U.S. patent application number 13/939919 was filed with the patent office on 2013-11-07 for fast dissolving tablet.
The applicant listed for this patent is Wyeth LLC. Invention is credited to Khawka Abdullah Abu-Izza, Kevin Scott Kinter, Vincent H. Li, Janos Szamosi.
Application Number | 20130296385 13/939919 |
Document ID | / |
Family ID | 34216383 |
Filed Date | 2013-11-07 |
United States Patent
Application |
20130296385 |
Kind Code |
A1 |
Szamosi; Janos ; et
al. |
November 7, 2013 |
Fast Dissolving Tablet
Abstract
The present invention relates to processes for the preparation
of tablets which dissolve rapidly in the mouth and provide an
excellent mouthfeel. The tablets of the invention comprise a
compound which melts at about 37.degree. C. or lower, have a low
hardness, high stability and generally comprise few insoluble
disintegrants which may cause a gritty or chalky sensation in the
mouth. Convenient and economically feasible processes by which the
tablets of the invention may be produced are also provided.
Inventors: |
Szamosi; Janos;
(Chesterfield, VA) ; Kinter; Kevin Scott; (Glen
Allen, VA) ; Li; Vincent H.; (Mechanicsville, VA)
; Abu-Izza; Khawka Abdullah; (Wayne, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Wyeth LLC |
Madison |
NJ |
US |
|
|
Family ID: |
34216383 |
Appl. No.: |
13/939919 |
Filed: |
July 11, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12855838 |
Aug 13, 2010 |
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13939919 |
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10643623 |
Aug 19, 2003 |
7799342 |
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12855838 |
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09731479 |
Dec 6, 2000 |
6733781 |
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10643623 |
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Current U.S.
Class: |
514/357 ;
514/570; 514/778 |
Current CPC
Class: |
A61K 9/0056 20130101;
A61P 43/00 20180101; A61K 9/2013 20130101; A61K 9/209 20130101;
A61K 31/192 20130101; A61K 9/2077 20130101; A61K 31/4402 20130101;
A61K 9/2031 20130101; A61K 31/137 20130101; A61K 9/2095 20130101;
A61K 9/2018 20130101 |
Class at
Publication: |
514/357 ;
514/778; 514/570 |
International
Class: |
A61K 9/00 20060101
A61K009/00 |
Claims
1-31. (canceled)
32. A tablet consisting of a fast dissolve granulation, an active
ingredient, corn starch, one saccharide selected from the group of
sorbitol, glucose, dextrose, fructose, maltose, xylitol, sucrose,
lactose, glucose, galactose, mannitol, a dextrate and a
maltodextrin and at least one non-saccharide containing excipient
selected from the group consisting of a sowing agent, a sweetening
agent, crosscarmellose sodium, a flavoring agent, a disintegrant, a
glidant and a silicon dioxide, wherein said fast dissolve
granulation consists essentially of some or all of said one
saccharide and one or more low melting point compound that melts or
softens at or below 37.degree. C., wherein the said one or more low
melting point compound comprises less than about 20% (wt/wt) of the
fast dissolve granulation and from about 0.01% to about 2.5%
(wt/wt) of the tablet, and wherein the tablet has a hardness of
less than 0.5 kP.
33. The tablet of claim 32 wherein the one saccharide is
mannitol.
34. The tablet of claim 32 wherein the one or more low melting
point compound is one or more compounds selected from the group
consisting of hydrogenated oil and partially hydrogenated oil.
35. The tablet of claim 34 wherein the hydrogenated oil or
partially hydrogenated oil is a vegetable oil.
36. A tablet consisting of a fast dissolve granulation, an active
ingredient, corn starch, one saccharide selected from the group of
sorbitol, glucose, dextrose, fructose, maltose, xylitol, sucrose,
lactose, glucose, galactose, mannitol, a dextrate and a
maltodextrin, and at least one non saccharide containing excipient
selected from the group consisting of a souring agent, a sweetening
agent, crosscarmellose sodium, a flavoring agent, a disintegrant, a
glidant and a silicon dioxide, wherein said fast dissolve
granulation consists essentially of said one saccharide and a low
melting point compound that melts or softens at or below 37'C
selected from the group consisting of hydrogenated vegetable oil
and partially hydrogenated vegetable oil, wherein the low melting
point compound comprises less than about 20% (wt/wt) of the fast
dissolve granulation and from about 0.01% to about 2.5% (wt/wt) of
the tablet, and wherein the tablet has a hardness of less than 0.5
kP.
37. The tablet of claim 36 wherein the saccharide is mannitol.
38.-40. (canceled)
Description
[0001] This application is a Continuation in Part of U.S. patent
application Ser. No. 09/731,479 filed Dec. 6, 2000, entitled "Fast
Dissolving Tablet," the contents of which are incorporated herein
in their entirety to the extent that it is consistent with this
invention and application.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The current invention relates to tablets of low hardness but
good physical stability, in particular fast dissolving tablets that
can be made at very low compression force, yet have acceptable
stability, and methods for preparing such tablets.
[0004] 2. Description of the Related Art
[0005] Several processes are presently available by which a tablet,
which dissolves quickly in the mouth, may be formulated. However,
various disadvantages are associated with these currently available
methods for producing fast dissolving tablets. For example the
addition of high levels of disintegrants is disclosed by Cousin et
al. (U.S. Pat. No. 5,464,632). Cousin et al. add two disintegrants
to the disclosed tablet formulations, for example 16% starch 1500
and 13.3% crossprovidone. The oral-disintegration time of these
tablets is 35 seconds to 45 seconds. However, tablets including
high levels of disintegrants have a chalky or dry feel when placed
in the mouth.
[0006] Another process for producing fast dissolving tablets
involves freeze drying or lyophilizing solutions or suspensions of
an active ingredient and matrix forming excipients. Pehley et al.
(U.S. Pat. No. 5,298,261) disclose freeze-drying a slurry or paste
comprising an active ingredient and excipients placed in blister
packets. Humbert-Droz et al. (WO 97/36879) disclose vacuum drying,
at room temperature or a slightly elevated temperature, a
suspension including the active drug, a sugar alcohol, PEG 600,
talc, sweeteners and flavors in preformed blisters. The
disadvantages of the freeze drying or vacuum drying methods are
time (very slow process), cost of the equipment (not done on
conventional tablet manufacturing equipment), and that it is
limited to low dose actives.
[0007] Fast-dissolving tablets may also be formulated by the
inclusion of effervescent coupled compounds. Wehling et al. (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 the tablet to moisture results in contact and
chemical reaction between the effervescent couple which leads to
gas production and tablet disintegration. For this reason, tablets
which include effervescent pairs are highly sensitive to moisture
and have an unpleasant mouthfeel.
