U.S. patent application number 16/641564 was filed with the patent office on 2020-06-11 for pharmaceutical suspensions for bismuth subsalicylates.
The applicant listed for this patent is L. Perrigo Company. Invention is credited to Inderdeep S. BHATIA, David R. CASSIDAY, Bruce D. JOHNSON, Carlos O. PAZ.
Application Number | 20200179411 16/641564 |
Document ID | / |
Family ID | 63528912 |
Filed Date | 2020-06-11 |
View All Diagrams
United States Patent
Application |
20200179411 |
Kind Code |
A1 |
BHATIA; Inderdeep S. ; et
al. |
June 11, 2020 |
PHARMACEUTICAL SUSPENSIONS FOR BISMUTH SUBSALICYLATES
Abstract
The invention is directed to pharmaceutical compositions for
suspending bismuth subsalicylate and methods of use thereof.
Formulations of the present invention include at least three-gum
systems to prevent the settling out of heavy particles in solution
and do not include magnesium aluminum silicate. The pharmaceutical
compositions may be used to treat gastrointestinal disorders.
Inventors: |
BHATIA; Inderdeep S.;
(Kalamazoo, MI) ; CASSIDAY; David R.; (Caledonia,
MI) ; JOHNSON; Bruce D.; (Byron Center, MI) ;
PAZ; Carlos O.; (Fairview, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
L. Perrigo Company |
Allegan |
MI |
US |
|
|
Family ID: |
63528912 |
Appl. No.: |
16/641564 |
Filed: |
August 24, 2018 |
PCT Filed: |
August 24, 2018 |
PCT NO: |
PCT/US2018/047966 |
371 Date: |
February 24, 2020 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
62550143 |
Aug 25, 2017 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0095 20130101;
A61K 31/625 20130101; A61K 31/60 20130101; A61P 1/04 20180101; A61K
9/08 20130101; A61K 47/36 20130101; A61P 1/12 20180101; A61K 47/38
20130101; A61K 31/60 20130101; A61K 33/245 20130101; A61K 33/245
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/625 20060101
A61K031/625; A61K 47/38 20060101 A61K047/38; A61K 47/36 20060101
A61K047/36; A61K 9/08 20060101 A61K009/08 |
Claims
1. A pharmaceutical composition comprising: a) bismuth
subsalicylate; b) microcrystalline cellulose; c) xanthan gum; and
d) an excipient selected from the group consisting of:
carboxymethyl cellulose, carrageenan, and hydroxyethyl cellulose,
or combinations thereof.
2. (canceled)
3. The composition of claim 1, wherein said excipient is
hydroxyethyl cellulose.
4. The composition of claim 1, wherein said composition comprises
bismuth subsalicylate in an amount of from about 10 mg/mL to about
60 mg/mL.
5-9. (canceled)
10. The composition of claim 1, wherein said composition comprises
bismuth subsalicylate in an amount of about 52.5 mg/mL.
11. The composition of claim 1, wherein said composition comprises
carboxymethyl cellulose and hydroxyethyl cellulose.
12. The composition of claim 1, wherein said composition comprises
xanthan gum in an amount of from about 0.50 mg/mL to about 5.0
mg/mL.
13-15. (canceled)
16. The composition of claim 1, wherein said composition comprises
hydroxyethyl cellulose in an amount of from about 0.45 mg/mL to
about 2.0 mg/mL.
17. (canceled)
18. The composition of claim 1, wherein said composition comprises
a mixture of carboxymethyl cellulose and microcrystalline
cellulose.
19-20. (canceled)
21. The composition of claim 18, wherein the mixture of
carboxymethyl cellulose and microcrystalline cellulose is present
in an amount of about 17.1 mg/mL.
22. (canceled)
23. The composition of claim 21, wherein the ratio of the mixture
of carboxymethyl cellulose and microcrystalline cellulose to
xanthan gum is from about 2:1 to about 20:1.
24. (canceled)
25. The composition of claim 1, wherein said composition has a
sedimentation rate of from about 0.001 mm/day to about 0.015 mm/day
at 23.degree. C. as determined by x-ray measurement.
26. (canceled)
27. The composition of claim 1, wherein said composition has a
viscosity of from about 800 cps to about 2400 cps.
28. (canceled)
29. The composition of claim 1, wherein the pH of the composition
is from about 4.0 to about 5.5.
30-31. (canceled)
32. A pharmaceutical composition comprising: a) bismuth
subsalicylate; b) xanthan gum; c) hydroxyethyl cellulose; and d) a
mixture of microcrystalline cellulose and carboxymethyl
cellulose.
33. The composition of claim 32, wherein the ratio of the mixture
of microcrystalline cellulose and carboxymethyl cellulose to
hydroxyethyl cellulose is from about 6:1 to about 250:1.
34. (canceled)
35. The composition of claim 32, wherein the ratio of the mixture
of microcrystalline cellulose and carboxymethyl cellulose to
xanthan gum is from about 5:1 to about 13:1.
36-43. (canceled)
44. A method of treating a gastrointestinal disorder in a patient
in need thereof, comprising administering to the patient a
composition comprising: a) bismuth subsalicylate; b)
microcrystalline cellulose; c) xanthan gum; and d) an excipient
selected from the group consisting of: carboxymethyl cellulose,
carrageenan, and hydroxyethyl cellulose, or combinations
thereof.
45-54. (canceled)
55. The method of claim 44, wherein said composition comprises
xanthan gum in an amount of from about 0.50 mg/mL to about 5.0
mg/mL.
56-66. (canceled)
67. The method of claim 44, wherein said composition has a
viscosity of from about 800 cps to about 2400 cps.
68-69. (canceled)
70. A process for producing a composition of claim 1, comprising:
forming a gum premix comprising glycerin, simethicone, hydroxyethyl
cellulose, and xanthan gum in a first vessel; forming a dye premix
comprising an aqueous mixture of dye compounds in a second vessel;
forming a third mixture comprising water, microcrystalline
cellulose, carboxymethyl cellulose, and bismuth subsalicylate in a
third vessel; and combining the gum premix, dye premix and third
mixture together to produce the composition.
71-85. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. .sctn.
119(e) to U.S. Provisional Application 62/550,143 filed on Aug. 25,
2017. The disclosure of this prior application is considered part
of the disclosure of this application and is hereby incorporated by
reference in its entirety.
FIELD OF INVENTION
[0002] The invention is directed to pharmaceutical compositions for
suspending bismuth subsalicylate and methods of use thereof.
Formulations of the present invention include three-gum systems to
prevent the settling out of heavy particles. The pharmaceutical
compositions may be used to treat gastrointestinal disorders.
BACKGROUND OF THE INVENTION
[0003] Bismuth subsalicylate has been used for decades for the
relief of gastrointestinal disorders such as upset stomach and
diarrhea. Bismuth subsalicylate is typically found in a suspension
using magnesium aluminum silicate as part of the gum system.
