U.S. patent application number 15/133062 was filed with the patent office on 2016-08-11 for pharmaceutical formulation.
The applicant listed for this patent is Reckitt Benckiser LLC. Invention is credited to Nils Ahlgren, Venkatesh Balasubramanian, Craig Belongie, Ashfaq Khan, Neil Campbell Muir, Mark Nuttall, Jeannie Wong.
Application Number | 20160228386 15/133062 |
Document ID | / |
Family ID | 45688905 |
Filed Date | 2016-08-11 |
United States Patent
Application |
20160228386 |
Kind Code |
A1 |
Ahlgren; Nils ; et
al. |
August 11, 2016 |
Pharmaceutical Formulation
Abstract
A pharmaceutical composition in the form of a tablet including a
first portion and a second portion, wherein the first portion
includes guaifenesin having an immediate release profile and a
second drug having a sustained release profile, and wherein the
second portion includes guaifenesin having a sustained release
profile. The second drug can be in the form of a drug-resin
complex. The second drug can be either an anti-tussive or a
decongestant. The drug-resin complex includes a drug complexed to
an ion exchange resin. The ion exchange resin can be a polystyrene
sulfonate resin, polacrilex resin, polacrilin potassium,
cholestyramine resin, or a colestyramine resin. The drug-resin
complex can be provided with a coating, the coating thickness being
selected to obtain the desired release profile. The drug-resin
complex can be provided with a coating level of from 5% to 50%. The
coating level can be from 10% to 35%.
Inventors: |
Ahlgren; Nils; (Parsippany,
NJ) ; Nuttall; Mark; (Parsippany, NJ) ; Wong;
Jeannie; (Parsippany, NJ) ; Balasubramanian;
Venkatesh; (Parsippany, NJ) ; Belongie; Craig;
(Parsippany, NJ) ; Khan; Ashfaq; (Parsippany,
NJ) ; Muir; Neil Campbell; (Parsippany, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Reckitt Benckiser LLC |
Parsippany |
NJ |
US |
|
|
Family ID: |
45688905 |
Appl. No.: |
15/133062 |
Filed: |
April 19, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13021240 |
Feb 4, 2011 |
9339478 |
|
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15133062 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/09 20130101;
A61P 11/00 20180101; A61K 31/485 20130101; A61K 9/4808 20130101;
A61K 31/09 20130101; A61K 31/137 20130101; A61K 9/5042 20130101;
A61K 9/2027 20130101; A61K 9/5026 20130101; A61K 9/5047 20130101;
A61K 2300/00 20130101; A61P 11/14 20180101; A61K 9/2054 20130101;
A61K 2300/00 20130101; A61K 31/485 20130101; A61K 31/137 20130101;
A61K 2300/00 20130101; A61K 9/209 20130101; A61P 11/10 20180101;
A61K 45/06 20130101; A61P 11/02 20180101; A61K 9/20 20130101 |
International
Class: |
A61K 31/09 20060101
A61K031/09; A61K 9/20 20060101 A61K009/20; A61K 9/48 20060101
A61K009/48; A61K 9/50 20060101 A61K009/50; A61K 31/485 20060101
A61K031/485; A61K 9/24 20060101 A61K009/24 |
Claims
1. A pharmaceutical composition comprising: a first portion; and a
second portion; wherein the first portion comprises guaifenesin
having an immediate release profile and a second drug having a
sustained release profile; and wherein the second portion comprises
guaifenesin having a sustained release profile.
2. The pharmaceutical composition as claimed in claim 1, wherein
the second portion comprises a release-delaying matrix comprising a
hydrophilic polymer and a water-insoluble polymer.
3. The pharmaceutical composition as claimed in claim 1, wherein
the second drug comprises codeine.
4. The pharmaceutical composition as claimed in claim 2, wherein
the hydrophilic polymer comprises hydroxypropyl
methylcellulose.
5. The pharmaceutical composition as claimed in claim 2, wherein
the water-insoluble polymer comprises a carbomer.
6. The pharmaceutical composition as claimed in claim 1, wherein
the second drug is in the form of a coated drug-resin complex.
7. The pharmaceutical composition as claimed in claim 1, wherein
the second drug is selected from the group consisting of an
anti-tussive and a decongestant.
8. The pharmaceutical composition as claimed in claim 1, wherein
the second drug is selected from the group consisting of codeine,
pseudoephedrine, phenylephrine, dextromethorphan and
hydrocodone.
