U.S. patent application number 10/495007 was filed with the patent office on 2005-03-10 for orodispersible tablets containing fexofenadine.
Invention is credited to Chenevier, Philippe, Faham, Amina, Marechal, Dominique.
Application Number | 20050053654 10/495007 |
Document ID | / |
Family ID | 25542381 |
Filed Date | 2005-03-10 |
United States Patent
Application |
20050053654 |
Kind Code |
A1 |
Faham, Amina ; et
al. |
March 10, 2005 |
Orodispersible tablets containing fexofenadine
Abstract
The present invention concerns orodispersible tablets, which are
able to disintegrate in the buccal cavity upon contact with saliva
by formation of an easy-to-swallow suspension, in less than 60
seconds, preferably in less than 40 seconds, containing
fexofenadine in the form of coated granules, and a mixture of
excipients comprising at least one disintegrating agent, a soluble
diluent agent, a lubricant and optionally a swelling agent, a
permeabilising agent, sweeteners, flavoring agents and colors; the
process for obtaining such orodispersible tablets and the coated
granules incorporated therein and the use of said orodispersible
tablets in the treatment of seasonal allergic rhinitis.
Inventors: |
Faham, Amina; (Montreal,
CA) ; Marechal, Dominique; (Lavas, CA) ;
Chenevier, Philippe; (Montreal, CA) |
Correspondence
Address: |
CAESAR, RIVISE, BERNSTEIN,
COHEN & POKOTILOW, LTD.
11TH FLOOR, SEVEN PENN CENTER
1635 MARKET STREET
PHILADELPHIA
PA
19103-2212
US
|
Family ID: |
25542381 |
Appl. No.: |
10/495007 |
Filed: |
October 25, 2004 |
PCT Filed: |
November 14, 2002 |
PCT NO: |
PCT/EP02/14917 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10495007 |
Oct 25, 2004 |
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|
09995975 |
Nov 16, 2001 |
|
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6723348 |
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Current U.S.
Class: |
424/464 |
Current CPC
Class: |
A61K 9/5026 20130101;
A61K 9/0056 20130101; A61P 43/00 20180101; A61K 9/1611 20130101;
A61P 11/00 20180101; A61K 9/1635 20130101; A61P 37/08 20180101;
A61K 31/445 20130101 |
Class at
Publication: |
424/464 |
International
Class: |
A61K 009/20 |
Claims
1-13. (canceled)
14. Granules of fexofenadine, or one of its pharmaceutically
acceptable salts, wherein the granules are coated and contain:
microcrystals of fexofenadine, or one of its pharmaceutically
acceptable salts, at least one binder selected from the group
consisting of cellulosic polymers, such as ethylcellulose,
hydroxypropylcellulose and hydroxypropylmethylcellulose, acrylic
polymers such as insoluble acrylate ammoniomethacrylate copolymer,
polyacrylate or polymethacrylic copolymer, povidones, copovidones,
polyvinylalcohols, alginic acid, sodium alginate, starch,
pregelatinized starch, sucrose and its derivatives, guar gum,
polyethylene glycol and mixtures thereof.
15. Granules according to claim 14 which further contain a diluent
agent selected from the group consisting of microcrystalline
cellulose, sucrose, dicalcium phosphate starches, lactose, polyols
of less than 13 carbon atoms such as mannitol, xylitol, sorbitol,
maltitol, pharmaceutically acceptable amino acids such as glycin,
and their mixtures, an antistatic agent selected from the group
consisting of micronised or non micronised talc, fumed silica,
precipitated and colloidal silica, a sweetening agent or a coloring
agent.
16. Granules according to claim 14, which further comprise a
disintegrating agent selected from the group consisting of
croscarmellose, crospovidone and mixtures thereof or a surfactant
which can be an anionic, nonionic, cationic or amphoteric
surfactant.
17. Granules according to claim 15, comprising: from 10% to 95% of
fexofenadine, or one of the pharmaceutically acceptable salts
thereof, at most 20% by weight of the binder, relative to the
weight of fexofenadine, or one of the pharmaceutically acceptable
salts thereof, at most 5% of the antistatic agent, relative to the
weight of said granules.
18. Granules according to claim 17, comprising: from 50% to 70% of
fexofenadine, or one of the pharmaceutically acceptable salts
thereof, at most 10% by weight of the binder, relative to the
weight of fexofenadine, or one of the pharmaceutically acceptable
salts thereof, at most 2% by weight of the antistatic agent,
relative to the weight of said granules.
19. Granules according to claim 17, further comprising a diluent
agent for the balance to 100%.
20. Granules according to claim 18, further comprising a diluent
agent for the balance to 100%.
21. Granules according to claim 14, wherein they are coated with a
coating composition containing at least one coating polymer
selected rom the group consisting of cellulosic polymers such as
ethylcellulose, hydroxypropylcellulose and
hydroxypropylmethylcellulose, acrylic polymers such as insoluble
acrylate amoniomethacrylate copolymer, polyacrylate or methacrylic
copolymers, and mixtures thereof.
22. Granules according to claim 21, wherein the coating composition
further contains permeabilizing agents, plasticizers, soluble
agents, disintegrating agents or surfactants.
23. Granules according to claim 14 comprising: from 10% to 95% of
granules of fexofenadine, or one of its pharmaceutically acceptable
salts. from 5 to 90% of a coating polymer, the percentages being
expressed by weight relative to the weight of the granules of the
fexofenadine, or one of its pharmaceutically acceptable salts. from
0 to 10% of a permeabilising agent, the percentages being expressed
by weight relative to the weight of the coating polymer.
24. Granules according to claim 23 comprising: from 40 to 75% of
granules of fexofenadine, or one of its pharmaceutically acceptable
salts, from 10 to 70% of a coating polymer, the percentages being
expressed by weight relative to the weight of the granules of the
fexofenadine, or one of its pharmaceutically acceptable salts. from
0 to 10% of colloidal silica as permeabilising agent, the
percentages being expressed by weight relative to the weight of the
coating polymer.
