U.S. patent application number 10/842433 was filed with the patent office on 2005-11-17 for method and composition for treating rhinitis.
Invention is credited to Carlsson, Anders, Pereswetoff-Morath, Lena.
Application Number | 20050255154 10/842433 |
Document ID | / |
Family ID | 34968224 |
Filed Date | 2005-11-17 |
United States Patent
Application |
20050255154 |
Kind Code |
A1 |
Pereswetoff-Morath, Lena ;
et al. |
November 17, 2005 |
Method and composition for treating rhinitis
Abstract
A pharmaceutical composition for the treatment of rhinitis by
nasal or ocular administration comprises zwitterionic cetirizine,
polar lipid liposome, a pharmaceutical acceptable aqueous carrier
and, optionally, a pharmaceutically acceptable buffer capable of
providing a pH of from pH 4.0 to pH 8.0, with the proviso that, if
the polar lipid comprises phospholipid, the amount of phospholipid
in the composition from is from 10 mg per mL to 120 mg per mL. Also
disclosed are methods for its preparation and methods for treating
rhinitis by its nasal or ocular administration.
Inventors: |
Pereswetoff-Morath, Lena;
(Spanga, SE) ; Carlsson, Anders; (Stockholm,
SE) |
Correspondence
Address: |
DICKSTEIN SHAPIRO MORIN & OSHINSKY LLP
1177 AVENUE OF THE AMERICAS (6TH AVENUE)
41 ST FL.
NEW YORK
NY
10036-2714
US
|
Family ID: |
34968224 |
Appl. No.: |
10/842433 |
Filed: |
May 11, 2004 |
Current U.S.
Class: |
424/450 ;
514/255.04 |
Current CPC
Class: |
A61K 9/0048 20130101;
A61P 37/08 20180101; A61K 9/127 20130101; A61P 43/00 20180101; Y10S
977/907 20130101; A61K 9/0043 20130101; A61P 37/00 20180101; A61P
11/02 20180101; Y10S 977/906 20130101; A61K 31/495 20130101 |
Class at
Publication: |
424/450 ;
514/255.04 |
International
Class: |
A61K 031/495; A61K
009/127 |
Claims
1. 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 4.0 to pH 8.0, with the proviso that, if
the polar lipid comprises phospholipid, the amount of phospholipid
in the composition is from 10 mg per mL to 120 mg per mL.
2. The composition of claim 1, wherein the amount of phospholipid
is from 17 mg per mL to 120 mg per mL.
3. The composition of claim 1, wherein the amount of phospholipid
is from 35 mg per mL to 70 mg per mL.
4. The composition of claim 1, wherein said pH is from 5.0 to
7.0.
5. The composition of claim 1, wherein the zwitterionic cetirizine
has been obtained from a chloride or nitrate salt of
cetirizine.
6. The composition of claim 5, wherein the salt is cetirizine
dinitrate.
7. The composition of claim 1, wherein the buffer is selected from
phosphate buffer, citrate buffer, acetate buffer.
8. The composition of claim 1 comprising cetirizine or a salt of
cetirizine in an amount of from 1 mg/mL to 23 mg/mL calculated on
the zwitterionic form.
9. The composition of claim 1, comprising cetirizine or a salt of
cetirizine in an amount of from 5.5 mg/mL to 22 mg/mL.
10. The composition of claim 1 wherein the liposome is based on a
phospholipid or on a mixture of phospholipids.
11. The composition of claim 10, wherein the phospholipid is
selected from the group consisting of phosphatidylcholine,
phosphatidylglycerol, phosphatidylinositol, phosphatidic acid, and
phosphatidylserine
12. The composition of claim 10, wherein at least one phospholipid
is of natural origin.
13. The composition of claim 10, wherein at least one phospholipid
is of synthetic or semi-synthetic origin.
14. The composition of claim 1, wherein the liposome is based on a
glycolipid or a mixture of glycolipids.
15. The composition of claim 1, wherein the liposome consists of a
glycolipid or a mixture of glycolipids.
16. The composition of claim 14, where the glycolipid is
glycoglycerolipid.
17. The composition of claim 16, wherein the glycoglycerolipid
comprises galactoglycerolipid.
18. The composition of claim 16, wherein glycoglycerolipid
comprises digalactosyldiacylglycerol.
19. The composition of claim 18, wherein glycoglycerolipid
substantially consists of digalactosyldiacylglycerol.
