U.S. patent application number 15/520752 was filed with the patent office on 2017-10-26 for novel pharmaceutical formulation.
The applicant listed for this patent is RECKITT BENCKISER LLC. Invention is credited to RAGHU CAVATUR, KEVIN CHEN, MATTHEW JAMES KASER, HONGCHUN QIU.
Application Number | 20170304296 15/520752 |
Document ID | / |
Family ID | 53298924 |
Filed Date | 2017-10-26 |
United States Patent
Application |
20170304296 |
Kind Code |
A1 |
CAVATUR; RAGHU ; et
al. |
October 26, 2017 |
NOVEL PHARMACEUTICAL FORMULATION
Abstract
The present invention is directed to a pharmaceutical
composition comprising a pharmaceutically effective amount of
guaifenesin, naproxen and at least one further active which is
selected to be an antitussive, a decongestant or an
antihistamine.
Inventors: |
CAVATUR; RAGHU; (PARSIPPANY,
NJ) ; CHEN; KEVIN; (PARSIPPANY, NJ) ; KASER;
MATTHEW JAMES; (PARSIPPANY, NJ) ; QIU; HONGCHUN;
(BASKING RIDGE, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
RECKITT BENCKISER LLC |
PARSIPPANY |
NJ |
US |
|
|
Family ID: |
53298924 |
Appl. No.: |
15/520752 |
Filed: |
October 21, 2015 |
PCT Filed: |
October 21, 2015 |
PCT NO: |
PCT/GB2015/053151 |
371 Date: |
April 20, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62066532 |
Oct 21, 2014 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/192 20130101;
A61K 45/06 20130101; A61P 11/00 20180101; A61K 31/192 20130101;
A61K 47/36 20130101; A61P 11/14 20180101; A61K 47/12 20130101; A61K
9/2054 20130101; A61K 9/209 20130101; A61K 31/137 20130101; A61K
47/20 20130101; A61K 47/02 20130101; A61K 47/32 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 31/09 20130101; A61K 31/137 20130101;
A61K 31/485 20130101; A61K 47/38 20130101; A61K 47/26 20130101;
A61K 31/485 20130101; A61K 31/09 20130101; A61P 11/10 20180101 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61K 47/36 20060101 A61K047/36; A61K 47/32 20060101
A61K047/32; A61K 47/26 20060101 A61K047/26; A61K 47/20 20060101
A61K047/20; A61K 47/12 20060101 A61K047/12; A61K 47/02 20060101
A61K047/02; A61K 45/06 20060101 A61K045/06; A61K 31/192 20060101
A61K031/192; A61K 47/38 20060101 A61K047/38; A61K 31/09 20060101
A61K031/09 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 21, 2015 |
GB |
1506755.6 |
Claims
1. A pharmaceutical composition comprising a pharmaceutically
effective amount of guaifenesin, naproxen and at least one further
active which is selected to be an antitussive, a decongestant or an
antihistamine.
2. A composition as claimed in claim 1, wherein the at least one
other drug is selected from an antitussive such as
dextromethorphan, codeine, codeine phosphate, codeine sulphate,
diphenhydramine citrate, and diphenhydramine hydrochloride, a
decongestant such as phenylephrine hydrochloride,
phenylpropanolamine hydrochloride, pseudoephedrine or ephedrine, an
antihistamine such as chlorpheniramine maleate, brompheniramine
maleate, phenindamine tartrate, pyrilamine maleate, doxylamine
succinate, phenyltoloxamine citrate, diphenhydramine hydrochloride,
promethazine, and clemastine fumerate, or a combination
thereof.
3. A composition as claimed in claim 2, wherein the at least one
other drug is dextromethorphan or pseudoephedrine.
4. A composition as claimed in claim 3, wherein the expectorant is
guaifenesin, the analgesic is naproxen and the antitussive is
dextromethorphan.
5. A composition as claimed in claim 4, wherein the ratio of
guaifenesin:naproxen:dextromethorphan is from about 40:8:1 to about
10:3:1.
6. A composition as claimed in claim 5, wherein the ratio of
guaifenesin:naproxen:dextromethorphan is from 22:4:1 to 17:3:1.
7. A composition as claimed in claim 5, wherein the ratio of
guaifenesin:naproxen:dextromethorphan is 20:3.67:1.
8. A composition as claimed in claim 1, wherein the ratio of
guaifensin:naproxen is from about 1:1 to about 10:1.
9. A composition as claimed in claim 8, wherein the ratio of
guaifensin:naproxen is from about 2:1 to about 7:1.
10. A composition as claimed in claim 8, wherein the ratio of
guaifensin:naproxen is from about 4:1 to about 6:1.
11. A composition as claimed in claim 2, wherein the ratio of
naproxen:dextromethorphan is from about 1:1 to about 10:1.
12. A composition as claimed in claim 11, wherein the ratio of
naproxen:dextromethorphan is from about 2:1 to about 7:1.
13. A composition as claimed in claim 11, wherein the ratio of
wherein the ratio of naproxen:dextromethorphan is from about 3:1 to
about 5:1.
14. A composition as claimed in claim 1, wherein composition
comprises immediate and sustained release portions.
15. A composition as claimed in claim 14, wherein the composition
is provided with both sustained-release and immediate-release
portions comprising the expectorant.
16. A composition as claimed in claim 14, wherein the naproxen is
incorporated into the composition such that it is the sole active
in the portion in which it is contained.
17. A composition as claimed in claim 14, wherein the composition
is provided with both sustained-release and immediate-release
portions comprising guaifenesin.
18. A composition as claimed in claim 14, wherein the composition
comprises a first immediate release portion which comprises
guaifenesin and a decongestant or an antitussive, a second
immediate release portion which comprises naproxen, and a sustained
release portion which comprises guaifenesin.
19. A composition as claimed in claim 1, wherein the composition
comprises: (a) 50-85% Guaifenesin; (b) up to 5% Dextromethorphan or
a pharmaceutically acceptable salt thereof; and (c) 5-30% Naproxen
or a pharmaceutically acceptable salt thereof.
20. A composition as claimed in claim 1, wherein the composition
comprises: (a) 55-65% Guaifenesin; (b) 1-5% Dextromethorphan or a
pharmaceutically acceptable salt thereof; (c) 5-15% Naproxen or a
pharmaceutically acceptable salt thereof; (d) 1-10% Controlled
release polymers; (e) 0.1-10% Binders; (f) 0.1-5% Disintegrants;
(g) 5-25% Diluents; and (h) up to 1% Lubricants.
21. A composition as claimed in claim 20, wherein the composition
comprises: (a) 55-65% Guaifenesin; (b) 1-5% Dextromethorphan or a
pharmaceutically acceptable salt thereof; (c) 5-15% Naproxen or a
pharmaceutically acceptable salt thereof; (d) 1-8% Hypromellose;
(e) 10-25% Microcrystalline cellulose; (f) 0.1-2.5% Povidone; (g)
0.1-4.0% Croscarmellose Sodium; (h) 0.1-2.0% Hydroxyethyl
Cellulose; and (i) up to 1% Magnesium stearate.
22. A composition as claimed in claim 21, wherein the composition
comprises: (a) 58-63% Guaifenesin; (b) 2-3.5% Dextromethorphan or a
pharmaceutically acceptable salt thereof; (c) 10-12% Naproxen or a
pharmaceutically acceptable salt thereof; (d) 1-2% Hypromellose;
(e) 15-25% Microcrystalline cellulose; (f) 1-2% Povidone; (g)
0.5-2.5% Croscarmellose sodium; (h) 0.5-1% Hydroxyethyl cellulose;
and (i) up to 0.5% Magnesium stearate.
23. A composition as claimed in claim 20, wherein the composition
comprises: (a) 55-65% Guaifenesin; (b) 1-5% Dextromethorphan or a
pharmaceutically acceptable salt thereof; (c) 5-15% Naproxen or a
pharmaceutically acceptable salt thereof; (d) 1-8% Hypromellose;
(e) 10-25% Microcrystalline cellulose; (f) 0.1-2.5% Povidone; (g)
0.1-2.0% Carbomer; (h) 0.1-2.0% Sodium Starch Glycolate; (i) up to
1% Magnesium stearate; and
24. A composition as claimed in claim 23, wherein the composition
comprises: (a) 59-65% Guaifenesin; (b) 3-5% Dextromethorphan or a
pharmaceutically acceptable salt thereof; (c) 10-12% Naproxen or a
pharmaceutically acceptable salt thereof; (d) 1-6% Hypromellose;
(e) 10-20% Microcrystalline cellulose; (f) 0.3-1% Povidone; (g)
0.5-1% Carbomer; (h) 0.1-0.5% Sodium Starch Glycolate; and (i) up
to 1% Magnesium stearate.
25. A composition as claimed in claim 20, wherein the composition
comprises: (a) 59-65% Guaifenesin; (b) 3-5% Dextromethorphan or a
pharmaceutically acceptable salt thereof; (c) 10-12% Naproxen or a
pharmaceutically acceptable salt thereof; (d) 1-6% Hypromellose;
(e) 10-20% Microcrystalline cellulose; (f) 0.3-1% Povidone; (g)
0.5-1% Carbomer; (h) 1-2% Croscarmellose sodium; (i) 0.1-0.5%
Sodium Starch Glycolate; and (j) up to 1% Magnesium stearate.
26. A composition as claimed in claim 1, wherein the composition
comprises: (a) 64-69% Guaifenesin; (b) 3-5% Dextromethorphan or a
pharmaceutically acceptable salt thereof; (c) 12-15% Naproxen or a
pharmaceutically acceptable salt thereof; (d) 3-5% Hypromellose;
(e) 9-15% Microcrystalline cellulose; (f) 0.4-0.65% Povidone; (g)
0.75-1.3% Carbomer; (h) 0.5-1% Magnesium stearate; and (i)
0.25-0.5% Sodium starch glycolate.
27. A composition as claimed in claim 26, wherein the composition
further comprises: (j) 0.5-1.5% Lactose; (k) 2.5-3.5% Sodium lauryl
sulphate; and (l) 0.1-1.5% Croscarmellose sodium.
28. A composition as claimed in claim 1, wherein the composition
comprises: (a) 64-69% Guaifenesin; (b) 3-5% Dextromethorphan or a
pharmaceutically acceptable salt thereof; (c) 12-15% Naproxen or a
pharmaceutically acceptable salt thereof; (d) 0.1-0.6%
Hypromellose; (e) 9-15% Microcrystalline cellulose; (f) 0.4-0.65%
Povidone; (g) 0.75-1.3% Carbomer; (h) 0.5-1% Magnesium stearate;
and (i) 0.25-0.5% Sodium starch glycolate.
29. A composition as claimed in claim 28, wherein the composition
further comprises one or more of: (j) 0.5-1.5% Lactose; (k)
2.5-3.5% Sodium lauryl sulphate; and (l) 0.1-1.5% Croscarmellose
sodium.
30. A composition as claimed in claim 1, wherein the composition
comprises: (a) 63-66% Guaifenesin; (b) 3-5% Dextromethorphan or a
pharmaceutically acceptable salt thereof; (c) 10-12% Naproxen or a
pharmaceutically acceptable salt thereof; (d) 1.75-3.0%
Hypromellose; (e) 11-13% Microcrystalline cellulose; (f) 1-2%
Povidone; (g) 0.5-0.75% Croscarmellose Sodium; (h) 1-2% Carbomer;
(i) 0.1-0.5% Magnesium stearate; and (j) 0.5-1.5% Lactose.