25. Granules according to claim 24, comprising from 25 to 55% of a
coating polymer.
26. Granules according to claim 23, comprising fexofenadine
hydrochloride.
27. Coated granules of fexofenadine, or one of its pharmaceutically
acceptable salts, according to claim 14, which are coated with a
coating layer containing fexofenadine wherein the granules and the
coating layer comprise each from 70% to 95% by weight of
fexofenadine, or one of the pharmaceutically acceptable salts
thereof, the balance to 100% being formed with at least one
binder.
28. Coated granules of fexofenadine, or one of its pharmaceutically
acceptable salts, according to claim 27, which are coated with a
coating layer containing fexofenadine wherein the granules and the
coating layer comprise each from 80% to 95% by weight of
fexofenadine, or one of the pharmaceutically acceptable salts
thereof, the balance to 100% being formed with at least one
binder.
29. Process for the preparation of granules according to claim 14
wherein it comprises the successive steps consisting in: dry mixing
the microcrystals of the fexofenadine or one of its
pharmaceutically acceptable salts; granulating the mixture obtained
in the above step by spraying of a solution or suspension of at
least one binder, coating the thus obtained granules with a
suspension of a coating composition, drying the thus obtained
coated granules.
30. Process for the preparation of granules according to claim 15,
wherein it comprises the successive steps consisting in: dry mixing
the microcrystals of the fexofenadine or one of its
pharmaceutically acceptable salts with an antistatic agent or a
diluent agent; granulating the mixture obtained in the above step
by spraying of a solution or suspension of at least one binder,
coating the thus obtained granules with a suspension of a coating
composition, drying the thus obtained coated granules.
31. Process for the preparation of granules according to claim 27
wherein it comprises the successive steps consisting in: dry mixing
the microcrystals of the fexofenadine or one of its
pharmaceutically acceptable salts; granulating the mixture obtained
in the above step by spraying of a solution or suspension of at
least one binder, applying a layer over the thus obtained granules
by spraying thereon a suspension, or a solution comprising
fexofenadine, or one of its pharmaceutically acceptable salts with
at lease one binder, coating the thus obtained granules with a
suspension of a coating composition, drying the thus obtained
coated granules.
32. Process according to claim 31 wherein it comprises the
successive steps consisting in: dry mixing the microcrystals of the
fexofenadine or one of its pharmaceutically acceptable salts with
an antistatic agent or a diluent agent; granulating the mixture
obtained in the above step by spraying of a solution or suspension
of a least one binder, applying a layer over the thus obtained
granules by spraying thereon a suspension, or a solution comprising
fexofenadine, or one of its pharmaceutically acceptable salts with
at least one binder, coating the thus obtained granules with
suspension of a coating composition, drying the thus obtained
coated granules.
33. Process for the preparation of tablets according to claim 31,
comprising the successive steps consisting in: preparing coated
granules of fexofenadine, or one of its pharmaceutically acceptable
salts, dry mixing coated granules and a mixture of excipients
consisting of at least one disintegrating agent and a soluble
diluent agent, compressing the mixture of coated granules and
excipients into a tablet.
34. Process for the preparation of tablets according to claim 31,
wherein the mixture of excipients further comprises a lubricant, a
permeabilising agent, a swelling agent, sweeteners, an antistatic
agent, flavorings and colors.
35-36. (canceled).
Description
FIELD OF THE INVENTION
[0001] The present invention concerns orodispersible tablets
comprising coated granules of fexofenadine. The invention also
concerns said coated granules of fexofenadine, a process for the
preparation thereof and the use of said orodispersible tablets.
[0002] In the context of the present invention, the term
"orodispersible tablets" means tablets which are able to
disintegrate in the buccal cavity in less than 60 seconds,
preferably in less than 40 seconds, upon contact with saliva by
formation of an easy-to-swallow suspension.
[0003] The disintegration time corresponds to the time between the
moment when the tablet is placed in the buccal cavity in contact
with saliva and the moment when the suspension (resulting from the
disintegration without chewing of the tablet) is swallowed
BACKGROUND OF THE INVENTION
[0004] Fexofenadine is a well known synthetic antiallergenic with
the chemical name
(.+-.)-4-[1-hydroxy-4-[4(hydroxydiphenylmethyl)-1-piperidin-
yl]-butyl].alpha.,.alpha.-dimethyl benzeneacetic acid.
[0005] Fexofenadine, a metabolite of terfenadine, is an
antihistamine with selective peripheral H1-receptor antagonist
activity.
[0006] Fexofenadine is known from e.g. U.S. Pat. No. 4,254,129. It
is acknowledged in the art and is commercially available, in
particular as an oral tablet or capsule, under the trade name
Allegra.RTM..
[0007] The tablets, commercially available under the trade name
Allegra.RTM. contain 30, 60, or 180 mg fexofenadine hydrochloride
(depending on the dosage) and, as excipients, croscarmellose
sodium, magnesium stearate, microcrystalline cellulose and
pregelatinized starch. Said tablets are coated with a film coating
based on hydroxypropyl methylcellulose, mixture of iron oxides,
polyethylene glycol, povidone, silicone dioxide, and titanium
dioxide.
[0008] Fexofenadine is highly active via oral administration. While
numerous pharmaceutical compositions for oral administration have
been proposed, there still exists a need for commercially
acceptable fexofenadine formulations for oral administration with
good patient convenience and acceptance, especially for children or
the elderly.
[0009] One particular difficulty in the formulation of fexofenadine
in oral pharmaceutical compositions is its unpleasant, strong
bitter taste and aftertaste.