20. The composition of claim 14, wherein the glycolipid is a
glycosphingolipid.
21. The composition of claim 14, wherein the glycolipid is a
glycophosphatidylinositol.
22. The composition of claim 1 comprising at least one antioxidant,
chelating agent, preservative, or viscosity-increasing agent.
23. 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, with the proviso that, if the polar lipid comprises
phospholipid, the amount of phospholipid in the composition is from
10 to 120 mg per mL, comprising (a) providing a polar lipid or a
mixture of polar lipids that is swellable in aqueous media; (b)
providing an aqueous solution of cetirizine and buffer having a pH
of from pH 4 to pH 8; (c) adding the polar lipid to the aqueous
solution while stirring, thereby forming a cetirizine liposome
preparation; (d) optionally adjusting the pH of the preparation to
a desired value within the range of from pH 4 to pH 8 by adding an
acid or a base; (e) optionally adding water or saline or a buffer
having a pH of from pH 4 to pH 8 to the preparation to obtain a
desired final batch volume; (f) homogenising the preparation to
obtain said pharmaceutical composition.
24. The process of claim 23, wherein the amount of phospholipid in
the composition is from 17 to 120 mg per mL.
25. The process of claim 23, wherein the amount of phosphlipid in
the composition is from 35 mg to 70 mg per mL.
26. The process of claim 23, wherein the pH is from from pH 5.0 to
pH 7.0.
27. The process of claim 23, wherein said mixture of swellable
polar lipids has be pre-treated with organic solvent.
28. The process of claim 23, wherein homogenisation comprises at
least one of vigorous mechanical mixing, shaking, vortexing, or
rolling.
29. The process of claim 22, additional comprising reduction of
liposome size.
30. The process of claim 29, wherein the reduction of liposome size
comprises extrusion through a membrane filter or high-pressure
homogenization or both.
31. A method for the manufacture of a pharmaceutical composition
for the treatment of rhinitis comprising combining 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 to 120 mg per mL.
32. The method of claim 31, wherein the polar lipid is
glycoglycerolipid.
33. The method of claim 32, wherein the glycoglycerolipid comprises
galactoglycerolipid.
34. A method of treating rhinitis comprising nasal administration
of a pharmacologically effective amount of the composition of claim
1.
35. A method of treating rhinitis comprising ocular administration
of a pharmacologically effective amount of the composition claim 1.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a method for treating
rhinitis, and to a corresponding pharmaceutical composition.
BACKGROUND OF THE INVENTION
[0002] 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.
[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.
Oral or local antihistamines are first line treatment, and nasal
steroids second line treatment 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.
[0004] 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.
[0005] The main clinical affects of 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. At present cetirizine dihydrochloride is not an
approved medicine for local administration, although it has been
administered in that manner in clinical trials.
[0006] Some effect was seen on symptoms when cetirizine (presumably
as di-hydrochloride) 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 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.
In another trial (Francillon C, Pcoud 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. 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 April
1991; 46(4):242-4).
[0007] 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).
[0008] The lipophilicity behaviour of the cationic (anion:
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 been studied
(Plemper van Balen G et al. Lipophilicity behaviour of the
zwitterionic antihistamine cetirizine in phosphatidylcholine
liposomes/water systems. Pharm. Res. 2001; 18:694-701. The aim with
the study was to gain insight into the mechanism of interaction of
the various electrical species of cetirizine with membranes. In
respect of the cationic species, both hydrophobic and electrostatic
interactions were found to be involved. The authors consider the
zitterionic 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, to be prevented from entry into the liposomal membrane by
rendering the formation of lipophilic folded conformers of
cetirizine more difficult.
OBJECTS OF THE INVENTION
[0009] It is an object of the present invention to provide a
pharmaceutical composition for nasal administration of cetirizine
that protects the nasal mucosa from irritation by the active
agent.
[0010] It is another object of the present invention to provide a
pharmaceutical composition for ocular administration of cetirizine
that protects the ocular mucosa from irritation by the active
agent.
[0011] Still another object of the present invention is to provide
a process for the manufacture of this composition.
[0012] 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.
[0013] Further object of the invention will become apparent from
the study of the following summary of the invention, the
description of preferred embodiments thereof, and the appended
claims.
SUMMARY OF THE INVENTION
[0014] 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.
[0015] According to the present invention is disclosed 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.
[0016] 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.
[0017] It is preferred for the composition of the invention to
comprise 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.
