U.S. patent application number 12/293857 was filed with the patent office on 2009-08-20 for orally disintegrating tablets.
Invention is credited to Pradnya Bagde, Anilkumar S. Gandhi, Hetal N. Morvekar, Pratibha S. Pilgaonkar, Maharukh T. Rustomjee.
Application Number | 20090208576 12/293857 |
Document ID | / |
Family ID | 38562805 |
Filed Date | 2009-08-20 |
United States Patent
Application |
20090208576 |
Kind Code |
A1 |
Gandhi; Anilkumar S. ; et
al. |
August 20, 2009 |
Orally Disintegrating Tablets
Abstract
The present invention describes a directly compressible
composite prepared by co-processing a water-soluble excipient and
calcium silicate. The present invention further describes the
incorporation of the co-processed composite into a tablet
formulation. The orally disintegrating tablets are of optimal
mechanical strength and disintegrate within 60 seconds in the oral
cavity.
Inventors: |
Gandhi; Anilkumar S.;
(Mumbai, IN) ; Bagde; Pradnya; (Mumbai, IN)
; Morvekar; Hetal N.; (Mumbai, IN) ; Pilgaonkar;
Pratibha S.; (Mumbai, IN) ; Rustomjee; Maharukh
T.; (Mumbai, IN) |
Correspondence
Address: |
Mallinckrodt Inc.
675 McDonnell Boulevard
HAZELWOOD
MO
63042
US
|
Family ID: |
38562805 |
Appl. No.: |
12/293857 |
Filed: |
March 30, 2007 |
PCT Filed: |
March 30, 2007 |
PCT NO: |
PCT/IN07/00138 |
371 Date: |
September 22, 2008 |
Current U.S.
Class: |
424/479 ;
424/474 |
Current CPC
Class: |
A61P 25/04 20180101;
A61P 29/00 20180101; A61K 9/2009 20130101; A61K 9/0056 20130101;
A61K 9/2081 20130101; A61K 9/1652 20130101; A61P 25/18 20180101;
A61K 9/2018 20130101; A61K 47/38 20130101; A61K 9/1611 20130101;
A61K 47/26 20130101; A61K 9/1623 20130101; A61P 25/24 20180101;
A61K 9/1635 20130101; A61K 47/02 20130101; A61P 25/28 20180101 |
Class at
Publication: |
424/479 ;
424/474 |
International
Class: |
A61K 9/36 20060101
A61K009/36; A61K 9/28 20060101 A61K009/28 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 31, 2006 |
IN |
498/MUM/2006 |
Claims
1. A directly compressible composite for an orally disintegrating
tablet comprising at least one water-soluble excipient and calcium
silicate prepared by co-processing.
2. A directly compressible composite as claimed in claim 1, wherein
the water soluble excipient is a carbohydrate, a water soluble salt
or a polyhydric alcohol or its derivative.
3. A directly compressible composite as claimed in claim 2, wherein
the water soluble carbohydrate is a monosaccharide, disaccharide,
oligosaccharide or polysaccharide.
4. A directly compressible composite as claimed in claim 3, wherein
the monosaccharide is xylose, glucose, mannose, fructose,
galactose, and sorbitol.
5. A directly compressible composite as claimed in claim 3, wherein
the disaccharide is maltose, lactose, cellobiose, sucrose, mannitol
and trehalose.
6. A directly compressible composite as claimed in claim 3, wherein
the oligosaccharide is raffinose and dextrates.
7. A directly compressible composite as claimed in claim 3, wherein
the polysaccharide is maltodextrins.
8. A directly compressible composite as claimed in claim 2, wherein
the water soluble salt is sodium chloride.
9. A directly compressible composite as claimed in claim 2, wherein
the water soluble polyhydric alcohol is propylene glycol,
polyethylene glycol and glycerin.
10. A directly compressible composite as claimed in claim 1,
wherein calcium silicate has an aspect ratio of about 1:1 to about
2.5:1 and an oil absorption of from about 20 ml/100 gm to 220
ml/100 gm.
11. A directly compressible composite as claimed in claim 1 wherein
the ratio of at least one water-soluble excipient and calcium
silicate is from about 50:1 to about 1:50.
12. A directly compressible composite as claimed in claim 1 wherein
the ratio of at least one water-soluble excipient and calcium
silicate is preferably from about 30:1 to about 1:30 and more
preferably from about 20:1 to about 1:20.
13. A directly compressible composite as claimed in claim 1 wherein
the composite has not less than 40% of particles less than 150
microns.
14. A directly compressible composite as claimed in claim 1 wherein
the composite has loss on drying of less than 2% w/w.
15. A directly compressible composite as claimed in claim 1 wherein
the composite has porosity of at least about 50%.
16. A method for producing a directly compressible composite as
claimed in claim 1, wherein co-processing involves processes such
as physical mixing, wet mixing, complexation, precipitation, spray
drying, lyophilization, microencapsulation, spray congealing, hot
melt, gas antisolvent or rapid evaporation of supercritical solvent
methods employed with supercritical fluid processing.
17. A method for producing a directly compressible composite as
claimed in claim 1, wherein co-processing involves spray
drying.
18. A method for producing a directly compressible composite as
claimed in claim 1, wherein the spray drying method comprises: a.
Dissolving the water soluble excipient in water. b. Adding calcium
silicate with stirring to solution of step-a. c. Homogenising the
blend to make it uniform. d. Drying the mixture in an air stream,
e. Forming the co-processed excipient.
19. A method for producing a directly compressible composite
wherein the spray drying method comprises: a. Dissolving mannitol
in water. b. Adding calcium silicate under stirring to solution of
step-a. c. Homogenising the blend to make it uniform. d. Drying the
mixture in an air stream, e. Forming the co-processed
excipient.