Bismuth subsalicylate is a heavy material that is difficult to keep
in suspension, and is difficult to re-suspend once it has settled
at the bottom of a bottle. To date, most commercial formulations of
bismuth subsalicylate have been suspended with the aid of magnesium
aluminum silicate.
[0004] However, magnesium aluminum silicate is a mined clay and may
contain trace amounts of lead. There is a desire to minimize the
lead in pharmaceutical compositions.
[0005] Previous formulations of bismuth subsalicylate with reduced
magnesium aluminum silicate are described in U.S. Pat. Nos.
9,486,640 and 9,486,436. U.S. Pat. No. 9,486,460 describes a
bismuth-containing pharmaceutical agent, gellan gum and magnesium
aluminum silicate. U.S. Pat. No. 9,486,436 describes complex
manufacturing methods for making pharmaceutical suspensions with
magnesium aluminum silicate, gellan gum, bismuth, and methyl
cellulose.
[0006] Disclosed herein are pharmaceutical compositions that are
three-gum systems without magnesium aluminum silicate. Accordingly,
the compositions described herein minimize the use of magnesium
aluminum silicate without sacrificing the ability of the
compositions to keep the bismuth subsalicylate in suspension.
SUMMARY OF THE INVENTION
[0007] The present invention includes pharmaceutical compositions
and methods of treating gastrointestinal disorders using
pharmaceutical compositions. In one aspect of the invention, the
composition comprises bismuth subsalicylate, microcrystalline
cellulose, xanthan gum, and an excipient selected from the group
consisting of: carboxymethyl cellulose (CMC), carageenan, and
hydroxyethyl cellulose (HEC), or combinations thereof.
[0008] In another aspect of the invention, pharmaceutical
compositions comprising bismuth subsalicylate may be used to treat
gastrointestinal disorders. In some embodiments, the
gastrointestinal disorder is selected from diarrhea, indigestion,
heartburn, and nausea.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 shows a rheogram comparing sample compositions 18,
21, 22, and 43 according to an embodiment of the present
invention
[0010] FIG. 2 shows a rheogram of sample composition 24 according
to an embodiment of the present invention.
[0011] FIG. 3 shows a rheogram comparing sample compositions 22 and
23 according to an embodiment of the present invention.
[0012] FIG. 4 shows dispersion fingerprints of pharmaceutical
compositions taken with LUMiSizer.RTM. using STEP technology
according to an embodiment of the present invention.
[0013] FIG. 5 shows a sediment formation analysis as determined by
X-Ray analysis using LUMiReader.RTM. X-Ray equipment of
pharmaceutical formulations at 23.degree. C. according to an
embodiment of the present invention.
[0014] FIG. 6 is a plot comparing the sedimentation profiles of the
composition of Method C (diamonds), the commercially available
H.E.B. Max Strength (triangles), and the commercially available
Pepto Bismol Ultra (squares)
[0015] FIG. 7A is a sedimentation fingerprint of the composition of
Method C.
[0016] FIG. 7B is a sedimentation fingerprint of the commercially
available H.E.B. Max Strength.
[0017] FIG. 7C is a sedimentation fingerprint of the commercially
available Pepto Bismol Ultra.
[0018] FIG. 8 is a plot of the sedimentation profile of a 1037.6 g
batch of the composition of Method C.
[0019] FIG. 9A is a sedimentation fingerprint of the Sample Before
Hold from a 1037.6 g batch of the composition of Method C.
[0020] FIG. 9B is a sedimentation fingerprint of the Top Sample
After Hold from a 1037.6 g batch of the composition of Method
C.
[0021] FIG. 9C is a sedimentation fingerprint of the Bottom Sample
After Hold from a 1037.6 g batch of the composition of Method
C.
DETAILED DESCRIPTION OF THE INVENTION
[0022] As used herein, the term "three-gum system" refers to a
suspension composition according to the present invention, wherein
the composition includes at least three different
polysaccharide-based thickening agents. Examples of thickening
agents include, but are not limited to, agar, alginic acid,
carrageenan, corn starch, carboxymethyl cellulose (CMC),
hydroxyethyl cellulose (HEC), guar gum, hydroxypropyl cellulose,
hypromellose (hydroxypropyl methyl cellulose), methylcellulose,
pectin, sodium alginate, tragacanth, and xanthan gum.
[0023] The pharmaceutical compositions of the present invention
provide a suspension formulation for minimizing heavy particle
sedimentation in solution. In one aspect of the invention, the
composition comprises bismuth subsalicylate, microcrystalline
cellulose, xanthan gum, and an excipient selected from the group
consisting of: carboxymethyl cellulose, carageenan, and
hydroxyethyl cellulose, or combinations thereof. In another aspect
of the invention, the composition comprises bismuth subsalicylate,
Avicel.RTM. RC-591, xanthan gum, and hydroxyethyl cellulose.
[0024] Pharmaceutical compositions of the present invention
comprise bismuth subsalicylate. Bismuth subsalicylate is known to
treat temporary gastrointestinal disorders such as diarrhea,
indigestion, heartburn, and nausea. In some embodiments, the
pharmaceutical composition comprises bismuth subsalicylate in an
amount of from about 10 mg/mL to about 60 mg/mL. In some
embodiments, the pharmaceutical composition comprises bismuth
subsalicylate in an amount of from 17.5 mg/mL to about 53.0 mg/mL.
In some embodiments, the pharmaceutical composition comprises
bismuth subsalicylate in an amount of from about 15 mg/mL to about
20 mg/mL. In further embodiments, the pharmaceutical composition
comprises bismuth subsalicylate in an amount of about 17.5
mg/mL.
[0025] In some embodiments, pharmaceutical compositions of the
present invention may contain a double dose of bismuth
subsalicylate. In some embodiments, the pharmaceutical composition
comprises bismuth subsalicylate in an amount of from about 32.5
mg/mL to about 37.5 mg/mL.
[0026] In some embodiments, pharmaceutical compositions of the
present invention may contain a triple does of bismuth
subsalicylate. In some embodiments, the pharmaceutical composition
comprises bismuth subsalicylate in an amount of from about 50 mg/mL
to about 55 mg/mL. In further embodiments, the pharmaceutical
composition comprises bismuth subsalicylate in an amount of about
52.5 mg/mL.
[0027] In some embodiments, the pharmaceutical composition does not
comprise magnesium aluminum silicate. Magnesium aluminum silicate
is a mined clay, and may contain traces of lead. There is a desire
to minimize lead in pharmaceutical compositions. Pharmaceutical
compositions of the present invention have been formulated to
suspend heavy particles of bismuth subsalicylate without using
magnesium aluminum silicate.
[0028] In some embodiments, the pharmaceutical composition
comprises hydroxyethyl cellulose. In some embodiments, the
pharmaceutical composition comprises hydroxyethyl cellulose in an
amount of from about 0.10 mg/mL to about 1.5 mg/mL. In some
embodiments, the pharmaceutical composition comprises hydroxyethyl
cellulose in an amount of from about 0.45 mg/mL to about 0.95
mg/mL. In some embodiments, the pharmaceutical composition
comprises hydroxyethyl cellulose in an amount of about 0.88 mg/mL.