9. The pharmaceutical composition as claimed in claim 6, wherein
the coated drug-resin complex comprises an ion exchange resin.
10. The pharmaceutical composition as claimed in claim 9, wherein
the ion exchange resin is selected from the group consisting of a
polystyrene sulfonate resin, polacrilex resin, polacrilin
potassium, cholestyramine resin, a colestyramine resin, and a
sodium polystyrene sulfonate resin.
11. The pharmaceutical composition as claimed in claim 6, wherein
the coating level of the coated drug-resin complex is from 5% to
50%.
12. The pharmaceutical composition as claimed in claim 11, wherein
the coating level is from 10% to 35%.
13. A pharmaceutical composition comprising: a first portion; and a
second portion; wherein the first portion comprises guaifenesin
having an immediate release profile and a second drug in the form
of a coated drug-resin complex having a sustained release profile;
and wherein the second portion comprises guaifenesin having a
sustained release profile.
14. The pharmaceutical composition as claimed in claim 13, wherein
the coated drug-resin complex comprises a coated codeine polistirex
complex.
15. The pharmaceutical composition as claimed in claim 13, wherein
the coated drug resin complex has a coating level of 30% and has
the following dissolution profile in USP apparatus 1 (baskets) at
50 rpm in 0.1N HCl at 37.degree. C.: TABLE-US-00009 Time (hours)
Average % Codeine released 1 18-48 2 27-57 6 42-72 12 51-81
16. The pharmaceutical composition as claimed in claim 13, wherein
the coated drug resin complex has a coating level of 30% and has
the following dissolution profile in USP apparatus 1 (baskets) at
50 rpm in 0.1N HCl at 37.degree. C.: TABLE-US-00010 Time (hours)
Average % Codeine released 1 33 2 42 6 57 12 66
17. The pharmaceutical composition as claimed in claim 13, wherein
the coated drug resin complex has a coating level of 15% and has
the following dissolution profile in USP apparatus 1 (baskets) at
50 rpm in 0.1N HCl at 37.degree. C.: TABLE-US-00011 Time (hours)
Average % Codeine released 1 30-60 2 43-73 6 64-94 12 at least
73
18. The pharmaceutical composition as claimed in claim 13, wherein
the coated drug resin complex has a coating level of 15% and has
the following dissolution profile in USP apparatus 1 (baskets) at
50 rpm in 0.1N HCl at 37.degree. C.: TABLE-US-00012 Time (hours)
Average % Codeine released 1 45 2 58 6 79 12 88
19. A pharmaceutical composition comprising: a first portion; and a
second portion; wherein the first portion comprises guaifenesin
having an immediate release profile and a second drug having a
sustained release profile; wherein the second portion comprises
guaifenesin having a sustained release profile; wherein the total
amount of guaifenesin is between 500 mg and 1300 mg; wherein the
total amount of the second drug is up to 100 mg; and wherein the
ratio of the total quantity of guaifenesin to the second drug in
the same portion is from 1:1 to 30:1 (by weight).
20. The pharmaceutical composition as claimed in claim 19, wherein
the second portion comprises a release-delaying matrix comprising a
hydrophilic polymer and a water-insoluble polymer.
21. The pharmaceutical composition as claimed in claim 19, wherein
the second drug comprises codeine.
22. The pharmaceutical composition as claimed in claim 20, wherein
the hydrophilic polymer comprises hydroxypropyl
methylcellulose.
23. The pharmaceutical composition as claimed in claim 20, wherein
the water-insoluble polymer comprises a carbomer.
24. The pharmaceutical composition as claimed in claim 19, wherein
the second drug is in the form of a coated drug-resin complex.
25. The pharmaceutical composition as claimed in claim 19, wherein
the second drug is selected from the group consisting of an
anti-tussive and a decongestant.
26. The pharmaceutical composition as claimed in claim 19, wherein
the second drug is selected from the group consisting of codeine,
pseudoephedrine, phenylephrine, dextromethorphan and
hydrocodone.
27. The pharmaceutical composition as claimed in claim 24, wherein
the coated drug-resin complex comprises an ion exchange resin.
28. The pharmaceutical composition as claimed in claim 27, wherein
the ion exchange resin is selected from the group consisting of a
polystyrene sulfonate resin, polacrilex resin, polacrilin
potassium, cholestyramine resin, a colestyramine resin, and a
sodium polystyrene sulfonate resin.