[0008] Tablets formed by compression under low compression force
also dissolve more rapidly than tablets formed by high compression
force. However, tablets produced by these processes have a high
degree of friability. Crumbling and breakage of tablets prior to
ingestion may lead to uncertainty as to the dosage of active
ingredient per tablet. Furthermore, high friability also causes
tablet breakage leading to waste during factory handling.
[0009] The present invention addresses these and other problems
associated with the prior art. The invention provides
fast-dissolving tablets of low hardness, low friability and high
stability which have the added advantage of cost-effective methods
of manufacture and are amenable to established manufacturing and
packaging methods. In particular, the fast-dissolving tablets of
the invention melt rapidly in the mouth and provide an excellent
mouth feel.
SUMMARY OF THE INVENTION
[0010] The present invention advantageously provides compositions
and methods for preparing a fast dissolving tablet of low hardness
but good physical stability that can be made at very low
compression force.
[0011] Thus, the invention provides a tablet comprising a low
melting point compound that melts or softens at or below 37.degree.
C., a water soluble excipient, and an active ingredient.
Preferably, the low melting point compound comprises from about
0.01% to about 20% (wt/wt) of the composition (e.g., 0.01, 0.1, 1,
2.5, 5, 7.5, 10, 12, 14, 16, 18, or 20% (wt/w). Preferably, the
tablet has a hardness of about 3 kP or less, more preferably about
2 kP or less, and still more preferably about lkP or less.
Preferably, the minimum hardness of the tablet is about 0.1 kP,
although lower values, including 0.050, are possible. When
established manufacturing and packaging methods are used the low
melting point compound preferably comprises about 0.01% to about 2%
(wt/wt) of the composition and the tablet hardness is preferably
about 1.0 to about 2.0 kP and more preferably between about 1.2 and
about 1.5 kP.
[0012] The invention further provides a method of producing a
tablet composition. The method comprises combining an active agent
(also termed "active ingredient" or "active") with a fast
dissolving granulation. The fast dissolving granulation comprises a
low melting point compound and a water soluble excipient.
Preferably, the low melting point compound is present in an amount
that will yield values (i.e., content thereof) of about 0.01% to
about 20% (wt/wt) in a final tablet composition (e.g., 0.01, 0.1,
1, 2, 2.5, 5, 7.5, 10, 12, 14, 16, 18, or 20% (wt/wt)).
[0013] The accompanying Detailed Description, Examples and Drawings
further elaborate the invention and its advantages.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 shows a graph of tablet hardness as a function of
compression force for tablets of the invention prepared by a melt
granulation process (diamonds), and tablets prepared by direct
compression (squares).
[0015] FIG. 2 shows a graph of friability as a function of tablet
hardness; "Number of Rotations" indicates a number of rotations in
a Friabilator which occur before a tablet breaks. Tablets prepared
by melt granulation (diamonds) or by direct compression (squares)
were evaluated.
[0016] FIG. 3 shows a graph of time onset of disintegration (T1) as
a function of compression force for tablets of the invention
(diamonds) and for tablets formed by direct compression
(squares).
[0017] FIG. 4 shows a graph of disintegration time (T2) as a
function of compression force for tablets of the invention
(diamonds) and for tablets formed by direct compression
(squares).
[0018] FIG. 5 shows a graph of disintegration time as a function of
the friability (as measured by the number of rotations in a
Friabilator before a first tablet breaks) for tablets of the
invention (diamonds) and for tablets formed by direct compression
(squares).
[0019] FIG. 6 shows a graph of time to dissolve (mean of
disintegration time in seconds for 34 samples of a tablet of the
invention (MG), two types of tablets formed by direct compression
(DC1 and DC2), and a commercial fast dissolving tablet
(KIDTAB.RTM.).
[0020] FIG. 7 shows a graph of grittiness score (adjusted mean
determined by least squares from ANOVA). Subjects scored this
sensory attribute on a scale of 1 (low grittiness) to a 9 (high
grittiness). Tablets were as described for FIG. 6.
[0021] FIG. 8 shows a graph of chalkiness score (adjusted mean
determined by least squares from ANOVA). Subjects scored this
sensory attribute on a scale of (low chalkiness) to a 9 (high
chalkiness). Tablets were described for FIG. 6.
[0022] FIG. 9 shows a graph of overall preference ranking for each
product (as described in FIG. 6), represented by the percentage of
subjects ranking each product 1.sup.st, 2.sup.nd, 3.sup.rd, or
4.sup.th.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0023] The current invention provides fast dissolving tablet
formulations that can be formed by compression into a conventional
tablet. Tablet friability is lower than conventional fast
dissolving tablets prepared by low compression. The fast dissolving
tablet has at least one compound (or "component") which partially
or fully melts or softens at or below body temperature and a water
soluble excipient. Surprisingly, it has been found that use of the
component which partially or fully melts below body temperature in
an amount of about 0.01% to about 2.5% wt. in the tablet provides
for a fast dissolving tablet composition that is conveniently
amenable to established tablet manufacturing processes and
equipment and to established packaging methods. Amenable to
established tablet and manufacturing processes and equipment is
taken to mean that the composition (which forms the tablet) may be
processed with conventional manufacturing equipment with minimal
occurrence of malformed product and/or the need for special
equipment maintenance procedures. The low melting point compound
may be hydrophilic or hydrophobic. The tablets of the invention may
also include an active ingredient and may also include one or more
disintegrants, flavors, colorants, sweeteners, souring agents,
glidants or lubricants.
[0024] The hardness of the tablets is low (less than or equal to
about 3 kP), preferably less than or equal to about 2 kP, and more
preferably less than or equal to about 1 kP, with a minimum
hardness of about 0.1 kP (e.g., 0.05, 0.07, 0.1, 0.2, 0.3, 0.4,
0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.3, 1, 6, 1.9, 2.0, 2.1, 2.3, 2.5,
2.7, 2.8, or 3.0 kP). In embodiments well suited to established
manufacturing and packaging methods, the tablet hardness is
preferably about 1.2 to about 1.5 kP. In other embodiments,
hardness ranges from about 0.2 to about 1 kP. Attributes such as
(1) fast stable dissolution; (2) good tablet mouth feel; and (3)
good tablet physical stability are of greater importance than
minimum and maximum values of tablet hardness. Nevertheless, the
tablets are somewhat pliable, and are less fragile than
conventional tablets that have the same crushing strength. The
tablets have an excellent mouthfeel resulting from the low melting
point component which melts or softens in the mouth to produce a
smooth feel and masks the grittiness of insoluble ingredients.