[0018] The 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.
[0019] 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.
[0020] Numerous patents and scientific papers on liposomes have
been published and the technical field of applying various lipid
derivatives in combination with amphiphatic compounds such as
phospholipids are well known to those skilled in the art. 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.
[0021] Liposomes may be based on phospholipids, in particular
phosphatidylcholine (PC), phosphatidylglycerol (PG),
phosphatidylinositol (PI), phosphatidic acid (PA),
phosphatidylserine (PS), or mixtures thereof.
[0022] The phospholipids of the invention comprise polar and
non-polar groups linked to a backbone entity carrying hydroxyl
groups, such as glycerol. According to a preferred embodiment of
the invention the phospholipid is of natural origin, preferably
membrane phospholipid. According to another preferred embodiment of
the invention the phospholipid is of synthetic or semi-synthetic
origin.
[0023] Phospholipids can be represented by the general formula I
1
[0024] wherein R.sub.1 and R.sub.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.sub.3 represents an amide or ester bonding group, such
as --CH.sub.2--CHOH--CH.sub.2OH (phosphatidylglycerol),
--CH.sub.2--CH.sub.2--CH.sub.2--N(CH.sub.3).sub.3
(phosphatidylcholine), --CH.sub.2--CH.sub.2--NH.sub.2
(phosphatidylethanolamine), H (phosphatidic acid),
--CH.sub.2--CH(NH.sub.2)--COOH (phosphatidylserine).
[0025] Particularly preferred phospholipids are those swelling in
water, which are capable of spontaneous liposome formation. For 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.
[0026] If 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.
[0027] The liposome formation can be performed at room temperature
or any other temperature above 0.degree. 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.
[0028] According to a first preferred aspect of the invention the
polar lipid comprises or, more preferred, consists of glycolipid.
In this application, 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).
[0029] According to a second preferred aspect of the invention
glycolipid is a glycoglycerolipid. In this application the term
glycoglycerolipid designates a glycolipid containing one or more
glycerol residues. According to a particularly preferred aspect of
the invention glycoglycerolipid comprises or consists of
galactoglycerolipid, preferably digalactosyldiacylglycerol of the
general formula (II) 2
[0030] R.sub.1 and R.sub.2 having the same meaning as in general
formula (I).
[0031] According to a third preferred aspect of the invention
glycolipid is a glycosphingolipid. In this application the term
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. Preferably 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.
[0032] According to a fourth preferred aspect of the invention
glycolipid is a glycophosphatidylinositol. In this application the
term glycophosphatidylinositol designates glycolipid which contains
saccharides glycosidically linked to the inositol moiety of
phosphatidylinositols.
[0033] The 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.
[0034] 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.
[0035] 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, possible unsaturated fatty acid
residues therein, from oxidation.
[0036] 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, phenoxyethanol, and phenylethyl
alcohol.
[0037] To retain the composition of the invention at its
application site it can also comprise viscosity-increasing agent
such as, for instance, hydrophilic polymers like
polyethyleneglycol, cellulose derivatives such as
hydroxypropylmethyl cellulose.
[0038] 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.
[0039] According to the invention is also disclosed a process for
preparing a composition of the aforementioned kind. Preferably 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.
[0040] In particular, according to the present invention, is
disclosed 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
[0041] (a) providing a polar lipid or a mixture of polar lipids
that is swellable in aqueous media;
[0042] (b) providing an aqueous solution of cetirizine and buffer
having a pH of from pH 4 to pH 8;
[0043] (c) adding the polar lipid to the aqueous solution while
stirring, thereby forming a cetirizine liposome preparation;
[0044] (d) optionally adjusting the pH of the preparation to a
desired value within the range of from pH 4 to pH 8 by adding an
acid or a base;
[0045] (e) optionally adding water or saline to the preparation to
obtain a desired final batch volume;
[0046] (f) homogenising the preparation to obtain said
pharmaceutical composition.
[0047] 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.
[0048] 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. Depending on the lipid or lipid
mixture used and the other conditions 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.
[0049] A preferred dispersion method is vigorous mechanical mixing
by, for instance, high speed homogenisation, such as by means of an
Ultra Turrax.RTM. (Jankel & Kuhnke, Germany) homogeniser, but
shaking, vortexing and rolling can also be performed.
[0050] 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.
[0051] Surprisingly it was found that the presence of cetirizine in
a liposome vehicle resulted in a reduction of liposome size.