31. A composition as claimed in claim 30, wherein the composition
further includes: (k) 2-3% Sodium Lauryl Sulphate.
32. A composition as claimed in claim 1, wherein the composition
comprises: (a) 64-66% Guaifenesin; (b) 3-5% Dextromethorphan or a
pharmaceutically acceptable salt thereof; (c) 11-13% Naproxen or a
pharmaceutically acceptable salt thereof; (d) 1.75-3.0%
Hypromellose; (e) 6-8.5% Microcrystalline cellulose; (f) 1-2%
Povidone; (g) 1-5% Croscarmellose Sodium; (h) 0.5-1% Carbomer; (i)
0.5-1% Magnesium stearate; and (j) 0.5-1% Crospovidone.
33. A composition as claimed in claim 32, wherein the composition
further includes one or more of: (k) 2-3% Sodium Lauryl Sulphate;
and (l) 6-7% Sodium Bicarbonate.
34. A composition as claimed in claim 1, wherein the composition
comprises: (a) 64-66% Guaifenesin; (b) 3-5% Dextromethorphan or a
pharmaceutically acceptable salt thereof; (c) 11-13% Naproxen or a
pharmaceutically acceptable salt thereof; (d) 1.75-3.0%
Hypromellose; (e) 6-8.5% Microcrystalline cellulose; (f) 1-2%
Povidone; (g) 1-5% Croscarmellose Sodium; (h) 0.5-1% Carbomer; and
(i) 0.5-1% Magnesium stearate.
35. A composition as claimed in claim 1, wherein the composition
comprises: (a) 62-65% Guaifenesin; (b) 3-5% Dextromethorphan or a
pharmaceutically acceptable salt thereof; (c) 11-13% Naproxen or a
pharmaceutically acceptable salt thereof; (d) 1.75-3.0%
Hypromellose; (e) 6-8.5% Microcrystalline cellulose; (f) 1-2%
Povidone; (g) 1-5% Croscarmellose Sodium; (h) 0.5-1% Carbomer; and
(i) 0.5-1% Magnesium stearate; (j) 2-3% Sodium Lauryl Sulphate; and
(k) 5-8% Sodium Bicarbonate.
36. A composition as claimed in claim 1, wherein the composition
comprises: (a) 58-60% Guaifenesin; (b) 2-3% Dextromethorphan or a
pharmaceutically acceptable salt thereof; (c) 10-11% Naproxen or a
pharmaceutically acceptable salt thereof; (d) 2-3% Hypromellose;
(e) 7-8% Microcrystalline cellulose; (f) 1-2% Povidone; (g) 2-3%
Croscarmellose Sodium; (h) 0.1-0.2% Magnesium stearate; (i) 0.5-1%
Crospovidone; (j) 1-3% Hydroxyethyl cellulose; (k) 2-3% Sodium
Lauryl Sulphate; and (l) 9-10% Sodium bicarbonate.
37. A composition as claimed in claim 1, wherein the composition
comprises: (a) 64-66% Guaifenesin; (b) 3-5% Dextromethorphan or a
pharmaceutically acceptable salt thereof; (c) 11-13% Naproxen or a
pharmaceutically acceptable salt thereof; (d) 2-3% Hypromellose;
(e) 6-7% Microcrystalline cellulose; (f) 1-2% Povidone; (g)
0.1-0.5% Magnesium stearate; (h) 7-10% Crospovidone; and (i) 1-3%
Hydroxyethyl cellulose.
38. A pharmaceutical dosage form which comprises at least three
distinct portions wherein two of the portions have immediate
release characteristics and a third portion has modified release
characteristics, wherein one of the immediate release portions
comprises an expectorant and a second active which is an
antitussive or a decongestant and the second immediate release
portion comprises an analgesic having a half-life of twelve hours
and wherein the modified release portion comprises guaifenesin and
a second active which is an antitussive or a decongestant.
39. A pharmaceutical dosage form as claimed in claim 38, wherein
the dosage form comprises a first composition which comprises both
immediate and modified release portions of the expectorant and the
second active which is an antitussive or a decongestant and a
second composition which comprises an analgesic having a
therapeutic effect of twelve hours.
40. A pharmaceutical dosage form as claimed in claim 38, wherein
the analgesic is the sole active in the portion in which it is
contained.
41. A composition as claimed in claim 1, wherein an
analgesic-containing immediate release portion comprises: (a)
50-52% Naproxen or a pharmaceutically acceptable salt thereof; (b)
35-40% Microcrystalline cellulose; (c) up to 5% Povidone; (d) 5-8%
Croscarmellose sodium; and (e) up to 1% Magnesium stearate.
42. A composition as claimed in claim 1 wherein an
analgesic-containing immediate release portion comprises: (a)
70-75% Naproxen or a pharmaceutically acceptable salt thereof; (b)
20-25% Microcrystalline cellulose; (c) up to 5% Povidone; and (d)
up to 1% Magnesium stearate.
43. A composition as claimed in claim 1, wherein an
analgesic-containing immediate release portion comprises: (a)
70-75% Naproxen or a pharmaceutically acceptable salt thereof; (b)
5-10% Microcrystalline cellulose; (c) up to 5% Povidone; (d) up to
1% Magnesium stearate; (e) 5-10% Lactose; and (f) up to 5%
Croscarmellose sodium.
44. A composition as claimed in claim 1, wherein an
analgesic-containing immediate release portion comprises: (a)
70-75% Naproxen or a pharmaceutically acceptable salt thereof; (b)
5-10% Microcrystalline cellulose; (c) up to 5% Povidone; (d) up to
1% Magnesium stearate; (e) 5-10% Lactose; and (f) 5-10%
Croscarmellose sodium.
45. A composition as claimed in claim 1, wherein an
analgesic-containing immediate release portion comprises: (a)
70-75% Naproxen or a pharmaceutically acceptable salt thereof; (b)
5-10% Microcrystalline cellulose; (c) up to 5% Povidone; (d) up to
1% Magnesium stearate; (e) up to 5% Lactose; and (f) 15-20% Sodium
Lauryl Sulphate.
46. A composition as claimed in claim 1, wherein an
analgesic-containing immediate release portion comprises: (a)
70-75% Naproxen or a pharmaceutically acceptable salt thereof; (b)
5-10% Microcrystalline cellulose; (c) up to 5% Povidone; (d) up to
1% Magnesium stearate; (e) up to 2% Croscarmellose sodium; and (f)
15-20% Sodium Lauryl Sulphate.
47. A composition as claimed in claim 1, wherein a
guaifenesin-containing immediate release portion comprises: (a)
30-40% Guaifenesin; (b) up to 5% Dextromethorphan or a
pharmaceutically acceptable salt thereof; (c) 50-60%
Microcrystalline cellulose; (d) up to 7% Povidone; (e) up to 7%
Croscarmellose sodium; and (f) up to 1% Magnesium stearate.
48. A composition as claimed in claim 1, wherein a
guaifenesin-containing immediate release portion comprises: (a)
40-50% Guaifenesin; (b) up to 5% Dextromethorphan or a
pharmaceutically acceptable salt thereof; (c) 40-50%
Microcrystalline cellulose; (d) up to 5% Hypromellose; (e) up to 5%
Sodium starch glycolate; and (f) up to 1% Magnesium stearate.
49. A composition as claimed in claim 1, wherein a
guaifenesin-containing immediate release portion comprises: (a)
50-65% Guaifenesin; (b) up to 5% Dextromethorphan or a
pharmaceutically acceptable salt thereof; (c) 25-40%
Microcrystalline cellulose; (d) up to 5% Povidone; (e) up to 5%
Croscarmellose sodium; and (f) up to 1% Magnesium stearate.
50. A composition as claimed in claim 1, wherein a modified release
portion comprises: (a) 80-90% Guaifenesin; (b) up to 5%
Dextromethorphan or a pharmaceutically acceptable salt thereof; (c)
up to 10% Hypromellose; (d) up to 5% Carbomer; and (e) up to 1.55%
Magnesium stearate.
51. A composition as claimed in claim 1, wherein a modified release
portion comprises: (a) 80-90% Guaifenesin; (b) 3-6%
Dextromethorphan or a pharmaceutically acceptable salt thereof; (c)
up to 5% Hypromellose; (d) up to 2% Hydroxy ethylcellulose; (e) up
to 5% Microcrystalline cellulose; and (f) up to 1% Magnesium
stearate.
52. A composition as claimed in claim 1, wherein a modified release
portion comprises: (a) 80-90% Guaifenesin; (b) 3-6%
Dextromethorphan or a pharmaceutically acceptable salt thereof; (c)
up to 5% Hypromellose; (d) up to 5% Hydroxy ethylcellulose; (e) up
to 5% Microcrystalline cellulose; and (f) up to 1% Magnesium
stearate.
53. A composition as claimed in claim 1, wherein a modified release
portion comprises: (a) 85-90% Guaifenesin; (b) 4-5%
Dextromethorphan or a pharmaceutically acceptable salt thereof; (c)
3-6% Hypromellose; (d) 1-3% Carbomer; and (e) 0.5-1% Magnesium
stearate.
54. A composition as claimed in claim 1, wherein a modified release
portion comprises: (a) 90-93% Guaifenesin; (b) 4-6%
Dextromethorphan or a pharmaceutically acceptable salt thereof; (c)
1-3% Carbomer; and (d) 0.5-1% Magnesium stearate.
Description
[0001] The present invention relates to a novel pharmaceutical
formulation.
[0002] In particular, the present invention is directed to a
sustained release formulation for oral administration comprising
guaifenesin, naproxen and at least one additional active drug
ingredient.
[0003] Pharmaceutical compositions comprising combinations of
actives are well-known in the prior art. For example, many OTC cold
& flu remedies include an anti-inflammatory together with an
antitussive or cough suppressant. In addition, there are a number
of pain killers which are based on a combination of one or more of
ibuprofen, aspirin, paracetamol and codeine. There are also
available immediate release products which combine more than two
actives. For example, the Tylenol.RTM. range includes products
which combine paracetamol, dextromethorphan & guaifenesin.
However, as these products are immediate release products re-dosing
is required every 4 to 6 hours in order to maintain a therapeutic
effect.
[0004] However, there is no specific teaching in the prior art of a
sustained release dosage form containing guaifenesin, an analgesic
and at least one other pharmaceutically active agent which is
capable of sustaining a therapeutic effect for each of the actives
for at least twelve hours.
[0005] Such a combination would be advantageous to develop as it
would provide an individual relief from the symptoms of a cough,
cold, or flu for an extended period of up to 12 hours. In
particular, it would be desirable to develop a product which
contains actives that can provide relief from the symptoms of a
cough or cold as well as an analgesic. The low solubility of
analgesics, however, can impact the dissolution of other active
compounds in a combination product. This is particularly true in
conventional extended release products where release control is
dependent on the erosion of a polymer matrix.
[0006] In the area of solid single-dose combination products, such
as tablets or caplets, most of the prior art is directed towards
combinations of two different actives, each active being contained
in a separate layer from the other with the third layer acting as a
barrier to prevent any negative interactions between the
active-containing layers.
