprises acidic
glycosphingolipids such as sialoglycosphingolipids,
uronoglycosphingolipids, sulfoglycosphingolipids,
phosphoglycosphingolipids, and phosphonoglycosphingolipids. The
glycosphingolipid can be ceramide, monohexosylceramide,
dihexosylceramide, sphingomyelin, lysosphingomyelin, sphingosine,
or a mixture thereof. Preferably the glycosphingolipid is
sphingomyelin or products derived therefrom. The sphingomyelin
content is preferably established by chromatographic methods,
Sphingomyelin may be extracted from milk, preferably bovine milk,
brain, egg yolk or erythrocytes from animal blood, preferably
sheep. For the avoidance of doubt, synthetic and semi-synthetic
sphingolipids are comprised by the invention.
[0043] The glycolipid may alternatively be a
glycophosphatidylinositol. In the context of the present invention,
the term "glycophosphatidylinositol" designates a glycolipid
containing saccharides glycosidically linked to the inositol moiety
of phosphatidylinositols.
[0044] Preferred glycolipids include digalactosyldiacylglycerol
(DGDG).
[0045] Preferred polar lipids (such as phospholipids) are those
that swell to a measurable degree in water and/or those which are
capable of spontaneous liposome formation.
[0046] If the polar (e.g. phospho-) lipid does not swell
spontaneously in water, the skilled person will appreciate that it
is nevertheless possible to obtain liposomes by adding a more
polar, swellable (e.g. phospho-) lipid, such as an anionic (e.g.
phospho-) lipid (e.g. phosphatidylglycerol).
[0047] Liposome formation may be performed at above about 0.degree.
C. (e.g. room temperature) if the phase transition temperature of
the acyl chains (chain melting; gel-to-liquid crystals) is below
the freezing point of water.
[0048] Whichever polar lipid substance (or combination thereof) is
used, suitable total amounts/concentrations of lipid(s) that may be
employed in preparation of a composition of the invention are in
the range of about 10 mg/mL to about 120 mg/mL. Compositions of the
invention that may be mentioned include those in which, when the
polar lipid comprises phospholipid (whether in combination with
another lipid or otherwise), the amount of phospholipid(s) in the
composition is from about 10 (e.g. about 17, such as about 20)
mg/mL to about 120 mg/mL, more preferably from about 25 (e.g. about
35) mg to about 100 (e.g., about 70, such about 50, e.g. about 40)
mg/mL.
[0049] Compositions of the invention may also comprise an
antioxidant, such as .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 or vitamin E.
[0050] According to the invention a chelating agent may be used to
reduce the metal ion catalysed oxidation of phospholipid and/or
cetirizine. Examples of 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, any unsaturated fatty acid residues
that may be present therein, from oxidation.
[0051] The composition of the invention can comprise one or more
preservatives. Examples of common preservatives for liquid
pharmaceutical compositions are benzalkonium chloride, benzoic
acid, butylated hydroxyanisole, butylparaben, chlorbutanol,
ethylparaben, methylparaben, propylparaben, phenoxyethanol or
phenylethyl alcohol.
[0052] In order to retain the composition of the invention at its
application site it may also comprise viscosity-increasing agent
such as, for instance, hydrophilic polymers like
polyethyleneglycol, or crosslinked polyvinylpyrrolidone and/or
cellulose derivatives such as hydroxypropylmethyl cellulose.
Viscosity increasing agents may also function as protective
colloids to physically stabilise the composition of the invention
prior to administration.
[0053] Compositions of the invention may also comprise flavourings
(e.g. lemon, menthol or peppermint powder) and/or sweeteners (e.g.
neohesperidin).
[0054] Compositions of the invention may also comprise
tonicity-modifying agents, such as sodium chloride; potassium
chloride, glycerol, glucose, dextrose, sucrose, mannitol, etc.
[0055] Optional additives, including buffering agents,
preservatives, viscosity-increasing agents, antioxidants,
tonicity-modifying agents and chelating agents should be selected,
in terms of their identity and the amounts employed, 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 well within the understanding of the
skilled person. Suitable amounts of such ingredients are however in
the range about 0.01 mg/mL to about 10 mg/mL.
[0056] There is also provided a process for preparing compositions
of the invention. We have surprisingly found that liposomes may be
prepared by direct swelling of the polar lipids in an aqueous
medium without the addition of any other excipients such as charged
lipids and/or surfactants etc., which are normally required.