Unlike other fast dissolving tablets, the disintegration of this
fast dissolving tablet occurs by a combination of melting,
disintegration of the tablet matrix, and dissolution of water
soluble excipient. Therefore, a dry feels does not occur.
Disintegration time is 10 to 30 seconds (e.g., 10, 12, 14, 16, 18,
20, 22, 24, 26, 28 or 30 seconds), depending on the tablet size and
amount of insoluble ingredients, e.g., coated active. Even though
the tablet contains a low melting point ingredient, it is
relatively stable to high temperatures. Heating the tablet above
the melting point of its low melting point component will not
significantly reduce its physical stability.
[0025] The friability of conventional tablets is measured by the
percentage weight loss after a typical friability test (rotating 10
tablets in a friability apparatus for 100 rotations). This test is
very harsh for conventional fast dissolving tablets and so cannot
be used to measure their friability. Fast dissolving tablets made
by a prior art method of direct compression at low force crumble
after a few rotations in the friability apparatus. Fast dissolving
tablets manufactured by the method in the current invention can
withstand 20-50 rotations in the friability apparatus before any
tablet breaks. After 20 rotations, the friability (% weight lost)
is typically less than 1%.
[0026] The term "low melting point compound" may include any edible
compound which melts or softens at or below 37.degree. C. which is
suitable for inclusion in the tablets of the invention. Materials
commonly used for manufacturing suppositories usually have a
melting point at or just below body temperature and can be used in
the invention. The low melting point compound can be hydrophilic or
hydrophobic.
[0027] Examples of hydrophilic low-melting point compounds include,
but are not limited to, polyethylene glycol; the preferred mean
molecular weight range of polyethylene glycol for use in the
tablets of the invention is from about 900 to about 1000. Mixtures
of polyethylene glycol with different molecular weights (200, 300,
400, 550, 600, 1450, 3350, 8000 or 10,000) are within the scope of
the invention if the mixture melts or softens at or below 37
degrees celsius.
[0028] Examples of hydrophobic low-melting point compounds include,
but are not limited to, low melting point triglycerides,
monoglycerides and diglycerides, semisynthetic glyceride (e.g.,
EUTECOL.RTM., GELUCIRE.RTM. (gatteffosse)), hydrogenated oils,
hydrogenated oil derivatives or partially hydrogenated oils (e.g.,
partially hydrogenated palm kernel oil and partially hydrogenated
cottonseed oil), fatty acid esters such as myistyl lactate, stearic
acid and palrnitic acid esters, cocoa butter or its artificial
substitutes, palm oil/palm oil butter, and waxes or mixtures of
waxes, which melt at 37.degree. C. or below. In preferred
embodiments, the hydrogenated oil is Wecobec M. To be effective in
the tablet compositions, the low melting point compound must be
edible.
[0029] Mono-di- and triglycerides are rarely used as pure
components. Hydrogenated vegetable oils and solid or semisolid fats
are usually mixtures of mono-di and triglycerides. The melting
point of the fat or hydrogenated vegetable oil is characteristic of
the mixture and not due to a single component. Witepsol (brand name
by Condea), Supocire (brand name by Gattefosse), and Novata (brand
name by Henkel) are commonly used in manufacturing suppositories,
because they melt at body temperature. All are mixtures of
triglycerides, monoglycerides and diglycerides.
[0030] In preferred embodiments, the low melting point compound
comprises from about 0.01% to about 20%, by weight, of a tablet
composition (e.g., about 0.01, 0.1, 1, 2.5, 5, 7.5, 10, 12, 14, 15,
16, 18 or 20% (wt/wt). Concentration of low melting point compound
in the amount of about 0.01% to about 2% (wt/wt) of the tablet are
preferable when established manufacturing and packaging methods are
used. The tablets of the present invention also include a water
soluble excipient. As used herein, the term "water soluble
excipient" refers to a solid material or mixture of materials that
is orally ingestible and readily dissolves in water. Examples of
water soluble excipients include but are not limited to
saccharides, amino acids, and the like. Saccharides are preferred
water soluble excipients. Preferably, the saccharide is a mono-,
di- or oligosaccharide. Examples of saccharides which may be added
to the tablets of the invention may include sorbitol, glucose,
dextrose, fructose, maltose and xylitol (all monosaccharides);
sucrose, lactose, glucose, galatose and mannitol (all
disaccharides). In a specific embodiment, exemplified below, the
saccharide is lactose. Preferably, the saccharide is mannitol.
Other suitable saccharides are oligosaccharides. Examples of
oligosaccharides are dextrates and maltodextrins. Modified
saccharides such as sucralose or other artificial sweeteners such
as saccharin or aspartame, for example, may be used. Other water
soluble excipients may include amino acids such as alanine,
arginine, aspartic acid, asparagine, cysteine, glutamic acid,
glutamine, glycine, histidine, isoleucine, leucine, lysine,
methionine, phenylalanine, proline, serine, threonine, tryptophan,
tyrosine and valine. Glycine and lysine are preferred amino
acids.
[0031] In preferred embodiments, the water soluble excipient
comprises from about 25% to about 97.5%, by weight, of a tablet
composition. The preferred range is about 40% to about 80%. For
example, tablet compositions comprising about 25, 30, 35, 40, 45,
50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 97.5%, by weight, of the
excipient, e.g. monosaccharide, disaccharide, polysaccharide,
modified saccharide, artificial sweetener or mixtures thereof are
within the scope of the invention.
[0032] As used herein, the term "about" (or "approximately") means
a particular value can have a range acceptable to those of skill in
the art given the nature of the value and method by which it is
determined. In a specific embodiment, the term means within 50% of
a given value, preferably within 20%, more preferably within 10%,
and more preferably still within 5%.
Active Ingredients
[0033] As used herein, the term "active ingredient" or "active
agent" refers to one or more compounds that have some
pharmacological property. Accordingly, more than one type of active
ingredient compound may be added to the tablets of the invention.
The tablets of the invention may comprise any active ingredient
which may be orally administered to a subject. Tablets including
active ingredients in amounts appropriate for the desired
pharmacological properties at the dosage administration can be
formulated. Any amount of active ingredient that does not
significantly affect beneficial tablet features, such as hardness,
friability and mouthfeel are within the scope of the invention.
Placebo tablets, which lack an "active ingredient" having a known
pharmacologic activity, are also within the scope of the invention.
An "active ingredient" of a placebo can be the water soluble
excipient (i.e., lacking any identifiable "active"), a different
water soluble compound, or any non-active compound.