In some embodiments, the pharmaceutical composition comprises
hydroxyethyl cellulose in an amount of from about 1.0 mg/mL to
about 2.0 mg/mL. In some embodiments, the pharmaceutical
composition comprises hydroxyethyl cellulose in an amount of from
about 1.25 mg/mL to about 1.75 mg/mL. In some embodiments, the
pharmaceutical composition comprises hydroxyethyl cellulose in an
amount of about 1.5 mg/mL.
[0029] In some embodiments, the pharmaceutical composition
comprises carboxymethyl cellulose. In some embodiments,
carboxymethyl cellulose is added to change the viscosity of the
pharmaceutical composition. Without being bound to any particular
theory, it is believed that there is an interaction between
salicylates and carboxymethyl cellulose which may affect the
viscosity and pH of the pharmaceutical composition. In other
embodiments, the carboxymethyl cellulose is carboxymethyl cellulose
9.
[0030] In some embodiments, the composition comprises Avicel.RTM.
RC-591 (AVICEL). AVICEL RC-591 is a mixture of sodium carboxymethyl
cellulose and microcrystalline cellulose. AVICEL RC-591 is a water
dispersible organic hydrocolloid used in the preparation of
pharmaceutical suspensions and emulsions. The colloidal
microcrystalline cellulose may provide a structured dispersion
vehicle while the carboxymethyl cellulose may facilitate dispersion
and serve as a protective colloid. In some embodiments, the
pharmaceutical composition comprises AVICEL RC-591 in an amount of
from about 10 mg/mL to about 30 mg/mL. In some embodiments, the
pharmaceutical composition comprises AVICEL RC-591 in an amount of
from about 14 mg/mL to about 20 mg/mL. In some embodiments, the
pharmaceutical composition comprises AVICEL RC-591 in an amount of
about 17.1 mg/mL. In some embodiments, the pharmaceutical
composition comprises AVICEL RC-591 in an amount of about 17.5
mg/mL.
[0031] Pharmaceutical compositions of the present invention may
comprise xanthan gum. Xanthan gum may be used to prevent separation
of components in pharmaceutical compositions. Xanthan gum is also
known to suspend solid particles. In some embodiments, the
pharmaceutical composition comprises xanthan gum in an amount of
from about 0.50 mg/mL to about 5.0 mg/mL. In some embodiments, the
pharmaceutical composition comprises xanthan gum in an amount of
from about 1.5 mg/mL to about 3.5 mg/mL. In some embodiments, the
pharmaceutical composition comprises xanthan gum in an amount of
about 2.0 mg/mL. In some embodiments, the pharmaceutical
composition comprises xanthan gum in an amount of about 2.9
mg/mL.
[0032] In some embodiments, the pharmaceutical composition
comprises simethicone or a simethicone emulsion. In some
embodiments, simethicone is added to the pharmaceutical composition
to improve mouthfeel. In some embodiments, simethicone is added to
the pharmaceutical composition to reduce foaming. In some
embodiments, the pharmaceutical composition comprises simethicone
in an amount of from about 0.001 mg/mL to about 0.02 mg/mL. In some
embodiments, the pharmaceutical composition comprises simethicone
in an amount of about 0.01 mg/mL.
[0033] In some embodiments of the invention, the pharmaceutical
composition may contain a mixture of carboxymethyl cellulose and
microcrystalline cellulose. In some embodiments the pharmaceutical
composition may contain a ratio of the mixture of carboxymethyl
cellulose and microcrystalline cellulose to xanthan gum from about
2:1 to about 20:1. In other embodiments, the ratio of the mixture
of carboxymethyl cellulose and microcrystalline cellulose to
xanthan gum is from about 4:1 to about 15:1.
[0034] The LUMiSizer employs Step-technology to measure across the
whole sample instantaneously. Like human fingerprints, suspensions
also have unique fingerprints based on their interactions with
light at specified wavelengths. The pharmaceutical compositions of
the present invention have a unique fingerprint compared to other
samples.
[0035] It is an object of the present invention to prevent
sedimentation of particulates in a pharmaceutical composition.
Sedimentation rates may be determined using LUMiReader X-Ray using
STEP technology. STEP technology obtains Space- and Time-resolved
Extinction Profiles over the length of the sample. In a STEP
analysis, parallel light is transmitted through a sample and is
detected by sensors to determine particle concentration. STEP
analysis also includes placing samples in a centrifuge to simulate
composition settling over time. In some embodiments, pharmaceutical
compositions of the present invention may be analyzed at 23.degree.
C. In some embodiments, pharmaceutical compositions of the present
invention have sedimentation rates of from about 0.001 mm/day to
about 0.012 mm/day at 23.degree. C. as determined by X-Ray
measurement.
[0036] Pharmaceutical compositions of the present invention have an
appropriate viscosity. If a solution is too viscous, it is
difficult to administer and has a poor mouthfeel. Similarly,
pharmaceutical compositions with low viscosities may be "watery" or
"chalky" and have a poor mouthfeel and may result in sedimentation.
In some embodiments, pharmaceutical compositions of the present
invention have a viscosity of from about 600 cps to about 2000 cps.
In some embodiments, the pharmaceutical composition has a viscosity
of from about 900 cps to about 1400 cps. Viscosity determinations
for compositions of the present invention were taken using a
Brookfield Viscometer DV-I Prime at a speed of 30 RPM using a LV3
spindle.
[0037] Pharmaceutical compositions of the present invention
preferably have a pH value of from about 4 to about 5. In some
embodiments, the pharmaceutical composition has a pH of from about
4.1 to about 4.6. In some embodiments, the pharmaceutical
composition has a pH of from about 4.3 to about 4.4.
[0038] In some embodiments, the ratio of carboxymethyl cellulose to
total salicylates in the pharmaceutical composition is adjusted to
change one or more of pH and viscosity. Yield value is a measurable
quantity similar to, but not dependent on, viscosity. It can be
thought of as the initial resistance to flow under stress, hence,
it is also referred to as yield stress. Particles dispersed in a
medium will remain suspended if the yield value of the medium is
sufficient to overcome the effect of gravity or buoyancy on those
particles. Yield value was measured using Thermo-Haake
Rheostress.
[0039] In some embodiments, the pharmaceutical composition of the
present invention achieves or approaches a yield value while
remaining a flowable (not gelatinous) composition.
[0040] In another aspect of the invention, a pharmaceutical
composition may comprise: [0041] a) bismuth subsalicylate; [0042]
b) a mixture of microcrystalline cellulose and carboxymethyl
cellulose; [0043] c) xanthan gum; and [0044] d) hydroxyethyl
cellulose.
[0045] In some embodiments of the invention, the pharmaceutical
composition may comprise a ratio of the mixture of microcrystalline
cellulose and carboxymethyl cellulose to hydroxyethyl cellulose
from about 3:1 to about 300:1. In other embodiments, the ratio of
the mixture of microcrystalline cellulose and carboxymethyl
cellulose to hydroxyethyl cellulose is from about 6:1 to about
250:1.