20. An orally disintegrating tablet formulation having optimal
mechanical strength comprising a. at least one pharmaceutically
active ingredient or a nutraceutical agent b. composites produced
by co-processing of at least one water soluble excipient and
calcium silicate. c. At least one other excipient. such that the
tablet has optimal mechanical strength and a disintegration time of
about 60 seconds in the oral cavity,
21. An orally disintegrating tablet as claimed in claim 20, wherein
the active ingredient is selected from gastrointestinal function
conditioning agents anti-inflammatory agents, including, but not
limited to aceclofenac, ibuprofen, diclofenac, flubiprofen,
piroxicam, sulindac, and celecoxib; analgesics, including, but not
limited to acetaminophen, fentanyl, tramadol and aspirin; agents
for erectile dysfunction therapy, including, but not limited to
sildenafil and apomorphine; anti-migraines, including, but not
limited to sumatriptan, rizatriptan, zolmitriptan, naratriptan and
ergotamin; antihistaminic agents, including, but not limited to
loratadine, fexofenadine, pseudoephedrine and cetirizine;
cardiovascular agents, including, but not limited to nitroglycerine
and isosorbide dinitrate; diuretics, including, but not limited to
furocemide and spironolactone; anti-hypertensive agents, including,
but not limited to propranolol, amlodipine, felodipine, nifedipine,
captoprile, ramiprile, atenolol, and diltiazem; anti-hypolipidemic
agents, including, but not limited to simvistatin, atrovastatin,
and pravastatin; anti-ulcer agents, including, but not limited to
cimietidine, ranitidine, famotidine, omeprazole, esomeprazole,
rabeprazole and lansoprazol; anti emetics, including, but not
limited to meclizine hydrochloride, ondansetron, granisetron,
ramosetron, and tropisetron; anticoagulants such as ticlopidine
hydrochloride, dicumarol, or warfarin potassium; antiepileptics
such as phenyloin sodium, and lamotrigine, anti-asthmatic agents,
including, but not limited to aminophylline, theophylline,
terbuttaline, fenoterol, formoterol, and ketotifen; brain
metabolism altering drugs such as meclofenoxate hydrochloride;
minor tranquilizers such as oxazolam, diazepam, clonazepam,
clotiazepam, medazepam, temazepam, fludiazepam, nitrazepam,
alprazolam, lorazepam or chlordiazepoxide; anti-depressants,
including, but not limited to fluoxetine, mirtazepine, escitalopram
and sertraline; drugs for treatment of parkinson's disease or
restless leg syndrome such as ropinirole hydrochloride; drug for
alzheimer's disease such as memantine; drugs for schizophrenia such
as risperidone, olanzepine and aripiprazole; oral antibacterial and
antifungal agents such as penicillin, ampicillin, amoxicillin,
cephalexin, erythromycin ethylsuccinate, acampicillin
hydrochloride, minocycline hydrochloride, chloramphenicol,
tetracycline, erythromycin, fluconazole, itraconazole,
ketoconazole, miconazole or terbinafine; synthetic antibacterial
agents such as nalidixic acid, piromidic acid, pipemidic acid
trihydrate, enoxacin, cinoxacin, ofloxacin, norfloxacin,
ciprofloxacin hydrochloride, or sulfamethoxazole trimethoprim;
antipasmodics such as propantheline bromide, atropine sulfate,
oxapium bromide, timepidium bromide, antitussive, anti-asthmatic
agents; muscle relaxants such as chlorphenesin carbamate,
tolperisone hydrochloride, eperisone hydrochloride, tizanidine
hydrochloride, mephenesin, chlorozoxazone, phenprobamate,
methocarbamol, chlormezanone, pridinol mesylate, afloqualone,
baclofen, or dantrolene sodium; oral antidiabetic agents such as
glibenclamide, tolbutamide, or glymidine sodium; circulatory agents
such as ubidecarenone or ATP-2Na; iron preparations such as ferrous
sulfate or dried ferrous sulfate; vitamins such as vitamin B1,
vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin A, vitamin
D, vitamin E, vitamin K or folic acid; pollakiuria remedies such as
flavoxate hydrochloride, oxybutynin hydrochloride, terodiline
hydrochloride, or 4-diethylamino-1,1-dimethyl-2-butynyl
(I)-a-cyclohexyl-oc-phenylglycolate hydrochloride;
angiotensin-converting enzyme inhibitors such as enalapril maleate,
anti-viral agents such as trisodium phosphonoformate, didanosine,
dideoxycytidine, azido-deoxythymidine, didehydro-deoxythymidine,
adefovir dipivoxil, abacavir, amprenavir, delavirdine, efavirenz,
indinavir, lamivudine, nelfinavir, nevirapine, ritonavir,
saquinavir or stavudine and combinations thereof.
22. An orally disintegrating tablet as claimed in claim 20, wherein
nutraceutical ingredients include agents that have a beneficial
effect on human health such as coenzyme Q-10, chondroitoin,
echinacea, ephedra, glucosamine, garlic, ginkgo biloba, ginseng,
grape seed extract, guarana, hawthorn, herbs, kava, kola nut,
lutein, St. John's wort, vinpocetine, and yohimbe and combinations
thereof.
23. An orally disintegrating tablet as claimed in claim 20, wherein
excipient is selected from a group of one or more binders,
disintegrants, superdisintegrants, diluents, salivating agents,
surfactants, flavors, sweeteners, colorants, diluents, souring
agents, suitable taste masking agents, viscosity builders, glidants
or lubricants, solubilizers, and stabilizers.
24. An orally disintegrating tablet as claimed in claim 23, wherein
the super disintegrant is natural, modified or pregelatinized
starch, crospovidone, croscarmellose sodium, sodium starch
glycolate, low-substituted hydroxypropyl cellulose as well as
effervescent disintegrating systems.
25. An orally disintegrating tablet as claimed in claim 24, wherein
the preferred super disintegrants are crospovidone and starch.
26. An orally disintegrating tablet as claimed in claim 23, wherein
the binder is starch, pregelatinized starch, cellulose derivatives,
such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl
cellulose (HPC) and carboxymethyl cellulose (CMC) and their
salts.
27. An orally disintegrating tablet as claimed in claim 23, wherein
the diluent is starch, dicalcium phosphate, microcrystalline
cellulose and the like.
28. An orally disintegrating tablet as claimed in claim 23, wherein
the lubricant is magnesium stearate, calcium stearate, stearic
acid, talc, and sodium fumarate stearate.
29. An orally disintegrating tablet as claimed in claim 23, wherein
the glidant is selected from colloidal silica, silica gel,
precipitated silica and combinations thereof.
30. An orally disintegrating tablet as claimed in claim 23, wherein
the salivating agent is micronised polyethylene glycol, sodium
chloride and precipitated micronised silica.
31. An orally disintegrating tablet as claimed in claim 23, wherein
the sweetener is aspartame, stevia extract, glycyrrhiza,
saccharine, saccharine sodium, acesulfame, sucralose and
dipotassium glycyrrhizinate.
32. An orally disintegrating tablet of claim 20 wherein the wicking
time of the tablets is less than 60 seconds
33. An orally disintegrating tablet of claim 20 wherein the lag
time for mouth disintegration is less than 10 seconds
34. An orally disintegrating tablet of claim 20 wherein the
disintegration time is less than 60 seconds in the oral cavity
35. An orally disintegrating tablet formulation having optimal
mechanical strength comprising a. at least one pharmaceutically
active ingredient or a nutraceutical agent b. composites produced
by co-processing of mannitol and calcium silicate. c. At least one
other excipient. such that the tablet has optimal mechanical
strength and a disintegration time of about 60 seconds in the oral
cavity,
Description
FIELD OF INVENTION
[0001] The present invention provides a tablet with optimal
mechanical strength, which when placed in the oral cavity rapidly
dissolves or disintegrates without water preferably within about 60
seconds.
[0002] More particularly, the present invention relates to
composites produced by co-processing of at least one water-soluble
excipient and at least one water insoluble excipient such as
calcium silicate and their use in orally disintegrating
tablets.
