U.S. patent application number 10/993272 was filed with the patent office on 2005-04-28 for rapidly disintegrating methylcellulose tablets.
This patent application is currently assigned to SmithKline Beecham Corporation. Invention is credited to Daggy, Bruce, Mehta, Naresh I., Nayak, Priyashri.
Application Number | 20050089560 10/993272 |
Document ID | / |
Family ID | 26735831 |
Filed Date | 2005-04-28 |
United States Patent
Application |
20050089560 |
Kind Code |
A1 |
Daggy, Bruce ; et
al. |
April 28, 2005 |
Rapidly disintegrating methylcellulose tablets
Abstract
The present invention relates to a rapidly disintegrating tablet
for oral administration. The tablet has methylcellulose, a diluent,
and a crosprovidone. There is also a process for treating
constipation in a human.
Inventors: |
Daggy, Bruce; (Pine Brook,
NJ) ; Mehta, Naresh I.; (Ledgewood, NJ) ;
Nayak, Priyashri; (Randolph, NJ) |
Correspondence
Address: |
CHARLES N.J. RUGGIERO, ESQ.
OHLANDT, GREELEY, RUGGIERO & PERLE, L.L.P.
10th FLOOR
ONE LANDMARK SQUARE
STAMFORD
CT
06901-2682
US
|
Assignee: |
SmithKline Beecham
Corporation
|
Family ID: |
26735831 |
Appl. No.: |
10/993272 |
Filed: |
November 19, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10993272 |
Nov 19, 2004 |
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10464968 |
Jun 19, 2003 |
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10464968 |
Jun 19, 2003 |
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09485627 |
Feb 14, 2000 |
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6350469 |
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09485627 |
Feb 14, 2000 |
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PCT/US98/17405 |
Aug 21, 1998 |
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60056899 |
Aug 22, 1997 |
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60087662 |
Jun 2, 1998 |
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Current U.S.
Class: |
424/464 |
Current CPC
Class: |
A61K 31/717 20130101;
A61K 9/2077 20130101; A61K 31/716 20130101; A61K 9/2059 20130101;
A61K 9/2009 20130101; A61K 9/2054 20130101; A61K 9/0056 20130101;
A61P 1/10 20180101 |
Class at
Publication: |
424/464 |
International
Class: |
A61K 009/20 |
Claims
1-28. (canceled)
29. A rapidly disintegrating tablet for oral administration
comprising a methylcellulose; a diluent; and a crosprovidone.
30. The tablet of claim 29, wherein the methylcellulose is an
intragranulated methylcellulose.
31. The tablet of claim 29, wherein the diluent is an edible
calcium salt.
32. The tablet of claim 31, wherein the edible calcium salt is
selected from the group consisting of dibasic calcium phosphate
dihydrate, calcium phosphate anhydrous, tribasic calcium phosphate,
and any mixtures thereof.
33. The tablet of claim 29, further comprising a disintegrating
agent other than crospovidone.
34. The tablet of claim 29, wherein the disintegrating agent is an
intragranular disintegrant.
35. The tablet of claim 29, wherein the disintegrating agent is
present in an amount about 3% w/w to about 8% w/w.
36. The tablet of claim 29, wherein the disintegrating agent is
selected from the group consisting of sodium starch glycolate,
sodium carboxymethylcellulose, sodium croscarmellose,
carboxymethylcellulose, veegum, alginate, agar, tragacanth, locust
bean, karaya, pectin, and any mixtures thereof.
37. The tablet of claim 29, further comprising a binding agent.
38. The tablet of claim 37, wherein the binding agent in an
intragranular binding agent.
39. The tablet of claim 37, wherein the binding agent is present in
an amount about 4% w/w to about 6.5% w/w.
40. The tablet of claim 37, wherein the binding agent is selected
from the group consisting of PVP, hydroxypropylcellulose,
hydroxypropyl methylcellulose, acacia, gelatin, tragacanth,
pregelatinized starch, starch, and any mixtures thereof.
41. The tablet of claim 29, further comprising a wetting agent.
42. The tablet of claim 41, wherein the wetting agent is selected
from the group consisting of sodium lauryl sulfate, magnesium
lauryl sulfate, and any mixture thereof.
43. The tablet of claim 29, further comprising a lubricating
agent.
44. The tablet of claim 43, wherein the lubricating agent is
selected from the group consisting of magnesium stearate, calcium
stearate, sodium stearate, colloidal silicon dioxide, Syloid,
stearic acid, talc, and any mixtures thereof.
45. The tablet of claim 29, further comprising a second diluent
that is an ingredient that is separate from the diluent.
46. The tablet of claim 45, wherein the second diluent is selected
from the group consisting of microcrystalline cellulose, corn
starch, pregelatinized starch, and any mixtures thereof.
47. The tablet of claim 29, wherein the methylcellulose has a
viscosity of >1000 centipoise.
48. The tablet of claim 29, wherein the methylcellulose has a
viscosity of >2000 centipoise.
49. The tablet of claim 29, wherein the methylcellulose has a
viscosity of >3000 centipoise.
50. The tablet of claim 29, wherein the methylcellulose has a
viscosity of >4000 centipoise.
51. The tablet of claim 29, wherein the tablet will disintegrate in
water in about 25 minutes to about 30 minutes.
52. The tablet of claim 51, wherein the methylcellulose is present
in an amount about 450 mg to about 550 mg.
53. The tablet of claim 51, wherein the methylcellulose is present
in an amount about 500 mg.
54. The tablet of claim 29, wherein the tablet will disintegrate in
water in about 15 minutes to about 24 minutes.
55. The tablet of claim 29, wherein the tablet will disintegrate in
water in less than about 15 minutes.
56. The tablet of claim 55, wherein the methylcellulose is present
in an amount about 200 mg to about 300 mg.
57. The tablet of claim 55, wherein the methylcellulose is present
in an amount about 250 mg.
58. A process for treating constipation in a human, which process
comprises ingestion by the human of the tablet of claim 29.
59. A process for treating constipation in a human, which process
comprises ingestion by the human of the tablet of claim 37.
60. A process for treating constipation in a human, which process
comprises ingestion by the human of the tablet of claim 41.
61. A process for treating constipation in a human, which process
comprises ingestion by the human of the tablet of claim 43.
62. A process for treating constipation in a human, which process
comprises ingestion by the human of the tablet of claim 53.
63. A process for treating constipation in a human, which process
comprises ingestion by the human of the tablet of claim 57.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to an improved process for
preparing compressed methylcellulose containing tablets which meet
USP disintegration standards.
BACKGROUND OF THE INVENTION
[0002] The history of cellulose ethers, such as methylcellulose and
carboxymethylcellulose suggests that these agents are effective as
bulk laxatives. Their mechanism of action involves increasing both
the water content of, and the bulk content of the stool, as well as
lubricating the stool; thereby relieving constipation.