[0046] In some embodiments, the ratio of the mixture of
microcrystalline cellulose and carboxymethyl cellulose to xanthan
gum is from about 3:1 to about 15:1. In other embodiments, the
ratio of the mixture of microcrystalline cellulose and
carboxymethyl cellulose to xanthan gum is from about 5:1 to about
13:1.
[0047] In some embodiments, the pharmaceutical composition contains
a ratio of xanthan gum to hydroxyethyl cellulose from about 1:1 to
about 40:1. In other embodiments, the ratio of xanthan gum to
hydroxyethyl cellulose is from about 1.3:1 to about 20:1.
[0048] In another aspect of the invention, pharmaceutical
compositions comprising bismuth subsalicylate may be used to treat
gastrointestinal disorders. In some embodiments, the
gastrointestinal disorder is selected from diarrhea, indigestion,
heartburn, and nausea.
[0049] In one aspect, the invention includes a pharmaceutical
composition comprising: [0050] a) bismuth subsalicylate; [0051] b)
microcrystalline cellulose; [0052] c) xanthan gum; and [0053] d) an
excipient selected from the group consisting of: carboxymethyl
cellulose, carrageenan, and hydroxyethyl cellulose, or combinations
thereof.
[0054] In one embodiment, the composition consists essentially of:
[0055] a) bismuth subsalicylate; [0056] b) microcrystalline
cellulose; [0057] c) xanthan gum; and [0058] d) an excipient
selected from the group consisting of: carboxymethyl cellulose,
carrageenan, and hydroxyethyl cellulose, or combinations
thereof.
[0059] In one embodiment, said excipient is hydroxyethyl
cellulose.
[0060] In one embodiment, said composition comprises bismuth
subsalicylate in an amount of from about 10 mg/mL to about 60
mg/mL.
[0061] In a further embodiment, said composition comprises bismuth
subsalicylate in an amount of from about 17.5 mg/mL to about 53
mg/mL.
[0062] In another further embodiment, said composition comprises
bismuth subsalicylate in an amount of from about 15 mg/mL to about
20 mg/mL.
[0063] In still a further embodiment, said composition comprises
bismuth subsalicylate in an amount of about 17.5 mg/mL.
[0064] In another embodiment, said composition comprises bismuth
subsalicylate in an amount of about 32.5 mg/mL to about 37.5
mg/mL.
[0065] In another further embodiment, said composition comprises
bismuth subsalicylate in an amount of about 35 mg/mL.
[0066] In another embodiment, said composition comprises bismuth
subsalicylate in an amount of about 52.5 mg/mL.
[0067] In one embodiment, said composition comprises carboxymethyl
cellulose and hydroxyethyl cellulose.
[0068] In one embodiment, said composition comprises xanthan gum in
an amount of from about 0.50 mg/mL to about 5.0 mg/mL.
[0069] In a further embodiment, said composition comprises xanthan
gum in an amount of from about 1.0 mg/mL to about 3.0 mg/mL.
[0070] In a further embodiment, said composition comprises xanthan
gum in an amount of about 2.0 mg/mL.
[0071] In another further embodiment, said composition comprises
xanthan gum in an amount of about 2.9 mg/mL.
[0072] In one embodiment, said composition comprises hydroxyethyl
cellulose in an amount of from about 0.45 mg/mL to about 2.0
mg/mL.
[0073] In a further embodiment, said composition comprises
hydroxyethyl cellulose in an amount of about 1.5 mg/mL.
[0074] In one embodiment, said composition comprises a mixture of
carboxymethyl cellulose and microcrystalline cellulose.
[0075] In a further embodiment, the mixture of carboxymethyl
cellulose and microcrystalline cellulose is present in an amount of
from about 14 mg/mL to about 20 mg/mL.
[0076] In one embodiment, the mixture of carboxymethyl cellulose
and microcrystalline cellulose comprises a spray dried blend of
carboxymethyl cellulose and microcrystalline cellulose.
[0077] In a further embodiment, the mixture of carboxymethyl
cellulose and microcrystalline cellulose is present in an amount of
about 17.1 mg/mL.
[0078] In another further embodiment, the mixture of carboxymethyl
cellulose and microcrystalline cellulose is present in an amount of
about 17.5 mg/mL.
[0079] In one embodiment, the ratio of the mixture of carboxymethyl
cellulose and microcrystalline cellulose to xanthan gum is from
about 2:1 to about 20:1.
[0080] In a further embodiment, the ratio of the mixture of
carboxymethyl cellulose and microcrystalline cellulose to xanthan
gum is from about 4:1 to about 15:1.
[0081] In one embodiment, said composition has a sedimentation rate
of from about 0.001 mm/day to about 0.015 mm/day at 23.degree. C.
as determined by x-ray measurement.
[0082] In a further embodiment, said composition has a
sedimentation rate of from about 0.001 mm/day to about 0.012 mm/day
at 23.degree. C. as determined by x-ray measurement.
[0083] In one embodiment, said composition has a viscosity of from
about 800 cps to about 2400 cps.
[0084] In a further embodiment, said composition has a viscosity of
from about 1200 cps to about 2000 cps.
[0085] In one embodiment, the pH of the composition is from about
4.0 to about 5.5.
[0086] In a further embodiment, the pH of the composition is from
about 4.9 to about 5.0.
[0087] In another further embodiment, the pH of the composition is
from about 4.3 to about 4.4.
[0088] In another aspect, the invention includes a pharmaceutical
composition comprising: [0089] a) bismuth subsalicylate; [0090] b)
xanthan gum; [0091] c) hydroxyethyl cellulose; and [0092] d) a
mixture of microcrystalline cellulose and carboxymethyl
cellulose.
[0093] In one embodiment, the ratio of the mixture of
microcrystalline cellulose and carboxymethyl cellulose to
hydroxyethyl cellulose is from about 6:1 to about 250:1.
[0094] In a further embodiment, the ratio of the mixture of
microcrystalline cellulose and carboxymethyl cellulose to
hydroxyethyl cellulose is from about 11:1 to about 12:1.
[0095] In still a further embodiment, the ratio of the mixture of
microcrystalline cellulose and carboxymethyl cellulose to xanthan
gum is from about 5:1 to about 13:1.
[0096] In still a further embodiment, the ratio of the mixture of
microcrystalline cellulose and carboxymethyl cellulose to xanthan
gum is from about 5.5:1 to about 6.5:1.
[0097] In one embodiment, the ratio of xanthan gum to hydroxyethyl
cellulose is from about 1.3:1 to about 20:1.
[0098] In a further embodiment, the ratio of xanthan gum to
hydroxyethyl cellulose is from about 1.9:1 to about 2.0:1.
[0099] In one embodiment, the mixture of carboxymethyl cellulose
and microcrystalline cellulose comprises a spray dried blend of
carboxymethyl cellulose and microcrystalline cellulose.
