U.S. patent application number 10/183771 was filed with the patent office on 2004-01-01 for rapidly disintegrating antihistamine formulation.
Invention is credited to Kositprapa, Unchalee, Nangia, Avinash, Podhipleux, Nilobon, Yuk, Samuel.
Application Number | 20040001885 10/183771 |
Document ID | / |
Family ID | 29779197 |
Filed Date | 2004-01-01 |
United States Patent
Application |
20040001885 |
Kind Code |
A1 |
Kositprapa, Unchalee ; et
al. |
January 1, 2004 |
Rapidly disintegrating antihistamine formulation
Abstract
The invention relates to a rapidly disintegrating oral
antihistamine dosage formulation and method of preparing the
rapidly disintegrating formulation wherein the formulation is
designed to dissolve in the buccal cavity of the patient.
Inventors: |
Kositprapa, Unchalee;
(Davie, FL) ; Podhipleux, Nilobon; (Weston,
FL) ; Nangia, Avinash; (Weston, FL) ; Yuk,
Samuel; (Boca Raton, FL) |
Correspondence
Address: |
Martin P. Endres, Esq.
HEDMAN & COSTIGAN, P.C.
1185 Avenue of the Americas
New York
NY
10036
US
|
Family ID: |
29779197 |
Appl. No.: |
10/183771 |
Filed: |
June 27, 2002 |
Current U.S.
Class: |
424/465 ;
514/255.04; 514/290; 514/53; 514/57; 514/60 |
Current CPC
Class: |
A61K 31/7012 20130101;
A61K 31/495 20130101; A61K 31/473 20130101; A61K 9/0056
20130101 |
Class at
Publication: |
424/465 ;
514/255.04; 514/290; 514/53; 514/57; 514/60 |
International
Class: |
A61K 031/495; A61K
031/473; A61K 031/7012; A61K 009/20 |
Claims
We claim:
1. A rapidly disintegrating oral antihistamine dosage formulation
consisting essentially of: a) 5-40 weight percent of antihistamine
or pharmaceutically acceptable salt thereof; b) 40-90 weight
percent of a filler; c) 0.5-10 weight percent of a binder; d) 0.5
to 10 weight percent of a flavoring agent; and e) 1-15 weight
percent of a disintegrant.
2. The dosage formulation of claim 1 wherein the filler is a
mixture of water soluble and water insoluble fillers.
3. The dosage formulation of claim 2 wherein the water soluble
filler comprises at least 50% of the total amount of filler in the
dosage formulation.
4. The dosage formulation of claim 2 wherein the water soluble
filler comprises at least 60% of the total amount of filler in the
dosage formulation.
5. The dosage formulation of claim 2 wherein the water soluble
filler comprises at least 70% of the total amount of filler in the
dosage formulation.
6. The dosage formulation of claim 1 wherein the antihistamine is
selected from the group consisting of astemizole, azatadine,
cetrizine, descarboethoxyloratadine, fexofenadine, loratadine or a
pharmaceutically acceptable salt thereof.
7. The dosage formulation of claim 1 wherein the antihistamine is
loratadine.
8. The dosage formulation of claim 1 wherein the filler is selected
from the group consisting of lactose, starch, dextrose, sucrose,
fructose, maltose, mannitol, sorbitol, kaolin, microcrystalline
cellulose, powdered cellulose or combinations of the foregoing.
9. The dosage formulation of claim 1 wherein the binder is a water
soluble polymer.
10. The dosage formulation of claim 8 wherein the water soluble
polymer is selected from the group consisting of polyvinyl alcohol,
polyvinylpyrrolidone, methylcellulose, hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, hydroxymethyl cellulose and
combinations of the foregoing.
11. The dosage formulation of claim 1 wherein the disintegrant is
selected from the group consisting of corn starch, croscarmelose
sodium, crospovidone sodium starch glycolate or any combination of
the foregoing.
12. The dosage formulation of claim 10 wherein the disintegrant is
crospovidone or sodium starch glycolate.
13. The dosage formulation of claim 1 wherein the taste enhancing
agent is an artificial sweetener or a flavorant.
14. The dosage formulation of claim 12 wherein the taste enhancing
agent comprises a mixture of artificial sweeteners and
flavorants.