[0057] According to a further aspect of the invention, there is
provided a process for preparing a composition of the invention,
which process comprises:
(a) providing a polar lipid or a mixture of polar lipids that
is/are swellable in aqueous media; (b) providing an aqueous
solution of cetirizine; (c) adding the polar lipid or mixture to
the aqueous solution with stirring, thereby forming a cetirizine
liposome preparation; (d) optionally adjusting the pH of the
preparation to a desired value within the range of from about pH 4
(e.g. 4.0) to about pH 8 (e.g. 8.0), preferably from about pH 5
(e.g. 5.0) to about pH 7 (e.g. 7.0), by adding an acid or a base
(e.g. hydrochloric acid and/or sodium hydroxide at an appropriate
concentration (e.g. 1M)); (e) optionally adding buffer solution or,
more preferably, water or saline to the preparation to obtain a
desired final batch volume; and (f) homogenising the preparation to
obtain said pharmaceutical composition.
[0058] Solutions/liquids may be purged with nitrogen or argon at a
suitable stage in the above process, if and as appropriate.
[0059] In the context of the present invention, a lipid may be said
to be swellable in aqueous media if, when placed in contact with
such a medium, it swells to a measurable degree.
[0060] Buffers may preferably be added to the aqueous solution of
drug (and/or drug may be added to an aqueous buffer solution) prior
to the addition of lipid. This notwithstanding, the person skilled
in the art will be aware of the inherent buffering effect of
zwitterionic cetirizine.
[0061] The formation of the liposomes of the invention may be
facilitated by the spontaneous swelling of the polar lipid in water
forming a lamellar liquid crystalline phase having a maximum water
content of about 35% by weight or higher depending on the nature of
the polar lipid, Depending on the lipid or lipid mixture used and
other conditions, spontaneous formation of liposomes may be
achieved when excess water is added to this lamellar phase. If
spontaneous formation is not achieved, the formation of liposomes
may be accomplished by the mechanical dispersion step (i.e. the
homogenisation step (f) of the above process) of the lamellar
liquid-crystalline phase in excess water.
[0062] Homogenisation/dispersion methods include vigorous
mechanical mixing, for instance by means of an Ultra Turrax.RTM.
(Jankel & Kuhnke, Germany), Shaking, vortexing and rolling may
also be performed as part of the homogenisation step of the above
process.
[0063] A homogeneous size distribution of the liposomes of the
invention may be desirable and may be obtained by extrusion through
a membrane filter, such as one made of polycarbonate, with a pore
size of about 100 nm. Membrane filters may be procured from Avestin
Inc., Canada.
[0064] A reduced average liposome size and narrowed liposome size
distribution may preferably also be obtained when the liposomal
dispersion is subjected to high-pressure homogenisation with a
suitable homogeniser (Rannie APV, type 7.30 VH, Rannie AS, Denmark)
at, for example, between about 300 bar and about 1000 bar, such as
between about 400 bar and about 900 bar, e.g. about 500 to about
800 bar for between about 4 and about 8 (e.g. 7, such as 6)
cycles.
[0065] Surprisingly, we have found that the presence of cetirizine
results in a reduction of liposome size. Smaller liposomes are
generally advantageous because they are more stable physically and,
due to their higher surface area/volume ratio, are more easily
resorbed by the mucosa.
[0066] We prefer that the diameter of liposomes in compositions of
the invention is less than about 200 nm (e.g. between about 40 to
about 100 nm), as measured by, for example, laser diffraction or
dynamic light scattering, e.g. as described hereinafter.
[0067] Furthermore, the above-mentioned process for the preparation
of compositions of 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 appropriate and/or necessary to treat them with organic
solvent prior to the addition of the aqueous solvent. For example,
the lipids may be dissolved in a volatile solvent or solvent
mixture, such as chloroform or chloroform/methanol. The solution
may then be deposited on the surfaces of a round-bottomed flask as
the solvent is removed by rotary evaporation under reduced
pressure. An excess volume of aqueous buffer containing the drug
may then be added to the dry thin film of lipids, which may then be
allowed to swell to form liposomes.