[0003] Cellulose ethers have been administered as bulk laxatives in
dosage forms comprising of tablets, suspensions, and bulk powders;
the latter as sugar-free or in compositions containing high amounts
of sugar.
[0004] Cellulose ethers administered as suspensions in water may
contain high concentrations of sucrose or other sugars and flavors.
In such formulations, the sugar competes with the cellulose ether
for available water, thereby preventing the cellulose ether from
hydrating sufficiently to form a gel. The advantages of using a
suspension formulation is that the cellulose ether is dispersed
sufficiently to avoid any significant lumping in the digestive
tract. However, these suspensions are viscous, semi-gelatinous, and
visually unappealing to the consumer. Another disadvantage is the
unpalatability of the suspensions due to the slimy mouth feel and
extreme sweetness of such suspensions. Hence, these dosage forms
have not gained significant consumer acceptance.
[0005] Bulk powders of cellulose ethers often exhibit lumping of
individual particles and gelation and thus, remain undissolved as
they pass through the digestive tract. Additionally, administration
of bulk powders has caused cramping, nausea, and vomiting in some
patients. Therefore, bulk powders are not the preferred dosage form
for cellulose ethers.
[0006] Palatable and visually appealing bulk powders have, however,
been accomplished by addition of water or another aqueous liquid to
a dry powder mix of a water-soluble cellulose ether and a
dispersing agent/sweetening component, typically sugar. This
technology is disclosed in South African patent No. 84,1044,
published Sep. 26, 1984. The pitfall with these compositions is
that they contain about 400 calories of nutritive value per dose,
primarily due to the high sugar content. This high caloric value is
not acceptable to the average consumers or to users suffering from
blood sugar disorders, including diabetics. Elderly people are
normally, the common strata of the population that suffers from
constipation and the more frequent users of laxatives, and are also
commonly suffering with blood sugar disorders. The consumption of
large quantities of sugar could aggravate blood sugar
disorders.
[0007] Sugar encrusted cellulose ethers have been proposed as
alternatives to the bulk powders containing high amounts of sugar.
Such formulations have 1) less sugar such as natural sugar or
combination of sugars such as sucrose, glucose, fructose or corn
syrup solids; 2) lower caloric value; and 3) are readily dispersed
in cold aqueous liquids.
[0008] Citrucel.RTM. Orange Flavor, a bulk forming laxative
containing methylcellulose as its active ingredient, was first
introduced into the market in 1986. This product contains 15 g of
sucrose in a 19 g adult dose, which corresponds to a 2 g dose of
methylcellulose. To decrease the sugar content of this product, a
natural flavored formula lower in caloric value, and containing
only 1 g sucrose, was developed and introduced in 1988. Additional
patent protection for this product has focused on producing a
sugar-free and virtually calorie-free powder. The product has a
sugar-free sweetener, a dispersing agent, other excipients, and
flavoring and was marketed in 1991 as Sugar Free Citrucel.RTM.
Orange Flavor.
[0009] There still remains a need in the art to develop a rapidly
disintegrating solid dosage form of a bulk agent, preferably
methylcellulose, which is convenient to take and transport, sugar
free, and easily administered to the consumer having blood sugar
disorders or diabetics, for instance.
SUMMARY OF THE INVENTION
[0010] The present invention relates to an improved process for
preparing methylcellulose tablets which are readily dispersible and
meet United States Pharmacopoeia standards for disintegration. The
methylcellulose is compressed into tablets which contain an edible
calcium salt, in preferred w/w ratios. Preferably the tablets
rapidly disintegrate, in-vitro in 0.1N hydrochloric acid and water
at 37.sup..+-.0.5.degree. C.
DETAILED DESCRIPTION OF THE INVENTION
[0011] There is a common belief that tabletted cellulose ethers do
not readily dissolve in the digestive tract because these cellulose
ethers are highly hygroscopic. The outer portion of the tablet is
said to form a gel-like hydrate that prevents the tablet from
breaking up and greatly retards the hydration of the inner portion
of the tablet. The present invention overcomes this art recognized
problem and involves preparation of a novel composition, and
process of making, by which a rapidly disintegrating tablet of
methylcellulose is prepared.
[0012] The tablets are prepared by a novel process involving a
high-shear wet granulation method, followed by fluidized bed
drying, milling, mixing with the other ingredients, and
compression.
[0013] The present invention is to a methylcellulose tablet which
comprises methylcellulose having a viscosity of >1000
centipoise, and at least one excipient selected from an edible
calcium salt. It is recognized that the formulation will also
include diluents and fillers well known to the skilled artisan.
[0014] The tablet formulations of the present invention are
advantageous over other dosage forms of methylcellulose because of
their convenience of administration and rapid disintegration. This
is in contrast to tablets of methylcellulose, formulated as 100%
w/w methylcellulose in a 0.5 gm caplet which have been found not to
disintegrate in 0.1N HCl solution, using a conventional dissolution
apparatus even after two hours. The present tablets should
disintegrate in 0.1N HCl from about 20 to about 30 minutes,
preferably from about 10 to about 19 minutes, and more preferably
less than 10 minutes; and in water, the tablets should disintegrate
from about 25 to about 30 minutes, preferably from about 15 to
about 24 minutes, and more preferably less than 15 minutes.
[0015] It has been found that low molecular weight (mw)
methylcellulose is less effective for use as a laxative, and
therefore is less desirable for use in a rapidly disintegrating
tablet formulation. Higher molecular weight methylcellulose is
therefore both desirable and necessary in the present invention.
The fibers must have a sufficient viscosity to gel and retain water
in the gut to provide the stool bulking and softening for laxation
use.
[0016] By using the testing methods for methylcellulose under
standard conditions, such as those found in the USP XXII, p. 894,
Apparent Viscosity method for Methylcellulose, or as discussed in
Handbook of Pharmaceutical Excipients, APhA, a preferred
methylcellulose for use herein should have a viscosity of >1000
centipoises (cps), preferably >2000 centipoises, more preferably
>3000 centipoises, and most preferably >4000 centipoise.
Higher molecular weight methylcellulose than those described is
also desirable, however, the commercially availability of this
grade of methylcellulose being the limiting feature. At present the
upper limit commercially available is about 6000 cps, which is
encompassed within the scope of this invention. One presently
available methylcellulose product for use herein is Methocel A4M,
made by Dow Chemical Company, Midland Mich. as Dow Methocel A4M,
having a viscosity of about 3000 to about 5,600 cps, which is
within 75 to 140% of the desired target viscosity herein.
[0017] Some of the additional diluents or fillers for use in this
formulation are preferably swellable agents, and may include, but
are not limited to, various grades of microcrystalline cellulose,
such as Avicel PH101, Avicel PH102, & Avicel PH200; Corn
starch; or Starch 1500.