15. The dosage formulation of claim 1 wherein the antihistamine is
5-20 weight percent of the formulation, the filler is 60-85 weight
percent of the dosage formulation, the binder is 1-5 weight percent
of the dosage formulation, the taste enhancing agent is 1-7 weight
percent of the dosage formulation and the disintegrant is 2.5-10
weight percent if the dosage formulation.
16. A rapidly disintegrating oral antihistamine dosage formulation
consisting of: a) 5-20 weight percent of loratadine or
pharmaceutically acceptable salt thereof; b) 60-86 weight percent
of a filler wherein at least 50 percent of the filler is water
soluble; c) 1-5 weight percent of a binder; d) 1-7 weight percent
of a taste enhancing agent; e) 2.5-10 weight percent of a
disintegrant and f) 0-5% of conventional tablet processing
aids.
17. A method for manufacturing a rapidly disintegrating oral
antihistamine oral dosage formulation comprising: a) preparing a
wet granulation consisting essentially of an antihistamine, a
binder and 40-70 weight percent of a first allotment of filler
based upon the total weight of the filler employed in the final
dosage formulation; b) blending the antihistamine granules from
step (a) with a disintegrant, a taste enhancing agent and 30-60
weight percent of a second allotment of filler based upon the total
weight of the filler employed in the final dosage formulation; and
c) compressing the blend of step (b) into a tablet.
18. The method recited in claim 17 wherein the first and second
allotments of filler are mixtures of water soluble and water
insoluble fillers.
19. The method recited in claim 18 wherein the first allotment of
filler comprises 75-100 percent of the total amount of water
insoluble filler used in formulation.
20. A product prepared according to the method recited in claim 17.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to the field of oral dosage
forms and in particular the field of rapidly disintegrating oral
dosage formulations that disintegrate rapidly in the saliva of the
buccal cavity and can be swallowed easily with or without drinking
water. As used in this application the term "rapidly
disintegrating" means that the dosage formulation dissolves in an
aqueous media within 5 minutes, preferably less than two minutes
and most preferably less than one minute.
BACKGROUND OF THE INVENTION
[0002] Antihistamines are a well known class of pharmaceutically
active compounds, some of which are described in U.S. Pat. Nos.
5,869,479, 5,691,370 and Remington's 20.sup.th Ed., pages 1464-1470
which are incorporated herein by reference. Piperidinoalkanol
derivatives which are disclosed in U.S. Pat. No. 4,996,061 and
incorporated herein by reference are a particular class of
antihistamine. Loratadine is a specific type of piperidinoalkanol
and is disclosed in U.S. Pat. No. 4,282,233 as an antihistamine
with little or no sedative effect. Schering Corporation currently
markets a rapidly disintegrating form of loratadine under the
tradename CLARITIN REDITABS. CLARITIN REDITABS contain 10 mg of
micronized loratadine and disintegrate in the mouth within seconds
after placement on the tongue, allowing its contents to be
subsequently swallowed with or without water. CLARITIN REDITABS
also contain citric acid, gelatin, mannitol and mint flavoring. See
Physicians' Desk Reference, 52.sup.nd Ed., pp. 2613-2615.
[0003] Another antihistamine is the active metabolite of
loratadine, known as descarboethoxyloratadine.
Descarboethoxyloratadine is disclosed in U.S. Pat. No. 4,659,716
and is prepared by the removal of the carboethoxy moiety from the
loratadine molecule. Still other antihistamines that are known and
can be used in the present invention are astemizole, azatadine,
cetirizine, fexofenadine and pharmaceutically acceptable salts of
these compounds.
[0004] Rapidly disintegrating dosage formulations are known in the
art. Some rapidly disintegrating dosage formulations are described
in U.S. Pat. Nos. 4,371,516; 5,298,261; 5,587,180; 5,720,974;
5,807,576; 5,866,163; 5,869,098 and 6,048,541 which are
incorporated herein by reference. The prior art rapidly
disintegrating formulations require complicated processing
techniques such as lyophilazation foam techniques or specialized
excipients.
[0005] It is therefore an objective of the present invention to
provide a safe and effective rapidly disintegrating oral
antihistamine dosage formulation that can be economically be
prepared.