[0068] The compositions of the invention are useful in the
treatment of any indication for which cetirizine is known to be
indicated, including rhinitis. The term "rhinitis" will be
understood to include any irritation and/or inflammation of the
nose, whether allergic or non-allergic, including seasonal rhinitis
(e.g. caused by outdoor agents such as pollen; hay fever) and/or
perennial rhinitis (e.g. caused by house dust mites, indoor mold
etc), as well as the symptoms thereof.
[0069] According to a further aspect of the invention, there is
provided a method for the treatment of rhinitis comprising the
(e.g. nasal) administration of a pharmacologically-effective amount
of a composition of the invention to a person suffering from or
susceptible to that disorder.
[0070] For the avoidance of doubt, by "treatment" we include the
therapeutic treatment, as well as the symptomatic treatment, the
prophylaxis, or the diagnosis, of a condition.
[0071] The compositions of the invention may be administered by way
of a nasal spray, nasal drops and/or eye drops. It is also possible
to administer compositions of the invention as a fine mist to the
lungs by nebulization. For nasal administration, any
state-of-the-art device suitable for producing sprays of aqueous
liposomal dispersions may be used.
[0072] Wherever the word "about" is employed herein in the context
of dimensions (e.g. pH values, sizes, temperatures, pressures,
etc.) and amounts (e.g. amounts, weights and/or concentrations of
individual constituents in a composition or a component of a
composition, proportions of drug inside/outside the liposomal
structures, absolute doses of active ingredient, etc.), it will be
appreciated that such variables are approximate and as such may
vary by .+-.10%, for example .+-.5% and preferably .+-.2% (e.g.
.+-.1%) from the numbers specified herein.
[0073] The compositions of the invention, and the above-mentioned
process that may be employed for their preparation, have the
advantages that are mentioned hereinbefore. In particular,
compositions of the invention may reduce the incidence of
inconvenient side-effects (and in particular irritation) that are
normally observed with e.g. nasally-administered cetirizine
formulations.
[0074] Compositions of the invention are easy to manufacture and
enable the production of liposomal-based formulations that are in a
ready-to-use form, avoiding the need for reconstitution prior to
administration.
[0075] Compositions of the invention may also have the advantage
that they may be prepared using established pharmaceutical
processing methods and employ materials that are approved for use
in foods or pharmaceuticals or of like regulatory status.
[0076] Compositions of the invention may also have the advantage
that they may be more efficacious than, be less toxic than, be
longer acting than, be more potent than, produce fewer side effects
than, be more easily absorbed than, and/or have a better
pharmacokinetic profile than, and/or have other useful
pharmacological, physical, or chemical properties over,
pharmaceutical compositions known in the prior art, whether for use
in the treatment of rhinitis or otherwise.
[0077] The invention is illustrated by way of the following
examples.
EXAMPLE 1
TABLE-US-00001 [0078] TABLE 1 Batch formula Cetirizine dinitrate*
22.2 g Phospholipid (from soybean**) 70.0 g Disodium phosphate,
dihydrate; Na.sub.2HPO.sub.4 2H.sub.2O 21.3 g Potassium
dihydrogenphosphate; KH.sub.2PO.sub.4 11.0 g 1M Hydrochloric acid
and/or 1M sodium hydroxide to pH 7.0 Water for injection to 2.0 L
*White solid, crystallized from THF/acetonitrile/water 2:1:0.28.
Obtained from commercially available cetirizine dihydrochloride via
neutralisation of the free base with nitric acid. **Lipoid S75,
Lipoid GmbH, Germany
[0079] General procedure. For weights and volumes reference is made
to Table 1 above. A buffer solution was prepared by dissolving the
buffering agents disodium phosphate dihydrate
(Na.sub.2HPO.sub.42H.sub.2O) and potassium dihydrogen phosphate
(KH.sub.2PO.sub.4) in 1600 mL water (80% of the total batch volume)
in a 2000 mL volumetric flask. The weighed amount of active agent
was added to the buffer solution and dissolved by stirring with a
magnetic stirrer, followed by addition of 100 mL of aqueous 1M
sodium hydroxide. The phospholipid was separately weighed and added
to the cetirizine solution. Stirring was continued until a well
dispersed suspension had been formed, the pH of which was adjusted
to pH 7.0.+-.0.1 with 1.0 M NaOH or 1.0 M HCl. The volume of the
preparation was then brought to the final batch volume of 2000 mL.