[0007] WO 00/059479 discloses a novel pharmaceutical dosage form
that provides pulsatile delivery of methylphenidate. WO 99/17745
describes a controlled-release monolithic system for oral
administration comprising a disintegrating layer, an erodible layer
and a swelling layer, of which two are external and one is
intermediate, each layer containing one or more drugs.
[0008] According to a first aspect of the present invention there
is provided a pharmaceutical composition comprising a
pharmaceutically effective amount of at least three different
pharmaceutical actives selected from expectorant, an analgesic and
at least one further active which is selected to be an antitussive,
a decongestant or an antihistamine wherein the composition provides
a therapeutic effect in respect of each active for a period of up
to 12 hours.
[0009] Typically the analgesic is selected to be an NSAID. The
NSAID can be selected from naproxen, ketoprofen, diclofenac,
ibuprofen or flurbiprofen.
[0010] The expectorant can be guaifenesin.
[0011] The at least one other drug can be selected from an
antitussive such as dextromethorphan, codeine, codeine phosphate,
codeine sulphate, diphenhydramine citrate, and diphenhydramine
hydrochloride, a decongestant such as phenylephrine hydrochloride,
phenylpropanolamine hydrochloride, pseudoephedrine or ephedrine, an
antihistamine such as chlorpheniramine maleate, brompheniramine
maleate, phenindamine tartrate, pyrilamine maleate, doxylamine
succinate, phenyltoloxamine citrate, diphenhydramine hydrochloride,
promethazine, and clemastine fumerate, or a combination thereof.
Preferred actives are dextromethorphan or pseudoephedrine.
[0012] The total amount of expectorant can be from about 200
mg-2400 mg, preferably about 600 mg-1200 mg. A preferred amount of
expectorant is 600 mg. In an alternative embodiment, a preferred
amount is 1200 mg.
[0013] The total amount of analgesic can be from about 5-4000 mg,
preferably 110-220 mg. A preferred amount of analgesic is 110 mg.
In an alternative embodiment, a preferred amount is 220 mg.
[0014] When the other drug is selected to be dextromethorphan, the
total amount of said dextromethorphan can be from about 10-120 mg,
preferably 15-60 mg. More preferably, the amount of
dextromethorphan is 25-35 mg. A preferred amount of
dextromethorphan is 30 mg. In an alternative embodiment, a
preferred amount is 60 mg.
[0015] When the at least one other drug is selected to be
pseudoephedrine, the total amount of said pseudoephedrine can be
from about 10-240 mg, preferably 60-120 mg.
[0016] In a preferred combination of pharmaceutically active
ingredients the expectorant is guaifenesin, the analgesic is
naproxen and the antitussive is dextromethorphan.
[0017] The ratio of guaifenesin:naproxen:dextromethorphan can be
from about 40:8:1 to about 10:3:1. A preferred ratio from 22:4:1 to
17:3:1. A most preferred ratio is 20:3.67:1.
[0018] The ratio of guaifensin:naproxen can be from about 1:1 to
about 10:1, preferably from about 2:1 to about 7:1, more preferably
from about 4:1 to about 6:1. A preferred ratio is about 5.45:1.
[0019] The ratio of the naproxen:dextromethorphan can be from about
1:1 to about 10:1, preferably from about 2:1 to about 7:1, more
preferably from about 3:1 to about 5:1. A preferred ratio is about
3.67:1.
[0020] When an active other than dextromethorphan is used the ratio
of naproxen:antitussive/decongestant/antihistamine can be from 10:1
to 2:1.
[0021] When flurbiprofen is selected to be the analgesic, the ratio
of expectorant:analgesic:antitussive/decongestant/antihistamine can
be from 25:5:1 to 5:0.5:1. The ratio of expectorant:analgesic can
be from 10:1 to 5:1. The ratio of
analgesic:antitussive/decongestant/antihistamine can be from
1:1.5-1:0.2.
[0022] When ibuprofen is selected to be the analgesic, the ratio of
expectorant:analgesic:antitussive/decongestant/antihistamine can be
from 25:30:1 to 5:5:1. The ratio of expectorant:analgesic can be
from 1:1 to 1:5. The ratio of
analgesic:antitussive/decongestant/antihistamine can be from
30:1-5:1.
[0023] When diclofenac is selected to be the analgesic, the ratio
of expectorant:analgesic:antitussive/decongestant/antihistamine can
be from 25:5:1 to 5:0.5:1. The ratio of expectorant:analgesic can
be from 20:1 to 5:1. The ratio of
analgesic:antitussive/decongestant/antihistamine can be from
1:2-1:0.2.
[0024] When ketoprofen is selected to be the analgesic, the ratio
of expectorant:analgesic:antitussive/decongestant/antihistamine can
be from 25:5:1 to 5:0.5:1. The ratio of expectorant:analgesic can
be from 10:1 to 5:1. The ratio of
analgesic:antitussive/decongestant/antihistamine can be from
1:1.5-1:0.2.
[0025] The composition can be in the form of one or more tablets,
caplets, or capsules, gel, elixir, suspension, syrup, emulsion,
powder, or granules. Typically, the composition is in the form of
either a soft capsule or a hard gel capsule. When the composition
is in the form of more than one tablets or caplets, the more than
one tablets or caplets are contained within a single capsule. The
capsule can be made of any suitable material, but is typically made
of a gelatin material, hydroxyl propyl methyl cellulose or an
alginate. The capsule can be in the form of either a soft capsule
or a hard gel capsule.
[0026] The composition can comprise immediate and sustained release
portions. As set forth herein, "portion" means a part of a whole,
either separated or integrated with it. Thus, a product with two or
more portions may have, but does not necessarily require, separate
or discrete structural elements. As further set forth herein
"sustained release" refers to a type of "modified release", and
these terms are used interchangeably throughout.
[0027] The analgesic can be incorporated into the composition such
that it is the sole active in the portion in which it is
contained.
[0028] Typically, the composition is provided with both
sustained-release and immediate-release portions comprising the
expectorant.
[0029] In a preferred embodiment the composition comprises a first
immediate release portion which comprises guaifenesin and a
decongestant or an antitussive, a second immediate release portion
which comprises naproxen, and a sustained release portion which
comprises guaifenesin and a decongestant or an antitussive. In
further preferred embodiments the antitussive can be selected to be
dextromethorphan or the decongestant can be selected to be
pseudoephedrine.
[0030] According to a second aspect of the present invention there
is provided a pharmaceutical composition comprising a
pharmaceutically effective amount of guaifenesin, naproxen and at
least one further active which is selected to be an antitussive, a
decongestant or an antihistamine.
[0031] The at least one other drug can be selected from an
antitussive such as dextromethorphan, codeine, codeine phosphate,
codeine sulphate, diphenhydramine citrate, and diphenhydramine
hydrochloride, a decongestant such as phenylephrine hydrochloride,
phenylpropanolamine hydrochloride, pseudoephedrine or ephedrine, an
antihistamine such as chlorpheniramine maleate, brompheniramine
maleate, phenindamine tartrate, pyrilamine maleate, doxylamine
succinate, phenyltoloxamine citrate, diphenhydramine hydrochloride,
promethazine, and clemastine fumerate, or a combination thereof.
Preferred actives are dextromethorphan or pseudoephedrine.
[0032] The total amount of guaifenesin can be from about 200
mg-2400 mg, preferably about 600 mg-1200 mg. A preferred amount of
expectorant is 600 mg. In an alternative embodiment, a preferred
amount is 1200 mg.
[0033] The total amount of naproxen can be from about 5-400 mg,
preferably 110-220 mg. A preferred amount of analgesic is 110 mg.
In an alternative embodiment, a preferred amount is 220 mg.
[0034] When the other drug is selected to be dextromethorphan, the
total amount of said dextromethorphan can be from about 10-120 mg,
preferably 15-60 mg. More preferably, the amount of
dextromethorphan is 25-35 mg. A preferred amount of
dextromethorphan is 30 mg. In an alternative embodiment, a
preferred amount is 60 mg.
[0035] When the at least one other drug is selected to be
pseudoephedrine, the total amount of said pseudoephedrine can be
from about 10-240 mg, preferably 60-120 mg.
[0036] In a preferred combination of pharmaceutically active
ingredients the expectorant is guaifenesin, the analgesic is
naproxen and the antitussive is dextromethorphan.
[0037] The ratio of guaifenesin:naproxen:dextromethorphan can be
from about 40:8:1 to about 10:3:1. A preferred ratio from 22:4:1 to
17:3:1. A most preferred ratio is 20:3.67:1.
[0038] The ratio of guaifensin:naproxen can be from about 1:1 to
about 10:1, preferably from about 2:1 to about 7:1, more preferably
from about 4:1 to about 6:1. A preferred ratio is about 5.45:1.
[0039] The ratio of the naproxen:dextromethorphan can be from about
1:1 to about 10:1, preferably from about 2:1 to about 7:1, more
preferably from about 3:1 to about 5:1. A preferred ratio is about
3.67:1.
[0040] When an active other than dextromethorphan is used the ratio
of naproxen:antitussive/decongestant/antihistamine can be from 10:1
to 2:1.
[0041] The composition can be in the form of one or more tablets,
caplets, or capsules, gel, elixir, suspension, syrup, emulsion,
powder, or granules. Typically, the composition is in the form of a
capsule. When the composition is in the form of more than one
tablets or caplets, the more than one tablets or caplets are
contained within a single capsule. The capsule can be made of any
suitable material, but is typically made of a gelatin material.
[0042] The composition can comprise immediate and sustained release
portions.
[0043] Typically, the composition is provided with both
sustained-release and immediate-release portions comprising the
expectorant.
[0044] The naproxen can be incorporated into the composition such
that it is the sole active in the portion in which it is
contained.
[0045] Typically, the composition is provided with both
sustained-release and immediate-release portions comprising
guaifenesin.
[0046] In a preferred embodiment the composition comprises a first
immediate release portion which comprises guaifenesin and a
decongestant or an antitussive, a second immediate release portion
which comprises naproxen, and a sustained release portion which
comprises guaifenesin. In further preferred embodiments the
antitussive can be selected to be dextromethorphan or the
decongestant can be selected to be pseudoephedrine.
[0047] The composition can be in the form of a tablet, caplet,
capsule, gel, elixir, suspension, syrup or emulsion. Typically, the
composition is in the form of a capsule.
[0048] In a particularly preferred embodiment of the composition of
the first and second embodiments, the composition comprises
guaifenesin, naproxen and dextromethorphan.
[0049] The composition according to either of the first or second
aspect can comprise: [0050] (a) 50-85% Guaifenesin; [0051] (b) up
to 5% Dextromethorphan or a pharmaceutically acceptable salt
thereof; and [0052] (c) 5-30% Naproxen or a pharmaceutically
acceptable salt thereof;
[0053] The composition according to either of the first or second
aspect can comprise: [0054] (a) 55-65% Guaifenesin; [0055] (b) 1-5%
Dextromethorphan or a pharmaceutically acceptable salt thereof;
[0056] (c) 5-15% Naproxen or a pharmaceutically acceptable salt
thereof; [0057] (d) 1-10% Controlled release polymers; [0058] (e)
0.1-10% Binders; [0059] (f) 0.1-5% Disintegrants; [0060] (g) 5-25%
Diluents; and [0061] (h) up to 1% Lubricants.