29. The pharmaceutical composition as claimed in claim 25, wherein
the coating level of the coated drug-resin complex is from 5% to
50%.
30. The pharmaceutical composition as claimed in claim 29, wherein
the coating level is from 10% to 35%.
31. The pharmaceutical composition as claimed in claim 19, wherein
the second drug is also the sustained release portion.
32. The pharmaceutical composition as claimed in claim 20, wherein
the weight ratio of hydrophilic polymer to water-insoluble polymer
is from 1:1 to 9:1.
33. The pharmaceutical composition as claimed in claim 20, wherein
the weight ratio of hydrophilic polymer to water-insoluble polymer
is from 3:2 to 6:1.
34. The pharmaceutical composition as claimed in claim 20, wherein
the weight ratio of hydrophilic polymer to water-insoluble polymer
is from 2:1 to 4:1.
35. The pharmaceutical composition as claimed in claim 19, wherein
the total amount of guaifenesin is between 600 mg to 1200 mg.
36. The pharmaceutical composition as claimed in claim 19, wherein
the formulation contains 1200 mg of guaifenesin.
37. The pharmaceutical composition as claimed in claim 19, wherein
the formulation contains 600 mg of guaifenesin.
38. The pharmaceutical composition as claimed in claim 19, wherein
the total amount of the second drug is between 20-80 mg.
39. The pharmaceutical composition as claimed in claim 21, wherein
the composition contains an amount of codeine that is
therapeutically equivalent to 60 mg of codeine phosphate.
40. The pharmaceutical composition as claimed in claim 21, wherein
the composition contains an amount of codeine that is
therapeutically equivalent to 30 mg of codeine phosphate.
41. The pharmaceutical composition as claimed in claim 21, wherein
the composition comprises 600 mg of guaifenesin and an amount of
codeine that is therapeutically equivalent to 30 mg of codeine
phosphate.
42. The pharmaceutical composition as claimed in claim 21, wherein
the composition comprises 600 mg of guaifenesin and an amount of
codeine that is therapeutically equivalent to 30 mg of codeine
phosphate.
43. The pharmaceutical composition as claimed in claim 21, wherein
the immediate release portion comprises microcrystalline cellulose,
crospovidone and magnesium stearate.
44. The pharmaceutical composition as claimed in claim 21, wherein
ratio of the total quantity of guaifenesin to codeine in the same
portion is from 1:1 to 25:1 (by weight).
45. The pharmaceutical composition as claimed in claim 19, wherein
the ratio of the immediate release quantity of guaifenesin to the
sustained release quantity of guaifenesin is from 1:1 to 1:15 (by
weight).
46. The pharmaceutical composition as claimed in claim 19, wherein
the ratio of the immediate release quantity of guaifenesin to the
sustained release quantity of guaifenesin is from 2:3 to 1:11 (by
weight).
47. The pharmaceutical composition as claimed in claim 19, wherein
the at least 60% of guaifenesin particles used to make the
pharmaceutical composition has a particle size in the range of from
25 .mu.m to 2.0 mm.
48. The pharmaceutical composition as claimed in claim 19, wherein
the formulation comprises immediate release and sustained release
portions each comprising abutting planar layers which form a
bi-layer tablet.
49. The pharmaceutical composition as claimed in claim 19, wherein
the formulation comprises a capsule that contains discrete or
associated immediate release and sustained release portions.
50. The pharmaceutical composition as claimed in claim 19, wherein
the sustained release portion is coated by a layer of the immediate
release portion.
51. The pharmaceutical composition as claimed in claim 19, wherein
each drug in the formulation exhibits a therapeutic effect for a
period of 12 hours.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of application Ser. No.
13/021,240, filed 4 Feb. 2011, which is incorporated herein by
reference in its entirety as if fully set forth below.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention is directed to a novel pharmaceutical
composition comprising guaifenesin and a second drug. In
particular, the present application is directed to a novel
pharmaceutical composition comprising guaifenesin and a second drug
which is an antitussive or a decongestant. More particularly, the
present application is directed to a composition comprising
guaifenesin having both immediate and extended release profiles and
codeine having an immediate release profile.
[0004] 2. Description of Related Art
[0005] Compounds such as codeine are known to have both antitussive
and pain relieving properties. The antitussive effect occurs at a
lower dose than that needed to provide pain relief.