[0018] The edible calcium salts suitable for use herein include but
are not limited to, dibasic calcium phosphate dihydrate, calcium
phosphate anhydrous, and tribasic calcium phosphate; or mixtures
thereof. A preferred edible calcium salt is the dibasic calcium
phosphate dihydrate salt, which salt also provides good
compressibility.
[0019] If microcrystalline cellulose is added, it is preferably
from about 50 to 180 microns in size, more preferably about 50.
Avicel PH 101 has a mean particle size of about 50; Avicel PH 102
has a mean particle size of about 100; and Avicel PH 200 has a mean
particle size of about 190 microns. Preferably the preferred
microcrystalline cellulose is Avicel PH 101.
[0020] It is noted that the ratio of methylcellulose to edible
calcium salt, and additional diluents will depend upon the diluent
chosen, and is within the skill of the art to determine with
preciseness the necessary ratios.
[0021] Suitable ratios for particular diluents however, are
described below:
[0022] For Methylcellulose:Dibasic calcium phosphate, dihydrate,
from about 2 to about 4:1, preferably from about 2.6-3.1:1;
[0023] For Methylcellulose:Calcium phosphate, anhydrous from about
2 to about 4:1, preferably from about 3.1:1
[0024] Methylcellulose:Tribasic calcium phosphate, WG.RTM. from
about 2 to about 4:1, preferably from about 3.1:1
[0025] For Methylcellulose:microcrystalline cellulose, from about
2:1 to about 14:1. Preferably for Avicel PH 101 from about
2.2-13.5:1; for Avicel PH 102 from about 2.4-8.3:1; and for Avicel
PH 200 from about 2.4-4:1.
[0026] For Methylcellulose:Corn starch from about 7.5 to about 15,
preferably from about 13.5:1;
[0027] For Methylcellulose:Starch 1500, from about 2.0 to about
5.0:1, preferably from about 2.4:1;
[0028] For Methylcellulose:Explotab, from about 5 to about 25:1,
preferably from about 8.1 to about 21.3:1.
[0029] It is recognized that with the edible calcium salt, the
formulation must also have an ingredient which keeps the granules
together, i.e. a binding agent. A preferred binding agent is PVP,
or the alternative agents noted below.
[0030] In addition to the above noted edible calcium salt(s),
optional diluents or fillers, and binding agent(s), the formulation
may also include additional components such as, but are not limited
to, a wetting agent, (super)disintegrant(s), a second binding
agent(s), dye(s) or colouring agents, and lubricants, which are
preferably used to prepare a tablet that is wetted readily, and is
rapidly disintegrated in 0.1N hydrochloric acid and water, the USP
test standard test for methylcellulose.
[0031] A preferred wetting agent is sodium lauryl sulfate.
[0032] A preferred lubricant is magnesium stearate.
[0033] A preferred binding agent is polyvinylpyrrolidone, or PVP,
such as Povidone 29K/32. Preferably, the PVP is present in an
amount of about 4 to about 6.5% w/w.
[0034] A preferred disintegrating agent is sodium starch glycolate,
such as Explotab.RTM.. Preferably, the sodium starch glycolate is
present in an amount of about 3 to about 8% w/w.
[0035] As various excipents and diluents will be formulated
together, and used in combination herein, suggested % w/w ratios
for various formulations are presented below. While not all of
these ratios include the edible calcium salts, these are merely
illustrative of the invention and the skilled artisan will readily
recognize how to formulate the product of this invention with the
addition of the edible calcium salts.
[0036] Sodium lauryl sulfate:Explotab:Dibasic calcium phosphate,
dihydrate:Povidone 29K/32:Magnesium stearate include:
0.38-0.40:3.5-7.9:20.6-24.8:4.0-6.5:0.5-1.0
[0037] Sodium lauryl sulfate:Explotab:Tribasic calcium phosphate
WG.RTM.: Povidone 29K/32:Magnesium stearate include:
0.40:3.5:21.6:6.4:1.0
[0038] Sodium lauryl sulfate:Explotab:Calcium phosphate, anhydrous:
Povidone 29K/32:Magnesium stearate include:
0.40:3.5:21.6:6.4:1.0
[0039] Methylcellulose:sodium lauryl sulfate (SLS), from about 60
to about 170:1, preferably from about 155:1-170:1;
[0040] Methylcellulose:Povidone, preferably PVP 29K/32, from about
8 to about 22:1, preferably from about 10.4:1-16.7:1;
[0041] Methylcellulose:Magnesium stearate from about 50 to about
150;1, preferably from about 58-132:1;
[0042] Sodium lauryl sulfate:Explotab:Avicel PH 101.RTM.: Povidone
29K/32:Magnesium stearate include:
0.35-0.46:3.05-6.17:4.38-27.13:4.38-6.- 66:0.76-1.14
[0043] Sodium lauryl sulfate:Explotab:Avicel PH 102.RTM.: Povidone
29K/32:Magnesium stearate include:
0.35-0.46:4.9-6.17:9.21-25.53:4.38-6.6- 6:0.76-1.14
[0044] Sodium lauryl sulfate:Avicel PH 200.RTM.: Povidone
29K/32:Magnesium stearate include:
0.38-0.42:19.27-25.53:5.99-6.66:0.94-1.04
[0045] Sodium lauryl sulfate:Explotab:Corn starch: Povidone
29K/32:Magnesium stearate include:
0.36-0.38:3.66-7.07:4.35-4.68:4.35-4.6- 8:0.88-0.95
[0046] Sodium lauryl sulfate:Explotab:Starch 1500.RTM.: Povidone
29K/32:Magnesium stearate include:
0.36-0.38:3.66-7.07:24.05-25.89:4.35-4- .68:0.88-0.95
[0047] Not wishing to be limited to the explicit excipients noted
above, the following alternative agents may also be used
herein.
[0048] Alternatives lubricants to magnesium stearate include, but
are not limited to, calcium stearate, sodium stearate, Cab-O-Sil,
Syloid, stearic acid and talc.
[0049] Alternatives binding agents to PVP include but are not
limited to, hydroxypropylcellulose, hydroxypropyl methylcellulose,
acacia, gelatin, tragacanth, pregelatinized starch and starch.
[0050] Alternatives disintegrants to Explotab.RTM. include but are
not limited to, sodium carboxymethylcellulose, Ac-di-sol.RTM.,
carboxymethylcellulose, veegum, alginates, agar, guar, tragacanth,
locust bean, karaya, pectin, and crospovidone.
[0051] Alternative wetting agents to sodium lauryl sulfate, include
but are not limited to, magnesium lauryl sulfate.
[0052] All of these formulations can be prepared with and without
sugar. A sugar-free formulation has the advantage that it can be
administered easily to consumers with blood sugar disorders or to
diabetics in need of such preparations.