[0062] A preferred embodiment of the composition according to
either of the first or second aspect can comprise: [0063] (a)
55-65% Guaifenesin; [0064] (b) 1-5% Dextromethorphan or a
pharmaceutically acceptable salt thereof; [0065] (c) 5-15% Naproxen
or a pharmaceutically acceptable salt thereof; [0066] (d) 1-8%
Hypromellose; [0067] (e) 10-25% Microcrystalline cellulose; [0068]
(f) 0.1to 2.5% Povidone; [0069] (g) 0.1to 4.0% Croscarmellose
Sodium; [0070] (h) 0.1to 2.0% Hydroxy Ethyl Cellulose; and [0071]
(i) up to 1% Magnesium stearate.
[0072] An alternative preferred embodiment can comprise: [0073] (a)
58-63% Guaifenesin; [0074] (b) 2-3.5% Dextromethorphan or a
pharmaceutically acceptable salt thereof; [0075] (c) 10-12%
Naproxen or a pharmaceutically acceptable salt thereof; [0076] (d)
1-2% Hypromellose; [0077] (e) 15-25% Microcrystalline cellulose;
[0078] (f) 1-2% Povidone; [0079] (g) 0.5-2.5% Croscarmellose
sodium; [0080] (h) 0.5 to 1% Hydroxyethyl cellulose; and [0081] (i)
up to 0.5% Magnesium stearate.
[0082] In an alternative embodiment the composition can comprise:
[0083] (a) 55-65% Guaifenesin; [0084] (b) 1-5% Dextromethorphan or
a pharmaceutically acceptable salt thereof; [0085] (c) 5-15%
Naproxen or a pharmaceutically acceptable salt thereof; [0086] (d)
1-8% Hypromellose; [0087] (e) 10-25% Microcrystalline cellulose;
[0088] (f) 0.1 to 2.5% Povidone; [0089] (g) 0.1to 2.0% Carbomer;
[0090] (h) 0.1 2.0% Sodium Starch Glycolate; [0091] (i) up to 1%
Magnesium stearate; and
[0092] An alternative preferred embodiment can comprise: [0093] (a)
59-65% Guaifenesin; [0094] (b) 3-5% Dextromethorphan or a
pharmaceutically acceptable salt thereof; [0095] (c) 10-12%
Naproxen or a pharmaceutically acceptable salt thereof; [0096] (d)
1-6% Hypromellose; [0097] (e) 10-20% Microcrystalline cellulose;
[0098] (f) 0.3 to 1% Povidone; [0099] (g) 0.5-1% Carbomer; [0100]
(h) 0.1 to 0.5% Sodium Starch Glycolate; and [0101] (i) up to 1%
Magnesium stearate.
[0102] An alternative preferred embodiment can comprise: [0103] (a)
59-65% Guaifenesin; [0104] (b) 3-5% Dextromethorphan or a
pharmaceutically acceptable salt thereof; [0105] (c) 10-12%
Naproxen or a pharmaceutically acceptable salt thereof; [0106] (d)
1-6% Hypromellose; [0107] (e) 10-20% Microcrystalline cellulose;
[0108] (f) 0.3 to 1% Povidone; [0109] (g) 0.5-1% Carbomer; [0110]
(h) 1-2% Croscarmellose sodium; [0111] (i) 0.1 to 0.5% Sodium
Starch Glycolate; and [0112] (j) up to 1% Magnesium stearate.
[0113] An alternative preferred embodiment of the composition
according to either of the first or second aspect can comprise:
[0114] (a) 64-69% Guaifenesin; [0115] (b) 3-5% Dextromethorphan or
a pharmaceutically acceptable salt thereof; [0116] (c) 12-15%
Naproxen or a pharmaceutically acceptable salt thereof; [0117] (d)
3-5% Hypromellose; [0118] (e) 9-15% Microcrystalline cellulose;
[0119] (f) 0.4-0.65% Povidone; [0120] (g) 0.75-1.3% Carbomer;
[0121] (h) 0.5-1% Magnesium stearate; and [0122] (i) 0.25-0.5%
Sodium starch glycolate.
[0123] The composition can further comprise one or more of: [0124]
(j) 0.5-1.5% Lactose; [0125] (k) 2.5-3.5% Sodium lauryl sulphate;
and [0126] (l) 0.1-1.5% Croscarmellose sodium.
[0127] An alternative preferred embodiment of the composition
according to either of the first or second aspect can comprise:
[0128] (a) 64-69% Guaifenesin; [0129] (b) 3-5% Dextromethorphan or
a pharmaceutically acceptable salt thereof; [0130] (c) 12-15%
Naproxen or a pharmaceutically acceptable salt thereof; [0131] (d)
0.1-0.6% Hypromellose; [0132] (e) 9-15% Microcrystalline cellulose;
[0133] (f) 0.4-0.65% Povidone; [0134] (g) 0.75-1.3% Carbomer;
[0135] (h) 0.5-1% Magnesium stearate; and [0136] (i) 0.25-0.5%
Sodium starch glycolate.
[0137] The composition can further comprise one or more of: [0138]
(j) 0.5-1.5% Lactose; [0139] (k) 2.5-3.5% Sodium lauryl sulphate;
and [0140] (l) 0.1-1.5% Croscarmellose sodium.
[0141] An alternative preferred embodiment of the composition
according to either of the first or second aspect can comprise:
[0142] (a) 63-66% Guaifenesin; [0143] (b) 3-5% Dextromethorphan or
a pharmaceutically acceptable salt thereof; [0144] (c) 10-12%
Naproxen or a pharmaceutically acceptable salt thereof; [0145] (d)
1.75-3.0% Hypromellose; [0146] (e) 11-13% Microcrystalline
cellulose; [0147] (f) 1-2% Povidone; [0148] (g) 0.5-0.75%
Croscarmellose Sodium; [0149] (h) 1-2% Carbomer; [0150] (i)
0.1-0.5% Magnesium stearate; [0151] (j) 0.5-1.5% Lactose; and
optionally [0152] (k) 2-3% Sodium Lauryl Sulphate.
[0153] An alternative preferred embodiment of the composition
according to either of the first or second aspect can comprise:
[0154] (a) 64-66% Guaifenesin; [0155] (b) 3-5% Dextromethorphan or
a pharmaceutically acceptable salt thereof; [0156] (c) 11-13%
Naproxen or a pharmaceutically acceptable salt thereof; [0157] (d)
1.75-3.0% Hypromellose; [0158] (e) 6-8.5% Microcrystalline
cellulose; [0159] (f) 1-2% Povidone; [0160] (g) 1-5% Croscarmellose
Sodium; [0161] (h) 0.5-1% Carbomer; [0162] (i) 0.5-1% Magnesium
stearate; and [0163] (j) 0.5-1% Crospovidone.
[0164] The composition can further include one or more of: [0165]
(k) 2-3% Sodium Lauryl Sulphate; and [0166] (l) 6-7% Sodium
Bicarbonate.
[0167] An alternative preferred embodiment of the composition
according to either of the first or second aspect can comprise:
[0168] (a) 64-66% Guaifenesin; [0169] (b) 3-5% Dextromethorphan or
a pharmaceutically acceptable salt thereof; [0170] (c) 11-13%
Naproxen or a pharmaceutically acceptable salt thereof; [0171] (d)
1.75-3.0% Hypromellose; [0172] (e) 6-8.5% Microcrystalline
cellulose; [0173] (f) 1-2% Povidone; [0174] (g) 1-5% Croscarmellose
Sodium; [0175] (h) 0.5-1% Carbomer; and [0176] (i) 0.5-1% Magnesium
stearate.
[0177] An alternative preferred embodiment of the composition
according to either of the first or second aspect can comprise:
[0178] (a) 62-65% Guaifenesin; [0179] (b) 3-5% Dextromethorphan or
a pharmaceutically acceptable salt thereof; [0180] (c) 11-13%
Naproxen or a pharmaceutically acceptable salt thereof; [0181] (d)
1.75-3.0% Hypromellose; [0182] (e) 6-8.5% Microcrystalline
cellulose; [0183] (f) 1-2% Povidone; [0184] (g) 1-5% Croscarmellose
Sodium; [0185] (h) 0.5-1% Carbomer; and [0186] (i) 0.5-1% Magnesium
stearate; [0187] (j) 2-3% Sodium Lauryl Sulphate; and [0188] (k)
5-8% Sodium Bicarbonate.
[0189] An alternative preferred embodiment of the composition
according to either of the first or second aspect can comprise:
[0190] (a) 58-60% Guaifenesin; [0191] (b) 2-3% Dextromethorphan or
a pharmaceutically acceptable salt thereof; [0192] (c) 10-11%
Naproxen or a pharmaceutically acceptable salt thereof; [0193] (d)
2-3% Hypromellose; [0194] (e) 7-8% Microcrystalline cellulose;
[0195] (f) 1-2% Povidone; [0196] (g) 2-3% Croscarmellose Sodium;
[0197] (h) 0.1-0.2% Magnesium stearate; [0198] (i) 0.5-1%
Crospovidone; [0199] (j) 1-3% Hydroxyethyl cellulose; [0200] (k)
2-3% Sodium Lauryl Sulphate; and [0201] (l) 9-10% Sodium
bicarbonate.
[0202] An alternative preferred embodiment of the composition
according to either of the first or second aspect can comprise:
[0203] (a) 64-66% Guaifenesin; [0204] (b) 3-5% Dextromethorphan or
a pharmaceutically acceptable salt thereof; [0205] (c) 11-13%
Naproxen or a pharmaceutically acceptable salt thereof; [0206] (d)
2-3% Hypromellose; [0207] (e) 6-7% Microcrystalline cellulose;
[0208] (f) 1-2% Povidone; [0209] (g) 0.1-0.5% Magnesium stearate;
[0210] (h) 7-10% Crospovidone; and [0211] (i) 1-3% Hydroxyethyl
cellulose.
[0212] A preferred embodiment of the composition according to
either of the first or second aspect consists essentially of:
[0213] (a) 55-65% Guaifenesin; [0214] (b) 1-5% Dextromethorphan or
a pharmaceutically acceptable salt thereof; [0215] (c) 5-15%
Naproxen or a pharmaceutically acceptable salt thereof; [0216] (d)
1-8% Hypromellose; [0217] (e) 10-25% Microcrystalline cellulose;
[0218] (f) 0.1to 2.5% Povidone; [0219] (g) 0.1to 4.0%
Croscarmellose Sodium; [0220] (h) 0.1to 2.0% Hydroxy Ethyl
Cellulose; and [0221] (i) up to 1% Magnesium stearate.
[0222] An alternative preferred embodiment consists essentially of:
[0223] (a) 58-63% Guaifenesin; [0224] (b) 2-3.5% Dextromethorphan
or a pharmaceutically acceptable salt thereof; [0225] (c) 10-12%
Naproxen or a pharmaceutically acceptable salt thereof; [0226] (d)
1-2% Hypromellose; [0227] (e) 15-25% Microcrystalline cellulose;
[0228] (f) 1-2% Povidone; [0229] (g) 0.5-2.5% Croscarmellose
sodium; [0230] (h) 0.5 to 1% Hydroxyethyl cellulose; and [0231] (i)
up to 0.5% Magnesium stearate.