[0010] Another difficulty in the formulation of fexofenadine in
oral pharmaceutical compositions is the low solubility of
fexofenadine, especially in gastric conditions (solubility of 0.2
mg of fexofenadine HCl per ml of pH 1.2 aqueous buffer
solution).
[0011] It is therefore highly desirable to develop coated granules,
containing fexofenadine, which have taste-masking properties while
permitting rapid release of the active substance from the granules
and allowing rapid absorption in the body after oral
administration.
[0012] Furthermore, some patients, especially children and the
elderly, experience difficulties swallowing the tablets, even with
liquids.
[0013] It is estimated that 50% of the population have problems
swallowing the tablets. This leads to poor, or even noncompliance,
with the treatment and thus has a negative impact on the efficiency
of the treatment (H. Seager, 1998, J. Pharm. Pharmacol. 50,
375-382).
[0014] Oral disintegrable multiparticulate tablets have already
been described in U.S. Pat. No. 5,464,632, U.S. Pat. No. 6,106,861,
WO 00/27357 and WO00/51568, the contents of which are hereby
incorporated by reference. The active ingredient is in the form of
coated microcrystals or coated microgranules.
[0015] Up to now, no oral formulations of fexofenadine exist which
are specifically suitable for patients having difficulties when
swallowing or for patients taking the drugs with no liquids.
[0016] It is thus highly desirable to remedy this situation and to
develop an orodispersible tablet, containing fexofenadine, which
has taste-masking properties and presents a pleasant palatability
such that the administration of the tablet is not unpleasant for
the patient and which allows the obtaining of pharmacokinetic
parameters at least bioequivalent to those which are obtained with
conventional oral formulations of fexofenadine, for example tablets
such as those available under the trademark Allegra.RTM..
[0017] The Applicant has now surprisingly found that these
characteristics can be obtained by formulating a tablet containing
fexofenadine as active ingredient in the form of coated granules,
and a mixture of excipients containing at least one disintegrating
agent, a soluble diluent agent and a lubricant, and optionally a
swelling agent, an antistatic agent, a permeabilising agent,
sweeteners, flavoring agents and colors.
[0018] The present invention relates to orodispersible tablets
which are able to disintegrate in the buccal cavity upon contact
with saliva by formation of an easy-to-swallow suspension, in less
than 60 seconds, preferably in less than 40 seconds, such tablets
containing fexofenadine as active ingredient in the form of coated
granules, and a mixture of excipients comprising at least one
disintegrating agent, a soluble diluent agent, a lubricant and
optionally a swelling agent, an antistatic agent, a permeabilising
agent, sweeteners, flavoring agents and colors.
[0019] Surprisingly, although the tablets according to the
invention disintegrate in the buccal cavity and present a release
of the active ingredient which is equivalent to the conventional
formulation, they nevertheless have a pleasant taste.
[0020] Furthermore, the orodispersible tablets of the invention are
found to show high stability and physical integrity, e.g. during
storage, handling, packaging and the like, while maintaining very
good disintegration performance.
[0021] Fexofenadine may be used in the form of its racemate or a
single enantiomer, in free base form or in acid addition salt form
of the racemate or one of its single enantiomers. An acid addition
salt form may be prepared from the free base form in a conventional
manner and vice-versa. Examples of suitable acid addition salt
forms include hydrochloride, lactate and ascorbate, preferably
hydrochloride. Fexofenadine in the form of a hydrochloride salt is
preferred.
[0022] In a preferred embodiment, fexofenadine particles present a
particle size such that 100% of the particles have an average size
of less than 20 .mu.m.
[0023] In the tablets according to the invention, fexofenadine in
anyone of said forms is present as coated granules.
[0024] In the present patent application, the term "fexofenadine"
is employed for designating anyone of its specific forms.
[0025] According to an advantageous embodiment, the tablet
according to the invention, has a hardness of not less than 15 N,
when measured with the test method of the European Pharmacopeia
(2.9.8).
[0026] According to an advantageous embodiment, the tablet
according to the invention contains coated granules of
fexofenadine, or one of its pharmaceutically acceptable salts, and
a mixture of excipients, the ratio of the mixture of excipients to
the coated granules is 0.4 to 9, preferably 1.5 to 5 and even more
preferably 2 to 3 parts by weight, the mixture of excipients
comprising:
[0027] at least one disintegrating agent,
[0028] a soluble diluent agent,
[0029] a lubricant,
[0030] and optionally a permeabilising agent, a swelling agent, an
antistatic agent, sweeteners, flavoring agents and colors.
[0031] The disintegrating agent is selected from the group
consisting of croscarmellose, available as e.g. Ac-di-sol.RTM.,
crospovidone available as e.g. Kollidon CL.RTM., and mixtures
thereof.
[0032] According to an advantageous embodiment of the invention,
the soluble diluent agent used in the tablets presents binding
properties. The soluble diluent agent with binding properties
consists of a polyol having less than 13 carbon atoms and being
either in the form of a directly compressible product with an
average particle size of 100 to 500 .mu.m, or in the form of a
powder with an average particle size of less than 100 .mu.m, this
polyol preferably being selected from the group comprising
mannitol, xylitol, sorbitol and maltitol, it being Understood that
sorbitol cannot be used alone and that, in the case where there is
only one soluble diluent agent with binding properties, it is used
in the form of the directly compressible product, whereas in the
case where there are at least two soluble diluent agents with
binding properties, one is present in the directly compressible
form and the other is present in powder form, it then being
possible for the polyols to be the same, the ratio of directly
compressible polyol to powder polyol being 99/1 to 20/80,
preferably 80/20 to 20/80.
[0033] The proportion of disintegrating agent is from 3 to 15% by
weight, preferably 5 to 15% by weight, in the case of a mixture,
each disintegrating agent being comprised between 1 and 10% by
weight, preferably 5 to 10% by weight, and the proportion of
soluble diluent agent being 30 to 90% by weight, preferably 40 to
60% by weight, based in each case on the weight of the tablet.