[0053] Another advantageous property of the present invention is
that the formulations contain calcium, such as dibasic calcium
phosphate dihydrate. These formulations, for instance, will contain
approximately an 80 mg/dose, anticipating formulating a 0.5
gm/tablet.times.2 tablets/dose of methylcellulose. If desired the
amount of calcium can be increased in these tablets to provide
increased therapeutic value to the consumer.
[0054] The amount of methylcellulose present in each dose, as well
as the number of doses of laxative taken per day, will depend
somewhat on the age, sex, size of the patient, severity of the
patient's particular problem, the advice of the treating physician,
if any, and the particular taste and habits of the patient.
Accordingly, the tablets of this invention are advantageously
administered in a single dose which may contain as much as 500 to
1000 mg of methyl cellulose tablet, or in a plurality of smaller
doses containing as little as 250 mg per tablet. Most preferably,
for laxative effect, each tablet will contain about 500 mg
methylcellulose and the patient may take 1 to 2 tablets per dose.
This dosage, of 1000 mg should adequately provide optimal laxative
efficacy. Therefore, a preferred range of methylcellulose per
tablet is optimally from about 450 to 550 mg, preferably about 500
mg; or alternatively from about 200 to about 300 mg for a smaller
tablet, preferably about 250 mg; or even in increments of about 125
mg tablet, i.e. 75 to 175 mg per tablet.
[0055] While preferably the compressed tablets are uncoated, they
may, if desired, be coated with any suitable coating agent well
known in the art. Suitably the coating agents are those used for
immediate release purposes and will dissolve in the gastric juices.
Such coating agents are well known to those skilled in the art and
include, but are not limited to hydroxypropyl methylcellulose, or
methyl cellulose, or 20% w/w Opadry II, orange in water.
[0056] As will readily be seen by the working examples, there are
various combinations of intra and extragranular mixing which are
possible using the ingredients herein. All are encompassed within
the scope of this invention. Generally, the high viscosity
methylcellulose, such as Methocel A4M, will first be granulated
with a binder, such as povidone, a wetting agent, such as sodium
lauryl sulfate, and a suitable colouring agent to form the
intragranular mixture which is then granulated. These granular
components are then admixed with additional wetting agents, and
disintegrating agents and finally blended with lubricant. This
final granular mixture is then blended and compressed into the
tablets of the present invention.
[0057] Therefore, an aspect of the present invention is a process
for preparing a tablet formulation which comprises
[0058] a) blending together to form an intragranular mixture high
viscosity methylcellulose of >3000 cps, a wetting agent,
povidone or sodium starch glycolate, and an edible calcium salt;
and
[0059] b) adding to the mixture of step (a) a PVP aqueous solution,
or alternatively spraying the mixture of step (a) with a PVP
aqueous solution; and preparing granulates; and
[0060] c) blending together an extragranular mixture of an edible
calcium salt, a wetting agent; a lubricating agent; povidone or
sodium starch glycolate or a mixture thereof; and
[0061] d) compacting the granulates of step (b) with the
extragranular mixture of step (c).
[0062] Another aspect of the present invention is a process for the
manufacture of a pharmaceutical tablet, which process comprises
mixing
[0063] a) granulates comprising high viscosity methylcellulose of
>3000 cps, a wetting agent, povidone or sodium starch glycolate,
an edible calcium salt; and
[0064] b) blending together an extragranular mixture of an edible
calcium salt, a wetting agent; a lubricating agent; povidone or
sodium starch glycolate or a mixture thereof; and
[0065] c) compacting the granulates of step (b) with the granular
mixture of step (a); and
[0066] d) compressing into a tablet.
[0067] Another aspect of the present invention is the method of
relieving constipation by increasing the water content of the
stool, or by providing a lubricating effect on the stool in a
mammal in need thereof, which method comprises administering to
said mammal, an effective amount of a high viscosity
methylcellulose compressed into a tablet with a suitable
diluent.
[0068] Methods of Preparation
[0069] The following examples illustrates the invention but is not
intended to limit the scope thereof. All parts and percentages are
by weight unless otherwise indicated. The disintegration time of
the formulations described in the Tables below were obtained by
using a conventional disintegration apparatus.
EXAMPLE 1
[0070]
1TABLE I Swallowable Methylcellulose Tablets Formula Ingredient
g/tablet (% w/w) Phase A Methocel A4M 0.5000 67.27 Dibasic Calcium
phosphate, dihydrate 0.0370 4.98 Sodium lauryl sulfate 0.0015 0.20
Dye/Colouring agent 0.0010 0.13 Povidone 29K/32 0.0480 6.46 DI
water q.s. q.s. Phase B Phase A 0.5875 79.04 Sodium lauryl sulfate
0.0015 0.20 Sodium starch glycolate 0.0260 3.50 Dibasic Calcium
phosphate, dihydrate 0.1245 16.75 Magnesium stearate 0.0038 0.51
TOTAL 0.7433 100.00
[0071] The process of preparing the rapidly disintegrating tablet
of methylcellulose is carried out using specified quantities of
ingredients, such as those mentioned in TABLE I above, using the
following steps:
[0072] 1. Preparation of Povidone K29/32 (PVP) Solution
[0073] The specified amount of PVP was weighed and added to the
weighed quantity of water and stirred till all the PVP was
dissolved completely.
[0074] 2. Preparation of Phase A
[0075] Accurately weighed amounts of Methocel A4M, calcium
phosphate, dibasic dihydrate, sodium lauryl sulfate, and colouring
agent, such as any suitable FD&C Aluminium lake, were
transferred to a Key Hi-shear granulator and mixed for about 10
minutes with impellor speed at 135 rpm and chopper speed at 10%.
The PVP solution was sprayed onto the mixture in the granulator at
a rate of approx. >200 mL/min. Once addition of PVP solution was
complete, the chopper was stopped. The mixing was continued in the
granulator till resistance reads about 130-135 watts and the time
noted to reach that wattage. A sample was withdrawn from the wet
granulation to record loss on drying (% LOD). The moist granules
were dried in the Aeromatic Fluid bed dryer in portions till the %
LOD reading approximated 1.0-3.0%. The temperature of the air in
the fluid bed dryer was maintained at approx. 90-95.degree. C. and
the sample was found to be dry at an outlet air temperature of
approx. 32-52.degree. C. The dried granules were milled through a
12# screen in the Fitz Mill at a high speed. The granules were
weighed and percent yield calculated. The moisture content was
measured for the dry granules. A sample from the granules was
withdrawn and analyzed for particle size distribution, bulk and tap
density, flow index, and moisture studies. The granules were
weighed and ingredients of Phase B were calculated based on the
weight of remaining granules.