[0232] In an alternative embodiment the composition consists
essentially of: [0233] (a) 55-65% Guaifenesin; [0234] (b) 1-5%
Dextromethorphan or a pharmaceutically acceptable salt thereof;
[0235] (c) 5-15% Naproxen or a pharmaceutically acceptable salt
thereof; [0236] (d) 1-8% Hypromellose; [0237] (e) 10-25%
Microcrystalline cellulose; [0238] (f) 0.1 to 2.5% Povidone; [0239]
(g) 0.1to 2.0% Carbomer; [0240] (h) 0.1 2.0% Sodium Starch
Glycolate; [0241] (i) up to 1% Magnesium stearate; and
[0242] An alternative preferred embodiment consists essentially of:
[0243] (a) 59-65% Guaifenesin; [0244] (b) 3-5% Dextromethorphan or
a pharmaceutically acceptable salt thereof; [0245] (c) 10-12%
Naproxen or a pharmaceutically acceptable salt thereof; [0246] (d)
1-6% Hypromellose; [0247] (e) 10-20% Microcrystalline cellulose;
[0248] (f) 0.3 to 1% Povidone; [0249] (g) 0.5-1% Carbomer; [0250]
(h) 0.1 to 0.5% Sodium Starch Glycolate; and [0251] (i) up to 1%
Magnesium stearate.
[0252] An alternative preferred embodiment consists essentially of:
[0253] (a) 59-65% Guaifenesin; [0254] (b) 3-5% Dextromethorphan or
a pharmaceutically acceptable salt thereof; [0255] (c) 10-12%
Naproxen or a pharmaceutically acceptable salt thereof; [0256] (d)
1-6% Hypromellose; [0257] (e) 10-20% Microcrystalline cellulose;
[0258] (f) 0.3 to 1% Povidone; [0259] (g) 0.5-1% Carbomer; [0260]
(h) 1-2% Croscarmellose sodium; [0261] (i) 0.1 to 0.5% Sodium
Starch Glycolate; and [0262] (j) up to 1% Magnesium stearate.
[0263] An alternative preferred embodiment of the composition
according to either of the first or second aspect consists
essentially of: [0264] (a) 64-69% Guaifenesin; [0265] (b) 3-5%
Dextromethorphan or a pharmaceutically acceptable salt thereof;
[0266] (c) 12-15% Naproxen or a pharmaceutically acceptable salt
thereof; [0267] (d) 3-5% Hypromellose; [0268] (e) 9-15%
Microcrystalline cellulose; [0269] (f) 0.4-0.65% Povidone; [0270]
(g) 0.75-1.3% Carbomer; [0271] (h) 0.5-1% Magnesium stearate; and
[0272] (i) 0.25-0.5% Sodium starch glycolate.
[0273] An alternative preferred embodiment of the composition
according to either of the first or second aspect consists
essentially of: [0274] (a) 64-69% Guaifenesin; [0275] (b) 3-5%
Dextromethorphan or a pharmaceutically acceptable salt thereof;
[0276] (c) 12-15% Naproxen or a pharmaceutically acceptable salt
thereof; [0277] (d) 0.1-0.5% Hypromellose; [0278] (e) 9-15%
Microcrystalline cellulose; [0279] (f) 0.4-0.65% Povidone; [0280]
(g) 0.75-1.3% Carbomer; [0281] (h) 0.5-1% Magnesium stearate; and
[0282] (i) 0.25-0.5% Sodium starch glycolate.
[0283] An alternative preferred embodiment of the composition
according to either of the first or second aspect consists
essentially of: [0284] (a) 64-69% Guaifenesin; [0285] (b) 3-5%
Dextromethorphan or a pharmaceutically acceptable salt thereof;
[0286] (c) 12-15% Naproxen or a pharmaceutically acceptable salt
thereof; [0287] (d) 3-5% Hypromellose; [0288] (e) 9-15%
Microcrystalline cellulose; [0289] (f) 0.4-0.65% Povidone; [0290]
(g) 0.75-1.3% Carbomer; [0291] (h) 0.5-1% Magnesium stearate;
[0292] (i) 0.25-0.5% Sodium starch glycolate; [0293] (j) 0.5-1.5%
Lactose; and [0294] (k) 0.1-1.5% Croscarmellose sodium.
[0295] An alternative preferred embodiment of the composition
according to either of the first or second aspect consists
essentially of: [0296] (a) 64-69% Guaifenesin; [0297] (b) 3-5%
Dextromethorphan or a pharmaceutically acceptable salt thereof;
[0298] (c) 12-15% Naproxen or a pharmaceutically acceptable salt
thereof; [0299] (d) 0.1-0.6% Hypromellose; [0300] (e) 9-15%
Microcrystalline cellulose; [0301] (f) 0.4-0.65% Povidone; [0302]
(g) 0.75-1.3% Carbomer; [0303] (h) 0.5-1% Magnesium stearate;
[0304] (i) 0.25-0.5% Sodium starch glycolate; [0305] (j) 0.5-1.5%
Lactose; and [0306] (k) 0.1-1.5% Croscarmellose sodium.
[0307] An alternative preferred embodiment of the composition
according to either of the first or second aspect consists
essentially of: [0308] (a) 63-66% Guaifenesin; [0309] (b) 3-5%
Dextromethorphan or a pharmaceutically acceptable salt thereof;
[0310] (c) 10-12% Naproxen or a pharmaceutically acceptable salt
thereof; [0311] (d) 1.75-3.0% Hypromellose; [0312] (e) 11-13%
Microcrystalline cellulose; [0313] (f) 1-2% Povidone; [0314] (g)
0.5-0.75% Croscarmellose Sodium; [0315] (h) 1-2% Carbomer; [0316]
(i) 0.1-0.5% Magnesium stearate; and [0317] (j) 0.5-1.5%
Lactose.
[0318] An alternative preferred embodiment of the composition
according to either of the first or second aspect consists
essentially of: [0319] (a) 64-69% Guaifenesin; [0320] (b) 3-5%
Dextromethorphan or a pharmaceutically acceptable salt thereof;
[0321] (c) 12-15% Naproxen or a pharmaceutically acceptable salt
thereof; [0322] (d) 3-5% Hypromellose; [0323] (e) 9-15%
Microcrystalline cellulose; [0324] (f) 0.4-0.65% Povidone; [0325]
(g) 0.75-1.3% Carbomer; [0326] (h) 0.5-1% Magnesium stearate;
[0327] (i) 0.25-0.5% Sodium starch glycolate; [0328] (j) 2-3.5%
Sodium Lauryl Sulphate; and [0329] (k) 0.1-1.5% Croscarmellose
sodium.
[0330] An alternative preferred embodiment of the composition
according to either of the first or second aspect consists
essentially of: [0331] (a) 64-69% Guaifenesin; [0332] (b) 3-5%
Dextromethorphan or a pharmaceutically acceptable salt thereof;
[0333] (c) 12-15% Naproxen or a pharmaceutically acceptable salt
thereof; [0334] (d) 0.1-0.6% Hypromellose; [0335] (e) 9-15%
Microcrystalline cellulose; [0336] (f) 0.4-0.65% Povidone; [0337]
(g) 0.75-1.3% Carbomer; [0338] (h) 0.5-1% Magnesium stearate;
[0339] (i) 0.25-0.5% Sodium starch glycolate; [0340] (j) 2-3.5%
Sodium Lauryl Sulphate; and [0341] (k) 0.1-1.5% Croscarmellose
sodium.
[0342] An alternative preferred embodiment of the composition
according to either of the first or second aspect consists
essentially of: [0343] (a) 64-69% Guaifenesin; [0344] (b) 3-5%
Dextromethorphan or a pharmaceutically acceptable salt thereof;
[0345] (c) 12-15% Naproxen or a pharmaceutically acceptable salt
thereof; [0346] (d) 0.1-0.6% Hypromellose; [0347] (e) 9-15%
Microcrystalline cellulose; [0348] (f) 0.4-0.65% Povidone; [0349]
(g) 0.75-1.3% Carbomer; [0350] (h) 0.5-1% Magnesium stearate;
[0351] (i) 0.25-0.5% Sodium starch glycolate; [0352] (j) 2-3.5%
Sodium Lauryl Sulphate; and [0353] (k) 0.1-1.5% Croscarmellose
sodium.
[0354] An alternative preferred embodiment of the composition
according to either of the first or second aspect consists
essentially of: [0355] (a) 63-66% Guaifenesin; [0356] (b) 3-5%
Dextromethorphan or a pharmaceutically acceptable salt thereof;
[0357] (c) 10-12% Naproxen or a pharmaceutically acceptable salt
thereof; [0358] (d) 1.75-3.0% Hypromellose; [0359] (e) 11-13%
Microcrystalline cellulose; [0360] (f) 1-2% Povidone; [0361] (g)
0.5-0.75% Croscarmellose Sodium; [0362] (h) 1-2% Carbomer; [0363]
(i) 0.1-0.5% Magnesium stearate; [0364] (j) 0.5-1.5% Lactose; and
[0365] (k) 2-3% Sodium Lauryl Sulphate.
[0366] An alternative preferred embodiment of the composition
according to either of the first or second aspect consists
essentially of: [0367] (a) 64-66% Guaifenesin; [0368] (b) 3-5%
Dextromethorphan or a pharmaceutically acceptable salt thereof;
[0369] (c) 11-13% Naproxen or a pharmaceutically acceptable salt
thereof; [0370] (d) 1.75-3.0% Hypromellose; [0371] (e) 6-8.5%
Microcrystalline cellulose; [0372] (f) 1-2% Povidone; [0373] (g)
1-5% Croscarmellose Sodium; [0374] (h) 0.5-1% Carbomer; [0375] (i)
0.5-1% Magnesium stearate; [0376] (j) 0.5-1% Crospovidone; and
[0377] (k) 2-3% Hypromellose.
[0378] An alternative preferred embodiment of the composition
according to either of the first or second aspect consists
essentially of: [0379] (a) 64-66% Guaifenesin; [0380] (b) 3-5%
Dextromethorphan or a pharmaceutically acceptable salt thereof;
[0381] (c) 11-13% Naproxen or a pharmaceutically acceptable salt
thereof; [0382] (d) 1.75-3.0% Hypromellose; [0383] (e) 6-8.5%
Microcrystalline cellulose; [0384] (f) 1-2% Povidone; [0385] (g)
1-5% Croscarmellose Sodium; [0386] (h) 0.5-1% Carbomer; [0387] (i)
0.5-1% Magnesium stearate; [0388] (j) 0.5-1% Crospovidone; [0389]
(k) 2-3% Hypromellose; [0390] (l) 2-3% Sodium Lauryl Sulphate; and
[0391] (m) 6-7% Sodium Bicarbonate.
[0392] An alternative preferred embodiment of the composition
according to either of the first or second aspect consists
essentially of: [0393] (a) 58-60% Guaifenesin; [0394] (b) 2-3%
Dextromethorphan or a pharmaceutically acceptable salt thereof;
[0395] (c) 10-11% Naproxen or a pharmaceutically acceptable salt
thereof; [0396] (d) 2-3% Hypromellose; [0397] (e) 7-8%
Microcrystalline cellulose; [0398] (f) 1-2% Povidone; [0399] (g)
2-3% Croscarmellose Sodium; [0400] (h) 0.1-0.2% Magnesium stearate;
[0401] (i) 0.5-1% Crospovidone; [0402] (j) 1-3% Hydroxyethyl
cellulose; [0403] (k) 2-3% Sodium Lauryl Sulphate; and [0404] (l)
9-10% Sodium bicarbonate.