Smaller liposomes are generally more stable physically and, due to
their higher surface/volume ratio, easier resorbed by the
mucosa.
[0052] The preparation of the 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.
[0053] According to the present invention is also disclosed 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. For nasal
administration any state-of-the-art devices suitable for producing
sprays of aqueous liposomal dispersions can be used. It is also
possible to administer the composition of the invention by nasal
drops and even by inhalation of cetirizine liposome mist from a
nebulizer. A corresponding method of treatment according to the
invention by ocular administration is also dislosed. Preferably the
composition of ocular administration is in the form of eye
drops.
[0054] According to the present invention is furthermore disclosed
a method for the manufacture of 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.
[0055] In the following the invention will be explained in more
detail by reference to a number of preferred embodiments.
DESCRIPTION OF PREFERRED EMBODIMENTS
MANUFACTURE OF EXEMPLARY COMPOSITIONS OF THE INVENTION (EXAMPLES
1-4)
EXAMPLE 1
[0056]
1TABLE 1 Batch formula of the composition of the invention
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 1 M
Hydrochloric acid and/or 1 M 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
[0057] General procedure. For weights and volumes reference is made
to Table 1. A buffer solution is prepared by dissolving the
buffering agents disodium phosphate dihydrate
(Na.sub.2HPO.sub.4.2H.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
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. Stirring is continued until a well dispersed
suspension has been formed, the pH of which is adjusted to pH
7.0.+-.0.1 with 1.0 M NaOH or 1.0 M HCl. The volume of the
preparation is then brought to the final batch volume of 2000 mL.
The preparation is transferred to a 5 L glass vessel provided with
an Ultra Turrax.RTM. T25 homogeniser (Jankel & Kuhnke,
Germany). Homogenisation is carried out at 22000 rpm for 3.times.2
minutes interrupted by 10 min settling periods. 10 mL aliquots of
the thus obtained composition of the invention are removed from the
stirred dispersion and transferred to glass vials onto which spray
heads (VP7 or VP7D; Valois S. A., France) are either crimped on or
attached by screw fitting after filling. The stirred composition as
well as the composition aliquots in the vials is protected from
light.
[0058] Ultrasonication. Ultrasonication further reduces mean
particle size. In this method the vials with the homogenised
composition of the invention are placed in an ultrasonication bath
and sonicated for 2.times.10 minutes, whereupon the samples have an
almost clear appearance in comparison with the opaque composition
afforded by Ultra-Turrax.RTM. homogenisation.
[0059] 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.
2TABLE 2 Particle size reduction (composition of the invention)
Treatment Average size (nm) High speed homogenisation 940 High
speed homogenisation + 162 ultrasonication
EXAMPLE 2
[0060]
3TABLE 3 Batch formula of the composition of the invention
Cetirizine dinitrate 2.22 mg Phospholipid (soybean; Lipoid S75;
7.00 mg Lipoid GmbH, Germany) Citric acid, anhydrous 3.84 mg Sodium
hydroxide, solid 1.67 mg Ascorbic acid 0.20 mg EDTA sodium 0.20 mg
HCl, 1 M and/or NaOH, 1 M To pH 5.0 Water for injection To 200
mL
[0061] General procedure. For weights and volumes reference is made
to Table 3. 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.
[0062] In Table 4 the particle size reduction method is compared
with high speed homogenisation (Ultra Turrax.RTM. 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.degree. and at room temperature, using a ZET5104
sizing cell and auto:CONTIN analysis mode.
4TABLE 4 Particle size reduction (composition of the invention)
Cetirizine Z average Treatment (mg/mL) mean (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
[0063] The methods used for preparing these exemplary batch
compositions were adapted for preparing the following additional
compositions of the invention.