[0076] 3. Preparation of the Final Blend
[0077] To the weighed milled granules produced in Phase A above,
specified amounts of sodium lauryl sulfate, sodium starch glycolate
(Explotab.RTM.), and dibasic calcium phosphate, dihydrate were
added into the V-blender and mixed about 10 minutes. Magnesium
stearate was then added to the blend and mixed for an additional 3
minutes or so. Samples from different sections of the V-blender
were drawn and submitted for analyzing blend uniformity. A sample
from the final blend was analyzed for particle size distribution,
bulk and tap density, flow index, and moisture studies. The
granules were then weighed.
[0078] 4. Compression of Methylcellulose Tablets
[0079] The final blend was charged into the hopper of a Stokes
single punch `F` tablet press and compressed into caplets with a
suitable tooling. Target hardness desired is between 10 and 25,
preferably 8-12 SCU, a preferred target weight of each tablet of
less than 750 mg; an estimated friability of less than 2.0%, more
preferably less than 1.0%, and target disintegration times below 30
minutes in water and acid (shorter disintegration times, less than
10 minutes, more preferably less than 8 minutes, in 0.1N HCl and
less than 15 minutes in water, more preferably about 8 minutes, are
preferred). The tablets were packaged in Ziplock bags. The tablets
were tested for weight variation, hardness, disintegration in acid
and water, friability, moisture (% LOD), thickness, viscosity, and
content uniformity.
[0080] The formulation in TABLE I exhibited a disintegration time
of less than 5 minutes in 0.1N HCl and less than 9 minutes in water
by the conventional USP method using Disintegration Apparatus with
disks.
[0081] The disintegration time for the formulation of Table 1,
Example 1, was less than 5 minutes in 0.1N HCl was less than 9
minutes in water.
[0082] It is noted that Examples 2 to 6, and 11 to 15 are Avicel
based formulations, and Examples 7 to 10 are strach based
formulations which do not contain an edible calcium salt
excipients. These are merely for illustration purposes, and may be
formulated to include the edible calcium salts as desired using the
teachings of this invention and working examples 1, and 16 to
23.
EXAMPLE 2
[0083] A formulation containing both Avicel PH 101.RTM. and
Explotab.RTM., intra and extragranularly as shown in TABLE II
below, exhibited an average disintegration time of less than 1
minute in 0.1N HCl at 37.sup..+-.0.5.degree. C. using the automated
disintegration apparatus.
2TABLE II Swallowable Methylcellulose Tablets Formula Ingredient
g/tablet (% w/w) Phase A Methocel A4M 0.5000 60.31 Avicel PH 101
.RTM. 0.0370 4.46 Sodium lauryl sulfate 0.0015 0.18 Povidone 29K/32
0.0370 4.46 Explotab .RTM. 0.0300 3.62 DI water q.s. q.s. Phase B
Phase A 0.6055 73.03 Sodium lauryl sulfate 0.0017 0.21 Sodium
starch glycolate 0.0253 3.05 Avicel PH 101 .RTM. 0.1880 22.67
Magnesium stearate 0.0086 1.04 TOTAL 0.8291 100.00
EXAMPLE 3
[0084] A formulation containing Avicel PH101.RTM. intragranularly,
extragranular Avicel PH 102.RTM. and Explotab.RTM., intra and
extragranularly, as shown below in TABLE III exhibited an average
disintegration time of less than 3 minutes in 0.1N HCl at
37.sup..+-.0.5.degree. C. using the automated disintegration
apparatus.
3TABLE III Swallowable Methylcellulose Tablets Formula Ingredient
g/tablet (% w/w) Phase A Methocel A4M 0.5000 59.24 Avicel PH 101
.RTM. 0.0370 4.38 Sodium lauryl sulfate 0.0015 0.18 Povidone 29K/32
0.0370 4.38 Explotab .RTM. 0.0300 3.56 Dye/colouring agent 0.0040
0.47 DI water q.s. q.s. Phase B Phase A 0.6095 72.21 Sodium lauryl
sulfate 0.0015 0.18 Sodium starch glycolate 0.0220 2.61 Avicel PH
102 .RTM. 0.2035 24.11 Magnesium stearate 0.0075 0.89 TOTAL 0.8440
100.00
EXAMPLE 4
[0085] A formulation containing Avicel PH101.RTM. intragranularly,
extragranular Avicel PH 102.RTM. and Explotab.RTM. intra and
extragranularly as shown in TABLE IV below exhibited an average
disintegration time of less than 2 minutes in 0.1N HCl at
37.sup..+-.0.5.degree. C. using the automated disintegration
apparatus.
4TABLE IV Swallowable Methylcellulose Tablets Formula Ingredient
g/tablet (% w/w) Phase A Methocel A4M 0.5000 59.52 Avicel PH 101
.RTM. 0.0370 4.41 Sodium lauryl sulfate 0.0015 0.18 Povidone 29K/32
0.0370 4.41 Explotab .RTM. 0.0300 3.57 DI water q.s. q.s. Phase B
Phase A 0.6055 72.08 Sodium lauryl sulfate 0.0015 0.18 Sodium
starch glycolate 0.0220 2.62 Avicel PH 102 .RTM. 0.2035 24.23
Magnesium stearate 0.0075 0.89 TOTAL 0.8400 100.00
[0086] In an alternative embodiment of Example 4 a coated version
of the formulation shown in TABLE IV was tested for disintegration
time. The coating solution used was 20% w/w Opadry II, Orange in
water. The average disintegration time of coated tablets was less
than one minute in 0.1N HCl at 37.sup..+-.0.5.degree. C. using the
automated disintegration apparatus.
EXAMPLE 5
[0087] A formulation containing Avicel PH101.RTM. intragranularly,
extragranular Avicel PH 102.RTM. and Explotab.RTM. intra and
extragranularly as shown in TABLE V exhibited an average
disintegration time of less than one minute in 0.1N HCl at
37.sup..+-.0.5.degree. C. using the automated disintegration
apparatus.
5TABLE V Swallowable Methylcellulose Tablets Formula Ingredient
g/tablet (% w/w) Phase A Methocel A4M 0.5000 60.24 Avicel PH 101
.RTM. 0.0370 4.46 Sodium lauryl sulfate 0.0015 0.18 Povidone 29K/32
0.0370 4.46 Explotab .RTM. 0.0300 3.62 DI water q.s. q.s. Phase B
Phase A 0.6055 72.95 Sodium lauryl sulfate 0.0015 0.18 Sodium
starch glycolate 0.0110 1.33 Avicel PH 102 .RTM. 0.2045 24.64
Magnesium stearate 0.0075 0.90 TOTAL 0.8300 100.00
EXAMPLE 6
[0088] A formulation containing Avicel PH101.RTM. intragranularly,
extragranular Avicel PH102.RTM. and no Explotab.RTM. as shown in
TABLE VI below, exhibited an average disintegration time of less
than 3 minutes in 0.1N HCl and less than 2 minutes at
37.sup..+-.0.5.degree. C. using the automated disintegration
apparatus. The disintegration times using the conventional
apparatus were about 1 minute in acid and less than 2 minutes in
water.