BACKGROUND AND PRIOR ART
[0003] Design of an orally disintegrating tablet requires a
significant amount of research work in order to develop a process
that maintains enough porosity inside the compressed tablets for
fast dissolving or fast melting while maintaining the mechanical
strength of the tablet. Orally disintegrating dosage forms are
known in the art and some of the most commonly used techniques are
incorporated herein by reference. Current technologies involved in
many patents as well as existing commercial fast-dissolving tablets
utilize complicated processing techniques such as freeze-drying,
molding and sublimation or use of specialized excipients such as
effervescent couple, highly micronized agents or the likes.
[0004] Freeze drying is one common process for producing many
commercial fast dissolving tablets wherein a cake or wafer is
prepared by freeze drying a solution or suspension of the
medicament and suitable excipients in water or other solvents. Such
systems dissolve very rapidly on the tongue, due to their high
affinity for moisture and a very high porosity. U.S. Pat. No.
5,298,261 discloses freeze-drying a slurry or paste comprising an
active ingredient and excipients placed in blister packets. PCT
application WO 97/36879 discloses vacuum drying, at room
temperature or a slightly elevated temperature, a suspension
including the active drug, a sugar alcohol, PEG 6000, talc,
sweeteners and flavors in preformed blisters. However, the
freeze-drying process suffers from several disadvantages, primary
among these is that solutions employed for freeze-drying are
aqueous and, therefore, not suited for water sensitive medicaments.
It is also limited to low dose actives. The process itself is
typically laborious, costly and time-consuming. Finally, the
resultant dosage forms, in addition to being hygroscopic, tend to
be very soft and, therefore, require special moisture- and
impact-resistant packaging and require careful handling.
[0005] U.S. Pat. No. 5,464,632 claims use of high levels of
disintegrants such as 16% starch 1500 and 13.3% crospovidone for
disintegration time of 35 seconds to 45 seconds. However, such
tablets have a chalky or dry feel when placed in the mouth.
[0006] U.S. Pat. No. 5,178,878 discloses a rapidly dissolving oral
formulation that requires an extragranular microparticulate active
in conjunction with an effervescent agent incorporated into a
tableted matrix in order to achieve rapid oral disintegration. Many
fast-dissolving tablets are also formulated by the inclusion of
effervescent compounds. U.S. Pat. No. 5,178,878 and WO 91/04757
disclose the addition of an effervescent couple (such as sodium
bicarbonate and citric acid) to a tablet. Exposure of such tablet
to moisture results in contact and chemical reaction between the
effervescent couple which leads to gas production and tablet
disintegration. However, tablets which include effervescent pairs
are highly sensitive to moisture and require a specific, very
costly plant including special handling equipment,
controlled-humidity environments and special moisture resistant
packaging and also such preparations have an unpleasant mouth
feel.
[0007] Another orally disintegrating technique is spray drying
technology as explained in U.S. Pat. Nos. 5,958,471 and 6,165,511,
which includes preparing an aqueous solution of more than 80% of
one or more non-hygroscopic polyols and spraying the resulting
mixture into an air stream. The resulting composition of the
spray-drying process contains a filamentous structure. Similarly
PCT application WO03051338A1 relates to a method for producing a
directly compressible and highly compactible composition by
co-spray drying of mannitol and sorbitol solution resulting in
nonfilamentous microstructure. Both these patents describe use of
highly concentrated aqueous solutions, which are to be maintained
and sprayed at high temperature thus demanding special
equipment.
[0008] Another approach to develop orally disintegrating dosage
form involves optimal selection of excipients which would result in
desired disintegration time. These are typically compressed dosage
forms. EP 1145711 describes the preparation of flash-melt dosage
forms that disintegrated in the mouth in less than 25 second. They
consist of granules composed of a superdisintegrant (4-8%), a
dispersing agent such as calcium silicate (20-70%), a distributing
agent selected from amorphous silica, fumed silica, diatomaceous
earth, talc, kaolin, magnesium aluminum trisilicate, and a binder
(10 to 50% by weight). A larger amount of binder although may
produce stronger tablets, the disintegration time tend to increase.
To counter this, a large amount of dispersing and distributing
agent is included in the formulation which increases the weight of
the tablet and also the cost of the formulation may increase.
[0009] PCT application WO03045844A1 relates to synthetic calcium
metasilicate which when incorporated in a solid product
significantly increases the disintegration rate of the formed
product, when contacted by a substantially aqueous environment. The
reduction in disintegration time with calcium silicate is more
pronounced with immediate release tablets as tablets prepared with
calcium silicate has low porosity leading to increased
disintegration time in oral cavity. However use of calcium silicate
with conventional equipments leads to discoloration of the final
dosage form due to interaction of calcium silicate with some
metals. Calcium silicate due to its hydrophobic and static nature
results in blends with very poor flow properties causing weight and
content variation during compression into tablets. Further, it also
imparts a chalky taste to the dosage form.
[0010] In general, there are numerous other examples of specific
formulations that utilize one or more of the techniques or
mechanisms discussed above. Majority of these techniques possess
one or more of the above enumerated disadvantages to some extent
such as tedious and complex method of manufacturing, special
packaging and storage requirements, high cost, limitation on drug
load etc. Thus, there continues to be a need for a formulation that
mitigates or eliminates these disadvantages. The desired features
of such dosage form include quick disintegrability in an oral
cavity, a pleasant mouth feel and optimal mechanical strength even
in storage under a humidifying conditions.
[0011] It was surprisingly found that composites made by
co-processing of at least one water soluble excipient and at least
one water insoluble excipient such as calcium silicate, leads to a
formulation that rapidly disintegrates or dissolves on in the
mouth. Tablets made with these excipients are robust (e.g., low
friability, low ejection forces, hardness) enough to be processed
in high speed tableting machines and shipped in low cost packages,
and at the same time retain rapid disintegration or dissolution
properties. The tablets have a pleasant mouth feel and good
mechanical strength and such tablets also do not require special
handling or packaging conditions.
OBJECT OF INVENTION
[0012] It is an object of the present invention to develop an
orally disintegrating tablet with a disintegration time of less
than 60 seconds in the oral cavity.
[0013] It is yet another object of the present invention to develop
orally disintegrating tablets using composites prepared by
co-processing.
[0014] It is further an object of the present invention to prepare
composites by co-processing of at least one water soluble
excipients and at least one water insoluble excipients such as
calcium silicate and their use in orally disintegrating
tablets.
[0015] It is further an object of the present invention to prepare
composites by co-processing of at least one water soluble
excipients and at least one water insoluble excipients such as
calcium silicate by spray drying.
[0016] It is another object of the present invention is to prepare
composites by spray drying having porosity of greater than 50%
[0017] It is an object of the present invention to prepare
composites by co-processing of calcium silicate and mannitol by
spray drying and their use in orally disintegrating tablets.
[0018] It is yet another object of the present invention to develop
an orally disintegrating tablet with a wicking time of less than 60
seconds.