[0034] The lubricant is selected from the group consisting of
magnesium stearate, stearic acid, sodium stearyl fumarate,
micronised polyoxyethyleneglycol (micronised Macrogol 6000),
leukine, sodium benzoate and mixtures thereof.
[0035] The amount of lubricant is from 0 to 3%, preferably from 1
to 2% by weight, based on the weight of the tablet.
[0036] The lubricant can be dispersed within the mixture of
excipients, or according to an advantageous embodiment, sprayed
over the outer surface of the tablet. Thus, according to an
advantageous embodiment of the tablets of the invention, the
lubricant is in powder form and is, at least in part, disposed on
the surface of the tablets.
[0037] The permeabilising agent allows the creation of a
hydrophilic network which facilitates the penetration of saliva and
hence assists the disintegration of the tablet.
[0038] The permeabilising agent is selected from the group
comprising especially silica with a high affinity for aqueous
solvents, such as colloidal silica (Aerosil.RTM.), precipitated
silica (Sylod.RTM. FP 244), maltodextrins, .beta.-cyclodextrins and
mixtures thereof.
[0039] The amount of permeabilising agent is between 0 and 5%,
preferably from 0.5 to 2% by weight, based on the weight of the
tablet.
[0040] A swelling agent can be incorporated in the mixture of
excipients. Said swelling agent is selected from the group
consisting of starch, modified starch or microcristalline
cellulose.
[0041] An antistatic agent can be incorporated as a flow aid, said
antistatic agent being selected from the group consisting of
micronised or non micronised talc, fumed silica (Aerosil.RTM.
R972), colloidal silica (Aerosil.RTM.200), precipitated silica
(Sylod.RTM. FP 244), and mixtures thereof.
[0042] The sweetener which can be included in the mixture of
excipients, can be selected from the group consisting of especially
aspartam, potassium acesulfame, sodium saccharinate, neohesperidin
dihydrochalcone, sucralose, monoammonium glycyrrhizinate, and
mixtures thereof.
[0043] The flavorings and colors are those conventionally used in
pharmacy for the preparation of tablets.
[0044] The present invention also relates to the coated granules of
fexofenadine or one of its pharmaceutically acceptable salts.
[0045] The taste-masking of fexofenadine is achieved by coating
granulated microcrystals of fexofenadine with one or more
polymers.
[0046] According to an advantageous embodiment of the invention,
the granules of fexofenadine, or one of its pharmaceutically
acceptable salts, are characterized in that the granules are coated
and that they contain:
[0047] microcrystals of fexofenadine, or one of its
pharmaceutically acceptable salts,
[0048] at least one binder,
[0049] optionally a diluent agent, an antistatic agent, a
sweetening agent and/or a coloring agent.
[0050] Furthermore, the granulation excipients can also include
disintegrating agents and/or surfactants.
[0051] The binder is selected from the group consisting of
cellulosic polymers, such as ethylcellulose, hydroxypropylcellulose
and hydroxypropylmethyl cellulose, acrylic polymers, such as
insoluble acrylate ammoniomethacrylate copolymer, polyacrylate or
polymethacrylic copolymer, povidones, copovidones,
polyvinylalcohols, alginic acid, sodium alginate, starch,
pregelatinized starch, sucrose and its derivatives, guar gum,
polyethylene glycol, preferably an acrylic polymer, most preferably
Eudragit.RTM. E100, and mixtures thereof.
[0052] Optionally, in order to enhance the granulation of the
fexofenadine or one of its pharmaceutically acceptable salts, a
diluent agent is used.
[0053] The diluent agent is selected from the group consisting of
microcrystalline cellulose, sucrose, dicalcium phosphate, starches,
lactose and polyols of less than 13 carbon atoms, such as mannitol,
xylitol, sorbitol, maltitol, pharmaceutically acceptable amino
acids, such as glycin, and their mixtures.
[0054] The antistatic agent, which can be used as flow aid, is
selected from the group consisting of micronised or non micronised
talc, fumed silica (Aerosil.RTM. R972), colloidal silica
(Aerosil200), precipitated silica (Sylod.RTM. FP244) and mixtures
thereof.
[0055] Conventional pharmaceutically acceptable sweetening agents
and/or colouring agents can be incorporated into the granules of
fexofenadine.
[0056] In a particular embodiment, the granule of fexofenadine or
one of its pharmaceutically acceptable salts, is in the form of a
core of granulated microcrystals of fexofenadine, coated with at
least one layer comprising fexofenadine.
[0057] Said coated core is characterized in that the core and the
layer comprise each from 70% to 95%, preferably 80% to 95% by
weight of fexofenadine, or one of the pharmaceutically acceptable
salts thereof, the balance to 100% being formed with at least one
binder, and that said coated core is advantageously a sphere. Such
a specific structure has previously been described by the Applicant
in the French patent application FR 00 14803.
[0058] According to another embodiment of the invention, the
granules comprise:
[0059] from 10% to 95%, preferably from 50% to 70% of fexofenadine,
or one of the pharmaceutically acceptable salts thereof,
[0060] at most 20%, preferably at most 10% by weight of the binder,
relative to the weight of fexofenadine, or one of the
pharmaceutically acceptable salts thereof,
[0061] at most 5%, preferably 2% by weight of the antistatic agent,
relative to the weight of said granules
[0062] optionally a diluent agent for the balance to 100%.
[0063] In order to ensure efficient taste masking, and a
dissolution profile of the active substance such that more than 70%
of the active substance is released in 30 minutes, preferably more
than 90% is released in 30 minutes, the granules are coated with a
coating composition containing at least one coating polymer
selected from the group consisting of cellulosic polymers, acrylic
polymers and their mixtures.