The preparation was transferred to a 5 L glass vessel provided with
an Ultra Turrax.RTM. T25 homogeniser (Jankel & Kuhnke,
Germany). Homogenisation was carried out at 22000 rpm for 3.times.2
minutes interrupted by 10 minute settling periods. 10 mL aliquots
of the thus obtained composition were removed from the stirred
dispersion and transferred to glass vials onto which spray heads
(VP7 or VP7D; Valois S. A., France) were either crimped on or
attached by screw fitting after filling. The stirred composition as
well as the composition aliquots in the vials were protected from
light.
[0080] Ultrasonication was found to further reduce mean particle
size. In this method, the vials with the homogenised compositions
were placed in an ultrasonication bath and sonicated for 2.times.10
minutes, whereupon the samples had an almost clear appearance in
comparison with the opaque composition afforded by
Ultra-Turrax.RTM. homogenisation.
[0081] The aforementioned particle size reduction methods are
compared in Table 2. Particle size distribution was determined by
laser diffraction (Mastersizer 2000, Malvern Instrument, UK). A
Fraunhofer theory based method was used to calculate the particle
size of the high speed homogenised sample whereas a MIE
(2.50/0.001) theory based method was used for calculation of the
particle size of the sample additionally subjected to
sonication.
TABLE-US-00002 TABLE 2 Particle size reduction Treatment Mean
particle size (nm) High speed homogenisation 940 High speed
homogenisation + ultrasonication 162
EXAMPLE 2
TABLE-US-00003 [0082] TABLE 3 Composition Cetirizine dinitrate 2.22
g Phospholipid (soybean; Lipoid S75; Lipoid GmbH, 7.00 g Germany)
Citric acid, anhydrous 3.84 g Sodium hydroxide, solid 1.67 g
Ascorbic acid 0.20 g EDTA sodium 0.20 g HCl, 1M and/or NaOH, 1M to
pH 5.0 Water for injection to 200 mL
[0083] General procedure. For weights and volumes reference is made
to Table 3. A buffer solution was 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 was added and dissolved by stirring with a
magnetic stirrer. The phospholipid was separately weighed and added
to the cetirizine solution. Stirring was continued until a well
dispersed suspension had been formed, the pH of which was adjusted
to pH 5.0.+-.0.1 with 1.0 M NaOH and/or 1.0 M HCl. The volume of
the preparation was then brought to the final batch volume of 200
mL. The preparation was transferred to a high pressure homogeniser
(Rannie APV, type 7.30 VH, Rannie AS, Denmark) and homogenised at
500-800 bar for 5 cycles. Aliquots of the thus obtained composition
were removed from the collecting vessel and transferred to glass
vials.
EXAMPLE 3
[0084] In Table 4, a high pressure homogenation particle size
reduction method, as described in Example 2, is compared with high
speed homogenisation (Ultra Turrax.RTM. T25 homogeniser; Jankel
& Kuhnke, Germany), as described in Example 1. The composition
employed was that of Example 1, Particle size distribution was
determined by dynamic light scattering (Zetasizer 4, Malvern
Instruments, UK) at an angle of 90.degree. and at room temperature,
using a ZET5104 sizing cell and auto:CONTIN analysis mode.
TABLE-US-00004 TABLE 4 Particle size reduction Cetirizine Z average
mean Treatment (mg/mL) (nm) High speed homogenisation 11.1 282 High
pressure homogenisation at 500 bar 11.1 77 High pressure
homogenisation at 800 bar 11.1 50 High pressure homogenisation at
500 bar 0 130 High pressure homogenisation at 800 bar 0 121
[0085] The methods used for preparing these exemplary batch
compositions were adapted for preparing the following additional
examples.