[0100] In one embodiment, the mixture of carboxymethyl cellulose
and microcrystalline cellulose is commercially available as AVICEL
RC-591.
[0101] In another aspect, the invention includes an aqueous
pharmaceutical composition comprising: [0102] a) about 35 mg/mL
glycerin; [0103] b) about 0.01 mg/mL simethicone; [0104] c) about
1.5 mg/mL hydroxyethyl cellulose; [0105] d) about 2.9 mg/mL xanthan
gum; [0106] e) about 17.5 mg/mL of a mixture of carboxymethyl
cellulose and microcrystalline cellulose; [0107] f) from about 15
mg/mL to about 37 mg/mL bismuth subsalicylate; [0108] g) about 0.2
mg/mL salicylic acid; [0109] h) about 0.01 mg/mL sodium salicylate;
[0110] i) about 0.41 mg/mL sodium saccharin; [0111] j) about 0.35
mg/mL potassium sorbate; [0112] k) about 1.0 mg/mL
methylsalicylate; [0113] l) from about 0.05 mg/mL to about 0.07
mg/mL Red #22 D&C; and [0114] m) about 0.045 mg/mL to about
0.14 mg/mL Red #28 D&C.
[0115] In a further embodiment, the concentration of bismuth
subsalicylate is about 17.5 mg/mL, the concentration of Red #22
D&C is about 0.0563 mg/mL, and the concentration of Red #28
D&C is about 0.04814 mg/mL.
[0116] In another further embodiment, the concentration of bismuth
subsalicylate is about 35.0 mg/mL, the concentration of Red #22
D&C is about 0.06777 mg/mL, and the concentration of Red #28
D&C is about 0.1304 mg/mL.
[0117] In another aspect, the invention includes a method of
treating a gastrointestinal disorder in a patient in need thereof,
comprising administering to the patient a composition comprising:
[0118] a) bismuth subsalicylate; [0119] b) microcrystalline
cellulose; [0120] c) xanthan gum; and [0121] d) an excipient
selected from the group consisting of: carboxymethyl cellulose,
carrageenan, and hydroxyethyl cellulose, or combinations
thereof.
[0122] In another aspect, the invention includes a method of
treating a gastrointestinal disorder in a patient in need thereof,
consisting essentially of administering to the patient a
composition comprising: [0123] a) bismuth subsalicylate; [0124] b)
microcrystalline cellulose; [0125] c) xanthan gum; and [0126] d) an
excipient selected from the group consisting of: carboxymethyl
cellulose, carrageenan, and hydroxyethyl cellulose, or combinations
thereof.
[0127] In one embodiment, said excipient is hydroxyethyl
cellulose.
[0128] In one embodiment, said composition comprises bismuth
subsalicylate in an amount of from about 10 mg/mL to about 60
mg/mL.
[0129] In one embodiment, said composition comprises bismuth
subsalicylate in an amount of from about 17.5 mg/mL to about 53
mg/mL.
[0130] In another embodiment, said composition comprises bismuth
subsalicylate in an amount of from about 15 mg/mL to about 20 mg/mL
of the total composition.
[0131] In a further embodiment, said composition comprises bismuth
subsalicylate in an amount of about 17.5 mg/mL.
[0132] In another embodiment, said composition comprises bismuth
subsalicylate in an amount of about 32.5 mg/mL to about 37.5
mg/mL.
[0133] In a further embodiment, said composition comprises bismuth
subsalicylate in an amount of about 35 mg/mL.
[0134] In one embodiment, said composition comprises bismuth
subsalicylate in an amount of about 52.5 mg/mL.
[0135] In one embodiment, said composition comprises carboxymethyl
cellulose and hydroxyethyl cellulose.
[0136] In one embodiment, said composition comprises xanthan gum in
an amount of from about 0.50 mg/mL to about 5.0 mg/mL.
[0137] In a further embodiment, said composition comprises xanthan
gum in an amount of from about 1.0 mg/mL to about 3.0 mg/mL.
[0138] In still a further embodiment, said composition comprises
xanthan gum in an amount of about 2.0 mg/mL.
[0139] In another further embodiment, said composition comprises
xanthan gum in an amount of about 2.9 mg/mL.
[0140] In one embodiment, said composition comprises hydroxyethyl
cellulose in an amount of from about 0.45 mg/mL to about 2.0
mg/mL.
[0141] In a further embodiment, said composition comprises
hydroxyethyl cellulose in an amount of about 1.5 mg/mL.
[0142] In one embodiment, said composition comprises a mixture of
carboxymethyl cellulose and microcrystalline cellulose.
[0143] In a further embodiment, the mixture of carboxymethyl
cellulose and microcrystalline cellulose is present in an amount of
from about 14 mg/mL to about 20 mg/mL.
[0144] In still a further embodiment, the mixture of carboxymethyl
cellulose and microcrystalline cellulose is present in an amount of
about 17.1 mg/mL.
[0145] In another further embodiment, the mixture of carboxymethyl
cellulose and microcrystalline cellulose is present in an amount of
about 17.5 mg/mL.
[0146] In one embodiment, said composition has a sedimentation rate
of from about 0.001 mm/day to about 0.015 mm/day as determined by
x-ray measurement.
[0147] In a further embodiment, said composition has a
sedimentation rate of from about 0.001 mm/day to about 0.012 mm/day
as determined by x-ray measurement.
[0148] In one embodiment, said composition has a viscosity of from
about 800 cps to about 2400 cps.
[0149] In a further embodiment, said composition has a viscosity of
from about 1200 cps to about 2000 cps.
[0150] In one embodiment, said gastrointestinal disorder is
selected from diarrhea, indigestion, heartburn, and nausea.
[0151] In one aspect, the invention includes a process for
producing a composition described herein, comprising: [0152]
forming a gum premix comprising glycerin, simethicone, hydroxyethyl
cellulose, and xanthan gum in a first vessel; [0153] forming a dye
premix comprising an aqueous mixture of dye compounds in a second
vessel; [0154] forming a third mixture comprising water,
microcrystalline cellulose, carboxymethyl cellulose, and bismuth
subsalicylate in a third vessel; and [0155] combining the gum
premix, dye premix and third mixture together to produce the
composition.
[0156] In one embodiment, the glycerin, simethicone, hydroxyethyl
cellulose, and xanthan gum are added together and mixed for a time
from about 5 minutes to about 15 minutes to form the gum
premix.
[0157] In another embodiment, the glycerin, simethicone,
hydroxyethyl cellulose, and xanthan gum are mixed for about 10
minutes to form the gum premix.
[0158] In one embodiment, the glycerin, simethicone, hydroxyethyl
cellulose, and xanthan gum are mixed until homogenous to form the
gum premix.
[0159] In one embodiment, the dye premix is a mixture of water, Red
#22 D&C, and Red #28 D&C.
[0160] In a further embodiment, the dye premix is formed by adding
Red #22 D&C, and Red #28 D&C to hot water.