[0034] A non-limiting list of acceptable active ingredients may
include but is by no means limited to: 1) antipyretic analgesic
anti-inflammatory agents such as indomethacin, aspirin, diclofenac
sodium, ketoprofen, ibuprofen, mefenamic acid, dexamethasone,
dexamethasone sodium sulfate, hydrocortisone, prednisolone,
azulene, phenacetin, isopropylantipyrin, acetaminophen, benzydamine
hydrochloride, phenylbutazone, flufenamic acid, mefenamic acid,
sodium salicylate, choline salicylate, sasapyrine, clofezone or
etodolac; 2) antiulcer agents such as ranitidine, sulpiride,
cetraxate hydrochloride, gefarnate, irsogladine maleate,
cimetidine, lanitidine hydrochloride, famotidine, nizatidine or
roxatidine acetate hydrochloride; 3) coronary vasodilators such as
Nifedipine, isosorbide dinitrate, diltiazem hydrochloride,
trapidil, dipyridamole, dilazep dihydrochloride, methyl
2,6-dimethyl-4-(2-nitrophenyl)-5-(2-oxo-1,3,2-droxaphosphorinan-2-yl)-1,4-
-dihydropyridine-3-carboxylate, verapamil, nicardipine, nicardipine
hydrochloride or verapamil hydrochloride; 4) peripheral
vasodialtors such as ifenprodil tartrate, cinepazide maleate,
cyclandelate, cinnarizine or pentoxyfyline; 5) oral antibacterial
and antifungal agents such as pencillin, ampicillin, amoxicillin,
cefalexin, erythromycin ethylsuccinate, bacampicillin
hydrochloride, minocycline hydrochloride, chloramphenicol,
tetracyline, erythromycin, fluconazole, itraconazole, ketoconazole,
miconazole or terbinafine; 6) synthetic antibacterial agents such
as nalidixic acid, piromidic acid, pipemidic acid trihydrate,
enoxacin, cinoxacin, ofloxacin, norfloxacin, ciprofloxacin
hydrochloride, or sulfamethoxazole trimethoprim; 7) antipasmodics
such as popanthelinc bromide, atropine sulfate, oxapium bromide,
timepidium bromide, butylscopolamine bromide, rospium chloride,
butropium bromide, N-methylscopolamine methylsulfate, or
methyloctatropine bromidebutropium bromide; 8) antitussive,
anti-asthamitic agents such as theophylline, aminophylline,
methlephedrine hydrochloride, procaterol hydrochloride,
trimetoquinol hydrochloride, codeine phosphate, sodium
cromoglicate, tranilast, dextromethorphane hydrobromide, dimemorfan
phosphate, clobutinol hydrochloride, fominoben hydrochloride,
benproperine phosphate, tipepidine hibenzate, eprazinone
hydrochloride, clofedanol hydrochloride, ephedrine hydrochloride,
noscapine, carbetapentane citrate oxeladin tannate, or isoaminile
citrate; 9) broncyodilators such as diprophylline, salbutamol
sulfate, cloprenaline hydrochloride, formoterol fumarate,
orciprenalin sulfate, pirbuterol hydrochloride, hexoprenaline
sulfate, bitolterol mesylate, clenbuterol hydrochloride,
terbutaline sulfate, mabuterol hydrochloride, fenoterol
hydrobromide, or methoxyphenamine hydrochloride; 10) diuretics such
as furosemide, acetazolamide, trichlormethiazide, methyclothiazide,
hydrochlorothiazide, hydroflurnethiazide ethiazide,
cyclopenthiazide, spironolactone, triamterene, fluorothiazide,
piretanide, metruside, ethacrygnic acid, azosemide, or clofenamide;
11) muscle relaxants such as chlorphensin carbamate, tolperison
hydrochloride, eperisone hydrochloride, tizanidine hydrochloride,
mephenesin, chlorozoxazone, phenprobamate, methocarbamol,
chlormezanone, pridinol mesylate, afloqualone, baclofen, or
dantrolene sodium; 12) brain metabolism altering drugs such as
meclofenoxate hydrochloride; 13) minor tranquilizers such as
oxazolam, diazepam, clotiazepam, medazepam, temazepam, fludiazepam,
meprobamate, nitrazepam, or chlordiazepoxide; 14) major
tranquilizers such as sulpiride, clocapramine hydrochloride,
zotepine, chlorpromazinon, haloperidol; 15) .beta.-blockers such as
pindolol, propranolol hydrochloride, carteolol hydrochloride,
metoprolol tartrate, labetalol hydrochloride, acebutolol
hydrochloride, butethanol hydrochloride, alprenolol hydrochloride,
arotinolol hydrochloride, oxprenolol hydrochloride, nadolol,
bucumolol hydrochloride, indenolol hydrochloride, timolol maleate,
befunolol hydrochloride, or bupranolol hydrochloride; 16)
antiarrhythmic agents such as procainamide hydrochloride,
disopyramide, ajimaline, quinidine sulfate, aprindine
hydrochloride, propafenone hydrochloride, or mexiletine
hydrochloride; 17) gout suppressants allopurinol, probenecid,
colchine, sulfinpyrazone, benzbromarone, or bucolome; 18)
anticoagulants such as ticlopidine hydrochloride, dicumarol, or
warfarin potassium; 19) antiepileptic agents such as phenyloin,
sodium valproate, metharbital, or carbamazepine; 20)
antihistaminics such as chlorpheniramine maleate, cremastin
fumarate, mequitazine, alimenazine tartrate, or cycloheptazine
hydrochloride; 21) antiemetics such as difenidol hydrochloride,
metoclopramide, domperidone, betashistine mesylate, or trimebutine
maleate; 22) hypotensives such as dimethylaminoethyl reserpilinate
dihydrochloride, rescinnamine, methyldopa, prazosin hydrochloride,
bunazosin hydrochloride, clonidine hydrochloride, budralazine, or
urapidin; 23) sympathomimetic agents such as dihydroergotamine
mesylate, isoproterenol hydrochloride, or etilefrine hydrochloride;
24) expectorants such as bromhexine hydrochloride, carbocysteine,
ethyl cysteine hydrochloride, or methyl cysteine hydrochloride; 25)
oral antidiabetic agents such as glibenclamide, tolbutamide, or
glymidine sodium; 26) circulatory agents such as ubidecarenone or
ATP-2Na; 27) iron preparations such as ferrous sulfate or dried
ferrous sulfate; 28) vitamins such as vitamin B1, vitamin B2,
vitamin B6, vitamin B12, vitamin C, Vitamin A, vitamin D, vitamin
E, vitamin K or folic acid; 29) pollakiuria remedies such as
flavoxate hydrochloride, oxybutynin hydrochloride, terodiline
hydrochloride, or 4-diethylamino-1,1-dimethyl-2-butynyl
(I)-.alpha.-cyclohexyl-.alpha.-phenylglycolate hydrochloride
monohydrate; 30) angiotensin-converting enzyme inhibitors such as
enalapril maleate, alacepril, or delapril hydrochloride; 31)
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; 32) high potency analgesics such as
codeine, dihydrocodeine, hydrocodone, morphine, dilandid, dernoral,
fentanyl, pentazocine, oxycodone, pentazocine or propoxyphene; 33)
antihistamines such as Brompheniramine maleate; 34) nasal
decongestants such as phenylpropanolamine HCl and 35) antacids such
as calcium carbonate, calcium hydroxide, magnesium carbonate,
magesium hydroxide, potassium carbonate, potassium bicarbonate,
sodium carbonate, and sodium bicarbonate. Active ingredients in the
foregoing list may also have beneficial pharmaceutical effects in
addition to the one mentioned.