EXAMPLE 4
TABLE-US-00005 [0086] Cetirizine dinitrate 5.6 mg Phospholipid
(soybean; Lipoid S75; Lipoid GmbH, Germany) 35.0 mg Disodium
phosphate dihydrate; Na.sub.2HPO.sub.4 H.sub.2O 10.7 mg Potassium
dihydrogen phosphate; KH.sub.2PO.sub.4 5.5 mg 1M HCl and/or 1M NaOH
to pH 7.0 Water for injection to 1 mL
EXAMPLE 5
TABLE-US-00006 [0087] Cetirizine dinitrate 22.2 mg Phospholipid
(soybean; Lipoid S75; Lipoid GmbH, Germany) 35.0 mg Disodium
phosphate dihydrate; Na.sub.2HPO.sub.4 H.sub.2O 10.7 mg Potassium
dihydrogen phosphate; KH.sub.2PO.sub.4 5.5 mg 1M HCl and/or 1M NaOH
to pH 7.0 Water for injection to 1 mL
EXAMPLE 6
TABLE-US-00007 [0088] Cetirizine dinitrate 11.1 mg Phospholipid
(soybean; Lipoid S75; Lipoid GmbH, Germany) 70.0 mg Disodium
phosphate dihydrate; Na.sub.2HPO.sub.4 H.sub.2O 10.7 Potassium
dihydrogen phosphate; KH.sub.2PO.sub.4 5.5 mg 1M HCl and/or 1M NaOH
to pH 7.0 Water for injection to 1 mL
EXAMPLE 7
TABLE-US-00008 [0089] Cetirizine dinitrate 11.1 mg Phospholipid
(dioleoylphoshatidylcholine*) 35.0 Disodium phosphate, dihydrate;
Na.sub.2HPO.sub.4 2H.sub.2O 10.7 Potassium dihydrogen phosphate;
KH.sub.2PO.sub.4 5.5 1M HCl and/or 1M sodium hydroxide to pH 7.0
Water for injection to 1 mL *DOPC, Larodan Fine Chemicals,
Sweden
EXAMPLE 8
TABLE-US-00009 [0090] Cetirizine dinitrate 11.1 mg Phospholipid
(dioleoylphosphatidylglycerol*) 35.0 mg Disodium phosphate,
dihydrate; Na.sub.2HPO.sub.4 2H.sub.2O 10.7 mg Potassium dihydrogen
phosphate; KH.sub.2PO.sub.4 5.5 mg 1M HCl and/or 1M sodium
hydroxide to pH 7.0 Water for injection to 1 mL *DOPG, Avanti Polar
Lipids, AL, USA
EXAMPLE 9
TABLE-US-00010 [0091] Cetirizine dinitrate 11.1 mg Galactolipid
(digalactosyldiacylglycerol*) 35.0 mg Disodium phosphate,
dihydrate; Na.sub.2HPO.sub.4 2H.sub.2O 10.7 mg Potassium dihydrogen
phosphate; KH.sub.2PO.sub.4 5.5 mg 1M HCl and/or 1M sodium
hydroxide to pH 7.0 Water for injection to 1 mL *DGDG, Larodan Fine
Chemicals, Sweden
EXAMPLE 10
Nasal Irritation Test in a Dog Model
[0092] Cetirizine dinitrate (5.6, 11.1 and 22.2 mg/mL,
respectively, in the compositions of Examples 1, 4 and 5; shaken
rather than high speed or high pressure 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.
EXAMPLE 11
Ocular Irritation Test in a Rabbit Model
[0093] The potential irritating properties of the compositions of
the invention 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. Signs of conjunctival irritation
(redness) were observed in two rabbits in the group receiving the
composition containing 22.2 mg/mL cetirizine dinitrate. In the
first rabbit, a score 2 (diffuse, crimson colour, individual
vessels not easily discernable) on a scale graded 0 to 3 was noted
one hour after treatment. In the second rabbit, a score 1 (some
hyperaemic blood vessels) on a four grade scale was noted at 24 h.
In both cases the redness was not present at subsequent
observations, and was thus considered reversible. No other signs of
eye irritation were observed in any of the animals.
EXAMPLE 12
Nasal Irritation Test
[0094] A single dose (110 .mu.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; see Table 5 for
details) in each session. Formulations I, II, and III are
formulations of the examples above whereas reference formulation IV
was 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.
TABLE-US-00011 TABLE 5 Cetirizine Dinitrate Formulations Used in
Testing Nasal Irritation mg Phospholipid Formulation Composition
per mL Vehicle Features* I Example 1 35 High speed homogenised II
Example 1 35 High speed homogenised + ultrasonicated III Example 6
70 High speed homogenised + ultrasonicated IV Reference nil;
phosphate Plain buffered aqueous buffer solution *Refer to Table
2
[0095] 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).
[0096] The phospholipid formulations were better tolerated than the
plain buffer solution. Smaller liposomes seem to be of some
advantage. The mild discomfort reported by all subjects at 1 minute
had practically disappeared at 10 min for the two formulations (II
and III) that had reduced particle size by sonication. In contrast,
the initial mild discomfort reported for formulation I persisted at
10 minutes. Increasing the ratio of phospholipid to cetirizine did
not further improve the performance of the formulation.