[0019] It is yet another object of the present invention to develop
an orally disintegrating tablet with a lag time of less than 10
seconds.
[0020] It is yet another object of the present invention to develop
an orally disintegrating tablet with hardness of at least 10N.
SUMMARY OF INVENTION
[0021] According to a broad aspect of the invention is provided a
directly compressible composite for orally disintegrating tablets
comprising at least one water-soluble excipient and calcium
silicate prepared by co-processing.
[0022] According to another aspect of the invention is provided an
orally disintegrating tablet formulation having optimal mechanical
strength comprising [0023] a. at least one pharmaceutically active
ingredient or a nutraceutical agent [0024] b. composites produced
by co-processing of mannitol and calcium silicate. [0025] c. At
least one other excipient. such that the tablet has optimal
mechanical strength and a disintegration time of about 60 sec in
the oral cavity.
DETAILED DESCRIPTION
[0026] Solid pharmaceutical dosage forms that rapidly dissolve or
disintegrate in a glass of water or in the gastrointestinal tract
have been known in the art for many years. The obvious advantages
of the convenience of carrying dosage forms that will dissolve or
effervesce in water to release medicaments are well known. Rapid
disintegration technology is among the most exciting recent
developments in the pharmaceutical industry. Orally Disintegrating
Tablets are tablets that disintegrate/dissolve in the mouth rapidly
without administering extra water. These dosage forms provide the
convenience of a tablet formulation while allowing the ease of
swallowing provided by a liquid formulation. Such dosage forms due
to their ease of administration and pleasant mouth feel, may
encourage patients especially children, the elderly and
schizophrenic patients who have difficulty in swallowing
conventional tablets to adhere to daily medication regimens and
also allow the luxury of much more accurate dosing than oral
liquids. Yet another situation where such tablets would be useful
is where water may not be readily available to assist in swallowing
the tablet in specific conditions.
[0027] The term `Co-processed excipient` as used here refers to an
excipient composite in which at least two excipients are present in
close proximity to each other. In one of the embodiments such
excipient composite may have one excipient incorporated in the
particle structure of the other.
[0028] The term `porosity` as used here is a measure of void spaces
within the material and is measured as a fraction (between 0 to 1)
or as a percentage value (between 0 to 100%). Porosity is the ratio
of void space to bulk volume. It can be determined using the
following formula
Porosity=(Bulk volume-True volume)/Bulk volume
[0029] The term `wicking time` as used here provides time (seconds)
taken for water to wick into the tablet and completely wet the
tablet core. The wicking time test is used to evaluate the
performance of orally disintegrating tablets. The wicking time
determination is carried out in a petri plate (.about.10 cm in
diameter). The plate is layered with tissue papers of 0.25 mm
thick. The tissue paper is wetted with 10 ml water (preferably
colored using a water soluble dye) and allowed to soak for 30 sec.
A tablet is then placed on the wetted tissue paper and the time
taken by water to reach the surface of tablet and completely wet it
is recorded as the `wicking time`. The test may be appropriately
modified for tablets having weight of more than 200 mg.
[0030] The term `mouth dissolution time` as used here provides time
(seconds) taken for tablet to completely dissolve in the mouth
determined in and by human volunteers.
[0031] The term `lag time` as used here provides time (seconds)
taken for tablet to soften and start disintegrating after being
placed on the tongue determined in and by human volunteers.
[0032] The term `in vitro disintegration time` as used here refer
to the time taken for complete disintegration of the tablet as
determined using the USP disintegration apparatus.
Composites
[0033] Composites are blend of excipients obtained by co-processing
of at least one water soluble excipient and at least one water
insoluble excipient.
[0034] The water soluble excipients according to the embodiments of
the invention are excipients that are soluble in water. The
preferred examples include water soluble carbohydrates, salt or a
polyhydric alcohol or its derivative. The water soluble
carbohydrates can be a monosaccharide, disaccharide,
oligosaccharide or polysaccharide. Examples include but not limited
to monosaccharides such as glyceraldehyde, erythrose, threose,
ribose, arabinose, xylose, allose, altrose, glucose, mannose,
fructose, gulose, idose, galactose, talose and sorbitol;
disaccharides such as maltose, lactose, cellobiose, sucrose,
mannitol and trehalose; oligosaccharides such as raffinose,
stachyose, and dextrates; or polysaccharides such as maltodextrins,
starch, glycogen, cellulose, chitin, callose, galactomannan, xylan
and laminarin The saccharide is preferably at least one selected
from mannitol, lactose, saccharose, trehalose, xylitol and
erythritol. Preferably, the saccharide is mannitol. These water
soluble excipients can be employed alone or in combination. The
water soluble excipients also include but are not limited to
polyhydric alcohols like propylene glycol, polyethylene glycol,
glycerin or their derivatives, salts such as sodium chloride or
water soluble cellulose derivatives.
[0035] The water insoluble excipients according to the embodiments
of the invention are excipients that are not soluble in water.
These excipients include but are not limited to inorganic salts
such as calcium silicate-ortho, meta and alpha triclinic forms
thereof, magnesium trisilicate-ortho and meta forms thereof or
light anhydrous silicic acid, mica, synthetic aluminum silicate,
silicon dioxide, magnesium aluminum silicate, magnesium
metasilicate aluminate, celluloses such as microcrystalline
cellulose, crystalline cellulose, cellulose derivatives,
vinylpyrolidone derivatives, colloidal silicon dioxide etc. The
preferred water insoluble agent is calcium metasilicate. The most
preferred water insoluble agent is calcium silicate marketed by
Huber as Rxcipient FM1000 having an aspect ratio of about 1:1 to
about 2.5:1 and an oil absorption of from about 20 ml/100 gm to 220
ml/100 gm. It is a unique physical form of Calcium Silicate, which
reduces the disintegration time of a dosage form.
[0036] These water soluble and insoluble excipients may be present
in the composites in the ratio of 1:50 to 50:1. Preferably the
ratio can be 1:30 to 30:1 and more preferably 1:20 to 20:1.
[0037] Any process that ensures close proximity of water insoluble
excipient and water soluble excipient can be employed. Such process
would ensure intimate contact of water insoluble excipients and
water soluble excipients. Some of the preferred processes ensure
complete or partial covering of the water insoluble excipient by
water soluble excipient can be employed for the preparation of the
composites. The non-limiting processes may include physical mixing,
wet mixing, complexation, precipitation, spray drying,
lyophilization, microencapsulation, spray congealing, hot melt, gas
antisolvent or rapid evaporation of supercritical solvent methods
employed with supercritical fluid processing. The preferred method
for preparing composites is spray drying.