6TABLE VI Swallowable Methylcellulose Tablets Formula Ingredient
g/tablet (% w/w) Phase A Methocel A4M 0.5000 67.94 Avicel PH 101
.RTM. 0.0370 5.03 Sodium lauryl sulfate 0.0015 0.20 Povidone 29K/32
0.0370 5.03 Dye/Colouring Agent 0.0010 0.14 DI water q.s. q.s.
Phase B Phase A 0.5765 78.34 Sodium lauryl sulfate 0.0011 0.15
Avicel PH 102 .RTM. 0.1527 20.75 Magnesium stearate 0.0056 0.76
TOTAL 0.7359 100.00
EXAMPLE 7
[0089] A formulation containing corn starch intragranularly,
extragranular Starch 1500 and no Explotab.RTM. as shown in TABLE
VII exhibited an average disintegration time of less than 16
minutes in 0.1N HCl at 37.sup..+-.0.5.degree. C. using the
automated disintegration apparatus.
7TABLE VII Swallowable Methylcellulose Tablets Formula Ingredient
g/tablet (% w/w) Phase A Methocel A4M 0.5000 63.29 Corn starch
0.0370 4.68 Sodium lauryl sulfate 0.0015 0.19 Povidone 29K/32
0.0370 4.68 Dye/Colouring Agent 0.0010 0.13 DI water q.s. q.s.
Phase B Phase A 0.5765 72.97 Sodium lauryl sulfate 0.0015 0.19
Starch 1500 .RTM. 0.2045 25.89 Magnesium stearate 0.0075 0.95 TOTAL
0.7900 100.00
EXAMPLE 8
[0090] A formulation containing corn starch intragranularly,
extragranular Starch 1500 and intragranular Explotab.RTM. as shown
in TABLE VIII exhibited an average disintegration time of less than
14 minutes in 0.1N HCl at 37.sup..+-.0.5.degree. C. using the
automated disintegration apparatus.
8TABLE VIII Swallowable Methylcellulose Tablets Formula Ingredient
g/tablet (% w/w) Phase A Methocel A4M 0.5000 61.00 Corn starch
0.0370 4.51 Sodium lauryl sulfate 0.0015 0.18 Povidone 29K/32
0.0370 4.51 Explotab .RTM. 0.0300 3.66 Dye/Colouring Agent 0.0010
0.12 DI water q.s. q.s. Phase B Phase A 0.6065 73.98 Sodium lauryl
sulfate 0.0015 0.18 Starch 1500 .RTM. 0.2045 24.93 Magnesium
stearate 0.0075 0.91 TOTAL 0.8200 100.00
EXAMPLE 9
[0091] A formulation containing corn starch intragranularly,
extragranular Starch 1500 and intra as well as extragranular
Explotab.RTM. as shown in TABLE IX exhibited an average
disintegration time of less than 13 minutes in 0.1N HCl at
37.sup..+-.0.5.degree. C. using the automated disintegration
apparatus.
9TABLE IX Swallowable Methylcellulose Tablets Formula Ingredient
g/tablet (% w/w) Phase A Methocel A4M 0.5000 59.88 Corn starch
0.0370 4.43 Sodium lauryl sulfate 0.0015 0.18 Povidone 29K/32
0.0370 4.43 Explotab .RTM. 0.0300 3.59 Dye/Colouring Agent 0.0010
0.12 DI water q.s. q.s. Phase B Phase A 0.6065 72.63 Sodium lauryl
sulfate 0.0015 0.18 Starch 1500 .RTM. 0.2045 24.49 Explotab .RTM.
0.0150 1.80 Magnesium stearate 0.0075 0.90 TOTAL 0.8350 100.00
EXAMPLE 10
[0092] A formulation containing corn starch intragranularly,
extragranular Starch 1500 and intra as well as extragranular
Explotab.RTM. (in higher amounts than shown above in Example 9,
TABLE IX) as shown in TABLE X exhibited an average disintegration
time of less than 11 minutes in 0.1N HCl and less than 18 minutes
in water at 37.sup..+-.0.5.degree. C. using the automated
disintegration apparatus.
10TABLE X Swallowable Methylcellulose Tablets Formula Ingredient
g/tablet (% w/w) Phase A Methocel A4M 0.5000 58.82 Corn starch
0.0370 4.35 Sodium lauryl sulfate 0.0015 0.18 Povidone 29K/32
0.0370 4.35 Explotab .RTM. 0.0300 3.53 Dye/Colouring Agent 0.0010
0.12 DI water q.s. q.s. Phase B Phase A 0.6065 71.35 Sodium lauryl
sulfate 0.0015 0.18 Starch 1500 .RTM. 0.2045 24.05 Explotab .RTM.
0.0300 3.54 Magnesium stearate 0.0075 0.88 TOTAL 0.8500 100.00
EXAMPLE 11
[0093] Various formulation containing Avicel PH101.RTM.
intragranularly and different levels of extragranular Avicel
PH102.RTM. (as shown in Examples 6, 7, and 8 above) were made to
observe their effect on disintegration time of the tablets.
[0094] The formulation in TABLE XI, below, exhibited an average
disintegration time of less than one minute in 0.1N HCl and less
than 2 minutes in water at 37.sup..+-.0.5.degree. C. using the
automated disintegration apparatus. The conventional disintegration
apparatus yielded less than 1 minute in both acid and water.
11TABLE XI Swallowable Methylcellulose Tablets Formula Ingredient
g/tablet (% w/w) Phase A Methocel A4M 0.5000 62.42 Avicel PH 101
.RTM. 0.0370 4.62 Sodium lauryl sulfate 0.0015 0.19 Povidone 29K/32
0.0480 5.99 Dye/Colouring Agent 0.0010 0.12 DI water q.s. q.s.
Phase B Phase A 0.5875 73.34 Sodium lauryl sulfate 0.0015 0.19
Avicel PH 102 .RTM. 0.2045 25.53 Magnesium stearate 0.0075 0.94
TOTAL 0.8010 100.00
EXAMPLE 12
[0095] The formulation in TABLE XII exhibited an average
disintegration time of less than 5 minutes in 0.1N HCl and less
than 7 minutes in water at 37.sup..+-.0.5.degree. C. using the
automated disintegration apparatus. The conventional disintegration
apparatus yielded less than 5 minutes in acid and less than 8
minutes in water.
12TABLE XII Swallowable Methylcellulose Tablets Formula Ingredient
g/tablet (% w/w) Phase A Methocel A4M 0.5000 69.35 Avicel PH 101
.RTM. 0.0370 5.13 Sodium lauryl sulfate 0.0015 0.21 Povidone 29K/32
0.0480 6.66 Dye/Colouring Agent 0.0010 0.14 DI water q.s. q.s.