[0161] In one embodiment, the third mixture is formed by [0162] a)
combining water and a mixture of microcrystalline cellulose and
carboxymethyl cellulose in the third vessel; [0163] b) mixing until
the mixture of microcrystalline cellulose and carboxymethyl
cellulose is fully wetted; [0164] c) mixing the fully wetted
microcrystalline cellulose and carboxymethyl cellulose for at least
5 minutes; [0165] d) shearing the fully wetted microcrystalline
cellulose and carboxymethyl cellulose from step c; [0166] e) adding
bismuth subsalicylate and water to the third vessel; [0167] f)
mixing until the bismuth subsalicylate is fully wetted; and [0168]
g) mixing the resulting mixture for at least an additional 5
minutes.
[0169] In a further embodiment, step b further comprises two or
more separate additions of water.
[0170] In another further embodiment, the mixing in steps c and g
are each about 15 minutes.
[0171] In another further embodiment, the mixture of
microcrystalline cellulose and carboxymethyl cellulose is
commercially available as AVICEL RC-591.
[0172] In one embodiment, the gum premix is combined with the third
mixture in the third vessel prior to combining the dye premix.
[0173] In a further embodiment, the gum premix and third mixture
are mixed for at least 20 minutes.
[0174] In still a further embodiment, the gum premix and third
mixture are mixed for about 30 minutes.
[0175] In still a further embodiment, the resulting mixture is
combined with the dye premix, salicylic acid, sodium salicylate,
sodium saccharin, potassium sorbate, glycerin, and methylsalicylate
in the third mixing vessel.
[0176] In still a further embodiment, water is added to the
resulting mixture in the third mixing vessel and the resulting
mixture was mixed.
[0177] In still a further embodiment, the resulting mixture was
mixed for about 15 minutes.
EXAMPLES
Example 1: Methods of Batch Preparation
[0178] Pharmaceutical formulations of the present invention may
generally be prepared according to one of three general methods as
provided below.
[0179] Method A Batch Procedure
[0180] Gum Premix
[0181] Glycerin (35.00 g) was added to the gum premix vessel.
Xanthan gum (2.00 g) was then added to the gum premix vessel and
mixed for 10 minutes to disperse.
[0182] Dye Premix
[0183] 10 g of hot purified water was added to a dye premix vessel.
Then Red #22 D&C (0.0563 g) and Red #28 D&C (0.04814 g)
were added to the dye premix vessel and mixed for 10 minutes.
[0184] Batch Mix
[0185] A batch was created by addition of 930 g of cold water to a
mixing vessel. Then 17.07 g Avicel RC-591 was added to the mixing
vessel. The mixture was sheared for three minutes (equivalent of
2.1 turns). While shearing, the contents of the gum premix vessel
and the bismuth subsalicylate (17.50 g) was added to the batch and
sheared for an additional two minutes. The shearing was stopped,
and the batch was mixed for 30 minutes while the gums fully
hydrated. Then, 0.01 g salicylic acid, 0.68 g sodium salicylate,
0.41 g sodium saccharin, 0.38 g sorbic acid and the contents of the
dye premix vessel were added to the batch. Purified water was then
added to a final volume of one liter, and the batch was then mixed
for an additional 15 minutes.
[0186] Samples 1-43 were prepared according to Method A. Every
sample contained 0.41 g sodium saccharin, 0.38 g sorbic acid,
0.0563 g red #22 D&C, 0.0492 g red #28 D&C, and 1.00 g
methylsalicylate. The other ingredients were added in amounts
according to Tables 1a-8b below. All amounts in Tables 1a-8b are
provided in grams.
TABLE-US-00001 TABLE 1a Compositions prepared according to Method A
batch procedure. Sample water AVICEL glycerin Xanthan gum 1 917.97
30.00 50.00 2.30 2 976.43 12.24 10.00 1.22 3 956.43 12.24 30.00
1.22 4 947.34 19.55 30.00 3.00 5 954.34 12.73 30.00 2.82 6 957.62
10.00 30.00 2.27 7 946.89 20.91 30.00 2.09 8 956.98 11.36 30.00
1.55 9 950.35 18.18 30.00 1.36 10 954.8 14.09 30.00 1.00 11 952.53
15.45 30.00 1.91 12 943.61 23.64 30.00 2.64 13 946.44 22.27 30.00
1.18 14 950.62 16.82 30.00 2.45 15 943.16 25.00 30.00 1.73 16
947.89 20.00 30.00 2.00
TABLE-US-00002 TABLE 1b Compositions prepared according to Method A
batch procedure continued. bismuth salicylic sodium Viscosity
Sample subsalicylate acid salicylate pH (cp) 1 17.50 0.52 0.20
4.353 3000 2 17.50 0.52 0.20 3.523 204 3 17.50 0.52 0.20 3.559 188
4 17.50 0.52 0.20 3.838 1060 5 17.50 0.52 0.20 3.646 583.9 6 17.50
0.52 0.20 3.553 279.9 7 17.50 0.52 0.20 3.798 711.84 8 17.50 0.52
0.20 3.473 204 9 17.50 0.52 0.20 3.709 355.9 10 17.50 0.52 0.20
3.488 176 11 17.50 0.52 0.20 3.599 407.9 12 17.50 0.52 0.20 3.772
1048 13 17.50 0.52 0.20 3.731 499.9 14 17.50 0.52 0.20 3.674 651.9
15 17.50 0.52 0.20 3.788 959.8 16 17.50 0.42 0.30 3.806 723.8
TABLE-US-00003 TABLE 2a CMC 12 compositions prepared according to
Method A batch procedure. Xanthan CMC Sample water AVICEL glycerin
gum 12M31F 17 956.08 11.36 30.00 1.55 1.00
TABLE-US-00004 TABLE 2b CMC 12 compositions prepared according to
Method A batch procedure continued. bismuth salicylic sodium
Viscosity Sample subsalicylate acid salicylate pH (cp) 17 17.50
0.42 0.20 3.845 243.9
TABLE-US-00005 TABLE 3a CMC 9 compositions prepared according to
Method A batch procedure. Xanthan CMC Sample water AVICEL glycerin
gum 9M31F 18 945.89 20.00 30.00 2.00 2.00
TABLE-US-00006 TABLE 3b CMC 9 compositions prepared according to
Method A batch procedure continued. bismuth salicylic sodium
Viscosity Sample subsalicylate acid salicylate pH (cp) 18 17.50
0.42 0.30 4.164 1648
TABLE-US-00007 TABLE 4a Carageenan compositions prepared according
to Method A batch procedure. Xanthan Carrageenan Sample water
AVICEL glycerin gum Special 21 942.89 20.00 30.00 2.00 5.00
TABLE-US-00008 TABLE 4b Carageenan compositions prepared according
to Method A batch procedure continued. bismuth sodium Viscosity