[0405] An alternative preferred embodiment of the composition
according to either of the first or second aspect consists
essentially of: [0406] (a) 64-66% Guaifenesin; [0407] (b) 3-5%
Dextromethorphan or a pharmaceutically acceptable salt thereof;
[0408] (c) 11-13% Naproxen or a pharmaceutically acceptable salt
thereof; [0409] (d) 2-3% Hypromellose; [0410] (e) 6-7%
Microcrystalline cellulose; [0411] (f) 1-2% Povidone; [0412] (g)
0.1-0.5% Magnesium stearate; [0413] (h) 7-10% Crospovidone; and
[0414] (i) 1-3% Hydroxyethyl cellulose.
[0415] An alternative preferred embodiment of the composition
according to either of the first or second aspect consists
essentially of: [0416] (a) 62-65% Guaifenesin; [0417] (b) 3-5%
Dextromethorphan or a pharmaceutically acceptable salt thereof;
[0418] (c) 11-13% Naproxen or a pharmaceutically acceptable salt
thereof; [0419] (d) 1.75-3.0% Hypromellose; [0420] (e) 6-8.5%
Microcrystalline cellulose; [0421] (f) 1-2% Povidone; [0422] (g)
1-5% Croscarmellose Sodium; [0423] (h) 0.5-1% Carbomer; and [0424]
(i) 0.5-1% Magnesium stearate; [0425] (j) 2-3% Sodium Lauryl
Sulphate; and [0426] (k) 5-8% Sodium Bicarbonate.
[0427] An alternative preferred embodiment of the composition
according to either of the first or second aspect consists
essentially of: [0428] (a) 64-66% Guaifenesin; [0429] (b) 3-5%
Dextromethorphan or a pharmaceutically acceptable salt thereof;
[0430] (c) 11-13% Naproxen or a pharmaceutically acceptable salt
thereof; [0431] (d) 1.75-3.0% Hypromellose; [0432] (e) 6-8.5%
Microcrystalline cellulose; [0433] (f) 1-2% Povidone; [0434] (g)
1-5% Croscarmellose Sodium; [0435] (h) 0.5-1% Carbomer; and [0436]
(i) 0.5-1% Magnesium stearate.
[0437] According to a third aspect of the present invention there
is provided a pharmaceutical dosage form which comprises at least 3
distinct portions wherein 2 of the portions have immediate release
characteristics and a 3.sup.rd has modified release characteristics
wherein one of the immediate release portions comprises an
expectorant and a second active which is an antitussive or a
decongestant and the second immediate release portion comprises an
analgesic having a half-life of twelve hours and wherein the
modified release portion comprises guaifenesin and a second active
which is an antitussive or a decongestant.
[0438] The dosage form can comprise a first composition which
comprises both immediate and modified release portions of the
expectorant and the second active which is an antitussive or a
decongestant and a second composition which comprises an analgesic
having a therapeutic effect of twelve hours.
[0439] The analgesic can be incorporated into the composition such
that it is the sole active in the portion in which it is
contained.
[0440] In preferred embodiments of the compositions of the first,
second and third aspects of the present invention the
analgesic-containing immediate release portion can comprise: [0441]
(a) 50-52% Naproxen or a pharmaceutically acceptable salt thereof;
[0442] (b) 35-40% Microcrystalline cellulose; [0443] (c) up to 5%
Povidone; [0444] (d) 5-8% Croscarmellose sodium; and [0445] (e) up
to 1% Magnesium stearate.
[0446] In alternative preferred embodiments of the compositions of
the first, second and third aspects of the present invention the
analgesic-containing immediate release portion can comprise: [0447]
(a) 70-75% Naproxen or a pharmaceutically acceptable salt thereof;
[0448] (b) 20-25% Microcrystalline cellulose; [0449] (c) up to 5%
Povidone; [0450] (d) up to 1% Magnesium stearate.
[0451] In further alternative preferred embodiments of the
compositions of the first, second and third aspects of the present
invention the analgesic-containing immediate release portion can
comprise: [0452] (a) 70-75% Naproxen or a pharmaceutically
acceptable salt thereof; [0453] (b) 5-10% Microcrystalline
cellulose; [0454] (c) up to 5% Povidone; [0455] (d) up to 1%
Magnesium stearate; [0456] (e) 5-10% Lactose; and [0457] (f) up to
5% Croscarmellose sodium.
[0458] In further alternative preferred embodiments of the
compositions of the first, second and third aspects of the present
invention the analgesic-containing immediate release portion can
comprise: [0459] (a) 70-75% Naproxen or a pharmaceutically
acceptable salt thereof; [0460] (b) 5-10% Microcrystalline
cellulose; [0461] (c) up to 5% Povidone; [0462] (d) up to 1%
Magnesium stearate; [0463] (e) 5-10% Lactose; and [0464] (f) 5-10%
Croscarmellose sodium.
[0465] In further alternative preferred embodiments of the
compositions of the first, second and third aspects of the present
invention the analgesic-containing immediate release portion can
comprise: [0466] (a) 70-75% Naproxen or a pharmaceutically
acceptable salt thereof; [0467] (b) 5-10% Microcrystalline
cellulose; [0468] (c) up to 5% Povidone; [0469] (d) up to 1%
Magnesium stearate; [0470] (e) up to 5% Lactose; and [0471] (f)
15-20% Sodium Lauryl Sulphate.
[0472] In further alternative preferred embodiments of the
compositions of the first, second and third aspects of the present
invention the analgesic-containing immediate release portion can
comprise: [0473] (a) 70-75% Naproxen or a pharmaceutically
acceptable salt thereof; [0474] (b) 5-10% Microcrystalline
cellulose; [0475] (c) up to 5% Povidone; [0476] (d) up to 1%
Magnesium stearate; [0477] (e) up to 2% Croscarmellose sodium; and
[0478] (f) 15-20% Sodium Lauryl Sulphate.
[0479] In preferred embodiments of the compositions of the first,
second and third aspects of the present invention the
guaifenesin-containing immediate release portion can comprise:
[0480] (a) 30-40% Guaifenesin; [0481] (b) up to 5% Dextromethorphan
or a pharmaceutically acceptable salt thereof; [0482] (c) 50-60%
Microcrystalline cellulose; [0483] (d) up to 7% Povidone; [0484]
(e) up to 7% Croscarmellose sodium; and [0485] (f) up to 1%
Magnesium stearate.
[0486] In alternative preferred embodiments of the compositions of
the first, second and third aspects of the present invention
preferred embodiments of the compositions of the present the
guaifenesin-containing immediate release portion can comprise:
[0487] (a) 40-50% Guaifenesin; [0488] (b) up to 5% Dextromethorphan
or a pharmaceutically acceptable salt thereof; [0489] (c) 40-50%
Microcrystalline cellulose; [0490] (d) up to 5% Hypromellose;
[0491] (e) up to 5% Sodium starch glycolate; and [0492] (f) up to
1% Magnesium stearate.
[0493] In alternative preferred embodiments of the compositions of
the first, second and third aspects of the present invention
preferred embodiments of the compositions of the present the
guaifenesin-containing immediate release portion can comprise:
[0494] (a) 50-65% Guaifenesin; [0495] (b) up to 5% Dextromethorphan
or a pharmaceutically acceptable salt thereof; [0496] (c) 25-40%
Microcrystalline cellulose; [0497] (d) up to 5% Povidone; [0498]
(e) up to 5% Croscarmellose sodium; and [0499] (f) up to 1%
Magnesium stearate.
[0500] In preferred embodiments of the compositions of the first,
second and third aspects of the present invention the modified
release portion can comprise: [0501] (a) 80-90% Guaifenesin; [0502]
(b) up to 5% Dextromethorphan or a pharmaceutically acceptable salt
thereof; [0503] (c) up to 10% Hypromellose; [0504] (d) up to 5%
Carbomer; [0505] (e) up to 1.55% Magnesium stearate.
[0506] In alternative preferred embodiments of the compositions of
the first, second and third aspects of the present invention
preferred embodiments of the compositions of the present invention
the modified release portion can comprise: [0507] (a) 80-90%
Guaifenesin; [0508] (b) 3-6% Dextromethorphan or a pharmaceutically
acceptable salt thereof; [0509] (c) up to 5% Hypromellose; [0510]
(d) up to 2% Hydroxy ethylcellulose; [0511] (e) up to 5%
Microcrystalline cellulose; [0512] (f) up to 1% Magnesium
stearate.
[0513] In alternative preferred embodiments of the compositions of
the first, second and third aspects of the present invention
preferred embodiments of the compositions of the present invention
the modified release portion can comprise: [0514] (a) 80-90%
Guaifenesin; [0515] (b) 3-6% Dextromethorphan or a pharmaceutically
acceptable salt thereof; [0516] (c) up to 5% Hypromellose; [0517]
(d) up to 5% Hydroxy ethylcellulose; [0518] (e) up to 5%
Microcrystalline cellulose; [0519] (f) up to 1% Magnesium
stearate.
[0520] In preferred embodiments of the compositions of the first,
second and third aspects of the present invention the modified
release portion can comprise: [0521] (a) 85-90% Guaifenesin; [0522]
(b) 4-5% Dextromethorphan or a pharmaceutically acceptable salt
thereof; [0523] (c) 3-6% Hypromellose; [0524] (d) 1-3% Carbomer;
[0525] (e) 0.5-1% Magnesium stearate.
[0526] In preferred embodiments of the compositions of the first,
second and third aspects of the present invention the modified
release portion can comprise: [0527] (a) 90-93% Guaifenesin; [0528]
(b) 4-6% Dextromethorphan or a pharmaceutically acceptable salt
thereof; [0529] (c) 1-3% Carbomer; [0530] (d) 0.5-1% Magnesium
stearate.
[0531] In preferred embodiments of the compositions of the first,
second and third aspects of the present invention the
analgesic-containing immediate release portion consists essentially
of: [0532] (a) 50-52% Naproxen or a pharmaceutically acceptable
salt thereof; [0533] (b) 35-40% Microcrystalline cellulose; [0534]
(c) up to 5% Povidone; [0535] (d) 5-8% Croscarmellose sodium; and
[0536] (e) up to 1% Magnesium stearate.
[0537] In alternative preferred embodiments of the compositions of
the first, second and third aspects of the present invention the
analgesic-containing immediate release portion consists essentially
of: [0538] (a) 70-75% Naproxen or a pharmaceutically acceptable
salt thereof; [0539] (b) 20-25% Microcrystalline cellulose; [0540]
(c) up to 5% Povidone; [0541] (d) up to 1% Magnesium stearate.
[0542] In further alternative preferred embodiments of the
compositions of the first, second and third aspects of the present
invention the analgesic-containing immediate release portion
consists essentially of: [0543] (a) 70-75% Naproxen or a
pharmaceutically acceptable salt thereof; [0544] (b) 5-10%
Microcrystalline cellulose; [0545] (c) up to 5% Povidone; [0546]
(d) up to 1% Magnesium stearate; [0547] (e) 5-10% Lactose; and
[0548] (f) up to 5% Croscarmellose sodium.
