U.S. patent application number 11/027680 was filed with the patent office on 2005-09-15 for sustained-release pharmaceutical formulations containing mizolastine.
This patent application is currently assigned to SANOFI-SYNTHELABO. Invention is credited to Chariot, Maryvonne, Lewis, Gareth, Montel, Jean.
Application Number | 20050202089 11/027680 |
Document ID | / |
Family ID | 9489799 |
Filed Date | 2005-09-15 |
United States Patent
Application |
20050202089 |
Kind Code |
A1 |
Chariot, Maryvonne ; et
al. |
September 15, 2005 |
Sustained-release pharmaceutical formulations containing
mizolastine
Abstract
A sustained-release pharmaceutical formulation containing
mizolastine, a core formed of a sustained-release table containing
mizolastine combined with a fatty matrix and an organic acid, the
tablet being coated.
Inventors: |
Chariot, Maryvonne; (La
Ville Du Bois, FR) ; Lewis, Gareth; (Dourdan, FR)
; Montel, Jean; (Chatou, FR) |
Correspondence
Address: |
JACOBSON HOLMAN PLLC
400 SEVENTH STREET N.W.
SUITE 600
WASHINGTON
DC
20004
US
|
Assignee: |
SANOFI-SYNTHELABO
Paris
FR
|
Family ID: |
9489799 |
Appl. No.: |
11/027680 |
Filed: |
January 3, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11027680 |
Jan 3, 2005 |
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09605054 |
Jun 28, 2000 |
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09605054 |
Jun 28, 2000 |
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09125810 |
Aug 26, 1998 |
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6165507 |
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09125810 |
Aug 26, 1998 |
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PCT/FR97/00355 |
Feb 28, 1997 |
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Current U.S.
Class: |
424/472 ;
514/269 |
Current CPC
Class: |
A61P 11/06 20180101;
A61K 9/2013 20130101; A61K 9/2866 20130101; A61P 37/08 20180101;
A61K 31/506 20130101; A61P 27/14 20180101; A61P 43/00 20180101 |
Class at
Publication: |
424/472 ;
514/269 |
International
Class: |
A61K 031/513; A61K
009/24 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 4, 1996 |
FR |
9602662 |
Claims
1-7. (canceled)
8. A coated sustained release tablet, consisting essentially of
from 0.5% to 12% by weight of mizolastine, a fatty matrix, an
organic acid and a coating.
9. A coated sustained release tablet according to claim 8, which
has a dissolution profile which is pH independent.
10. A coated sustained release tablet, consisting essentially of
mizolastine, a fatty matrix, an organic acid, and a coating, the
coated tablet having a dissolution profile which is pH independent,
the organic acid being a member selected from the group consisting
of maleic, tartaric, malic, fumaric, lactic, citric, adipic and
succinic acid in the form of a racemate or an isomer.
11. A pharmaceutical dosage form which comprises a coated tablet
having a sustained-release core, said core comprising a combination
of: a) mizolastine as active principle; b) a fatty matrix; and c)
an organic acid; wherein the coated tablet has a dissolution
profile wherein about 50% of the mizolastine is dissolved in 1
hour, and 100% of the mizolastine is dissolved in 3 to 5 hours.
12. A sustained-release pharmaceutical dosage form according to
claim 11 wherein the weight ratio of the mizolastine to the organic
acid is between 0.3 and 1.
13. A sustained-release pharmaceutical dosage form according to
claim 11 wherein the fatty matrix is a member selected from the
group consisting of hydrogenated castor oil, a hydrogenated
lecithin, a long-chain fatty acid and a triglyceride esterified
with one, two or three medium-chain fatty acids.
14. A sustained-release pharmaceutical dosage form according to
claim 11 wherein the organic acid is a member selected from the
group consisting of maleic, tartaric, malic, fumaric, lactic,
citric, adipic and succinic acid in the form of a racemate or an
isomer.
15. A sustained-release pharmaceutical dosage form according to
claim 11 wherein the organic acid is L-tartaric acid.
16. A sustained-release pharmaceutical dosage form according to
claim 15 wherein the ratio between the mizolastine and the
L-tartaric acid is 0.5.
17. A sustained-release pharmaceutical dosage form according to
claim 9 which contains from 1 to 25 mg of mizolastine.