Other Tablet Ingredients
[0035] The term "tablet" refers to a pharmacological composition in
the form of a small, essentially solid pellet of any shape. Tablet
shapes may be cylindrical, spherical, rectangular, capsular or
irregular. The term "tablet composition" refers to the substances
included in a tablet. A "tablet composition constituent" or tablet
constituent" refers to a compound or substance which is included in
a tablet composition. These can include, but are not limited to,
the active and any excipients in addition to the low melting point
compound and the water soluble excipient(s). An excipient is any
ingredient in the tablet except the active. In addition to the low
melting point compound excipients may include, for example,
binders, disintegrants, flavorants, colorants, glidants, souring
agents and sweeteners.
[0036] For purposes of the present application, "binder" refers to
one or more ingredients added before or during granulation to form
granules and/or promote cohesive compacts during compression. A
"binder compound" or "binder constituent" is a compound or
substance which is included in the binder. Binders of the present
invention include, at least, the low melting point compound.
[0037] Additionally, and optionally, other substances commonly used
in pharmaceutical formulations can be included such as flavors
(e.g., strawberry aroma, raspberry aroma, cherry flavor, magnasweet
135, key lime flavor, grape flavor trusil art 5-11815, fruit
extracts and prosweet), flavor enhancers and sweeteners (e.g.,
aspartame, sodium saccharine, sorbitol, glucose, sucrose), souring
agents (e.g. citric acid), dyes or colorants.
[0038] The tablet may also contain one or more glidant materials
which improve the flow of the powder blend and minimize tablet
weight variation, Glidants such as silicone dioxide may be used in
the present invention.
[0039] Additionally, the tablets of the invention may include
lubricants (e.g. magnesium stearate) to facilitate ejection of the
finished tablet from dies after compression and to prevent tablets
from sticking to punch faces and each other.
[0040] Any method of forming a tablet of the invention into a
desired shape which preserves the essential features thereof is
within the scope of the invention.
Tablet Formation
[0041] A preferred method of forming the tablet compositions of the
invention includes preparing a fast dissolving granulation by
mixing a low-melting point compound, (preferably a hydrogenated
oil, partially hydrogenated oil or hydrogenated oil derivative) and
a water soluble excipient, (preferably a saccharide or modified
saccharide). The term "fast dissolving granulation" refers to a
composition of the low melting point compound and the water soluble
excipient prepared for use as a granulation in the manufacture of
tablets of the invention. A portion of the fast dissolving
granulation may then be added to the remaining ingredients.
However, methods of forming the tablets of the invention wherein
all tablet constituents are combined simultaneously or wherein any
combination of tablet constituents are combined separate from the
other constituents are within the scope of the invention.
[0042] Granulation end point can be determined visually (visual
inspection) or by using a load cell that measures power
consumption. Tablet manufacturing and granulation routinely employ
both techniques.
[0043] The tablet compositions of the invention can be formed by
melt granulation which is a preferred method. In particular, the
melt granulation can be prepared in a high shear mixer (e.g. high
sheer granulation process), low shear mixer or fluid bed
granulator. An example of high shear mixer is Diosna (this is a
brand name by Diosna Dierks & Sohne GmbH). Examples of low
shear mixers are various tumbling mixers (e.g., twin shell blenders
or V-blender). Examples of fluid bed granulators are Glatt and
Aeromatic fluid bed granulators.
[0044] There are at least three ways of manufacturing the
granulation: [0045] Melting the low melting point ingredient, then
combining (e.g., by spraying) it with the water soluble
ingredient(s) (including the water soluble excipient) in the
granulator and mixing until granules form. [0046] Loading the water
soluble excipient in the granulator and spraying the molten low
melting point compound on it while mixing. [0047] Combining the two
(water soluble component (including the water soluble excipient)
and low melting point component) and possibly other ingredients and
mixing while heating to a temperature around a higher than the
melting point of the low melting point component until the granules
form.
[0048] After the granulation congeals, it may be milled and/or
screened. Examples of mills that can be used are CoMill, Stokes
Oscillator (these are brand names). Any mills that are commonly
used for milling tablet granulations may be used.
[0049] Melt extrusion can be used to form the fast dissolving
granulation. An example of an extruder that can be used is Nica (a
brand name by Niro-Aeromatic). The low melting point compound and
the water soluble saccharide (or other excipient) are mixed and
heated in a planetary mixer bowl (low shear mixer) that is usually
part of the extruder. The soft mass is then fed to the extrusion
chamber and forced through small holes or orifices to shape it into
thin rods or cylinders. After the extruded material congeals it can
be milled or spheronized using standard equipment. In the
spheronization step, the extrudate is dumped onto the spinning
plate of the spheronizer and broken up into small cylinders with a
length equal to their diameter, then rounded by frictional forces
(See, International Journal of Pharmaceutics 1995, 116:131-146,
especially p. 136).
[0050] Spray congealing or prilling can also be used to form the
tablet compositions of the invention. Spray congealing includes
atomizing molten droplets of compositions which, may include low
melting point compound, low melting point compound and selected
tablet ingredients, or the entire tablet composition onto a
surface. The surface may be an inert mechanical support, a carrier
surface or in embodiments in which the spray contain droplets only
part of the tablet components a second portion of the tablet
composition. Equipment that can be used for spray congealing
includes spray driers (e.g., Nero spray drier) and a fluid bed
coater/granulation with top spray (e.g., Glatt fluid bed
coater/granulator). In preferred embodiments, a fast-dissolve
granulation is formed wherein, preferably a water soluble
excipient, more preferably a saccharide, is suspended in a molten
low melting point ingredient and spray congealed. After spray
congealing, the resulting composition is allowed to cool and
congeal. Following congealing of the mixture, it is screened or
sieved and mixed with remaining tablet constituents. Spray
congealing processes wherein fast-dissolve granulations comprising
any combination of low melting point compound and other tablet
constituents are melted and spray congealed onto other tablet
constituents are within the scope of the present invention. Spray
congealing processes wherein all tablet constituents, including the
low-melting point compound, are mixed, the low melting point
compound is melted and the mixture is spray congealed onto a
surface are also within the scope of the invention.