TABLE-US-00012 TABLE 6 Nasal irritation test in healthy volunteers
Formu- Rhinor- Itching/ Burning/ TOTAL lation Congestion rhea
sneezing Pain Taste SCORE 1 minute post-administration I 0 3 1 6.5
1 11.5 II 0 1 1 6 0 8 III 0 0 1 5.5 0 6.5 IV 0 6 2 14.5 2 24.5 10
minutes post-administration I 0 1 1 6 4 12 II 0 0 0 2 2 4 III 0 0 1
1 4.5 6.5 IV 0 1 1 8 3 13 30 minutes post-administration I 0 0 1 1
3 5 II 0 0 1 0 0 1 III 0 0 0 1 1 2 IV 0 0 0 1.5 1 2.5
EXAMPLE 13
Nasal Irritation Test
[0097] A single dose (110 .mu.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; see Table 7 for
details) in each session. The test was performed to investigate the
irritative properties of formulations with different membrane
lipids of natural and synthetic origin.
TABLE-US-00013 TABLE 7 Cetirizine dinitrate formulations used in
testing nasal irritation Formulation Composition Membrane lipid I
Example 1 Lipoid S75 Natural II Example 7
Dioleoylphoshatidylcholine Synthetic (DOPC) III Example 8
Dioleoylphoshatidylglycerol Synthetic (DOPG) IV Example 9
Digalactosyldiacylglycerol Natural (DGDG)
[0098] 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).
[0099] The formulations containing DOPC and DOPG were very well
tolerated with practically no reports of any kind at 1 minute. At
10 minutes there was still a tendency of better tolerability of
these two formulations as compared to the membrane lipids of
natural origin.
TABLE-US-00014 TABLE 8 Nasal irritation test in healthy volunteers
Formu- Rhinor- Itching/ Burning/ TOTAL lation Congestion rhea
sneezing Pain Taste SCORE 1 minute post-administration I 0 1 1 3 2
7 II 0 1 0 1 0 2 III 1 0 1 0 0 1 IV 0 1.5 2 2 4 9.5 10 minutes
post-administration I 0 1 0 2 3 6 II 0 0 0 1 2 3 III 0 0.5 0.5 1 2
4 IV 0.5 0.5 0 1 4 6 30 minutes post-administration I 1 0 0 0 0 1
II 0 0 0 0 0 0 III 0 0 1 0 1 2 IV 0 0 0 0 0 0
[0100] The following examples were also made in accordance with
procedures analogous to those described hereinbefore.
EXAMPLE 14
TABLE-US-00015 [0101] Cetirizine dinitrate 11.1 mg Phospholipid
(soybean; Lipoid S100; 35.0 mg Lipoid GmbH, Germany) Citric acid
19.2 mg Sodium hydroxide 8.4 mg 1M HCl and/or 1M NaOH to pH 5.5
Water for injection to 1 mL
EXAMPLE 15
TABLE-US-00016 [0102] Cetirizine dinitrate 11.1 mg Phospholipid
(soybean; Lipoid S100; 50.0 mg Lipoid GmbH, Germany) Citric acid
19.2 mg Sodium hydroxide 8.4 mg 1M HCl and/or 1M NaOH to pH 5.5
Water for injection to 1 mL
EXAMPLE 16
TABLE-US-00017 [0103] Cetirizine dinitrate 11.1 mg Phospholipid
(soybean; Lipoid S100; 35.0 mg Lipoid GmbH, Germany) EDTA 0.1 mg
Citric acid 19.2 mg Sodium hydroxide 8.4 mg 1M HCl and/or 1M NaOH
to pH 5.5 Water for injection to 1 mL
EXAMPLE 17
TABLE-US-00018 [0104] Cetirizine dinitrate 11.1 mg Phospholipid
(soybean; Lipoid S100; 35.0 mg Lipoid GmbH, Germany) Benzalkonium