18. A coated sustained-release tablet having: a) a core comprising
mizolastine, a fatty matrix and an organic acid; b) a dissolution
profile which is pH independent; c) an in vivo mizolastine release
which prevents any plasma peak; and d) a mizolastine
bioavailability which is not decreased relative to that of an
immediate release formulation; wherein the mizolastine comprises
from 0.5% to 12% by weight of the tablet.
19. A sustained-release tablet of claim 18 wherein the dissolution
profile is one in which about 30 to 70% of the mizolastine is
dissolved in 1 hour and 100% of the mizolastine is dissolved in 3
to 5 hours.
20. A sustained-release tablet of claim 18 wherein the weight ratio
between the mizolastine and the organic acid is between 0.3 and
1.
21. A sustained-release tablet of claim 18 wherein the fatty matrix
is a member selected from the group consisting of hydrogenated
castor oil, a hydrogenated lecithin, a long-chain fatty acid and a
triglyceride esterified with one, two or three medium-chain fatty
acids.
22. A sustained-release tablet of claim 18 wherein the organic acid
is a member selected from the group consisting of maleic, tartaric,
malic, fumaric, lactic, citric, adipic and succinic acid in the
form of a racemate or an isomer.
23. A sustained-release tablet of claim 18 wherein the organic acid
is L-tartaric acid.
24. A sustained-release tablet of claim 23 wherein the ratio
between the mizolastine and the L-tartaric acid is 0.5.
25. A sustained-release tablet of claim 18 wherein the core
contains from 1 to 25 mg of mizolastine.
26. A sustained-release tablet of claim 18 wherein the organic acid
has a pK of 2 or more.
27. A coated sustained-release tablet comprising from 1 to 25 mg of
mizolastine, a fatty matrix and L-tartaric acid, and the weight
ratio of the mizolastine and the L-tartaric acid is between 0.3 and
1.
28. A coated sustained-release tablet of claim 27, wherein the
ratio between the mizolastine and the L-tartaric acid is 0.5.
29. A coated sustained-release tablet of claim 28, wherein the
fatty matrix is hydrogenated castor oil.
30. A coated sustained-release tablet of claim 29, wherein the
tablet has a dissolution profile which is independent of pH and is
one in which about 50% of the mizolastine is dissolved in 1 hour
and 100% of the mizolastine is dissolved in 3 to 5 hours.
Description
[0001] The present invention relates to novel sustained-release
pharmaceutical formulations containing
2-[[1-[1-[(4-fluorophenyl)methyl]--
1H-benzimidazol-2-yl]piperid-4-yl]methylamino]-pyrimidin-4-ol or
2-[[1-[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]piperid-4-yl]methy-
lamino]-pyrimidine-4(1H)-one, or mizolastine, as active
principle.
[0002] Mizolastine is described in European patent EP
0,217,700.
[0003] Mizolastine binds to the H.sub.1 histamine receptor and
inhibits the degranulation of mastocytes in vitro and in vivo. It
can thus be used for the treatment of respiratory, cutaneous or
ocular allergies and various allergic manifestations.
[0004] During the oral administration of immediate-release
formulations containing mizolastine, undesirable sedative effects
have been observed which are associated with the existence of a
high peak in the plasma.
[0005] Consequently, it was necessary to find formulations for an
oral administration which have a profile of release of the active
principle such that it is possible to obtain a lower peak in the
plasma without decreasing the bioavailability.
[0006] The Applicant Company has based its research of such
formulations on the study of the kinetics of dissolution of
mizolastine. The reason for this is that mizolastine is a weak base
(pK 5.6) which is sparingly soluble in water (13 mg/l at neutral
pH) but much more soluble at acidic pH (11 g/l at pH 3); the first
gelatin capsules released 100% of mizolastine over 30 minutes in a
dissolution medium at pH 2 whereas only 40% were dissolved at pH
6.8.
[0007] Moreover, the release of mizolastine from the
sustained-release pharmaceutical form according to the invention
did not need to be influenced by the differences in pH in the
gastrointestinal tract.
[0008] The aim of the present invention is to propose formulations
containing mizolastine whose dissolution profile is as follows:
[0009] about 30 to 70% of mizolastine dissolved in 1 hour,
[0010] 100% of mizolastine dissolved in 3 to 5 hours, and
[0011] pH-independent profile.
[0012] The Applicant Company has shown that tablets containing a
core formed of a sustained-release tablet containing mizolastine
combined with a fatty matrix and with an organic acid, the said
tablet being coated to prevent degradation of the product by light,
are entirely suitable.