SUMMARY OF THE INVENTION
[0006] In the present invention, the filler is a mixture of water
soluble and water insoluble fillers. The rapidly disintegrating
oral dosage formulation of the present invention may also contain
conventional processing aids such as solubilizers, glidants and
lubricants. These conventional processing aids are well know to the
skilled artisan and are used in amounts that do not materially
affect the final properties of the dosage formulation.
[0007] The rapidly disintegrating oral dosage formulation of the
present invention can be prepared by any of the conventional
processing techniques known in the art, however, the preferred
method involves granulation and tableting of the granules. The most
preferred method involves: a) preparing a wet granulation of the
antihistamine, binder and 40-70 weight percent of filler based upon
the total weight of the filler employed in the final dosage
formulation; b) blending the antihistamine granules from step (a)
with the disintegrant, taste enhancing agent and 30-60 weight
percent of filler based upon the total weight of the filler
employed in the final dosage formulation; and c) compressing the
blend of step (b) into a tablet. If a mixture of water soluble and
water insoluble filler is employed in the dosage formulation,
75-100 percent, preferably 100% of the water insoluble filler,
should be used in preparation of the antihistamine granules.
DETAILED DESCRIPTION OF THE INVENTION
[0008] The rapidly disintegrating oral dosage formulation of the
present invention may comprise the following ingredients:
1 INGREDIENT PREFERRED MOST PREFERRED ANTIHISTAMINE 5-40% 5-20%
FILLER 40-90% 60-85% BINDER 0.5-10% 1-5% TASTE ENHANCING AGENT
0.5-10% 1-7% DISINTEGRANT 1-15% 2.5-10%
[0009] All the percentages in the above table are based on the
total weight of the dosage formulation.
[0010] Any antihistamine can be used in the present invention.
Preferred antihistamines are astemizole, azatadine, cetrizine,
descarboethoxyloratadine, fexofenadine, loratadine or a
pharmaceutically acceptable salt thereof. The term
"pharmacologically acceptable salts" encompasses both organic and
inorganic salts including, for example sodium, hydrochloric,
hydrofluoric, sulfuric, sulfonic, tartic, fumaric, hydrobromic,
glycolic, citric, maleic, sulfate, phosphoric, succinic, acetic,
nitric, benzoic, ascorbic, p-toluene sulfonic, benzenesulfonic,
naphthalenesulfonic, propionic, and the like.
[0011] The filler used in the formulation may be any
pharmaceutically acceptable filler. Some of the preferred fillers
are lactose, starch, dextrose, sucrose, fructose, maltose,
mannitol, sorbitol, kaolin, microcrystalline cellulose, powdered
cellulose or any combination of the foregoing. In a preferred
embodiment of the present invention, the filler consists of a
mixture of water soluble and water insoluble fillers. Preferably
the amount of the water soluble filler should be at least 50 weight
percent based upon the total weight of the filler, preferably at
least 60 weight percent based on the total weight of the filler and
most preferably at least 70 weight percent based on the total
weight of the filler.
[0012] The binder may be any pharmaceutically acceptable binder.
The binder is preferably a water soluble polymer of the group
consisting of polyvinyl alcohol, polyvinylpyrrolidone,
methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose
and any combination of the foregoing. Polyvinylpyrrolidone is the
most preferred binder.
[0013] The disintegrant used in the present invention can be
selected from the group consisting of corn starch, croscarmelose
sodium, crospovidone (polyplasdone XL-10, sodium starch glycolate
(EXPLOTAB or PRIMOJEL) or any combination of the foregoing. The
most preferred disintegrant is crospovidone or sodium starch
glycolate.