[0051] After spray congealing, the mixture may be milled and then
combined with other tablet constituents. Following formation of the
final tablet composition, the composition may be further processed
to form a tablet shape.
[0052] Mixing and milling of tablet constituents during the
preparation of a tablet composition may be accomplished by any
method which causes the composition to become mixed to be
essentially homogeneous. In preferred embodiments the mixers are
high-shear mixers such as the Diosna, CoMill or V-Blender.
[0053] Once tablet compositions are prepared, they may be formed
into various shapes. In preferred embodiments, the tablet
compositions are pressed into a shape. This process may comprise
placing the tablet composition into a form and applying pressure to
the composition so as to cause the composition to assume the shape
of the surface of the form with which the composition is in
contact. In preferred embodiments, the tablet is compressed into
the form at a pressure which will not exceed about 10 kN,
preferably less than 8 kN. For example, pressing the tablets at
less than 1, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9 or 10 kN
is within the scope of the invention. The tablets of the invention
generally have a hardness of about 3 kP or less; preferably the
tablets have a hardness of about 2 kP or less and more preferably
about 1 kP or less. For compositions subjected to established
manufacturing methods hardness of about 1 to about 2.0 is preferred
and harness of about 1.2 to about 1.5 is more preferable. In
another embodiment, for example, tablets of less than 0.1 kP
including tablets of about 0.05, 0.07 kP and tablets of about 0.2,
0.3, 0.4, 0.5, 0.6. 0.7, 0.8, 0.9, 1.0, 1.3, 1.6, 1.9, 2.0, 2.1,
2.3, 2.5, 2.7, 2.8, or 3.0 are within the scope of the invention.
Hydraulic presses such as a Carver Press or rotary tablet presses
such as the Stokes Versa Press are suitable means by which to
compress the tablet compositions of the invention.
[0054] Tablets may also be formed by tumbling melt granulation
(TMG) essentially as described in Maejima et al. Chemical
Pharmacology Bulletin (1997) 45(3): 518-524; which is incorporated
herein by reference. Tumbling melt granulation can be used for
preparing the melt granulation. It can be done in a tumbling mixer.
The molten low melting point compound is sprayed on the crystalline
saccharide and powdered saccharide in the blender and are mixed
until granules form. In this case, the low melting point ingredient
is the binder and the crystalline saccharide is the seed. An
alternative method is to combine the unmelted low melting point
ingredient, crystalline sugar (e.g., mannitol or lactose) in the
tumbling mixer and mix while heating to the melting point of the
low melting point binder or higher. The seed should be crystalline
or granular water soluble ingredient (saccharide), e.g., granular
mannitol, crystalline maltose, crystalline sucrose, or any other
sugar. An example of tumbling mixers is the twin-shell blender
(V-blender), or any other shape of tumbling mixers. Heating can be
achieved by circulating heated air through the chamber of the
granulator and by heating the bottom surface of the chamber. As the
seed material and the powdered tablet constituents circulate the
heated chamber, the low-melting point compound melts and adheres to
the seeds. The unmelted, powdered material adheres to the
seed-bound, molten low-melting point material. The spherical beads
which are formed by this process are then cooled and screen sifted
to remove nonadhered powdered material.
Example 1
Fast Dissolving Granulation
[0055] Compositions of Fast Dissolving Granulations. In these
compositions, the water soluble excipient is a saccharide. As
described above, the tablets of the invention may be formulated by
a method wherein a fast dissolving granulation, comprising a low
melting point compound and a water soluble excipient, is mixed
separately from other tablet constituents. A portion of the fast
dissolving granulation may then be combined with the other tablet
constituents. In this example, several specific examples of fast
dissolving granulations are set forth.
TABLE-US-00001 TABLE 1 Fast dissolving granulation formulations.
Fast Dissolving Granulation Low Melting Point Saccharide
Composition Compound (amount) (amount) 1 Wecobee M hydrogenated
mannitol powder (5 Kg) vegetable oil (1 Kg) 2 Gelucire 33/01
semisynthetic mannitol powder (1 Kg) glycerides (200 g) 3 Wecobee M
(150 g) crystalline maltose (100 g) mannitol powder (750 g) 4
polyethylene glycol 900 fructose powder (400 g) (100 g)
[0056] Fast dissolving granulations 1 and 2 were prepared by
heating the low melting point compound to 50.degree. C. At
50.degree. C., Wecobee M and Gelucire 33/01 become molten. The
molten material was gradually added to the mannitol powder in a
high shear granulator (Diosna). The granulation was mixed at high
speed. When the granulation end point was reached as determined by
visual inspection, the granulation was allowed to congeal. The
congealed granulation was then milled using a CoMill.
[0057] Granulation 3 was granulated by combining melted Wecobee M
with the mannitol in a high shear mixer (Robot Coupe) and blending
until the granules formed. Granulation 4 was made by combining the
melted PEG with fructose powder in a planetary mixer (low shear
mixer) and mixing until the granules formed. The granulations were
allowed to cool, then were screened.
Example 2
Fast dissolving ibuprofen tablets
[0058] The following is an example of a fast dissolving tablet
wherein the active ingredient is ibuprofen.
TABLE-US-00002 Ingredient Amount (mg tablet) Coated ibuprofen
(active ingredient) 121.9 (equivalent to 100 mg ibuprofen) Citric
acid (souring agent) 11.0 Magnasweet 135 (sweetening agent) 3.9
Aspartame (sweetening agent) 6.5 Cherry flavor (flavoring agent)
7.8 Crosscarmellose sodium (disintegrant) 39.0 Silicone dioxide
(glidant flow aid) 1.95 Magnesium stearate (lubricant) 3.25 Fast
dissolving granulation 4 457.9 Total 653.2
[0059] Ingredients were screened, then mixed in a V-blender.
Tablets were compressed using a hydraulic press (Carver Press) at
600 lb (about 2.7 kN). The tablets had a hardness of 0.2-0.5 and
disintegrated in less than 15 seconds.
Example 3
Fast Dissolving Antihistamine/Decongestant Tablets
[0060] The following is an example of a fast dissolving tablet
comprising the active ingredients of many common allergy
medications, Phenylpropanolamine HCl and Brompheniramine
maleate.