Phase B Phase A 0.5875 81.48 Sodium lauryl sulfate 0.0015 0.21
Avicel PH 102 .RTM. 0.1245 17.27 Magnesium stearate 0.0075 1.04
TOTAL 0.7210 100.00
EXAMPLE 13
[0096] The formulation in TABLE XIII exhibited an average
disintegration time of less than 10 minutes in 0.1N HCl and less
than 14 minutes in water at 37.sup..+-.0.5.degree. C. using the
automated disintegration apparatus. The conventional disintegration
apparatus yielded less than 14 minutes in acid and less than 22
minutes in water.
13TABLE XIII Swallowable Methylcellulose Tablets Formula Ingredient
g/tablet (% w/w) Phase A Methocel A4M 0.5000 76.10 Avicel PH 101
.RTM. 0.0370 5.63 Sodium lauryl sulfate 0.0015 0.23 Povidone 29K/32
0.0480 7.31 Dye/coloring agent 0.0010 0.15 DI water q.s. q.s. Phase
B Phase A 0.5875 89.42 Sodium lauryl sulfate 0.0015 0.23 Avicel PH
102 .RTM. 0.0605 9.21 Magnesium stearate 0.0075 1.14 TOTAL 0.6570
100.00
EXAMPLE 14
[0097] Two formulations containing Avicel PH101.RTM.
intragranularly with different levels of extragranular Avicel PH
200.RTM. (shown in TABLE XIV and XV below) were made to observe the
effect on disintegration time of tablets.
[0098] The formulation in TABLE XIV exhibited an average
disintegration time of less than 7 minutes in 0.1N HCl and less
than 9 minutes in water at 37.sup..+-.0.5.degree. C. using the
automated disintegration apparatus. The conventional disintegration
apparatus yielded less than 8 minutes in acid and less than 13
minutes in water.
14TABLE XIV Swallowable Methylcellulose Tablets Formula Ingredient
g/tablet (% w/w) Phase A Methocel A4M 0.5000 62.42 Avicel PH101
.RTM. 0.0370 4.62 Sodium lauryl sulfate 0.0015 0.19 Povidone 29K/32
0.0480 5.99 Dye/Coloring Agent 0.0010 0.12 DI water q.s. q.s. Phase
B Phase A 0.5875 73.34 Sodium lauryl sulfate 0.0015 0.19 Avicel
PH200 .RTM. 0.2045 25.53 Magnesium stearate 0.0075 0.94 TOTAL
0.8010 100.00
EXAMPLE 15
[0099] The formulation in TABLE XV exhibited an average
disintegration time of less than 4 minutes in 0.1N HCl and less
than 7 minutes in water at 37.sup..+-.0.5.degree. C. using the
automated disintegration apparatus. The conventional disintegration
apparatus yielded less than 5 minutes in acid and less than 9
minutes in water.
15TABLE XV Swallowable Methylcellulose Tablets Formula Ingredient
g/tablet (% w/w) Phase A Methocel A4M 0.5000 69.35 Avicel PH101
.RTM. 0.0370 5.13 Sodium lauryl sulfate 0.0015 0.21 Povidone 29K/32
0.0480 6.66 Dye/Coloring Agent 0.0010 0.14 DI water q.s. q.s. Phase
B Phase A 0.5875 81.48 Sodium lauryl sulfate 0.0015 0.21 Avicel
PH200 .RTM. 0.1245 17.27 Magnesium stearate 0.0075 1.04 TOTAL
0.7210 100.00
EXAMPLE 16
[0100] A formulation containing a calcium source from the
intragranular and extragranular excipient, dibasic calcium
phosphate, dihydrate with extragranular Explotab.RTM. is shown in
TABLE XVI.
[0101] The formulation in TABLE XVI exhibited an average
disintegration time of less than 6 minutes in 0.1N HCl and less
than 9 minutes in water at 37.sup..+-.0.5.degree. C. using the
automated disintegration apparatus. The conventional disintegration
apparatus yielded less than 5 minutes in acid and less than 12
minutes in water.
16TABLE XVI Swallowable Methylcellulose Tablets Formula Ingredient
g/tablet (% w/w) Phase A Methocel A4M 0.5000 66.93 Dibasic Calcium
phosphate, dihydrate 0.0370 4.95 Sodium lauryl sulfate 0.0015 0.20
F, D, and C Yellow #6 0.0010 0.13 Povidone 29K/32 0.0480 6.43 DI
water q.s. q.s. Phase B Phase A 0.5875 78.65 Sodium lauryl sulfate
0.0015 0.20 Sodium starch glycolate 0.0260 3.48 Dibasic Calcium
phosphate, dihydrate 0.1245 16.67 Magnesium stearate 0.0075 1.00
TOTAL 0.7470 100.00
EXAMPLE 17
[0102] A formulation containing a calcium source from the intra and
extragranular excipient, dibasic calcium phosphate, dihydrate with
a higher amount of extragranular Explotab.RTM. than in Example 17,
is shown below in TABLE XVII.
[0103] The formulation in TABLE XVII exhibited an average
disintegration time of less than 9 minutes in 0.1N HCl and less
than 14 minutes in water at 37.sup..+-.0.5.degree. C. using the
automated disintegration apparatus. The conventional disintegration
apparatus yielded less than 6 minutes in acid and less than 12
minutes in water.
17TABLE XVII Swallowable Methylcellulose Tablets Formula Ingredient
g/tablet (% w/w) Phase A Methocel A4M 0.5000 65.19 Dibasic Calcium
phosphate, dihydrate 0.0370 4.82 Sodium lauryl sulfate 0.0015 0.20
F, D, and C Yellow #6 0.0010 0.13 Povidone 29K/32 0.0480 6.26 DI
water q.s. q.s. Phase B Phase A 0.6105 79.60 Sodium lauryl sulfate
0.0015 0.20 Sodium starch glycolate 0.0230 3.00 Dibasic Calcium
phosphate, dihydrate 0.1245 16.23 Magnesium stearate 0.0075 0.97
TOTAL 0.7670 100.00
EXAMPLE 18
[0104] Formulations containing a calcium source from the intra and
extragranular excipient, dibasic calcium phosphate, dihydrate with
different levels of extragranular Explotab.RTM., in combination
with similar amount of intragranular Explotab.RTM., are shown below
in TABLE XVIII and XIX (Example 19).
[0105] The formulation in TABLE XVIII exhibited an average
disintegration time of less than 6 minutes in 0.1N HCl and less
than 11 minutes in water at 37.sup..+-.0.5.degree. C. using the
automated disintegration apparatus.