EXAMPLE 3
[0064]
5TABLE 5 Composition of the invention Cetirizine dinitrate 5.6 mg
Phospholipid (soybean; Lipoid S75; Lipoid GmbH, 35.0 mg Germany)
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 1 M HCl
and/or 1 M NaOH To pH 7.0 Water for injection To 1 mL
EXAMPLE 4
[0065]
6TABLE 6 Composition of the invention Cetirizine dinitrate 22.2 mg
Phospholipid (soybean; Lipoid S75; 35.0 mg Lipoid GmbH, Germany)
Disodium phosphate dihydrate; Na.sub.2HPO.sub.4.2H.sub.2O 10.7 mg
Potassium dihydroqen phosphate; KH.sub.2PO.sub.4 5.5 mg 1 M HCl
and/or 1 M NaOH To pH 7.0 Water for injection To 1 mL
EXAMPLE 5
[0066]
7TABLE 7 Composition of the invention Cetirizine dinitrate 11.2 mg
Phospholipid (soybean; Lipoid S75; Lipoid GrnbH, 70.0 mg Germany)
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 1 M HCl
and/or 1 M NaOH To pH 7.0 Water for injection To 1 mL
EXAMPLE 6
[0067]
8TABLE 8 Composition of the invention Cetirizine dinitrate 11.1 mg
Phospholipid (dioleoylphoshatidylcholine; DOPC, 35.0 Larodan Fine
Chemicals, Sweden) Disodium phosphate dihydrate;
Na.sub.2HPO.sub.4.2H.sub.2O 10.7 Potassium dihydrogen phosphate;
KH.sub.2PO.sub.4 5.5 1 M HCl and/or 1 M sodium hydroxide To pH 7.0
Water for injection To 1 mL
EXAMPLE 7
[0068]
9TABLE 9 Composition of the invention Cetirizin dinitrate 11.1 mg
Phospholipid (dioleoylphosphatidylglycerol; DOPG, 35.0 mg Avanti
Polar Lipids, AL, USA) Disodium phosphate dihydrate;
Na.sub.2HPO.sub.4.2H.sub.2- O 10.7 mg Potassium dihydrogen
phosphate; KH.sub.2PO.sub.4 5.5 mg 1 M HCl and/or 1 M sodium
hydroxide To pH 7.0 Water for injection To 1 mL
EXAMPLE 8
[0069]
10TABLE 10 Composition of the invention Cetirizine dinitrate 11.1
mg Galactolipid (digalactosyldiacylglycerol; DGDG, 35.0 mg Larodan
Fine Chemicals, Sweden) 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 1 M HCl and/or 1 M sodium hydroxide To pH
7.0 Water for injection To 1 mL
EXAMPLE 9
[0070] 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.
EXAMPLE 10
[0071] 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. 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 0-3 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 11
[0072] Nasal irritation test. 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) 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.
11TABLE 11 Cetirizine dinitrate formulations used in testing nasal
irritation mg Phospholipid Features per Formulation Composition mL
Vehicle Features I EXAMPLE 1 35 High speed homogenised II EXAMPLE 1
35 High speed homogenised + ultrasonicated III EXAMPLE 5 70 High
speed homogenised + ultrasonicated IV Reference nil; Plain buffered
aqueous phosphate solution buffer
[0073] 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).
[0074] The phospholipid formulations were better tolerated than the
plain buffer solution. Smaller liposomes seem to be of 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.
12TABLE 12 Nasal irritation test in healthy volunteers. Formu- Con-
Itching/ Burning/ TOTAL lation gestion Rhinorrhea sneezing Pain
Taste SCORE 1 min Post Administration I 0 3 1 6.5 1 11.5 II 0 1 1
6.0 0 8 III 0 0 1 5.5 0 6.5 IV 0 6 2 14.5 2 24.5 10 min 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 min Post Administration I 0 0 1 1 3 5 II 0 0 1 0 0
1 III 0 0 0 1 0 1 IV 0 0 0 1.5 1 2.5
EXAMPLE 12
[0075] Nasal irritation test. 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) in each session. The test was performed to
investigate the irritative properties of formulations with
different membrane lipids of natural and synthetic origin.
13TABLE 13 Cetirizine dinitrate formulations used in testing nasal
irritation Formulation Composition Membrane lipid I EXAMPLE 1
Lipoid S75 Natural II EXAMPLE 6 Dioleoylphoshatidylcholine
Synthetic (DOPC) III EXAMPLE 7 Dioleoylphoshatidylglycerol
Synthetic (DOPG) IV EXAMPLE 8 Digalactosyldiacylglycerol Natural
(DGDG)
[0076] 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).
[0077] The formulations containing DOPC and DOPG were very well
tolerated with practically no reports of any kind at 1 minute. At
10 minutes there is still a tendency of better tolerability of
these two formulations as compared to the membrane lipids of
natural origin.
14TABLE 14 Nasal irritation test in healthy volunteers. Formu- Con-
Itching/ Burning/ TOTAL lation gestion Rhinorrhea sneezing Pain
Taste SCORE 1 min 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 min 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
min 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
* * * * *