TABLE-US-00003 Ingredient Amount (mg/tablet) Phenylpropanolamine
HCI (active ingredient) 6.25 Brompheniramine maleate (active
ingredient) 1.0 Citric acid (souring agent) 6.0 Magnasweet 135
(sweetening agent) 1.80 Aspartame (sweetening agent) 4.5 Cherry
flavor (flavoring agent) 3.60 Corn Starch (anti-adherent) 30.0
Silicone dioxide (glidant flow aid) 3.0 Fast dissolving granulation
4 219.25 Magnesium stearate (lubricant) 2.1 Total 301.5
[0061] Tablets were compressed on a hydraulic press (Carver Press)
at approximately 3 kN. Tablet hardness was 0.2-0.5 kP and
disintegration time 10 seconds.
Example 4
Fast Dissolving Ibuprofen Tablets
[0062] The following is an example of a fast dissolving tablet
wherein the active ingredient is ibuprofen.
TABLE-US-00004 Ingredient Amount (mg/tablet) Coated ibuprofen
(active agent) 119.0 Citric Acid (souring agent) 20.0 Magnasweet
135 (sweetening agent) 7.5 Aspartame (sweetening agent) 7.5 Grape
flavor Trusil Art 5-11815 (flavoring agent) 5.00 Prosweet (flavor
and sweetness enhancer) 5.00 Crosscarmellose sodium (enhancer) 20.0
Corn Starch, NF (anti-adherent) 40.0 Silicone dioxide (Syloid 244)
(glidant flow aid) 5.00 Fast dissolving granulation 1 271 Total
500
[0063] Tablets were compressed using a rotary press (Stokes Versa
Press) at 3.3.-3.5 kN, resulting in a hardness of 0.2-0.9 kP. In
vivo disintegration time was 19 seconds (average of 34
subjects).
[0064] Sensory Study
[0065] The melt granulation tablets of Example 4 were evaluated for
in vivo disintegration time and mouthfeel in an in-house sensory
study. The comparator was Kidtab.RTM., an 80 mg acetaminophen fast
dissolving tablet prepared by direct compression. Two other
ibuprofen fast dissolving tablets prepared by direct compression
were also included in the study. The study included 34 subjects.
The subjects were asked to record the time for the tablet to
completely dissolve in the mouth and give scores for mouthfeel
attributes and overall liking of the product. The melt granulation
prototype (based on this invention) performed best on
disintegration time (FIG. 6) and mouthfeel attributes (least
grittiness (FIG. 7) and least chalkiness (FIG. 8)) and were ranked
best on the overall performance by the panelists. The following
table shows the ranking results of the sensory study on
disintegration time and mouthfeel attributes: MG is the melt
granulation tablet of the invention. DC1 and DC2 are the two direct
compression phototypes.
TABLE-US-00005 Ranking (1 = best, 4 = worst) Prototype/Product
Sensory Attribute DC1 MG Kidtab DC2 Time to dissolve (seconds) 2 1
4 3 Grittiness 4 1 2 3 Chalkiness 3 1 4 2 Overall Preference 4 1 2
3
[0066] The tablets of the invention were ranked the highest (1,
best) in all four categories tested (dissolution time, grittiness,
chalkiness and overall performance) against DC1, DC2 and
KIDTAB.
[0067] As illustrated in FIG. 6, the tablets of the invention
exhibited superior fast dissolving characteristics as compared to
the direct compression tablets which were also evaluated (DC1, DC2
and KIDTAB); the average time for the tablet of the invention (MG)
to dissolve was 19 seconds wherein the time for DC1, DC2 and KIDTAB
to dissolve were about 20, 22 and 25 seconds, respectively. The
tablets of the invention also exhibited a mouthfeel which was
superior to the DC1, DC2 and KIDTAB tablets. FIGS. 7 and 8 indicate
the 34 individuals who participated in the study perceived a lower
level of grittiness and chalkiness associated with the tablets of
the invention as compared to the direct compression tablets (DC1,
DC2 and KIDTAB).
[0068] Overall preference was also scored (least squares mean from
ANOVA) on a scale from 1 (most preferred) to 9 (least preferred).
As indicated in FIG. 9, the tablet of the invention scored highest
(2.11), followed by the KIDTAB.RTM. (2.29), and the two direct
compression tablets (DC2-2.52, DC1-03.05).
Example 5
Fast Dissolving Ibuprofen Tablets
[0069] The following is an example of a fast dissolving tablet
wherein the active ingredient is ibuprofen.
TABLE-US-00006 Ingredient (mg/tablet) Coated ibuprofen (active
agent) 238.0 Citric Acid (souring agent) 17.5 Magnasweet 135
(sweetening agent) 9.75 Aspartame (sweetening agent) 9.75 Key Lime
flavor (flavoring agent) 6.50 Vanilla powder (flavoring agent)
0.650 Corn Starch, NF (anti-adherent) 52.0 Silicone dioxide (Syloid
244) (glidant/flow acid) 6.50 Sodium stearyl fumarate (Pruv)
(lubricant) 4.88 Fast dissolving granulation 1 304 Total 650
[0070] Tablets were compressed using a rotary tablet press (Stokes
Versa Press) at 3 kN, resulting in a hardness of 0.35-0.60 kP. In
vivo disintegration time was 16 seconds.
Example 6
Compressibility and In Vitro Evaluation of Tablets
[0071] To compare fast dissolving tablets of the invention with
fast dissolving tablets prepared by direct compression, the
following two examples were prepared.
[0072] Melt granulation fast dissolving tablet:
TABLE-US-00007 Ingredient (mg/tablet) Ibuprofen microcaps 119.0
Citric Acid, anhydrous, fine granular 20.0 Magnasweet 135 7.5
Aspartame (Nutrasweet) 7.5 Cherry Berry flavor 4.25 Sweet AM 2.50
Crosscarmellose sodium 20.0 Corn Starch, NF 40.0 Silicone dioxide
(Syloid 244) 5.00 Fast dissolve granulation* 274.25 TOTAL 500 *The
granulation is 85.0% Mannitol powder, USP and 15.0% Wecobee M
(hydrogenated vegetable oil). The granulation was prepared similar
to granulation 1 in Table 1.
[0073] Direct compression fast dissolving tablet.
TABLE-US-00008 Ingredient mg/tablet Ibuprofen microcaps 119.0
Citric Acid, anhydrous, fine granular 20.0 Magnasweet 135 7.5
Aspartame (Nutrasweet) 7.5 Sweet AM 2.5 Fruit Punch flavor 3.50
Crosscarmellose sodium 20.0 Corn Starch, NF 40.0 Silicone dioxide
(Syloid 244) 5.00 Mg Stearate 3.50 Fast Dissolve granulation 271.5
TOTAL 500
[0074] Melt granulation tablets and direct compression tablets were
prepared based on the same formula, except that granular mannitol
was used instead of the fast dissolve melt granulation. The
compressibility of the two tablet formulations (melt granulation
and direct compression) were compared. The two blends were
compressed at different compression forces and the resulting
tablets were evaluated for hardness and in vitro disintegration
time. Tablet hardness (crushing strength) was measured using a high
resolution texture analyzer (Stable Microsystems) with an acrylic
cylindrical probe.