[0549] In further alternative preferred embodiments of the
compositions of the first, second and third aspects of the present
invention the analgesic-containing immediate release portion
consists essentially of: [0550] (a) 70-75% Naproxen or a
pharmaceutically acceptable salt thereof; [0551] (b) 5-10%
Microcrystalline cellulose; [0552] (c) up to 5% Povidone; [0553]
(d) up to 1% Magnesium stearate; [0554] (e) 5-10% Lactose; and
[0555] (f) 5-10% Croscarmellose sodium.
[0556] In further alternative preferred embodiments of the
compositions of the first, second and third aspects of the present
invention the analgesic-containing immediate release portion
consists essentially of: [0557] (a) 70-75% Naproxen or a
pharmaceutically acceptable salt thereof; [0558] (b) 5-10%
Microcrystalline cellulose; [0559] (c) up to 5% Povidone; [0560]
(d) up to 1% Magnesium stearate; [0561] (e) up to 5% Lactose; and
[0562] (f) 15-20% Sodium Lauryl Sulphate.
[0563] In further alternative preferred embodiments of the
compositions of the first, second and third aspects of the present
invention the analgesic-containing immediate release portion
consists essentially of: [0564] (a) 70-75% Naproxen or a
pharmaceutically acceptable salt thereof; [0565] (b) 5-10%
Microcrystalline cellulose; [0566] (c) up to 5% Povidone; [0567]
(d) up to 1% Magnesium stearate; [0568] (e) up to 2% Croscarmellose
sodium; and [0569] (f) 15-20% Sodium Lauryl Sulphate.
[0570] In preferred embodiments of the compositions of the first,
second and third aspects of the present invention the
guaifenesin-containing immediate release portion consists
essentially of: [0571] (a) 30-40% Guaifenesin; [0572] (b) up to 5%
Dextromethorphan or a pharmaceutically acceptable salt thereof;
[0573] (c) 50-60% Microcrystalline cellulose; [0574] (d) up to 7%
Povidone; [0575] (e) up to 7% Croscarmellose sodium; and [0576] (f)
up to 1% Magnesium stearate.
[0577] In alternative preferred embodiments of the compositions of
the first, second and third aspects of the present invention
preferred embodiments of the compositions of the present the
guaifenesin-containing immediate release portion consists
essentially of: [0578] (a) 40-50% Guaifenesin; [0579] (b) up to 5%
Dextromethorphan or a pharmaceutically acceptable salt thereof;
[0580] (c) 40-50% Microcrystalline cellulose; [0581] (d) up to 5%
Hypromellose; [0582] (e) up to 5% Sodium starch glycolate; and
[0583] (f) up to 1% Magnesium stearate.
[0584] In alternative preferred embodiments of the compositions of
the first, second and third aspects of the present invention
preferred embodiments of the compositions of the present the
guaifenesin-containing immediate release portion consists
essentially of: [0585] (a) 50-65% Guaifenesin; [0586] (b) up to 5%
Dextromethorphan or a pharmaceutically acceptable salt thereof;
[0587] (c) 25-40% Microcrystalline cellulose; [0588] (d) up to 5%
Povidone; [0589] (e) up to 5% Croscarmellose sodium; and [0590] (f)
up to 1% Magnesium stearate.
[0591] In preferred embodiments of the compositions of the first,
second and third aspects of the present invention the modified
release portion consists essentially of: [0592] (a) 80-90%
Guaifenesin; [0593] (b) up to 5% Dextromethorphan or a
pharmaceutically acceptable salt thereof; [0594] (c) up to 10%
Hypromellose; [0595] (d) up to 5% Carbomer; [0596] (e) up to 1.55%
Magnesium stearate.
[0597] In alternative preferred embodiments of the compositions of
the first, second and third aspects of the present invention
preferred embodiments of the compositions of the present invention
the modified immediate release portion consists essentially of:
[0598] (a) 80-90% Guaifenesin; [0599] (b) 3-6% Dextromethorphan or
a pharmaceutically acceptable salt thereof; [0600] (c) up to 5%
Hypromellose; [0601] (d) up to 2% Hydroxy ethylcellulose; [0602]
(e) up to 5% Microcrystalline cellulose; [0603] (f) up to 1%
Magnesium stearate.
[0604] In alternative preferred embodiments of the compositions of
the first, second and third aspects of the present invention
preferred embodiments of the compositions of the present invention
the modified immediate release portion consists essentially of:
[0605] (a) 80-90% Guaifenesin; [0606] (b) 3-6% Dextromethorphan or
a pharmaceutically acceptable salt thereof; [0607] (c) up to 5%
Hypromellose; [0608] (d) up to 5% Hydroxy ethylcellulose; [0609]
(e) up to 5% Microcrystalline cellulose; [0610] (f) up to 1%
Magnesium stearate.
[0611] In preferred embodiments of the compositions of the first,
second and third aspects of the present invention the modified
release portion consists essentially of: [0612] (a) 85-90%
Guaifenesin; [0613] (b) 4-5% Dextromethorphan or a pharmaceutically
acceptable salt thereof; [0614] (c) 3-6% Hypromellose; [0615] (d)
1-3% Carbomer; [0616] (e) 0.5-1% Magnesium stearate.
[0617] In preferred embodiments of the compositions of the first,
second and third aspects of the present invention the modified
release portion consists essentially of: [0618] (a) 90-93%
Guaifenesin; [0619] (b) 4-6% Dextromethorphan or a pharmaceutically
acceptable salt thereof; [0620] (c) 1-3% Carbomer; [0621] (d)
0.5-1% Magnesium stearate.
[0622] For the avoidance of doubt the present disclosure covers all
possible combinations of the preferred embodiments of the immediate
release analgesic-containing portion, the immediate release
guaifenesin-containing portion and the modified release containing
portion to give a composition having each of an immediate release
analgesic-containing portion, an immediate release
guaifenesin-containing portion and a modified release containing
portion.
[0623] Modified release polymers that can be used in the
compositions of the present invention include Acacia, Adipic Acid,
Agar, Alginic Acid, Aliphatic Polyesters, Calcium Alginate,
Carbomer, Carrageenan, Castor Oil, Cellaburate, Cellulose Acetate,
Ceratonia, Colophony, Copovidone, Glyceryl Behenate, Glyceryl
Monooleate, Glyceryl Monostearate, Glyceryl Palmitostearate,
Hydroxypropyl Betadex, Hydroxypropyl Cellulose, Hydroxyethyl
Cellulose, Hypromellose, Hypromellose Acetate Succinate,
Methylcellulose, Polacrilin Potassium, Polycarbophil, Polydextrose,
Polymethacrylates, Polyoxylglycerides, Polyvinyl Acetate
Dispersion, Shellac, Sodium Alginate, Sodium Hyaluronate, Modified
Starch, Sucrose Stearate, Microcrystalline Wax, White Wax, Yellow
Wax, Xanthan Gum, Zein.
[0624] Hydrophilic polymers suitable for use in the sustained
release portion include: one or more natural or partially or
totally synthetic hydrophilic gums such as acacia, gum tragacanth,
locust bean gum, guar gum, or karaya gum, modified cellulosic
substances such as methylcellulose, hydroxymethylcellulose,
hydroxypropyl methylcellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxyethylcellulose,
carboxyethylcellulose; proteinaceous substances such as agar,
pectin, carrageen, and alginates; and other hydrophilic polymers
such as carboxypolymethylene, gelatin, casein, zein, bentonite,
magnesium aluminium silicate, polysaccharides, modified starch
derivatives, and other hydrophilic polymers known to those of skill
in the art or a combination of such polymers.
[0625] These hydrophilic polymers gel and dissolve slowly in
aqueous acidic media thereby allowing the guaifenesin to diffuse
from the gel in the stomach. When the gel reaches the intestines,
it dissolves in controlled quantities in the higher pH medium,
where the guaifenesin itself is fairly absorbable, to allow
sustained release of guaifenesin throughout the digestive tract.
Preferred hydrophilic polymers are the hydroxypropyl
methylcelluloses such as those manufactured by The Dow Chemical
Company and known as METHOCEL ethers. In one preferred embodiment
of a sustained release formulation the hydrophilic polymer is a
METHOCEL ether known as METHOCEL E10M.
[0626] Water-insoluble polymers which arc suitable for use in the
sustained release portion are polymers which generally do not
dissolve in solutions of a pH below 5, and dissolve more slowly in
basic solutions than the hydrophilic polymer. Because the polymer
is insoluble in low pH environments such as those found in gastric
fluid, it aids in retarding drug release in those regions.
Likewise, because the polymer dissolves more slowly in solutions of
higher pH than hydrophilic polymers, it aids in retarding drug
release throughout the intestines. This overall delayed release
results in a more uniform serum concentration of guaifenesin.
[0627] The water-insoluble polymers suitable for use in the
sustained release portion include: polyacrylic acids, acrylic
resins, acrylic latex dispersions, cellulose acetate phthalate,
polyvinyl acetate phthalate, hydroxypropyl methylcellulose
phthalate, carbomer and other polymers common to those of skill in
the art. In a preferred embodiment, a sustained release formulation
comprises the acrylic resin CARBOPOL 974P supplied by BF
Goodrich.
[0628] The sustained release portion of the present invention may
further comprise pharmaceutical additives including, but not
limited to: lubricants such as magnesium stearate, calcium
stearate, zinc stearate, powdered stearic acid, hydrogenated
vegetable oils, talc, polyethylene glycol, and mineral oil;
colorants such as Emerald Green Lake and various FD&C colors;
binders such as sucrose, lactose, gelatin, starch paste, acacia,
tragacanth, povidone polyethylene glycol, Pullulan and corn syrup;
glidants such as colloidal silicon dioxide and talc; surface active
agents such as sodium lauryl sulfate, dioctyl sodium
sulfosuccinate, tricthanolamine, polyoxyethylene sorbitan,
poloxalkol, and quarternary ammonium salts; preservatives and
stabilizers; excipients such as lactose, mannitol, glucose,
fructose, xylose, galactose, sucrose, maltose, xylitol, sorbitol,
chloride, sulfate and phosphate salts of potassium, sodium, and
magnesium; and/or any other pharmaceutical additives known to those
of skill in the art.
[0629] Colorants include, but are not limited to, Emerald Green
Lake, FD&C Red #40, FD&C Yellow #6, FD&C Yellow #10, or
FD&C Blue #1. In one preferred embodiment, a sustained release
portion further comprises magnesium stearate and Emerald Green
Lake. In another preferred embodiment, a sustained release
formulation further comprises magnesium stearate and FD&C Blue
#1 Aluminium Lake Dye.
[0630] The immediate release portion may comprise guaifenesin and
various pharmaceutical additives such as disintegrants, lubricants,
colorants, binders, glidants, surface active agents, preservatives,
stabilizers, as described above and/or any other pharmaceutical
additives known to those of skill in the art. Examples of suitable
lubricant are as follows: Calcium Stearate, Glyceryl Behenate,
Leucine, Magnesium Stearate, Mineral Oil, Myristic Acid, Palm Oil,
Palmitic Acid, Poloxamer, Polyethylene Glycol, Potassium Benzoate,
Sodium Benzoate, Sodium Lauryl Sulfate, Sodium Stearate, Sodium
Stearyl Fumarate, Stearic Acid, Sucrose Stearate, Talc, Vegetable
Oil, Zinc Stearate. Examples of suitable disintegrants are as
follows: Carboxymethylcellulose Calcium, Carboxymethylcellulose
Sodium, Sodium Lauryl Sulphate, Sodium Bicarboant, Chitosan,
Coilloidal Sillicon Dioxide, Croscarmellose Sodium, Crospovidone,
Glycine, Guar Gum, Lactose, Magnesium Aluminum Silicate, Polacrilin
Potassium, Povidone, Sodium Alginate, Sodium Starch Glycolate.