[0006] In addition, compounds such as codeine are used in
combination with compounds that treat other symptoms of a
cough/cold or flu, e.g. expectorants, mucus thinning drugs,
decongestants and/or antihistamines. However, a dose of an
antitussive compound such as codeine typically provides a
therapeutic effect for about 2.5-3 hours, whereas many of the
compounds often used with this type of antitussive compound provide
therapeutically effective plasma concentrations per dose over a
period that is significantly different. For example, a dose of an
expectorant such as guaifenesin will usually provide relief for
about one hour, and decongestants usually provide relief for about
4 to 8 hours.
[0007] As a result, there is little benefit to be gained in
combining an antitussive such as codeine with a drug having a
shorter or longer therapeutically effective period in a single
dosage form. In such a combination, one drug (e.g. codeine) may
still provide the desired effect when the other drug has already
ceased to be effective, or the other drug may continue to exert its
effect, which would prevent administration of a further dose of the
antitussive.
[0008] It would be desirable if patients suffering from a
cough/cold/flu-type conditions, which an antitussive like codeine
would provide relief against could be combined with a different
drug, such as guaifenesin, in order to obtain relief from symptoms
that the antitussive does not treat.
[0009] Sustained release pharmaceutical formulations provide a
significant advantage over immediate release formulations to both
clinicians and their patients. Sustained release dosage forms
provide for fewer daily dose administrations than their immediate
release counterparts. For example, a standard dosage regimen for a
400 mg immediate release drug with a short half-life, such as
guaifenesin, requires administration three times within twelve
hours to maintain adequate bioavailability to achieve the desired
therapeutic effect.
[0010] Besides reducing the frequency of dosing and providing a
more consistent therapeutic effect, sustained release dosage forms
generally help reduce side effects caused by a drug. Because
sustained release dosage forms deliver the drug in slow,
incremental amounts versus the cyclic high and low concentrations
of immediate release formulations, it is easier for a patient's
body to digest the drug, thereby avoiding undesirable side-effects.
For patients who self-administer therapies, sustained release
dosage forms generally result in greater compliance due to the
lower frequency of dosing, lower quantity of dosage units to be
consumed, and reduced undesired side-effects.
[0011] Generally, sustained release formulations contain drug
particles mixed with or covered by a polymer material, or blend of
materials, which is resistant to degradation or disintegration in
the stomach and/or in the intestine for a selected period of time.
Release of the drug may occur by leeching, erosion, rupture,
diffusion or similar actions depending upon the nature of the
polymer material or polymer blend used.
[0012] Furthermore, most formulations that claim twelve hour
potency release almost their entire drug within six to eight hours,
making the formulation less therapeutically effective towards the
end of the twelve hour period. To prevent blood serum
concentrations of drug from falling below a therapeutically
effective level (C.sub.min) at extended time periods, many
manufacturers increase the drug strength of the dosage form. The
increase in drug strength, however, results in a concomitant
increase in side-effects.
[0013] Other pharmaceutical manufacturers have made tablets and
capsules containing a combination of an immediate release
formulation and a sustained release formulation to improve the
release profile of certain sustained release dosage forms. Although
this solution improves the Cmax and length of time before the drug
appears in the blood stream in some formulations, the extended
therapeutic effect is not improved.
[0014] Furthermore, medicaments have different solubility
properties and pH dependencies, which affect dissolution rate and
bioavailability. Bioavailability can also be affected by a number
of factors such as the amounts and types of adjuvants used, the
granulation process, compression forces (in tablet manufacturing),
surface area available for dissolution and environmental factors
such as agitation in the stomach and the presence or absence of
food. Due to these numerous factors, specific formulations play an
important role in the preparation of prolonged action solid dosage
forms, particularly in the preparation of solid dosage forms that
achieve appropriate bioavailability for optimum therapeutic
effect.
[0015] WO 01/082895 discloses a composition which comprises
immediate and sustained release portions, both of which contain
guaifenesin. WO 03/088952 discloses a composition which also
comprises guaifenesin-containing immediate and sustained release.
The specification exemplifies compositions which also include
dextromethorphan or pseudoephedrine.