[0064] Among the cellulosic polymers, ethylcellulose,
hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose
(HPMC), are advantageously used.
[0065] Among the acrylic polymers, insoluble acrylate
ammoniomethacrylate copolymer (Eudragit.RTM. RL100 or RS100 or
Eudragit.RTM. RL30D or RS30D), polyacrylate (Eudragit.RTM.NE30D),
or methacrylic copolymers (Eudragit.RTM. L100-55 or Eudragit.RTM.
L30D, Eudragit.RTM. E100, Eudragit.RTM. EPO . . . ) are
advantageously used, alone, in combination or in admixture with
pH-dependent polymers. Eudragit.RTM. E100 or a mixture of
Eudragit.RTM. EPO and Eudragit.RTM.NE30D are preferred.
[0066] In a preferred embodiment, the binder and the coating
polymer are the same polymer.
[0067] The prepared coating liquid is either water-based or
prepared with organic solvents. According to an advantageous
embodiment, this coating liquid is suitable to be sprayed with
conventional spray layering equipment, as for example a fluidized
bed equipped with a top insert or bottom (wurster) insert.
[0068] Optionally permeabilising agents, plasticizers, soluble
agents, disintegrating agents and surfactants are added as coating
additives.
[0069] The plasticizer is selected in the group consisting of
triacetine, triethylacetate, triethylcitrate (Eudraflex.RTM.),
ethylphthalate, or mixtures thereof. The plasticizer is used in
proportions of at most about 30%, preferably 10% by weight of the
coating polymers.
[0070] The soluble agents are selected in particular among the
polyols having less than 13 carbon atoms.
[0071] The disintegrating agent or a surfactant which could be
added during the granulation and the coating steps allow improved
dissolution.
[0072] The surfactant may be an anionic, nonionic, cationic or
amphoteric surfactant.
[0073] The disintegrating agent is selected from the group
consisting of croscarmellose, available as e.g. Ac-di-sol.RTM.,
crospovidone available as e.g. Kollidon CL.RTM., and mixtures
thereof.
[0074] The particle size range of coated granules comprising
fexofenadine, or one of its pharmaceutically acceptable salts is
adapted for obtaining an effective taste masking with an acceptable
coating factor and a good mouthfeel.
[0075] Advantageously the coated granules according to the
invention have a particle size distribution between 150 .mu.m and
500 .mu.m, preferably between 150 .mu.m and 425 .mu.m, such that at
least 50%, preferably at least 70% of the granules have a particle
size ranging between 150 and 425 .mu.m and less than 15% of the
granules have a particle size less than 150 .mu.m. The particle
sizes are measured according to conventional methods, preferably by
sieving.
[0076] A granulation step is needed in order to obtain such
particle size distribution.
[0077] In a particular embodiment, the coated granules according to
the invention comprise:
[0078] from 10% to 95%, preferably 40 to 75% of granules of
fexofenadine, or one of its pharmaceutically acceptable salts,
preferably fexofenadine HCl,
[0079] from 5 to 90%, preferably 10 to 70% and even more preferably
from 25 to 55% of a coating polymer, preferably Eudragit.RTM. E100,
the percentages being expressed by weight relative to the weight of
the granules of fexofenadine, or one of its pharmaceutically
acceptable salts,
[0080] from 0 to 10% of a permeabilising agent, preferably
colloidal silica, the percentages being expressed by weight
relative to the weight of the coating polymer.
[0081] Determination of workable proportions in any particular
instance will generally be within the capability of the person
skilled in the art. All indicated proportions and relative weight
ranges described above are accordingly to be understood as being
indicative of preferred or individually inventive teachings only
and not as limiting the invention in its broadest aspect.
[0082] Details concerning any of the excipients of the invention
may be found in Fiedler, H. P. "Lexikon der Hilfsstoffe fur
Pharmazie, Kosmetik und angrenzende Gebiete", Editio Cantor Verlag
Aulendorf, Aulendorf, 4th revised and expanded edition (1996);
"Handbook of Pharmaceutical Excipients", 2nd Edition, Editors A.
Wade and P. J. Weller (1994), Joint publication of American
Pharmaceutical Association, Washington, USA and The Pharmaceutical
Press, London, England; or may be obtained from the relevant
manufacturers, the contents of which are hereby incorporated by
reference.
[0083] The invention also relates to a process for the preparation
of coated granules of fexofenadine, which comprises the successive
steps consisting in:
[0084] dry mixing the microcrystals of fexofenadine or one of its
pharmaceutically acceptable salts optionally with an antistatic
agent and/or a diluent agent;
[0085] granulating the mixture obtained in the above step by
spraying of a solution or suspension of at least one binder,
[0086] optionally applying a layer over the thus obtained granules
by spraying thereon a suspension, or a solution comprising
fexofenadine, or one of its pharmaceutically acceptable salts with
at least one binder,
[0087] coating the thus obtained granules with a suspension of a
coating composition,
[0088] drying the thus obtained coated granules.
[0089] The invention also concerns a process for preparing
orodispersible tablets comprising coated granules of fexofenadine,
or one of its pharmaceutically acceptable salts.
[0090] The process comprises the successive steps consisting
in:
[0091] dry mixing the microcrystals of fexofenadine, or one of its
pharmaceutically acceptable salts, optionally with an antistatic
agent, a diluent agent, a permeabilising agent, a sweetening agent
and/or a coloring agent;
[0092] granulating the thus obtained mixture by spraying thereon a
solution or a suspension of at least one binder,
[0093] optionally applying a layer over the thus obtained granules
by spraying thereon a suspension, or a solution comprising
fexofenadine, or one of its pharmaceutically acceptable salts with
at least one binder.