[0038] Spray drying is an industrial process involving particle
formation and drying. It is highly suited for the continuous
production of dry solids in either powder, granulate or agglomerate
form from liquid feedstocks as solutions, emulsions and pumpable
suspensions. Therefore, spray drying is an ideal process where the
end-product must comply with precise quality standards regarding
particle size distribution, residual moisture content, bulk
density, and particle shape. Spray drying involves the atomization
of a liquid feedstock into a spray of droplets and contacting the
droplets with hot air in a drying chamber. The sprays are produces
by either rotary (wheel) or nozzle atomizers. Evaporation of
moisture from the droplets and formation of dry particles proceed
under controlled temperature and airflow conditions. Powder is
discharged continuously from the drying chamber. Operating
conditions and dryer design are selected according to the drying
characteristics of the product and powder specification.
[0039] There are a number of variables in the spray drying process
which include feed composition, feed viscosity, density, feed spray
rate, inlet temperature, outlet temperature, temperature
difference, atomization pressure, vacuum, residence time. All these
parameters can be varied in order to achieve the desired
product.
[0040] The process employed comprise of preparation of the slurry
of water-soluble and water insoluble excipient which was
homogenized using overhead stirrer, homogenizer etc. The feed can
be preheated during stirring before being fed to the spray drying
chamber. For spraying this dispersion a single fluid nozzle or a
two-fluid nozzle can be employed. Alternatively the feed may also
be sprayed using a rotating disk. The drying of the particles could
be achieved using any of the methods such as co-current flow,
counter current flow or mixed flow. The total solid content of the
feed could vary from about 2-75%, preferably from 5-60% and more
preferably from 10-50%.
[0041] The composites of at least one water soluble excipient and
at least one water insoluble excipient such as calcium silicate may
have certain desirable properties. The moisture content of the
composite as determined using loss on drying is preferably less
than 2%. The porosity of the composite plays a crucial role in the
performance of the orally disintegrating tablet. In order to have
disintegration time of less than 60 seconds, the porosity of the
composite should be at least about 50%. Another parameter which
determines the wicking time, disintegration time in oral cavity and
lag time is the particle size distribution of the composite. This
parameter also determines the flow of the blend ready for
compression into tablets. It is desirable that not less than 40% of
particles are less than 150 microns.
Active Ingredients
[0042] As used herein, the term "active ingredient" or "active
agent" refers to one or more compounds that have some
pharmacological property. There is no limitation to the active
ingredient (AI) that can be used with the present invention. Active
ingredients can be included in the said compositions as such or
coated with suitable taste masking agent. The compositions of the
invention contain at least one suitable pharmaceutical active
ingredient or nutraceutical active ingredients. Examples of
pharmaceutical ingredients that can be used include, but are not
limited to gastrointestinal function conditioning agents
anti-inflammatory agents, including, but not limited to
aceclofenac, diclofenac, ibuprofen flubiprofen, piroxicam,
sulindac, and celecoxib; analgesics, including, but not limited to
acetaminophen, fentanyl, tramadol and aspirin; agents for erectile
dysfunction therapy, including, but not limited to sildenafil and
apomorphine; anti-migraines, including, but not limited to
sumatriptan, rizatriptan, zolmitriptan, naratriptan and ergotamin;
antihistaminic agents, including, but not limited to loratadine,
fexofenadine, pseudoephedrine and cetirizine; cardiovascular
agents, including, but not limited to nitroglycerine and isosorbide
dinitrate; diuretics, including, but not limited to furocemide and
spironolactone; anti-hypertensive agents, including, but not
limited to propranolol, amlodipine, felodipine, nifedipine,
captoprile, ramiprile, atenolol, and diltiazem; anti-hypolipidemic
agents, including, but not limited to simvistatin, atrovastatin,
and pravastatin; anti-ulcer agents, including, but not limited to
cimietidine, ranitidine, famotidine, omeprazole, esomeprazole,
rabeprazole and lansoprazol; anti emetics, including, but not
limited to meclizine hydrochloride, ondansetron, granisetron,
ramosetron, and tropisetron; anticoagulants such as ticlopidine
hydrochloride, dicumarol, or warfarin potassium; antiepileptics
such as phenyloin sodium, and lamotrigine, anti-asthmatic agents,
including, but not limited to aminophylline, theophylline,
terbutaline, fenoterol, formoterol, and ketotifen; brain metabolism
altering drugs such as meclofenoxate hydrochloride; minor
tranquilizers such as oxazolam, diazepam, clonazepam, clotiazepam,
medazepam, temazepam, fludiazepam, nitrazepam, alprazolam,
lorazepam or chlordiazepoxide; anti-depressants, including, but not
limited to fluoxetine, mirtazepine, escitalopram and sertraline;
drugs for treatment of parkinson's disease or restless leg syndrome
such as ropinirole hydrochloride; drug for alzheimer's disease such
as memantine; drugs for schizophrenia such as risperidone,
olanzepine and aripiprazole; oral antibacterial and antifungal
agents such as penicillin, ampicillin, amoxicillin, cephalexin,
erythromycin ethylsuccinate, acampicillin hydrochloride,
minocycline hydrochloride, chloramphenicol, tetracycline,
erythromycin, fluconazole, itraconazole, ketoconazole, miconazole
or terbinafine; synthetic antibacterial agents such as nalidixic
acid, piromidic acid, pipemidic acid trihydrate, enoxacin,
cinoxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, or
sulfamethoxazole trimethoprim; antipasmodics such as propantheline
bromide, atropine sulfate, oxapium bromide, timepidium bromide,
antitussive, anti-asthmatic agents; muscle relaxants such as
chlorphenesin carbamate, tolperisone hydrochloride, eperisone
hydrochloride, tizanidine hydrochloride, mephenesin,
chlorozoxazone, phenprobamate, methocarbamol, chlormezanone,
pridinol mesylate, afloqualone, baclofen, or dantrolene sodium;
oral antidiabetic agents such as glibenclamide, tolbutamide, or
glymidine sodium; circulatory agents such as ubidecarenone or
ATP-2Na; iron preparations such as ferrous sulfate or dried ferrous
sulfate; vitamins such as vitamin B1, vitamin B2, vitamin B6,
vitamin B12, vitamin C, vitamin A, vitamin D, vitamin E, vitamin K
or folic acid; pollakiuria remedies such as flavoxate
hydrochloride, oxybutynin hydrochloride, terodiline hydrochloride,
or 4-diethylamino-1,1-dimethyl-2-butynyl
(I)-a-cyclohexyl-oc-phenylglycolate hydrochloride;
angiotensin-converting enzyme inhibitors such as enalapril maleate,
anti-viral agents such as trisodium phosphonoformate, didanosine,
dideoxycytidine, azido-deoxythymidine, didehydro-deoxythymidine,
adefovir dipivoxil, abacavir, amprenavir, delavirdine, efavirenz,
indinavir, lamivudine, nelfinavir, nevirapine, ritonavir,
saquinavir or stavudine.