Sample subsalicylate salicylic acid salicylate pH (cp) 21 17.50
0.42 0.30 3.720 939.8
TABLE-US-00009 TABLE 5a Table 5a. HEC and simethicone compositions
prepared according to Method A batch procedure. HEC Xanthan
Simethicone Sample water AVICEL glycerin 250 G gum emulsion 22
941.88 25.50 30.00 0.50 2.00 0.01 23 947.37 20.00 30.00 0.50 2.00
0.02
TABLE-US-00010 TABLE 5b HEC and simethicone compositions prepared
according to Method A batch procedure continued. bismuth salicylic
sodium Viscosity Sample subsalicylate acid salicylate pH (cp) 22
17.50 0.13 0.59 4.296 1968 23 17.50 0.13 0.59 4.329 1716
TABLE-US-00011 TABLE 6a CMC 9 and simethicone compositions prepared
according to Method A batch procedure. CMC Xanthan Simethicone
Sample water AVICEL glycerin 9M31F gum emulsion 24 946.37 20.00
30.00 1.50 2.00 0.02
TABLE-US-00012 TABLE 6b CMC 9 and simethicone compositions prepared
according to Method A batch procedure continued. bismuth salicylic
sodium Viscosity Sample subsalicylate acid salicylate pH (cp) 24
17.50 0.13 0.59 4.455 2839
TABLE-US-00013 TABLE 7a HEC compositions prepared according to
Method A batch procedure. Xanthan Sample water AVICEL glycerin HEC
250 G gum 25 947.39 20.00 30.00 0.50 2.00 26 940.91 25.50 30.00
1.50 2.00 27 957.31 10.00 30.00 0.10 2.00 28 955.91 10.00 30.00
1.50 2.00 29 949.36 17.75 30.00 0.80 2.00 30 942.81 25.50 30.00
0.10 2.00 31 957.81 10.00 30.00 0.10 2.00 32 942.31 25.50 30.00
0.10 2.00 33 940.91 25.50 30.00 1.50 2.00 34 956.91 10.00 30.00
1.50 2.00 35 940.41 25.50 30.00 1.50 2.00 36 942.31 25.50 30.00
0.10 2.00 37 957.81 10.00 30.00 0.10 2.00 38 949.97 17.07 30.00
0.88 2.00 39 949.77 17.07 30.00 0.88 2.20 40 949.97 17.07 30.00
0.88 2.00 41 949.97 17.07 30.00 0.88 2.00
TABLE-US-00014 TABLE 7b HEC compositions prepared according to
Method A batch procedure continued. bismuth salicylic sodium
Viscosity Sample subsalicylate acid salicylate pH (cp) 25 17.50
0.13 0.59 4.323 1612 26 17.50 0.10 0.60 4.438 2450 27 17.50 0.60
0.60 3.535 280 28 17.50 0.60 0.60 3.542 428 29 17.50 0.35 0.35
3.967 856 30 17.50 0.10 0.10 4.360 2248 31 17.50 0.60 0.10 3.424
264 32 17.50 0.10 0.60 4.359 1920 33 17.50 0.60 0.10 3.774 1416 34
17.50 0.10 0.10 4.074 448 35 17.50 0.60 0.60 3.836 1676 36 17.50
0.60 0.10 3.719 1008 37 17.50 0.10 0.60 4.089 348 38 17.50 0.01
0.68 4.398 1052 39 17.50 0.01 0.68 4.462 1064 40 35.00 0.01 0.68
4.300 1048 41 52.50 0.01 0.68 4.263 1072
TABLE-US-00015 TABLE 8a Simethicone compositions prepared according
to Method A Batch Procedure. Xanthan Simethicone Sample water
AVICEL glycerin gum emulsion 42 947.88 20.00 30.00 2.00 0.01 43
942.38 25.50 30.00 2.00 0.01
TABLE-US-00016 TABLE 8b Simethicone compositions prepared according
to Method A Batch Procedure continued. bismuth salicylic sodium
Viscosity Sample subsalicylate acid salicylate pH (cp) 42 17.50
0.42 0.30 3.796 771.8 43 17.50 0.13 0.59 4.237 1396
[0187] Method B Batch Procedure
[0188] A Waukesha Shear Pump inlet was connected to the outlet of a
mix tank. The Waukesha Shear Pump outlet was placed on the rim of
the mix tank to allow for recirculation down the wall of the tank.
Then, 173.0 kg cold purified water was added to the mix tank. The
baffles were set to at or between 0.degree. and 90.degree. and the
agitator was turned on. The agitator was adjusted to 140 RPM.
[0189] While continuing the mix, 3.00 kg glycerin USP was added to
a hydroxyethyl cellulose mix tank and agitation was started. Then
hydroxyethyl cellulose 250G (176 g) was added and mixed for 5
minutes. The mixing was continued until hydroxyethyl cellulose was
added.
[0190] Glycerin (3.00 kg) was added to a xanthan gum premix tank
and agitation was started. Then, xanthan Gum (0.400 kg) was added
and mixed for 5 minutes. Mixing was continued.
[0191] Avicel RC-591 (3.41 kg) was added to the mix tank. The
interior of the tank was rinsed with 5.0 kg cold purified water.
The mix tank outlet was opened and the shear pump started,
recirculating back into the mix tank. The mix tank was
recirculated, until the product was homogeneous. Then, 2.00 g of
simethicone emulsion was added to the mix tank. The contents of the
hydroxyethyl cellulose mix tank were then added to the mix tank.
The contents of the xanthan gum premix tank were then added to the
mix tank.
[0192] Bismuth subsalicylate USP (3.50 kg) was added to the mix
tank. The surface of the batch was sprayed with 10.0 kg cold
purified water to wet the material. The mix tank was recirculated
for 10 minutes, until the product was homogeneous. The mix tank
outlet was closed and the shear pump was stopped. 1.00 kg glycerin
USP was added to the mix tank. Salicylic acid (2.00 g), sodium
salicylate (136 g), sodium saccharin (82 g), and sorbic acid (76.0
g) were added to the mix tank. The tank walls and mixer shaft were
then washed with 1.0 kg cold water.
[0193] 3.0 kg of hot purified water was then added to the dye
premix. Then Red #22 D&C (9.63 g) followed by red #28 D&C
(9.63 g) to the dye premix. The dye mixture was then mixed for 2
minutes.
[0194] The dye mixture was added to the mix tank. The dye premix
tank was then rinsed with 1.0 kg hot purified water, and the water
was added to the mix tank. The mix tank was cooled to less than
30.degree. C., and the jackets were drained. Methylsalicylate (200
g) was then added to the mix tank. The container of
methylsalicylate was then rinsed with 1.0 kg cold purified water,
and the water was added to the mix tank. The batch was mixed for 15
minutes. The solution was transferred to a hold tank with an
attached impeller blade through the Waukesha Shear Pump. The
solution was held for 2 hours while mixing at 200 rpm. The agitator
was turned off and the jackets were drained.
[0195] Method C Batch Procedure
[0196] Gum Premix
[0197] 25.5 g Glycerin, 0.01 g Simethicone, 1.50 g hydroxyethyl
cellulose, and 2.90 g Xanthan Gum were added to a premix vessel and
mixed for 10 minutes.