[0094] coating the thus obtained granules by spraying thereon a
suspension, a dispersion or a solution of the coating
composition,
[0095] drying the thus obtained coated granules,
[0096] dry mixing coated granules and a mixture of excipients
consisting of at least one disintegrating agent, a soluble diluent
agent, and optionally a lubricant, a permeabilising agent, a
swelling agent, sweeteners, an antistatic agent, flavorings and
colors,
[0097] compressing the mixture of coated granules and excipients
into a tablet.
[0098] The lubricant can be mixed with the excipients for the
tablet, but can advantageously be sprayed on the surface of the
punches before tabletting.
[0099] In this process the mixing, granulating and coating steps
can be performed in different or in the same equipment, each step
being performed in the presence of a mixture of excipients which
are identical or different.
[0100] For granulating, high shear mixer, planetary mixer or
fluidized bed with insert used for bottom spray, granulation,
tangential spray granulation, top spray granulation can be used,
bottom spray granulation being preferred.
[0101] In an advantageous embodiment, each step is performed on a
fluidized air-bed, such as for example, but not limited to Glatt
GPCG-1, GPCG-3, GPCG-5 or GPCG 120.
[0102] For coating, bottom, top and tangential spray methods can be
used as well as layering method, bottom spray method of coating
being preferred.
[0103] For compressing the mixture of coated granules and
excipients into a tablet, various punches may be used, with
diameters comprised between 8 and 17 mm, depending upon the dosage
of the tablet.
[0104] Various shapes may be used, such as for example, flat shape,
advantageously with bevelled edges or polo punches.
[0105] The orodispersible tablets of the present invention show
rapid disintegration in the buccal cavity upon contact with saliva
without chewing, in less than 60 seconds, preferably in less than
40 seconds, have a pleasant taste and palatability and thus have
particularly good patient convenience and patient acceptance due to
their increased ease of administration and ingestion.
[0106] In addition the tablets of the invention show surprisingly
high physical stability and are easy to handle and package.
[0107] According to a preferred embodiment, the tablet of the
invention presents the following composition:
[0108] granules of Fexofenadine HCl coated with Eudragit.RTM.
E100,
[0109] and a mixture of excipients consisting of Eudragit.RTM.
E100, mannitol powder, mannitol granular, Crospovidone,
precipitated silica, sweeteners and flavors.
[0110] For the preparation of said tablets, isopropanol is used as
solvent and removed during the coating and granulation
processes.
[0111] According to an advantageous embodiment, the tablet of the
invention has the following composition:
[0112] Fexofenadine Coated Granules
1 Fexofenadine HCl 40-80% Eudragit .RTM. E100 20-60% Precipitated
silica 0-5%
[0113] the percentages being calculated by weight of coated
granules,
[0114] Excipients for the Formulation of the Tablet
2 Fexofenadine coated granules 10-45% Mannitol powder and/or
granular 50-90% Crospovidone 2-15% Precipitated silica 0-5%
Magnesium stearate 0-5% Sucralose 0-5% Flavors 0-2%
[0115] the percentages being calculated by weight of the
tablet.
[0116] For the preparation of said tablets, isopropanol is used as
solvent and removed during the coating and granulation
processes.
[0117] The tablets are particularly effective in treating seasonal
allergic rhinitis, in adults and children 6 years of age and
older.
[0118] The present invention also concerns-the use of a coated
granules of fexofenadine with a mixture of excipients, as described
above, for the manufacture of a medicament for the treatment of
symptoms associated with seasonal allergic rhinitis.
[0119] The present invention relates also to methods for the
treatment of symptoms associated with seasonal allergic rhinitis,
in which the tablets of fexofenadine according to the invention are
orally administered.
[0120] Symptoms treated effectively include sneezing, rhinorrhea,
itchy nose/palate/throat, itchy/watery, rhinitis.
[0121] The utility of the tablets of the present invention may be
observed in standard bioavailability tests or standard animal
models, for example ascertaining dosages of the present tablets
giving blood levels of fexofenadine hydrochloride equivalent to
blood levels having a therapeutical effect on administration of
known fexofenadine oral dosage forms, e.g. a tablet.
[0122] The appropriate dosage will, of course, vary depending upon,
for example, the host and the nature and severity of the condition
being treated. However, in general satisfactory results in animals
are indicated to be obtained by daily treatments. In humans an
indicated daily dosage is in the range from about 10 mg to about
500 mg per day, preferably from 30 mg to 180 mg, conveniently
administered, for example, in divided doses up to four times a day
or once daily. Preferred dosages, expressed as fexofenadine HCl,
for children 6 to 11 years of age are about 30 mg two times a day,
and for adults and children 12 years of age and older from about 60
mg two times a day, or 180 mg once a day.
[0123] The invention is illustrated more in detail in the following
examples.
EXAMPLES
[0124] Particle size of Fexofenadine HCl used for the manufacture
of granules of examples 1 to 4 is measured with conventional laser
equipment.
[0125] Particle size distribution has following
characteristics:
3 D.sub.10% 2.1 .mu.m D.sub.50% 5.3 .mu.m D.sub.90% 11.1 .mu.m
[0126] In the examples below, the following excipients are
used:
[0127] Methacrylic polymer sold under tradename Eudragit.RTM.EPO or
Eudragit.RTM. E100.
[0128] Polyacrylate sold under the tradename Eudragit.RTM.
NE30D.
[0129] Mannitol powder
[0130] Mannitol granular 300
[0131] Sucralose
[0132] Aspartam
[0133] Peppermint, wildberry as flavoring agents
[0134] Precipitated silica sold under the name Sylod FP244
[0135] Polyvinylpyrrolidone sold under the name PVP K90
[0136] Examples 1 to 4 relate to the preparation of coated granules
of fexofenadine.