chloride 0.1 mg Citric acid 19.2 mg Sodium hydroxide 8.4 mg 1M HCl
and/or 1M NaOH to pH 5.5 Water for injection to 1 mL
EXAMPLE 18
TABLE-US-00019 [0105] Cetirizine dinitrate 11.1 mg Phospholipid
(soybean; Lipoid S100; 35.0 mg Lipoid GmbH, Germany) Methylparaben
1.8 mg Propylparaben 0.2 mg Citric acid 19.2 mg Sodium hydroxide
8.4 mg 1M HCl and/or 1M NaOH to pH 5.5 Water for injection to 1
mL
EXAMPLE 19
TABLE-US-00020 [0106] Cetirizine dinitrate 11.1 mg Phospholipid
(soybean; Lipoid S100; 35.0 mg Lipoid GmbH, Germany) Butylated
hydroxytoluene (BHT) 0.1 mg Citric acid 19.2 mg Sodium hydroxide
8.4 mg 1M HCl and/or 1M NaOH to pH 5.5 Water for injection to 1
mL
EXAMPLE 20
TABLE-US-00021 [0107] Cetirizine dinitrate 11.1 mg Phospholipid
(soybean; Lipoid S100; 23.3 mg Lipoid GmbH, Germany) Phospholipid
(soybean; Lipoid S75-3 N; 11.7 mg Lipoid GmbH, Germany) Citric acid
19.2 mg Sodium hydroxide 8.4 mg 1M HCl and/or 1M NaOH to pH 5.5
Water for injection to 1 mL
EXAMPLE 21
TABLE-US-00022 [0108] Cetirizine dinitrate 11.1 mg Phospholipid
(soybean; Lipoid S100; Lipoid GmbH, 11.7 mg Germany) Phospholipid
(DMPC; Lipoid GmbH, Germany) 23.3 mg Citric acid 19.2 mg Sodium
hydroxide 8.4 mg 1M HCl and/or 1M NaOH to pH 5.5 Water for
injection to 1 mL
EXAMPLE 22
TABLE-US-00023 [0109] Cetirizine dinitrate 11.1 mg Phospholipid
(soybean; Lipoid S100; Lipoid GmbH, 17.5 mg Germany) Phospholipid
(DMPC; Lipoid GmbH, Germany) 17.5 mg Citric acid 19.2 mg Sodium
hydroxide 8.4 mg 1M HCl and/or 1M NaOH to pH 5.5 Water for
injection to 1 mL
EXAMPLE 23
TABLE-US-00024 [0110] Cetirizine dinitrate 11.1 mg Phospholipid
(soybean; Lipoid S100; Lipoid GmbH, 23.3 mg Germany) Phospholipid
(DMPC; Lipoid GmbH, Germany) 11.7 mg Citric acid 19.2 mg Sodium
hydroxide 8.4 mg 1M HCl and/or 1M NaOH to pH 5.5 Water for
injection to 1 mL
EXAMPLE 24
TABLE-US-00025 [0111] Cetirizine dinitrate 11.1 mg Phospholipid
(soybean; Lipoid S100; Lipoid GmbH, 35.0 mg Germany)
Hydroxypropylmethylcellulose (Metolose 60SH-50) 1.0 mg Citric acid
19.2 mg Sodium hydroxide 8.4 mg 1M HCl and/or 1M NaOH to pH 5.5
Water for injection to 1 mL
EXAMPLE 25
TABLE-US-00026 [0112] Cetirizine dinitrate 11.1 mg Phospholipid
(soybean; Lipoid S100; Lipoid GmbH, 35.0 mg Germany) Polyethylene
glycol (Macrogol 6000) 1.0 mg Citric acid 19.2 mg Sodium hydroxide
8.4 mg 1M HCl and/or 1M NaOH to pH 5.5 Water for injection to 1
mL
EXAMPLE 26
TABLE-US-00027 [0113] Cetirizine dinitrate 11.1 mg Phospholipid
(soybean; Lipoid S100; Lipoid GmbH, 35.0 mg Germany) Benzalkonium
chloride 0.1 mg Butylated hydroxytoluene (BHT) 0.1 mg Citric acid
19.2 mg Sodium hydroxide 8.4 mg 1M HCl and/or 1M NaOH to pH 5.5
Water for injection to 1 mL
EXAMPLE 27
TABLE-US-00028 [0114] Cetirizine dinitrate 11.1 mg Phospholipid
(soybean; Lipoid S100; Lipoid GmbH, 35.0 mg Germany) Benzalkonium
chloride 0.1 mg Butylated hydroxytoluene (BHT) 0.1 mg