[0014] The flavoring agent preferably are taste enhancing agents
and can include artificial sweeteners such as aspartame, saccharin,
dipotassium glycyrrhizinate, stevia, thaumatin and flavorants such
as citric acid, peppermint oil, wintergreen oil, menthol, lemon,
lime, orange grape, cherry and vanilla extract. Additional taste
enhancing agents are described in U.S. Pat. No. 6,027,746 and are
incorporated herein by reference. In a preferred embodiment of the
present invention, the flavoring agent is preferably a taste
enhancing agent and may comprise a mixture of artificial sweeteners
and flavorants. The present invention may also comprise
conventional processing aids such as tablet lubricants (magnesium
stearate, sodium stearate), glidants (colloidal silicon dioxide)
and wetting agents or solubilizers (sodium lauryl sulfate,
polysorbates). The processing aids are generally added to the
dosage formulation in small amounts (less than 2 weight percent)
and do not materially affect the properties of the final dosage
formulation. The following example illustrates the present
invention and is not intended to limit the scope of the present
invention.
EXAMPLE 1
[0015] An antihistamine tablet containing loratadine is prepared
according to the following procedure:
[0016] Stage I Homogenation
[0017] 0.333 kg of Povidone K-30 is added to purified water while
homogenizing with a homogenizer for 5 minutes at a speed greater
than about 1,200 r.p.m. to form a solution.
[0018] 0.033 kg of sodium lauryl sulfate is added to the solution.
The homogenizer speed is reduced to below 800 r.p.m. in order to
prevent excess foaming and homogenization is continued for about 2
minutes.
[0019] 3.333 kg of micronized loratadine is slowly added to the
solution and homogenized until the loratadine is completely
dispersed.
[0020] The homogenizer is rinsed and replaced with a mechanical
stirrer and the suspension is stirred continually throughout the
entire process.
[0021] Stage II Coating
[0022] 1.633 kg of Mannitol and 4.667 kg of microcrystalline
cellulose (Avicel.TM. PH101) are loaded onto a fluidized bed coater
and the drug suspension is sprayed onto the substrates. The inlet
air temperature is between 30 and 60.degree. C., outlet air
temperature is between 20 and 45.degree. C., atomization pressure
is between 0.8-3.5 bar, and the pump rate is about 20-120
ml/minute.
[0023] After the suspension is consumed, the pump is stopped and
the granules are dried in the fluidized bed coater for 20 minutes
at 30-40.degree. C. product temperature. If the amount of loss on
drying is greater than 2.5% then the granules are placed in an
oven. The granules are then placed through a co-mil equipped with a
#1143 screen and a 0.175" spacer at 800 to 1500 r.p.m. and
collected.
[0024] Stage III Blending/Granulation
[0025] The following materials as shown in TABLE I as blended for
10 minutes at 32 r.p.m.
2 TABLE I D-Mannitol 1.865 kg Colloidal silicon dioxide (Cab-O-Sil)
0.214 kg Citric Acid 0.088 kg Aspartame 0.188 kg Artificial Cherry
Flavor 0.188 kg Crospovidone (Polyplasdone) 0.588 kg Lactose,
monohydrate 3.5 kg
[0026] The blended mixture is passed through a comil equipped with
a #1143 sized stainless steel screen with a 0.175 spacer at
1200-1800 r.p.m. forming a powder blend.
[0027] The loratadine granules from STAGE III and powder blend are
blended for 10 minutes at 32 rpm.
[0028] Sodium stearate is passed through a 30 mesh screen and
blended for 10 minutes at 32 r.p.m. Unit dose samples are then
collected in separate containers.
[0029] Stage IV Compression
[0030] The blend is then compressed into tablets on a tablet press
using a 1/4 inch round flat-faced beveled-edge die. The tablet
hardness should range between 0.5 and 2.0 kPa, and preferably
around 0.75 to 1.5, most preferably about 1.2 kPa, measured by
techniques commonly used in the art.
[0031] The dosage form described herein can be used to provide fast
relief from colds, Flu, allergies, and other respiratory diseases.
In order to achieve fast release, the tablet is placed inside the
mouth of the patient. The tablet will rapidly disintegrate upon
contact with any aqueous media. In the mouth, the disintegrated
tablet is carried to the stomach where the drug is absorbed and
utilized by the patient to provide antihistamine therapy.
[0032] While certain preferred and alternative embodiments of the
invention have been set forth for purposes of disclosing the
invention, modifications to the disclosed embodiments may occur to
those who are skilled in the art. Accordingly, the appended claims
are intended to cover all embodiments of the invention and
modifications thereof which do not depart from the spirit and scope
of the invention.
* * * * *