Example 1
[0137] Granulating Step
[0138] 500 g of fexofenadine HCl mixed with 15 g of Sylod FP 244
were granulated in a fluidized bed with 465 g of a mixture of
Eudragit EPO/Eudragit NE30D (50/50) in water at 16%
(weight/weight).
[0139] Coating Step:
[0140] The thus obtained granules were coated in a fluidized bed
equipped with a top insert, by spraying thereon a dispersion of 465
g of a mixture of Eudragit EPO/Eudragit NE30D (50/50) in water at
16% (weight/weight).
[0141] The amount of coating was of 12.5% by weight with respect to
the weight of the granules of fexofenadine HCl.
[0142] The dissolution rates of the thus obtained coated granules
were measured with the following method:
4 Apparatus USP Apparatus II (Paddle method) Speed 50 rpm Volume
900 mL of HCl 0.001 N pH 3.0* Temperature 37.0.degree. C. .+-.
0.5.degree. C. Sampling (5 mL) 2.5, 7.5, 15, 30 and 60 minutes HPLC
Detection UV at 220 nm HPLC column Zorbax SB-Phenyl, 5 .mu.m, 4.6
.times. 250 mm. Injection volume 20 .mu.L Mobile Phase
Acetonitrile: 0.03 M Acetic acid containing Triethylamine pH 5.25
(36:64). Dissolution medium HCl 0.001 N adjusted to pH 3.0 .+-.
0.05 (if necessary) with o-Phosphoric acid.
[0143] The results are given in the following table 1:
5 TABLE 1 Dissolved fexofenadine in % (w/w) 5 minutes 55% 10
minutes 70% 15 minutes 75% 30 minutes 85%
[0144] More than 80% of fexofenadine is dissolved after 30 minutes,
taste-masking is efficient.
Example 2
[0145] Granulating Step
[0146] 500 g of fexofenadine HCl mixed with 15 g of Sylod FP244
were granulated in a fluidized bed with 30 g of an aqueous solution
of PVP K90 at 8% (weight/weight).
[0147] Coating Step:
[0148] The thus obtained granules were coated in a fluidized bed
equipped with a top insert, by spraying thereon a mixture of
Eudragit EPO/Eudragit NE30D (60/40) in water at 16%
(weight/weight)
[0149] The amount of coating was of 40% by weight with respect to
the weight of the granules of fexofenadine HCl.
[0150] The particle size distribution (Sieve method) is given in
the following table.
6TABLE 2 Sieve operture After Granulating step After Coating step
>0.500 mm 14.5% 5.7% 0.425 mm-0.500 mm 13.0% 24.1% 0.355
mm-0.425 mm 20.0% 9.5% 0.250 mm-0.355 mm 30.5% 28.9% 0.150 mm-0.250
mm 21.5% 31.5% <0.150 mm 0.5% 0.3%
[0151] The dissolution rates of said granules were measured as
indicated in example 1 above.
[0152] The results are given in the following table 3:
7 TABLE 3 Dissolved fexofenadine in % (w/w) 5 minutes 65% 10
minutes 85% 15 minutes 100% 30 minutes 100%
[0153] More than 80% of fexofenadine is dissolved after 30 minutes,
taste-masking is efficient.
Example 3
[0154] Granulating Step
[0155] 1000 g of fexofenadine HCl mixed with 30 g of Sylod FP 244
were granulated in a fluidized bed equipped with a Wurster insert
with 1 500 g of an solution of Eudragit E100 in isopropanol at 12%
(weight/weight).
[0156] Coating Step:
[0157] The thus obtained granules were coated in a fluidized bed
equipped with a top insert, by spraying thereon a polymeric
dispersion of 3 900 g of Eudragit E100 in isopropanol at 12%
(weight/weight) containing 1% of Sylod FP 244.
[0158] The amount of coating was of 38% by weight with respect to
the weight of the granules of fexofenadine HCl.
[0159] The particle size distribution (Sieve method) is given in
the following table.
8 TABLE 4 Sieve operture Coated granules >0.600 mm 0% 0.500
mm-0.600 mm 1.0% 0.425 mm-0.500 mm 9.2% 0.355 mm-0.425 mm 18.6%
0.250 mm-0.355 mm 36.2% 0.150 mm-0.250 mm 30.2% 0.090 mm-0.150 mm
3.4% <0.090 mm 1.4%
[0160] The dissolution rates of said granules were measured as
indicated in example 1 above.
[0161] The results are given in the following table 5:
9 TABLE 5 Dissolved fexofenadine in % (w/w) 5 minutes 55% 10
minutes 85% 15 minutes 95% 30 minutes 100%
[0162] More than 80% of fexofenadine is dissolved after 30 minutes,
taste-masking is efficient.
Example 4
[0163] Granulating Step
[0164] 1000 g of fexofenadine HCl mixed with 30 g of Sylod FP 244
were granulated in a planetary mixer with 400 g of an solution of
Eudragit E100 in isopropanol at 12% (weight/weight).
[0165] Coating Step:
[0166] The obtained granules were coated in a fluidized bed
equipped with a Wurster insert, by spraying thereon a solution of
Eudragit E100 in isopropanol at 10% (weight/weight) containing 1%
of Sylod FP 244.
[0167] The amount of coating was of 30% by weight with respect to
the weight of the granules of fexofenadine HCl.
[0168] The dissolution rates of said granules were measured as
indicated in example 1 above.
[0169] The results are given in the following table 6:
10 TABLE 6 Dissolved fexofenadine in % (w/w) 5 minutes 40% 10
minutes 80% 15 minutes 95% 30 minutes 100% 100% of fexofenadine is
dissolved after 30 minutes, taste-masking is efficient.
[0170] Examples 5-8 relate to the preparation of tablets.