Hydroxypropylmethylcellulose (Metolose 60SH-50) 10 mg Citric acid
19.2 mg Sodium hydroxide 8.4 mg 1M HCl and/or 1M NaOH to pH 5.5
Water for injection to 1 mL
EXAMPLE 28
TABLE-US-00029 [0115] Cetirizine dinitrate 11.1 mg Phospholipid
(soybean; Lipoid S100; Lipoid GmbH, 17.5 mg Germany) Phospholipid
(DMPC; Lipoid GmbH, Germany) 17.5 mg Benzalkonium chloride 0.1 mg
Butylated hydroxytoluene (BHT) 0.1 mg Citric acid 19.2 mg Sodium
hydroxide 8.4 mg 1M HCl and/or 1M NaOH to pH 5.5 Water for
injection to 1 mL
EXAMPLE 29
TABLE-US-00030 [0116] Cetirizine dinitrate 11.1 mg Phospholipid
(soybean; Lipoid S100; Lipoid GmbH, 23.3 mg Germany) Phospholipid
(DMPC; Lipoid GmbH, Germany) 11.7 mg Benzalkonium chloride 0.1 mg
Butylated hydroxytoluene (BHT) 0.1 mg Citric acid 19.2 mg Sodium
hydroxide 8.4 mg 1M HCl and/or 1M NaOH to pH 5.5 Water for
injection to 1 mL
EXAMPLE 30
TABLE-US-00031 [0117] Cetirizine dinitrate 11.1 mg Phospholipid
(soybean; Lipoid S100; Lipoid GmbH, 23.3 mg Germany) Phospholipid
(DMPC; Lipoid GmbH, Germany 11.7 mg Benzalkonium chloride 0.1 mg
Butylated hydroxytoluene (BHT) 0.1 mg Polyethylene glycol (Macrogol
6000) 10 mg Citric acid 19.2 mg Sodium hydroxide 8.4 mg 1M HCl
and/or 1M NaOH to pH 5.5 Water for injection to 1 mL
EXAMPLE 31
TABLE-US-00032 [0118] Cetirizine dinitrate 11.1 mg Phospholipid
(soybean; Lipoid S100; Lipoid GmbH, 29.2 mg Germany) Phospholipid
(DMPC; Lipoid GmbH, Germany 5.8 mg Benzalkonium chloride 0.1 mg
Butylated hydroxytoluene (BHT) 0.01 mg Povidone 1.0 mg Citric acid
19.2 mg Sodium hydroxide 8.4 mg 1M HCl and/or 1M NaOH to pH 5.5
Water for injection to 1 mL
EXAMPLE 32
TABLE-US-00033 [0119] Cetirizine dinitrate 11.1 mg Phospholipid
(soybean; Lipoid S100; Lipoid GmbH, 23.3 mg Germany) Phospholipid
(DMPC; Lipoid GmbH, Germany 11.7 mg Benzalkonium chloride 1.0 mg
Butylated hydroxytoluene (BHT) 0.1 mg Hydroxypropylmethylcellulose
(Metolose 60SH-50) 5.0 mg Citric acid 19.2 mg Sodium hydroxide 8.4
mg 1M HCl and/or 1M NaOH to pH 5.5 Water for injection to 1 mL
EXAMPLE 33
TABLE-US-00034 [0120] Cetirizine dihydrochloride 11.1 mg
Phospholipid (soybean; Lipoid S100; Lipoid GmbH, 35.0 mg Germany)
Ascorbic acid 1.0 mg Citric acid 19.2 mg Sodium hydroxide 8.4 mg 1M
HCl and/or 1M NaOH to pH 5.5 Water for injection to 1 mL
EXAMPLE 34
TABLE-US-00035 [0121] Cetirizine dihydrochloride 11.1 mg
Phospholipid (soybean; Lipoid S100; Lipoid GmbH, 35.0 mg Germany)
.alpha.-Tocopherol 1.0 mg Citric acid 19.2 mg Sodium hydroxide 8.4
mg 1M HCl and/or 1M NaOH to pH 5.5 Water for injection to 1 mL
EXAMPLE 35
TABLE-US-00036 [0122] Cetirizine dihydrochloride 11.1 mg
Phospholipid (soybean; Lipoid S100; Lipoid GmbH, 35.0 mg Germany)
Butylated hydroxytoluene (BHT) 0.1 mg Citric acid 19.2 mg Sodium
hydroxide 8.4 mg 1M HCl and/or 1M NaOH to pH 5.5 Water for
injection to 1 mL
* * * * *