BRIEF SUMMARY OF THE INVENTION
[0016] Briefly described, in a preferred form, the present
invention provides a pharmaceutical composition in the form of a
tablet comprising a first portion and a second portion wherein the
first portion comprises guaifenesin having an immediate release
profile and a second drug having a sustained release profile and
wherein the second portion comprises guaifenesin having a sustained
release profile.
[0017] Typically the second drug is in the form of a drug-resin
complex. The second drug can be either an anti-tussive or a
decongestant. Typically, the second drug can be selected from
codeine, pseudoephedrine, phenylephrine, dextromethorphan and
hydrocodone. Preferably the second drug is codeine
[0018] The drug-resin complex comprises a drug complexed to an ion
exchange resin. The ion exchange resin can be a polystyrene
sulfonate resin, polacrilex resin, polacrilin potassium,
cholestyramine resin, or a colestyramine resin. A preferred resin
is a sodium polystyrene sulfonate resin.
[0019] The drug-resin complex can be provided with a coating, the
coating thickness being selected to obtain the desired release
profile. The drug-resin complex can be provided with a coating
level of from 5% to 50%. The coating level can be from 10% to
35%.
[0020] The term `coating level` indicates the weight proportion of
the coated drug-resin complex that is the coating itself, for
example a coating level of 15% indicates that 15% of the overall
weight of the drug-resin complex is the coating layer.
[0021] In a preferred embodiment the drug resin complex having a
coating level of 30% has the following dissolution profile in USP
apparatus 1 (baskets) at 50 rpm in 0.1N HCl at 37.degree. C.:
TABLE-US-00001 Time (hours) Average % Codeine released 1 18-48 2
27-57 6 42-72 12 51-81
[0022] In another particularly preferred embodiment the drug resin
complex having a coating level of 30% has the following dissolution
profile in USP apparatus 1 (baskets) at 50 rpm in 0.1N HCl at
37.degree. C.:
TABLE-US-00002 Time (hours) Average % Codeine released 1 33 2 42 6
57 12 66
[0023] In another preferred embodiment the drug resin complex
having a coating level of 15% has the following dissolution profile
in USP apparatus 1 (baskets) at 50 rpm in 0.1N HCl at 37.degree.
C.
TABLE-US-00003 Time (hours) Average % Codeine released 1 30-60 2
43-73 6 64-94 12 at least 73
[0024] In a particularly preferred embodiment the drug-resin
complex having a coating level of 15% has the following dissolution
profile in USP apparatus 1 (baskets) at 50 rpm in 0.1N HCl at
37.degree. C.:
TABLE-US-00004 Time (hours) Average % Codeine released 1 45 2 58 6
79 12 88
[0025] Alternatively the drug-resin complex is uncoated.
[0026] The second drug can also be the sustained release
portion.
[0027] The portion having the sustained release guaifenesin can
comprise a release-delaying matrix comprising a hydrophilic polymer
and a water-insoluble polymer.
[0028] The release-delaying matrix can comprise hydrophilic polymer
and water-insoluble polymer in a weight ratio selected from 1:1 to
9:1, from 3:2 to 6:1, or from 2:1 to 4:1.
[0029] The total amount of guaifenesin can be between 500 mg and
1300 mg, preferably from 600 mg to 1200 mg. In a preferred
embodiment the formulation contains 1200 mg of guaifenesin. In an
alternative preferred embodiment the formulation contains 600 mg of
guaifenesin.
[0030] The total amount of the second drug can be up to 100 mg,
preferably 20-80 mg. In a preferred embodiment the composition
contains an amount of codeine that is therapeutically equivalent to
60 mg of codeine phosphate. In an alternative preferred embodiment
the composition contains an amount of codeine that is
therapeutically equivalent to 30 mg of codeine phosphate.
[0031] In a preferred embodiment the composition comprises 1200 mg
of guaifenesin and an amount of codeine that is therapeutically
equivalent to 60 mg of codeine phosphate. In an alternative
preferred embodiment the composition comprises 600 mg of
guaifenesin and an amount of codeine that is therapeutically
equivalent to 30 mg of codeine phosphate.
[0032] The immediate release portion comprises microcrystalline
cellulose, crospovidone and magnesium stearate.
[0033] Typically the second drug is codeine and the ratio of the
total quantity of guaifenesin to codeine in the same portion is
from 1:1 to 30:1; preferably from 1:1 to 25:1, by weight.