[0043] Examples of nutraceutical ingredients include, but are not
limited to any ingredient that is thought to have a beneficial
effect on human health. Such ingredients include coenzyme Q-10,
chondroitoin, echinacea, ephedra, glucosamine, garlic, ginkgo
biloba, ginseng, grape seed extract, guarana, hawthorn, herbs,
kava, kola nut, lutein, St. John's wort, vinpocetine, and
yohimbe.
[0044] The active ingredient may be present in any form such as its
normal form, taste masked form, enteric or controlled release form.
The taste masking can be carried out by any of the processes known
in the art, not limiting to complexation with cyclodextrins, ion
exchange resins or any other suitable agents. Taste masking can
also be achieved by coating with water soluble or insoluble
polymers or polymers having pH dependent solubility or waxes. Both
the enteric release and controlled release may demand for coating
of active ingredient or its granules with suitable retardants or
polymers.
[0045] The active ingredient may be incorporated in the formulation
in the powder form, granules, pellets, beads or any other form.
[0046] The tablets of the invention may include in addition to the
composite and an active ingredient, one or more binders,
disintegrants, superdisintegrants, diluents, salivating agents,
surfactants, flavors, sweeteners colorants, diluents, souring
agents, suitable taste masking agents, viscosity builders, glidants
or lubricants, solubilizers, and stabilizers.
[0047] The compositions of the invention also include at least one
super disintegrant selected from but not limited to natural,
modified or pregelatinized starch, crospovidone, croscarmellose
sodium, sodium starch glycolate, low-substituted hydroxypropyl
cellulose as well as effervescent disintegrating systems. Preferred
disintegrants in the invention include crospovidone and natural,
modified or pregelatinized starch. The amount of superdisintegrant
employed in the composition is about 2-50% by weight of the said
dosage form.
[0048] Examples of suitable binders include starch, pregelatinized
starch, cellulose derivatives, such as hydroxypropylmethyl
cellulose (HPMC), hydroxypropyl cellulose (HPC) and carboxymethyl
cellulose (CMC) and their salts. Examples of suitable diluents
include starch, dicalcium phosphate, microcrystalline cellulose and
the like.
[0049] Examples of the lubricant include but not limited to
magnesium stearate, calcium stearate, stearic acid, talc, and
sodium fumarate stearate. The compositions of the invention may
also include a glidant selected from colloidal silica, silica gel,
precipitated silica, or combinations thereof. The said compositions
may also include salivating agents such as but not limited to
micronised polyethylene glycol preferably of molecular weight 4000,
sodium chloride or precipitated micronised silica to improve the
disintegration properties of the said compositions.
[0050] In addition to above excipients, the compositions of the
invention also include at least one sweetening agent selected from
aspartame, stevia extract, glycyrrhiza, saccharine, saccharine
sodium, acesulfame, sucralose and dipotassium glycyrrhizinate; one
or more flavors e.g., mint flavour, orange flavour, lemon flavors,
strawberry aroma, vanilla flavour, raspberry aroma, cherry flavor,
magnasweet 135, key lime flavor, grape flavor trusil art 511815,
fruit extracts and colours or dyes. There is no limitation on color
or flavor that is useful in the present invention, and these
characteristics will likely be chosen based on the age of the
patient consuming the solid dosage form.
[0051] The term "solid dosage form" may refer to tablets, capsules,
granules, powders etc. However the most preferred dosage form is
tablet. The term tablet is construed to include a compacted or
compressed powder composition obtained by compressing or otherwise
forming the composition to form a solid having a defined shape.
Tablets in accordance with the invention may be manufactured using
conventional techniques of common tableting methods known in the
art such as direct compression, wet granulation, dry granulation
and extrusion/melt granulation. The preferred process is direct
compression which involves compression of drug-excipient blend
after mixing them for a definite time period.
[0052] The tablet may vary in shape such as oval, triangle, almond,
peanut, parallelogram, round, pentagonal, hexagonal, and
trapezoidal. The preferred shapes are round, oval and parallelogram
forms.
[0053] The performance of the orally disintegrating tablets can be
evaluated using a number of parameters namely wicking time,
disintegration time in oral cavity, in vitro disintegration time,
lag time etc. As per various embodiments of the present invention,
both the wicking time and disintegration time in oral cavity are
less than 60 seconds and the lag time is less than 10 seconds.
[0054] While the present invention has been described in terms of
its specific embodiments, certain modifications and equivalents
will be apparent to those skilled in the art and are intended to be
included within the scope of the present invention.
[0055] The details of the invention, its objects and advantages are
explained hereunder in greater detail in relation to non-limiting
exemplary illustrations.
EXAMPLES
Example 1
Orally Disintegrating Tablets Produced by Physical Mixing
TABLE-US-00001 [0056] TABLE 1 Composition of orally disintegrating
tablets Ingredients mg/tablet Mannitol 45.0 Maize starch 23.0
Microcrystalline cellulose 10.0 Croscarmellose sodium 3.5 Calcium
silicate 10.0 Aspartame 1.5 Colloidal silicon dioxide 0.8 Flavor
0.2 Polyethylene Glycol 5.0 Sodium stearyl fumarate 0.5 Total
100.0
[0057] All excipients except lubricant were blended in a blender to
get a uniform mass. The mass was lubricated and compressed into
tablets having following parameters:
TABLE-US-00002 Hardness (N) 10-30 Friability (%) 1.5% In vitro
Disintegration time (sec) 5-10 Disintegration time in oral cavity
(sec) 20-30
Tablets with desired friability and disintegration time were
obtained.
Example 2
(a) Co-Processing of Mannitol and Calcium Silicate by Spray
Drying
[0058] 180 gms of mannitol was dissolved in water at about
80.degree. C. temperature. In this solution 20 gms of calcium
silicate was added and stirred to get a uniform mass. The mass was
sprayed in the spray dryer under following conditions:
TABLE-US-00003 Inlet Temperature 180-200.degree. C. Outlet
Temperature 80-120.degree. C. Nozzle diameter 1 mm Feed rate
150-200 ml/Hr Atomisation pressure 0.7-1.2 Kg/cm.sup.2
The composites obtained were free flowing with bulk density in the
range of 0.3-0.5 gm/cc and having about 75% of particles below 150
microns.
(b) Spray Drying of Mannitol
[0059] Mannitol alone was also spray dried under above mentioned
conditions.
Example 3
Co-Processing of Mannitol, Sorbitol and Calcium Silicate by Spray
Drying
[0060] 160 gms of mannitol and 20 gms of sorbitol were dissolved in
water at 70-75.degree. C. temperature. In this solution 20 gms of
calcium silicate was added and stirred to get a uniform mass. The
mass was sprayed in the spray dryer under following conditions:
TABLE-US-00004 Inlet Temperature 180-200.degree. C. Outlet
Temperature 70-100.degree. C. Nozzle diameter 1 mm Feed rate
150-200 ml/Hr Atomisation pressure 3-4 Kg/cm.sup.2
The composites obtained were free flowing with bulk density of
0.4-0.5 gm/cc
Example 4
Co-Processing of Mannitol, Microcrystalline Cellulose and Calcium
Silicate by Spray Drying
[0061] 160 gms of mannitol was dissolved in water at about
70.degree. C. temperature. In this solution 20 gms of calcium
silicate and 20 gms of microcrystalline cellulose were added and
stirred to get a uniform mass. The mass was sprayed in the spray
dryer under same conditions as given in example 2. The composites
obtained were free flowing with bulk density of 0.4 gm/cc.