18TABLE XVIII Swallowable Methylcellulose Tablets Formula
Ingredient g/tablet (% w/w) Phase A Methocel A4M 0.5000 65.19
Dibasic Calcium phosphate, dihydrate 0.0370 4.82 Sodium lauryl
sulfate 0.0015 0.20 Sodium starch glycolate 0.0230 3.00 F, D, and C
Yellow #6 0.0010 0.13 Povidone 29K/32 0.0480 6.26 DI water q.s.
q.s. Phase B Phase A 0.6105 79.60 Sodium lauryl sulfate 0.0015 0.20
Sodium starch glycolate 0.0230 3.00 Dibasic Calcium phosphate,
dihydrate 0.1245 16.23 Magnesium stearate 0.0075 0.97 TOTAL 0.7670
100.00
EXAMPLE 19
[0106] The formulation in TABLE XIX exhibited an average
disintegration time of less than 9 minutes in 0.1N HCl and less
than 14 minutes in water at 37.sup..+-.0.5.degree. C. using the
automated disintegration apparatus.
19TABLE XIX Swallowable Methylcellulose Tablets Formula Ingredient
g/tablet (% w/w) Phase A Methocel A4M 0.5000 63.86 Dibasic Calcium
phosphate, dihydrate 0.0370 4.73 Sodium lauryl sulfate 0.0015 0.19
Sodium starch glycolate 0.0230 2.94 F, D, and C Yellow #6 0.0010
0.13 Povidone 29K/32 0.0480 6.13 DI water q.s. q.s. Phase B Phase A
0.6105 77.97 Sodium lauryl sulfate 0.0015 0.19 Sodium starch
glycolate 0.0390 4.98 Dibasic Calcium phosphate, dihydrate 0.1245
15.90 Magnesium stearate 0.0075 0.96 TOTAL 0.7830 100.00
EXAMPLE 20
[0107] Formulations containing a calcium source from the intra and
extragranular excipient, dibasic calcium phosphate, dihydrate with
extragranular Explotab.RTM.) are shown in TABLE XX and XXI (Example
21) below.
[0108] The formulation in TABLE XX exhibited an average
disintegration time of less than 5 minutes in 0.1N HCl and less
than 13 minutes in water at 37.sup..+-.0.5.degree. C. using the
automated disintegration apparatus.
20TABLE XX Swallowable Methylcellulose Tablets Formula Ingredient
g/tablet (% w/w) Phase A Methocel A4M 0.5000 66.89 Dibasic Calcium
phosphate, dihydrate 0.0370 4.95 Sodium lauryl sulfate 0.0015 0.20
F, D, and C Yellow #6 0.0010 0.13 Povidone 29K/32 0.0300 4.01 DI
water q.s. q.s. Phase B Phase A 0.5695 76.19 Sodium lauryl sulfate
0.0015 0.20 Sodium starch glycolate 0.0445 5.95 Dibasic Calcium
phosphate, dihydrate 0.1245 16.66 Magnesium stearate 0.0075 1.00
TOTAL 0.7475 100.00
EXAMPLE 21
[0109] The formulation in TABLE XXI exhibited an average
disintegration time of less than 7 minutes in 0.1N HCl and less
than 9 minutes in water at 37.sup..+-.0.5.degree. C. using the
conventional disintegration method.
21TABLE XXI Swallowable Methylcellulose Tablets Formula Ingredient
g/tablet (% w/w) Phase A Methocel A4M 0.5000 64.52 Dibasic Calcium
phosphate, dihydrate 0.0370 4.77 Sodium lauryl sulfate 0.0015 0.19
F, D, and C Yellow #6 0.0010 0.13 Povidone 29K/32 0.0480 6.19 DI
water q.s. q.s. Phase B Phase A 0.5875 75.81 Sodium lauryl sulfate
0.0015 0.19 Sodium starch glycolate 0.0235 3.03 Dibasic Calcium
phosphate, dihydrate 0.1550 20.00 Magnesium stearate 0.0075 0.97
TOTAL 0.7750 100.00
EXAMPLE 22
[0110] A formulation containing a calcium source from the intra and
extragranular excipient, calcium phosphate, anhydrous with
extragranular Explotab.RTM. is indicated in TABLE XXII.
[0111] The formulation in TABLE XXII exhibited an average
disintegration time of less than 11 minutes in 0.1N HCl and less
than 19 minutes in water at 37.sup..+-.0.5.degree. C. using the
conventional disintegration apparatus.
22TABLE XXII Swallowable Methylcellulose Tablets Formula Ingredient
g/tablet (% w/w) Phase A Methocel A4M 0.5000 66.93 Calcium
phosphate, Anhydrous 0.0370 4.95 Sodium lauryl sulfate 0.0015 0.20
F, D, and C Yellow #6 0.0010 0.13 Povidone 29K/32 0.0480 6.43 DI
water q.s. q.s. Phase B Phase A 0.5875 78.65 Sodium lauryl sulfate
0.0015 0.20 Sodium starch glycolate 0.0260 3.48 Calcium phosphate,
Anhydrous 0.1245 0.67 Magnesium stearate 0.0075 1.00 TOTAL 0.7470
100.00
EXAMPLE 23
[0112] A formulation containing a calcium source from the intra and
extragranular excipient, tribasic calcium phosphate WG.RTM. with
extragranular Explotab.RTM. is indicated in TABLE XXIII.
[0113] The formulation in TABLE XXIII exhibited an average
disintegration time of less than 13 minutes in 0.1N HCl and less
than 24 minutes in water at 37.sup..+-.0.5.degree. C. using the
conventional disintegration apparatus.
23TABLE XXIII Swallowable Methylcellulose Tablets Formula
Ingredient g/tablet (% w/w) Phase A Methocel A4M 0.5000 66.93
Tribasic Calcium phosphate, WG .RTM. 0.0370 4.95 Sodium lauryl
sulfate 0.0015 0.20 F, D, and C Yellow #6 0.0010 0.13 Povidone
29K/32 0.0480 6.43 DI water q.s. q.s. Phase B Phase A 0.5875 78.65
Sodium lauryl sulfate 0.0015 0.20 Sodium starch glycolate 0.0260
3.48 Tribasic Calcium phosphate, WG .RTM. 0.1245 16.67 Magnesium
stearate 0.0075 1.00 TOTAL 0.7470 100.00
[0114] All publications, including but not limited to patents and
patent applications, cited in this specification are herein
incorporated by reference as if each individual publication were
specifically and individually indicated to be incorporated by
reference herein as though fully set forth.
[0115] The above description fully discloses the invention
including preferred embodiments thereof. Modifications and
improvements of the embodiments specifically disclosed herein are
within the scope of the following claims. Without further
elaboration, it is believed that one skilled in the art can, using
the preceding description, utilize the present invention to its
fullest extent. Therefore the Examples herein are to be construed
as merely illustrative and not a limitation of the scope of the
present invention in any way. The embodiments of the invention in
which an exclusive property or privilege is claimed are defined as
follows.
* * * * *