[0075] in vitro disintegration was performed in a texture analyzer.
A tablet was held on a net that was then attached to a 1/4''
stainless steal ball probe. The disintegration medium was 5 ml of
water in a 50 ml beaker. The height of water was barely enough to
submerge the tablet, and the water temperature was kept at
37.+-.1.degree. C. The texture analyzer was instructed to apply a
small force (20 g) when the tablet hit the bottom of the beaker.
The time for disintegration onset and total disintegration time was
recorded.
[0076] Compressibility:
[0077] Fast dissolving tablets in general are soft and need to be
blister-packaged directly off the tablet press. The tablets
manufactured according to the invention can be compression or wet
granulation. For fast dissolving tablets containing a coated
active, it is important to compress at the lowest force possible so
that the coating will not be ruptured under compression. With the
melt granulation approach, tablets that are robust enough to
withstand packaging right off the tablet press were obtained using
a compression force as low as 2 kN, whereas for a similar direct
compression formulation, acceptable tablets could not be obtained
at compression forces below 5 kN (FIG. 1).
[0078] Hardness and Friability:
[0079] Although the melt granulation tablets had a lower hardness
compared to direct compression tablets that are compressed at the
same force (FIG. 1), the melt granulation tablets were somewhat
pliable and less fragile. As illustrated in FIG. 2, the softest
melt granulation prototype, with a hardness of about 0.2 kP, was
able to withstand at least 9 rotations in the friabilator
(friability apparatus) before any tablet breaks. At 0.5 kP, these
tablets survived 20-30 rotations. Direct compression tablets at
about 0.45 kP started breaking after 4 rotations, while the hardest
direct compression prototype with about 0.9 kP hardness only
survived 12 rotations. In the same friability test, Kidtab.RTM.
tablets (marketed fast dissolving tablets prepared by direct
compression) started breaking after 5-10 rotations. The average
hardness of Kidtab tablets was 1.8 kP. Moreover, at the end of the
test, the direct compression tablets showed more chipping around
the edges than melt granulation prototypes. Direct compression
tablets with hardness greater than 1 kP were not fast dissolving
(took 1 minute or more to dissolve in the mouth of a subject).
[0080] In Vitro Disintegration:
[0081] The onset of disintegration was faster for the melt
granulation prototypes compared to direct compression prototypes
prepared at the same compression force (FIG. 3). Furthermore, the
total time for in vitro disintegration was dependent on compression
force regardless of the formulation (FIG. 4). We obtained
acceptable tablets from the melt granulation processing low
compression force. Direct compression tablets could not be obtained
at the same compression force. Therefore, for tablets with similar
friability, the melt granulation approach produced faster
disintegration time (FIG. 5).
[0082] The melt granulation was less sensitive to small changes in
compression force, whereas for the direct compression formulation,
both hardness and onset of disintegration increased sharply with
increasing the compression force (FIGS. 1 and 3).
Example 7
Example of Melt Granulation Tablets with Higher Hardness
TABLE-US-00009 [0083] Ingredient mg/tablet Ibuprofen microcaps
(encapsulated ibuprofen) 121.9 Citric Acid, anhydrous, fine
granular 11.0 Magnasweet 135 4.0 Aspartame (Nutrasweet) 6.0 Cherry
flavor 6.0 Sweet AM 0.5 Crosscarmellose sodium 45.0 Corn Starch, NF
40.0 Silicone dioxide (Syloid 244) 2.50 Fast dissolve granulation
263.1 TOTAL 500 *The granulation is 85.0% Mannitol powder, USP and
15.0% Wecobee M (hydrogenated vegetable oil).
[0084] Tablets were compressed on Stokes Versapress. Compression
force was not recorded. Tablet hardness was 1.5 kP. The tablets had
a friability of less than 1.0% after 50 rotations in the
friabilator, i.e, lost less than 1% of their initial weight and no
tablet broke. Mean in vivo disintegration time was 25.8 seconds (12
subjects were asked to take the tablets and record the time it
takes for the tablet to completely dissolve without chewing).
Example 8
Example of Melt Granulation Tablets Amendable to Established Tablet
Manufacturing Process and Packaging Methods
Composition 1
TABLE-US-00010 [0085] Ingredient mg/tablet Ibuprofen microcaps
238.0 Sucralose 5.6 Citric acid 28.0 Lemon-lime flavor 1.4
Crosscamellose 28.0 Mannitol SD200 315.0 Corn starch 42.0 CabOSil
7.0 Fast Dissolve Granulation* 35.0
Composition 2
TABLE-US-00011 [0086] Ingredient mg/tablet Ibuprofen microcaps
238.0 Sucralose 5.6 Citric acid 28.0 Lemon-lime flavor 1.4
Crosscamellose 28.0 Mannitol SD200 280.0 Corn starch 42.0 CabOSil
7.0 Fast Dissolve Granulation* 70.0
Composition 3
TABLE-US-00012 [0087] Ingredient mg/tablet Ibuprofen microcaps
238.0 Sucralose 5.6 Citric acid 28.0 Lemon-lime flavor 1.4
Crosscamellose 28.0 Mannitol SD200 297.5 Corn starch 42.0 CabOSil
7.0 Fast Dissolve Granulation* 52.5 Note: The Fast Dissolve
Granulation* had 17% Wecobee and 83% mannitol powder, so the three
formulations had 0.85%, 1.7% and 1.275% Wecobee.
[0088] Compositions 1, 2 and 3 were compressed using a rotary press
(Stokes Versa Press) to a hardness range of 0.45-1.4 kP for
Composition 1, a hardness of 0.7-1.7 kP for composition 2 and a
hardness of 1.8 to 2.2 kP for Composition 3.
[0089] The present invention is not to be limited in scope by the
specific embodiments described herein. Indeed, various
modifications of the invention in addition to those described
herein will become apparent to those skilled in the art from the
foregoing description and the accompanying figures. Such
modifications are intended to fall within the scope of the appended
claims.
[0090] It is further to be understood that all values are
approximate, and are provided for description.
[0091] Patents, patent applications, publications, product
descriptions, and protocols are cited throughout this application,
the disclosures of which are incorporated herein by reference in
their entireties for all purposes.
* * * * *