Example 5
Co-Processing of Mannitol and Calcium Silicate by Spray Drying
[0062] 240 g Mannitol was dissolved in 4.0 liter water at room
temperature. In this solution 560 g of calcium silicate was added
and stirred to get a homogeneous mass. The mass was sprayed in the
spray dryer under following conditions:
TABLE-US-00005 Inlet Temperature 200-220.degree. C. Outlet
Temperature 80-120.degree. C. Nozzle diameter 2.0 mm Feed rate
70-90 ml/min Atomisation pressure 0.2 Kg/cm.sup.2
The composites obtained were free flowing with bulk density of
0.55-0.65 gm/cc and moisture content of less than 1.0% determined
by loss on drying. About 90% of the particles were of size less
than 150 microns and the composite had a desirable porosity of
63%.
Example 6
Co-Processing of Mannitol and Calcium Silicate by Spray Drying
[0063] 600.0 g Mannitol was dissolved in 3.0 liter water at room
temperature. In this solution 600.0 g of calcium silicate was added
and stirred to get a uniform mass. The mass was sprayed in the
spray dryer under following conditions:
TABLE-US-00006 Inlet Temperature 200-205.degree. C. Outlet
Temperature 105-125.degree. C. Nozzle diameter 2.0 mm Feed rate
70-90 ml/min Atomisation pressure 0.2 Kg/cm.sup.2
The composites obtained had moisture content of less than 1%,
porosity of 65% and were free flowing with bulk density of 0.6-0.8
gm/cc
Example 7
Co-Processing of Mannitol, Calcium Silicate and Polyethylene Glycol
by Spray Drying
[0064] 340.0 g Mannitol and 20.0 g of Polyethylene glycol were
dissolved in 2.0 liter water at room temperature. In this solution
40.0 gms of calcium silicate was added and stirred to get a uniform
mass. The mass was sprayed in the spray dryer under following
conditions:
TABLE-US-00007 Inlet Temperature 200-205.degree. C. Outlet
Temperature 105-125.degree. C. Nozzle diameter 2.0 mm Feed rate
70-90 ml/Hr Atomisation pressure 0.2 Kgf/cm.sup.2
The composites obtained were free flowing with bulk density of
0.5-0.7 gm/cc and moisture content 0.5%. The porosity of the
composite was 61%.
Example 8
Co-Processing of Mannitol and Calcium Silicate by Spray Drying
Using a Rotary Disc
[0065] 900.0 g Mannitol was dissolved in 5.0 liter water at room
temperature. In this solution 100.0 gms of calcium silicate was
added and stirred to get a uniform mass. The mass was sprayed in
the spray dryer under following conditions:
TABLE-US-00008 Inlet Temperature 200-205.degree. C. Outlet
Temperature 85-95.degree. C. Rotary disc radius 6.0 cm Rotary disc
speed 24000 rpm Feed rate 70-90 ml/Hr
The composites obtained possessed bulk density of 0.45-0.55 gm/cc
and had a good flow. The moisture content was about 0.6% with about
95% of particles below 150 microns.
Example 9
Tablet Formulation Using Composite of Mannitol and Calcium Silicate
and Spray Dried Mannitol
TABLE-US-00009 [0066] TABLE 2 Compositions of orally disintegrating
tablets using composites and spray dried mannitol A B Ingredients
mg/tablet mg/tablet Spray dried mannitol of example 2 45.0 --
Co-processed composite of example 2 -- 50.0 Starch 23.0 23.0
Microcrystalline cellulose 10.0 10.0 Croscarmellose sodium 3.5 3.5
Calcium silicate 10.0 5.0 Aspartame 1.5 1.5 Colloidal silicon
dioxide 0.8 0.8 Flavor 0.5 0.5 Polyethylene Glycol 5.0 5.0 Flavor
0.2 0.2 Sodium stearyl fumarate 0.5 0.5 Total 100.0 100.0
[0067] All excipients except lubricant were blended in a blender to
get a uniform mass. The mass was lubricated and compressed into
tablets having following parameters:
TABLE-US-00010 A B Hardness (N) 10-20 10-20 Friability (%) 0.85 1.0
In vitro Disintegration time (sec) 15-20 5-10 Disintegration time
in oral cavity (sec) 40-50 25-40
Robust tablets were obtained with low friability and desired
disintegration time.
Example 10
Tablet Formulation Using Composite of Mannitol, Microcrystalline
Cellulose and Calcium Silicate
TABLE-US-00011 [0068] TABLE 3 Compositions of orally disintegrating
tablets using composite of example 4 Ingredients mg/tablet
Coprocessed composite of example 4 55.0 Starch 23.0
Microcrystalline cellulose 5.0 Croscarmellose sodium 3.5 Calcium
silicate 5.0 Aspartame 1.5 Colloidal silicon dioxide 0.8 Flavor 0.5
Polyethylene Glycol 5.0 Flavor 0.2 Sodium stearyl fumarate 0.5
Total 100.0
[0069] All excipients except lubricant were blended in a blender to
get a uniform mass. The mass was lubricated and compressed into
tablets having following parameters:
TABLE-US-00012 Hardness (N) 10-20 Friability (%) 0.8-0.9 In vitro
Disintegration time (sec) 8-12 Disintegration time in oral cavity
(sec) 30-40
Robust tablets were obtained with low friability and desired
disintegration time.
Example 11
Wicking Test
[0070] The test is carried out to determine the rate of water
uptake by the orally disintegrating tablets. Five circular tissue
papers of about 10-cm diameter were placed in a petridish with a
10-cm diameter. Ten milliliters of water containing eosin, a
water-soluble dye, was added to the petridish. A tablet (100 mg
weight) was carefully placed on the surface of tissue paper. The
time required for water to reach the upper surface of the tablets
by capillary action was noted as the wicking time.
TABLE-US-00013 TABLE 4 Wicking time of various orally
disintegrating tablets Formulation Wicking Time (sec) Example 1
15-20 Example 9A 35-40 Example 9B 18-20 Example 10 20-22
[0071] Wicking time suggest that the spray dried composites
exhibits lesser wicking time indicating rapid disintegration of
these tablets. Between spray dried mannitol and the composite of
the present invention, the composite gives much reduced wicking
time.