[0034] The ratio of the immediate release quantity of guaifenesin
to the sustained release quantity of guaifenesin can be from 1:1 to
1:15, preferably from 2:3 to 1:11, by weight.
[0035] Typically, at least 60% of the guaifenesin particles used to
make the drug product have a particle size in the range of from 25
.mu.m to 2.0 mm. Typically, the guaifenesin particles have a
particle size in the range of from 50 .mu.m to 500 .mu.m.
[0036] The formulation can comprise immediate release and sustained
release portions each comprising abutting planar layers which form
a bi-layer tablet.
[0037] The formulation can comprise a capsule that contains
discrete or associated immediate release and sustained release
portions.
[0038] The sustained release portion can be coated by a layer of
the immediate release portion.
[0039] Each drug in the formulation can exhibit a therapeutic
effect for a period of 12 hours.
[0040] According to a second aspect of the present invention there
is provided the composition of the first aspect for temporary
treatment of bronchial mucus accumulation, cough and nasal
congestion.
[0041] According to another aspect of the present invention there
is provided tablets that comprise an immediate release and a
sustained release guaifenesin portion, as well as a second drug
with a sustained release profile. The second drug is a coated
drug-resin complex. Moreover, the second drug is at least contained
within the first portion which has the immediate release
guaifenesin.
[0042] The desired release profile of the second drug is obtained
through the thickness of the coating on the drug-resin complex.
Also, the second drug's release profile is independent of the
release profile of the second portion. This is in patentable
contrast to formulations in which the release profile is obtained
via mixing various amounts of hydrophobic and hydrophilic
polymers.
[0043] One distinct advantage of this invention is the ability to
independently control the release of the second active (i.e., the
coated drug-resin complex) without impacting the dissolution
properties of the guaifenesin. Prior art compositions cannot
provide this level of control. Furthermore, this formulation can
allow for the reduction of observed food effects for drugs that
show lipid variability in clinical evaluation and can also allow
for the protection of actives from compatibility concerns that may
lead to stability degradation.
[0044] According to another aspect of the present invention, a
pharmaceutical composition in the form of a tablet or capsule
comprises guaifenesin, coated codeine polistirex, hydroxypropyl
methylcellulose, microcrystalline cellulose, crospovidone, carbomer
934P, FD&C Blue and magnesium stearate.
[0045] The coated codeine polistirex complex can have a thickness
to obtain a desired release profile. The coated codeine polistirex
complex can be provided with a coating level of from 5% to 50%.
BRIEF DESCRIPTION OF THE DRAWING
[0046] The sole FIGURE is a chart of percent codeine released over
time, wherein CL Compressed refers to (a) the coating level of the
bead (15% or 30%) and (b) that the layer comprising the codeine
bead is compressed.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0047] To facilitate an understanding of the principles and
features of the various embodiments of the invention, various
illustrative embodiments are explained below. Although preferred
embodiments of the invention are explained in detail, it is to be
understood that other embodiments are contemplated. Accordingly, it
is not intended that the invention is limited in its scope to the
details of ingredients and arrangement of components set forth in
the following description or illustrated in the drawing. The
invention is capable of other embodiments and of being practiced or
carried out in various ways. Also, in describing the preferred
embodiments, specific terminology will be resorted to for the sake
of clarity.
[0048] It must also be noted that, as used in the specification and
the appended claims, the singular forms "a," "an" and "the" include
plural references unless the context clearly dictates otherwise.
For example, reference to an ingredient is intended also to include
composition of a plurality of ingredients. References to a
composition containing "a" constituent is intended to include other
constituents in addition to the one named.
[0049] Also, in describing the preferred embodiments, terminology
will be resorted to for the sake of clarity. It is intended that
each term contemplates its broadest meaning as understood by those
skilled in the art and includes all technical equivalents which
operate in a similar manner to accomplish a similar purpose.
[0050] Ranges may be expressed herein as from "about" or
"approximately" one particular value and/or to "about" or
"approximately" another particular value. When such a range is
expressed, other exemplary embodiments include from the one
particular value and/or to the other particular value.
[0051] By "comprising" or "containing" or "including" is meant that
at least the named compound, element, particle, or method step is
present in the composition or article or method, but does not
exclude the presence of other compounds, materials, particles,
method steps, even if the other such compounds, material,
particles, method steps have the same function as what is
named.