Example 5
[0171] Three types of tablets T.sub.1, T2, T3 were prepared using
coated granules of fexofenadine presenting different coating
ratios. The coated granules of fexofenadine were obtained as in
example 3 above but using the three different coating ratios of 30,
35 and 40. Then, an amount of each type of said coated granules
corresponding to 180 mg of fexofenadine HCl was thoroughly blended
for 15 minutes with the following tablet excipients.
11 Crospovidone 10% Silica 0.5% Magnesium stearate 0.5% Aspartame
2% Flavor 1% Mannitol powder(60 .mu.m)/granular (330 .mu.m) (2/1)
qs 100%
[0172] The percentages are expressed as percentage of the total
weight of a tablet.
[0173] The homogeneous obtained blend was introduced in a
tabletting machine equipped with 14 mm-diameter polo shape
punches.
[0174] These tablets T1, T2 and T3 were obtained.
[0175] For each tablet thus obtained, the weight, hardness,
disintegrating time in mouth, mouthfeel and taste were
measured.
[0176] The results are displayed in the table 7
12 TABLE 7 Tablets T1 T2 T3 Coated granule ratio 30 35 40 (% by
weight) Weight 920 mg 780 mg 690 mg Hardness 44 N 39 N 45 N
Disintegration time 15-20 sec. 15-20 sec 20-25 sec. in mouth
Mouthfeel Complies Complies Complies Taste Complies Complies
Complies T1, T2, T3 present an acceptable dissolution rate with
good taste and pleasant mouthfeel and disintegrate in buccal cavity
in less than 30 seconds.
Example 6
[0177] As in example 5, three types of tablets (T4, T5, T6)
presenting coated granules of fexofenadine with coating ratios of
30, 35, 40 were prepared but using an amount of fexofenadine HCl
equivalent to 30 mg per tablet.
[0178] The homogeneous obtained blend was introduced in a
tabletting machine equipped with polo shape punches as described in
the table.
[0179] Results are displayed in the table 8
13 TABLE 8 Tablets T4 T5 T6 Coated granule ratio 30 35 40 (% by
weight) Punch diameter 8 mm 7 mm 6 mm Weight 153 mg 131 mg 115 mg
Hardness 44 N 39 N 45 N Disintegration time 15-20 sec. 15-20 sec
20-25 sec. in mouth Mouthfeel Complies Complies Complies Taste
Complies Complies Complies Tablets T4, T5 and T6 present an
acceptable taste and pleasant mouthfeel and disintegrate in buccal
cavity in less than 30 seconds.
Example 7
[0180] Tablets T7 according to the formula of T2 of example 5 are
manufactured, using a ratio of Mannitol powder/Mannitol granular
ratio of 1/1, containing an amount of fexofenadine HCl equivalent
to 180 mg per tablet.
[0181] The homogeneous obtained blend was introduced in a
tabletting machine equipped with 14 mm-diameter polo shape
punches.
[0182] The disintegration time in the mouth, the mouthfeel and
taste were evaluated.
[0183] The results are displayed in the table 9.
14 TABLE 9 Tablets T7 Disintegration time in mouth 25 sec.
Mouthfeel Complies Taste Complies Tablets T7 with a mannitol
powder/granular ratio of 1/1 (w/w) present a good taste and
pleasant mouthfeel and disintegrate in buccal cavity in less than
30 seconds.
Example 8
[0184] Three types of tablets (T8, T9, T10 ) according to the
formula T2 of example 5 were manufactured but using three different
ratios of crospovidone of 5, 7.5 and 10% by weight.
[0185] The homogeneous obtained blend was introduced in a
tabletting machine equipped with 14mm-diameter polo shape.
[0186] Tablets T8, T9 and T10 were thus obtained. The
disintegrating time in mouth, the hardness, the mouthfeell and
taste were evaluated, the results are displayed in table 10.
15 TABLE 10 Tablets T8 T9 T10 Crospovidone ratio 5 7.5 10 (% by
weight) Hardness 44 N 45 N 45 N Disintegration time 20-25 sec.
20-25 sec 20-25 sec. in mouth Mouthfeel Complies Complies Complies
Taste Complies Complies Complies Tablets T8, T9 and T10 present an
acceptable taste and pleasant mouthfeel and disintegrate in buccal
cavity in less than 30 seconds.
Exemple 9
Pharmacokinetic Studies
[0187] A bioequivalence study was conducted with two tablets (T11
and T12) according to the invention versus Allegra.RTM. 180 mg
(Reference).
[0188] 15 subjects received T11 versus Reference and 13 subjects
received T12, each versus Reference
[0189] The respective compositions of T11 and T12 are given
below:
16 Fexofenadine HCl coated granules T11 T12 Fexofenadine HCl 48.4%
58.2% Eudragit E100 47.4% 37.7% Silica 4.2% 4.1%
[0190] Tablets
17 Coated granules corresponding to 30% 180 mg of Fexofenadine HCl
Crospovidone 5% Silica 0.5% Magnesium stearate 1% Sucralose 2%
Flavor 0.2% Mannitol powder(60 .mu.m)/granular (330 .mu.m) (1/1) qs
100%
[0191] Said tablets were prepared according to the process of
example 5 above. The tablets (Prototype and Reference) were
administered to fasting patients. Pharmacokinetic parameters
obtained for each prototype A and B and Reference are listed in
tables 11 and 12:
18TABLE 11 Test 1 (n = 15)-mean values AUC (CV) Cmax (CV) Tmax (CV)
Reference 3132.2 453.8 2.0 T11 3804.4 571.2 2.9 (% as exp. versus
reference) (121) (126) (144) T11 under fasting conditions has
slightly higher bioavailability relative to the reference.
[0192]
19 TABLE 12 Test 2 (n = 13)-mean values AUC Cmax Tmax Reference
3017.0 457.3 2.2 T12 3047.1 409.8 2.6 (% as exp. versus reference)
(101) (90) (115) T12 under fasting is bioequivalent relative to the
reference tablet.
* * * * *