[0013] The tablets according to the invention contain from 1 mg to
25 mg of mizolastine. These doses correspond to concentrations of
from 0.5% to 12% by weight of mizolastine.
[0014] The fatty matrix is made with hydrogenated castor oil or
with hydrogenated lecithins or long-chain fatty acids, for example
C.sub.12-C.sub.28 long chain fatty acids such as behenic acid, or
triglycerides esterified with medium-chain fatty acids, for example
C.sub.8-C.sub.18 fatty acids.
[0015] The organic acid preferably having a pK of 2 or more is
chosen from maleic, tartaric, malic, fumaric, lactic, citric,
adipic and succinic acids in the form of racemates or isomers.
According to the invention, the acid particularly preferred is
L-tartaric acid.
[0016] The weight ratio between the mizolastine and the organic
acid should be between 0.3 and 1. With L-tartaric acid, this ratio
is preferably equal to 0.5.
[0017] The tablets are prepared by granulation using the active
principle, the agent constituting the fatty matrix, the organic
acid and other excipients such as, for example, lactose, mannitol
and sugars or similar sugar-alcohols, microcrystalline cellulose,
starch, calcium phosphates and sulphates, polyvidone, and
substituted celluloses such as hydroxypropyl-cellulose,
hydroxypropylmethylcellulose or methylcellulose.
[0018] The granulation may be carried out in a wet phase, for
example in the presence of water or alcohol, or may be performed by
fusion or by compacting. The granulation step may optionally be
left out and the tablets prepared by direct tableting of the
mixture of mizolastine and the excipients.
[0019] Anhydrous colloidal silica and magnesium stearate are added
to the granules obtained and the mixture is tableted. The tablets
are then covered with a coating film by spraying them with a
coating solution in a machine with a fluidized-air bed or in a
coating turbine.
[0020] The example which follows illustrates the invention without
limiting it:
1 % (weight) Tablet mizolastine 4.8 hydrogenated castor oil 12.0
lactose 60.0 microcrystalline cellulose 9.6 L-tartaric acid 9.6
polyvidone 2.9 anhydrous colloidal silica 0.2 magnesium stearate
0.9 purified water Q.S. Total 100.0 Coating
methylhydroxypropylcellulose 74.0 titanium dioxide (E171) 18.5
propylene glycol 7.5 purified water Q.S. Total 100.0
[0021] The dissolution profile obtained with a formulation
according to the invention is given in FIG. 1.
[0022] This profile gives about 50% of product dissolved in 1 hour,
100% of product dissolved in 3 to 5 hours, and it is independent of
the pH.
[0023] The dissolution profile obtained with a formulation
identical to that of the invention but containing no L-tartaric
acid is given in FIG. 2.
[0024] The plasma kinetics of a pharmaceutical form according to
the invention containing 10 mg of mizolastine were studied in a
healthy volunteer after a single oral administration, compared with
a standard immediate-release gelatin capsule containing 10 mg of
mizolastine.
[0025] Table 1 presents the kinetic parameters and FIG. 3 the
curves of the plasma kinetics, obtained respectively with each
formulation; the plasma kinetics obtained with the pharmaceutical
form according to the invention makes it possible to prevent any
peak in the plasma without losing bioavailability.
[0026] The plasma kinetics of a pharmaceutical form according to
the invention were also studied in comparison with the same
formulation without L-tartaric acid.
[0027] The study was performed on twelve healthy volunteers after a
single oral administration of a tablet according to the invention
containing 10 mg of mizolastine or the same tablet without
L-tartaric acid.
[0028] Table 2 shows that the bioavailability of the formulation
containing no L-tartaric acid represents only 43% of that observed
with the formulation according to the invention containing
L-tartaric acid. The values of Cmax and the AUC values (0-.infin.)
are respectively 1.5 and 2 times as high for the formulation
containing L-tartaric acid as for that not containing any.
[0029] In addition, for the formulation with L-tartaric acid, the
min.-max. variation indices are much lower, which suggests great
uniformity in the release.
[0030] The results altogether show that the formulations according
to the invention have:
[0031] a pH-independent dissolution profile,
[0032] an in vivo release which prevents any peak in the
plasma,
[0033] a bioavailability which is not decreased relative to an
immediate-release formulation,
[0034] lower variability of the plasma kinetics results.
* * * * *