[0198] Dye Premix
[0199] 10 g of hot purified water was added to a dye premix vessel.
Then Red #22 D&C (0.0563 g) and Red #28 D&C (0.04814 g)
were added to the dye premix vessel and mixed for 10 minutes.
[0200] Batch Mix
[0201] A batch was created by the addition of 555 g cold water and
17.50 g AVICEL RC-591 to a mixing vessel. The batch was rinsed and
fully wetted with an additional 70 g cold water, and then mixed for
15 minutes. The batch was then sheared for 3 minutes (equivalent of
2.1 turns). 17.50 g bismuth subsalicylate USP was then added and
fully wetted with an additional 300 g cold water. The batch was
then mixed for 15 minutes. The gum premix was then added, and the
batch mixed for an additional 30 minutes. The dye premix, 0.20 g
salicylic acid, 0.01 g sodium salicylate, 0.41 g sodium saccharin,
0.35 g potassium sorbate, 9.5 g glycerin, and 1.0 g
methylsalicylate were then added to the batch. Purified water was
then added to a total volume of one liter, and then the batch was
mixed for an additional 15 minutes.
Example 2: Comparison of Selected Formulations of the Invention
with Commercial Products
[0202] Sample formulations were prepared according to the Method A
batch procedure described in Example 1. Amounts of Avicel, xanthan
gum, hydroxyethyl cellulose, and bismuth subsalicylate were
provided in the amounts shown in Table 9 below as Samples E-J and
compared against commercially available products (Samples A-D).
Sample J also included simethicone.
TABLE-US-00017 TABLE 9 Sample formulations containing bismuth
subsalicylate. Bismuth Avicel Xanthan HEC Subsalicylate Sample
Description Veegum Methocel (mg/L) (mg/L) (mg/L) (mg/L) A
Comparison 1 yes yes no no no 0.01750 B Comparison 2 yes yes no yes
no 0.01750 C Comparison 3 no no no yes yes 0.01750 D Comparison 4
yes yes no no no 0.01750 E Embodiment 1 no no 0.01707 0.00200
0.00088 0.01750 F Embodiment 2 no no 0.01707 0.00220 0.00088
0.01750 G Embodiment 3 no no 0.01707 0.00200 0.00088 0.03500 H
Embodiment 4 no no 0.02000 0.00200 0.00050 0.01750 I Embodiment 5
no no 0.01707 0.00200 0.00088 0.05250 J Embodiment 6 no no 0.01707
0.00200 0.00088 0.01750
Example 3: Rheometer Procedure and Rheogram Results
[0203] Rheograms of pharmaceutical compositions of the present
invention were taken according to the following procedure. A
quantity of suspension (.about.2 mL) was placed on a flat plate of
the rheometer. The base of the was raised to a gap distance of 0.7
mm to a rotating spindle plate. The temperature was equilibrated to
25.degree. C. and the top plate was rotated at a slow speed with a
ram to a higher speed for five minutes. The speed was held for 30
seconds and then the top plate speed was reduced over five minutes.
During the slowing the rheometer records the resistance to rotation
(torque) with respect to time.
[0204] Rheograms may be used to determine whether pharmaceutical
compositions of the present invention have appropriate shear stress
and shear flow for consumer use. Rheograms of pharmaceutical
compositions according to the following formulations are shown in
FIGS. 1-3.
Example 4: Dispersion Fingerprints
[0205] The dispersion of Samples A-I were tested using a
LUMiSizer.RTM. 650. Samples A-I were analyzed at start and final
times. Dispersion fingerprints of Samples A-I were tested. Results
of the dispersion fingerprints are shown in FIG. 4.
Example 5: Sedimentation Analysis
[0206] Sedimentation rates and sedimentation fingerprints of
selected compositions of the invention were determined by X-Ray
analysis using a LUMiReader X-Ray. Sedimentation fingerprints of
Samples A-J are provided in FIG. 5, and sedimentation rates are
provided in Table 10 below.
TABLE-US-00018 TABLE 10 Sediment formation rate of Samples A-J as
determined by X-Ray analysis. Sediment Formation Rate Sample
(mm/day) A 0.0353 B 0.0178 C 0.0102 D 0.0212 E 0.0052 F 0.0041 G
0.0267 H 0.0119 I 0.0620 J 0.0286
Example 6: Sedimentation Comparison to Commercial Products
[0207] The sedimentation profiles of the composition of Method C,
the commercially available H.E.B. Max Strength, and the
commercially available Pepto Bismol Ultra were obtained using an
8-channel LUMiFuge 1103-28 at a spin rate of 4,000 RPM. FIG. 6
provides evidence that the composition of Method C is more
resistant to sedimentation under the test conditions than either
commercial product. From the figure it can be seen that no
significant sedimentation of the composition of Method C takes
place over a time period of 5,000 seconds.
[0208] Sedimentation fingerprints of the composition of Method C,
the commercially available H.E.B. Max Strength, and the
commercially available Pepto Bismol Ultra, which were obtained
using the same instrument, also at a spin rate of 4,000 RPM over
5,000 seconds, are provided in FIGS. 7A-7C.
Example 7: Sedimentation Profile of a Bulk Batch
[0209] The sedimentation profile of a 1037.6 g batch of the
composition of Method C was obtained using an 8-channel LUMiFuge
1103-28 at a spin rate of 4,000 RPM. Following the Method C batch
procedure to produce the 1037.6 g batch, as described herein, a
sample was taken and tested immediately after the batch was
produced (Sample Before Hold). The bulk batch was then held in a
single vessel for 7 days, after which a sample was taken and tested
from the top of the batch (near the surface of the composition--Top
Sample After Hold), and another sample was taken and tested from
the bottom of the batch (Bottom Sample After Hold). FIG. 8 provides
the comparison of the sedimentation profiles of the three samples.
The sedimentation rate of the Sample Before Hold (diamonds) is
0.1177 .mu.m/min, the sedimentation rate of the Top Sample After
Hold (triangles) is 0.03629 .mu.m/min, and the sedimentation rate
of the Bottom Sample After Hold (squares) is 0.03830 .mu.m/min.
[0210] Sedimentation fingerprints of the Sample Before Hold, Top
Sample After Hold, and Bottom Sample After Hold, which were
obtained using the same instrument, also at a spin rate of 4,000
RPM over 5,000 seconds, are provided in FIGS. 9A-9C.
OTHER EMBODIMENTS
[0211] The foregoing disclosure has been described in some detail
by way of illustration and example, for purposes of clarity and
understanding. The invention has been described with reference to
various specific and preferred embodiments and techniques. However,
it should be understood that many variations and modifications can
be made while remaining within the spirit and scope of the
invention. It will be obvious to one of skill in the art that
changes and modifications can be practiced within the scope of the
appended claims. Therefore, it is to be understood that the above
description is intended to be illustrative and not restrictive. The
scope of the invention should, therefore, be determined not with
reference to the above description, but should instead be
determined with reference to the following appended claims, along
with the full scope of equivalents to which such claims are
entitled.
* * * * *