[0052] It is also to be understood that the mention of one or more
method steps does not preclude the presence of additional method
steps or intervening method steps between those steps expressly
identified. Similarly, it is also to be understood that the mention
of one or more components in a composition does not preclude the
presence of additional components than those expressly
identified.
[0053] Embodiments of the present invention will now be described,
by way of example only with reference to the accompanying FIGURE
which illustrates the dissolution profiles for the codeine from two
drug resin complexes, the first drug-resin complex being coated
such that it exhibits a slower release profile than the second
drug-resin complex and vice versa.
Coated Codeine Polistirex
TABLE-US-00005 [0054] Ingredient Example 1 (wt %) Example 2 (wt %)
Codeine Phosphate 33.25 40.375 Sodium Polystyrene 33.25 40.375
Sulfonate (Amberlite IRP69) Sorbitol 70% solution 3.50 4.25
Ethylcellulose 25.50 12.75 Triethyl Citrate 4.50 2.25 Total 100.0
100.0
[0055] The codeine resin can be made in the following way. A
suspension of codeine and the polystyrene sulfonate resin
(Amberlite IRP69) in an aqueous sorbitol solution is stirred for
4-6 hours and then filtered under pressure. The filtered solid is
then dried, and screened using a 40 mesh screen. The resulting
drug-resin beads are coated with a solution which contains
acetone/methanol/ethyl cellulose/triethyl citrate. The resulting
coated beads are screened using a 50 mesh screen.
[0056] The thickness of the coating used on the resin/active
particle is selected to ensure that the desired release profile is
achieved.
[0057] A tablet of the guaifenesin/codeine resin combination can be
made in the following way.
[0058] The modified-release portion containing guaifenesin as the
only active can be made in a similar way. Guaifenesin, hypromellose
(Methocel E10M), carbomer (Carbopol 974), and blue dye are blended
for about twenty minutes. Magnesium stearate is then added and
blending continued for about another ten minutes to prepare the
sustained release formulation.
[0059] The resulting tablet has the following amounts of each
component:
Layer 1--Immediate Release GGE and MR Codeine Polistirex
TABLE-US-00006 [0060] Example 1 Example 2 Ingredient (wt % (mg))
(wt % (mg)) Guaifenesin 32.39 (210.5) 32.39 (210.5) Coated Codeine
Polistirex 30.07 (195.4) 24.36 (158.3) Microcrystalline Cellulose
32.04 (208.3) 37.75 (245.4) Crospovidone 5.00 (32.50) 5.00 (32.50)
Magnesium Stearate 0.50 (3.30) 0.50 (3.30) Total 100.00 (650.00)
100.00 (650.00)
Layer 2--Modified Release GGE
TABLE-US-00007 [0061] Example 1 Example 2 Ingredient (wt % (mg))
(wt % (mg)) Guaifenesin 95.77 (1052.60) 95.77 (1052.60)
Hypromellose 2.42 (26.60) 2.42 (26.60) Carbomer 934P 1.14 (12.50)
1.14 (12.50) FD&C Blue 0.15 (1.60) 0.15 (1.60) Magnesium
Stearate 0.52 (5.70) 0.52 (5.70) Total 100.00 (1099.00) 100.00
(1099.00)
Final Tablet
TABLE-US-00008 [0062] Example 1 Example 2 Ingredient (wt % (mg))
(wt % (mg)) Guaifenesin 72.22 (1263.10) 72.22 (1263.10) Coated
Codeine Polistirex 11.17 (195.40) 9.05 (158.30) Hypromellose 1.52
(26.60) 1.52 (26.60) Microcrystalline Cellulose 11.91 (208.30)
14.03 (245.40) Crospovidone 1.86 (32.50) 1.86 (32.50) Carbomer 934P
0.71 (12.50) 0.71 (12.50) FD&C Blue 0.09 (1.60) 0.09 (1.60)
Magnesium Stearate 0.51 (9.00) 0.51 (9.00) Total 100.00 (1749.00)
100.00 (1749.00)
[0063] An advantage of the present invention is that there is
provided a formulation which allows independent controlled release
of the second active without impacting the dissolution properties
of the guaifenesin.
[0064] In addition, the formulation potentially allows for the
reduction of observed food effects for drugs that show lipid
variability in clinical evaluation and allows protection of actives
from compatibility concerns that may lead to stability
degradation
[0065] Further modifications and improvements can be made without
departing from the scope of the invention described herein.
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