Example 12
Orally Disintegrating Tablets of Drugs Having No Bitter Taste
TABLE-US-00014 [0072] TABLE 4 Compositions of orally disintegrating
tablets Ingredients mg/tablet mg/tablet Clonazepam 0.5 --
Loratadine -- 10.0 Composite of example 3 55.0 45.0 Starch 22.5
18.0 Croscarmellose sodium 3.5 4.0 Calcium silicate 5.0 5.0
Aspartame 1.5 2.0 Colloidal silicon dioxide 0.8 0.8 Flavor 5.0 0.5
Polyethylene Glycol 0.2 4.2 Sodium stearyl fumarate 0.5 0.5 Total
90.0 90.0
[0073] The drug and the composite was mixed to get a premix. This
premix was further mixed with other inactive ingredients,
lubricated and compressed into tablets. All the tablets had good
mouth feel and disintegrated in mouth within 60 sec.
Example 13
Orally Disintegrating Tablets of Tramadol Hydrochloride
TABLE-US-00015 [0074] Ingredients mg/tablet Taste masked tramadol
equivalent to 50 mg 108.0 tramadol hydrochloride Composite of
example 3 57.0 Starch 18.0 Microcrystalline cellulose 14.0
Croscarmellose sodium 4.5 Sucralose 0.25 Aspartame 2.0 Colloidal
silicon dioxide 0.8 Polyethylene Glycol 4.0 Flavor 0.75 Sodium
stearyl fumarate 0.5 Total 210
[0075] The drug and the composite was mixed to get a premix. This
premix was further mixed with other inactive ingredients,
lubricated and compressed into tablets.
[0076] All the tablets had good mouth feel and disintegrated in
mouth within 60 sec.
Example 14
Orally Disintegrating Tablets of Taste Masked Donepezil
TABLE-US-00016 [0077] Ingredients mg/tablet Taste masked Donepezil
equivalent to 45.0 10 mg Donepezil Composite of example 3 60.0
Starch 18.0 Microcrystalline cellulose 10.0 Croscarmellose sodium
5.5 Calcium silicate 5.0 Aspartame 3.0 Colloidal silicon dioxide
0.8 Sodium chloride 3.5 Flavor 0.2 Sodium stearyl fumarate 0.5
Total 150.0
[0078] The drug and the composite was mixed to get a premix. This
premix was further mixed with other inactive ingredients,
lubricated and compressed into tablets having a lag time of less
than 5 sec.
Example 15
Orally Disintegrating Tablets of High Dose Bitter Drug
Paracetamol
TABLE-US-00017 [0079] Ingredients mg/tablet Taste masked
paracetamol equivalent to 200 125 mg of paracetamol Coprocessed
composite of example 2 100 Starch 45 Microcrystalline cellulose 25
Croscarmellose sodium 7.0 Calcium silicate 10 Aspartame 4.0
Colloidal silicon dioxide 1.5 Polyethylene Glycol 5.5 Flavor 1.5
Sodium chloride 4.0 Sodium stearyl fumarate 1.5 Total 405
[0080] The drug and the composite were mixed to get a premix. This
premix was further mixed with other inactive ingredients,
lubricated and compressed into tablets. Tablets had desired wicking
time of about 55 sec and a good mouth feel.
Example 16
Taste-Masked Aripiprazole Incorporated in Tablets Along with
Spray-Dried ODT Excipient Prepared in Example 5
TABLE-US-00018 [0081] Ingredients (mg/tablet) Taste-masked
Aripiprazole 30.0 Equivalet to 10.0 mg Aripiprazole ODT Excipient
(example 5) 60.0 Maize starch 18.0 Microcrystalline cellulose 6.0
PEG 4000 5.0 Polyplasdone 7.5 Aspartame 1.0 Peppermint 0.5 Blue FD
& C 0.2 Magnesium stearate 1.0 Aerosil 200 0.8 Total 130.0
Process:
[0082] The ingredients were sieved through 40# sieve along with
taste-masked drug. The sieved mix was blended to homogenize,
lubricated and compressed to obtain 130 mg tablets of the following
properties:
TABLE-US-00019 Hardness (N) 15-22 Friability (%) 0.75
Disintegration time (sec) 15 Disintegration time in oral cavity
(sec) 30-40
Tablets had desired disintegration time of about 30-40 sec in oral
cavity and a good mouth feel. The lag time was about 4 seconds
Example 17
Taste-Masked Ropinirole Incorporated in Tablets Comprising Physical
Mix of Spray-Dried Mannitol and Calcium Silicate in the Ratio
9:1
TABLE-US-00020 [0083] Ingredients (mg/tablet) Taste-masked
ropinirole 10.0 equivalent to 2.5 mg ropinirole Coprocessed
excipient of example 6 30.0 Xylitol 17.0 Maize starch 8.0
Microcrystalline cellulose 10.0 PEG 4000 5.0 Polyplasdone 7.5
Aspartame 2.0 Peppermint 0.5 Blue FD & C 0.2 Magnesium stearate
1.0 Aerosil 200 8.8 Total 100.0
Process:
[0084] The ingredients were sieved through 40# sieve along with
taste-masked drug. The sieved mix was blended to homogenize,
lubricated and compressed to obtain 100 mg tablets of the following
properties:
TABLE-US-00021 Hardness (N) 20-25 Friability (%) 0.5 Wicking time
(sec) 30 Disintegration time in oral cavity (sec) 30
Example 18
Orally Disintegrating Tablets of Enteric Coated Esomeprazole
TABLE-US-00022 [0085] Ingredients (mg/tablet) Enteric-coated
esomeprazole pellets equivalent to 35.0 20 mg esomeprazole ODT
Excipient (example 7) 140.0 Silicified Microcrystalline cellulose
60.0 PEG 4000 5.0 Polyplasdone 7.5 Aspartame 0.45 Peppermint 0.25
Magnesium stearate 1.0 Aerosil 200 0.8 Total 250.0
Process:
[0086] The ingredients were sieved through 40# sieve along and was
blended to homogenize, lubricated and compressed to obtain 250 mg
tablets of the following properties:
TABLE-US-00023 Hardness (N) 40 Friability (%) 0.6 Wicking time
(sec) 45 Disintegration time in oral cavity (sec) 50
Example 19
Orally Disintegrating Tablets of Memantine
TABLE-US-00024 [0087] Ingredients (mg/tablet) Taste-masked
memantine 40.0 equivalent to 20.0 mg memantine ODT Excipient
(example 7) 115.0 Pregelatinised starch 18.0 Powdered cellulose
24.0 Sodium chloride 2.0 Polyplasdone 7.5 Sodium saccharine 1.0
Orange flavor 0.5 Blue FD & C 0.2 Magnesium stearate 1.0
Aerosil 200 0.8 Total 210.0
Process:
[0088] The ingredients were sieved through 40# sieve along with
taste-masked drug. The sieved mix was blended to homogenize,
lubricated and compressed to obtain 210 mg tablets of the following
properties:
TABLE-US-00025 Hardness (N) 45 Friability (%) 0.3 Wicking time
(sec) 48 Disintegration time in oral cavity (sec) 40-50
* * * * *