Examples of suitable diluents are as follows: Calcium Carbonate,
Calcium Lactate, Calcium Phosphate, Calcium Silicate, Calcium
Sulfate, Cellaburate, Cellulose Acetate, Microcrystalline
Cellulose, Silicified Microcrystalline Cellulose, Corn Syrup
Solids, Dextrates, Dextrin, Dextrose, Erythritol, Ethylcellulose,
Fructose, Inulin, Isomalt, Kaolin, Lactitol, Lactose, Magnesium
Carbonate, Magnesium Oxide, Maltitol, Maltodextrin, Maltose,
Mannitol, Triglycerides, Polydextrose, Simethicone, Sodium
Bicarbonate, Sodium Carbonate, Sodium Chloride, Sorbitol, Sucrose,
Sugar, Sulfobutylether .beta.-Cyclodextrin, Sunflower Oil, Talc,
Trehalose, Xylitol. Examples of suitable binders are as follows:
Attapulgite, Calcium Carbonate, Calcium Lactate, Ceratonia,
Colophony, Copovidone, Ethylcellulose, Ethylene Glycol and Vinyl
Alcohol Grafted Copolymer, Gelatin, Glucose, Hydroxethylmethyl
Celluose, Magnesium Aluminium Silicate, Methylcellulose,
Polycarbophil, Polydextrose, Polyethylene Oxide, Polymethacrylates,
Povidone, Pullulan, Vitamin E Polyethylene Glycol Succinate.
[0631] For the avoidance of any doubt, reference to a
pharmaceutically active compound includes all enantiomers and
stereoisomers thereof, and also all pharmaceutically acceptable
salts or esters thereof. For example, naproxen includes naproxen
sodium, pseudoephedrine includes pseudoephedrine hydrochloride,
dextromethorphan includes dextromethorphan hydrobromide.
[0632] In an alternative embodiment, the immediate release portion
which comprises guaifenesin may further comprise the additional or
more actives in the form of a drug/active-resin complex.
[0633] According to a fourth aspect of the present invention there
is provided a sustained-release polymer matrix which consists
essentially of a combination of a hydroxy propyl methyl cellulose
having a molecular weight of 100,000-500,000 and a hydroxyethyl
cellulose having a molecular weight of 500,000-2,000,000.
[0634] The molecular weight of hydroxyl propyl methyl cellulose can
200,000 to 300,000. A preferred molecular weight is 250,000.
[0635] The molecular weight of hydroxyethyl cellulose can 1,000,000
to 1,500,000. A preferred molecular weight is 1,300,000.
[0636] The ratio of the hydroxyl propyl methyl
cellulose:hydroxyethyl cellulose is from 1:1 to 3:1. A preferred
ratio is from 2:1 to 2.5:1. A more preferred ratio is 2.1:1.
[0637] According to a fifth aspect of the present invention there
is provided the use of a sustained release polymer matrix as
described in the fourth aspect in a pharmaceutical formulation.
[0638] The pharmaceutical formulation can comprise at least one
active selected from an expectorant, an analgesic, an
antihistamine, an antitussive, or a decongestant. The expectorant
can be selected to be guaifenesin or n-acetyl cysteine. The
analgesic can be selected to be naproxen, ketoprofen, diclofenac,
ibuprofen and flurbiprofen. The antitussive can be selected to be
dextromethorphan, codeine, codeine phosphate, codeine sulphate,
diphenhydramine citrate, and diphenhydramine hydrochloride. The
decongestant can be selected to be phenylephrine hydrochloride,
phenylpropanolamine hydrochloride, pseudoephedrine or ephedrine.
The antihistamine can be selected to be chlorpheniramine maleate,
brompheniramine maleate, phenindamine tartrate, pyrilamine maleate,
doxylamine succinate, phenyltoloxamine citrate, diphenhydramine
hydrochloride, promethazine, and clemastine fumerate, or a
combination thereof.
[0639] According to a sixth aspect of the present invention there
is provided a method of providing relief from the symptoms of
bronchial conditions, coughing and symptoms or diseases associated
with coughing comprising administering to an individual a
composition as described in the first, second or third aspects of
the present invention.
[0640] According to a seventh aspect of the present invention there
is provided the use of a composition as described in the first,
second or third aspects of the present invention for the
preparation of a medicament for the treatment of bronchial
conditions, coughing and diseases associated with coughing.
[0641] According to an eighth aspect of the present invention these
is provided an immediate release formulation of naproxen having an
improved dissolution profile.
[0642] In a preferred embodiment the composition can comprise:
[0643] (a) 50-52% Naproxen or a pharmaceutically acceptable salt
thereof; [0644] (b) 35-40% Microcrystalline cellulose; [0645] (c)
up to 5% Povidone; [0646] (d) 5-8% Croscarmellose sodium; and
[0647] (e) up to 1% Magnesium stearate.
[0648] In a further preferred embodiment the composition can
comprise: [0649] (a) 70-75% Naproxen or a pharmaceutically
acceptable salt thereof; [0650] (b) 20-25% Microcrystalline
cellulose; [0651] (c) up to 5% Povidone; [0652] (d) up to 1%
Magnesium stearate.
[0653] In a further preferred embodiment the composition can
comprise: [0654] (a) 70-75% Naproxen or a pharmaceutically
acceptable salt thereof; [0655] (b) 5-10% Microcrystalline
cellulose; [0656] (c) up to 5% Povidone; [0657] (d) up to 1%
Magnesium stearate; [0658] (e) 5-10% Lactose; and [0659] (f) up to
5% Croscarmellose sodium.
[0660] In a further preferred embodiment the composition can
comprise: [0661] (a) 70-75% Naproxen or a pharmaceutically
acceptable salt thereof; [0662] (b) 5-10% Microcrystalline
cellulose; [0663] (c) up to 5% Povidone; [0664] (d) up to 1%
Magnesium stearate; [0665] (e) 5-10% Lactose; and [0666] (f) 5-10%
Croscarmellose sodium.
[0667] In a further preferred embodiment the composition can
comprise: [0668] (a) 70-75% Naproxen or a pharmaceutically
acceptable salt thereof; [0669] (b) 5-10% Microcrystalline
cellulose; [0670] (c) up to 5% Povidone; [0671] (d) up to 1%
Magnesium stearate; [0672] (e) up to 5% Lactose; and [0673] (f)
15-20% Sodium Lauryl Sulphate.
[0674] In a further preferred embodiment the composition can
comprise: [0675] (a) 70-75% Naproxen or a pharmaceutically
acceptable salt thereof; [0676] (b) 5-10% Microcrystalline
cellulose; [0677] (c) up to 5% Povidone; [0678] (d) up to 1%
Magnesium stearate; [0679] (e) up to 2% Croscarmellose sodium; and
[0680] (f) 15-20% Sodium Lauryl Sulphate.
[0681] In a further preferred embodiment the composition can
consist essentially of: [0682] (a) 50-52% Naproxen or a
pharmaceutically acceptable salt thereof; [0683] (b) 35-40%
Microcrystalline cellulose; [0684] (c) up to 5% Povidone; [0685]
(d) 5-8% Croscarmellose sodium; and [0686] (e) up to 1% Magnesium
stearate.
[0687] In a further preferred embodiment the composition can
consist essentially of: [0688] (a) 70-75% Naproxen or a
pharmaceutically acceptable salt thereof; [0689] (b) 20-25%
Microcrystalline cellulose; [0690] (c) up to 5% Povidone; [0691]
(d) up to 1% Magnesium stearate.
[0692] In a further preferred embodiment the composition can
consist essentially of: [0693] (a) 70-75% Naproxen or a
pharmaceutically acceptable salt thereof; [0694] (b) 5-10%
Microcrystalline cellulose; [0695] (c) up to 5% Povidone; [0696]
(d) up to 1% Magnesium stearate; [0697] (e) 5-10% Lactose; and
[0698] (f) up to 5% Croscarmellose sodium.
[0699] In a further preferred embodiment the composition can
consist essentially of: [0700] (a) 70-75% Naproxen or a
pharmaceutically acceptable salt thereof; [0701] (b) 5-10%
Microcrystalline cellulose; [0702] (c) up to 5% Povidone; [0703]
(d) up to 1% Magnesium stearate; [0704] (e) 5-10% Lactose; and
[0705] (f) 5-10% Croscarmellose sodium.
[0706] In a further preferred embodiment the composition can
consist essentially of: [0707] (a) 70-75% Naproxen or a
pharmaceutically acceptable salt thereof; [0708] (b) 5-10%
Microcrystalline cellulose; [0709] (c) up to 5% Povidone; [0710]
(d) up to 1% Magnesium stearate; [0711] (e) up to 5% Lactose; and
[0712] (f) 15-20% Sodium Lauryl Sulphate.
[0713] In a further preferred embodiment the composition can
consist essentially of: [0714] (a) 70-75% Naproxen or a
pharmaceutically acceptable salt thereof; (b) 5-10%
Microcrystalline cellulose; [0715] (c) up to 5% Povidone; [0716]
(d) up to 1% Magnesium stearate; [0717] (e) up to 2% Croscarmellose
sodium; and [0718] (f) 15-20% Sodium Lauryl Sulphate.
[0719] Typically, the composition has a dissolution profile of
68-70% after 10 mins and 93-98% after 20 mins when tested using US
Pharmacopoeia apparatus 2 (paddles at 75 rpm at 37.degree. C.) in
Fessif media at pH 5.
[0720] Typically, the composition has a dissolution profile of
85-90% after 10 mins when tested using US Pharmacopoeia apparatus 2
(paddles at 75 rpm at 37.degree. C.) in Fessif media at pH 6.8.
[0721] Fessif is a term used in the art to mean Fed State Simulated
Intestinal Fluid. Fassif is a term used in the art to mean Fasted
State Simulated Intestinal Fluid.
[0722] As used herein, the term "about" means that the numerical
value is approximate and small variations would not significantly
affect the practice of the disclosed embodiments. Where a numerical
limitation is used, unless indicated otherwise by the context,
"about" means the numerical value can vary by +10% and remain
within the scope of the disclosed embodiments.
[0723] As used herein, the term "consisting essentially of" means
the composition contains the indicated components and may contain
additional components provided that the additional components that
are non-active and do not materially affect the composition's basic
characteristics. As used herein, the term "consisting of" means the
composition contains the only indicated components and excludes
other components.
[0724] As used herein, the term "up to" means a value greater than
zero. For example, the term "up to 1%" means that component is
present in the composition and can be present to an amount of 1%.
The term "up to 5%" means that the component is present in the
composition and can be present to an amount of 5%.
[0725] For the avoidance of doubt when the composition of the
present invention is in the form of a tablet or tablets, the values
given for both the ranges and amounts of the components in the
compositions of the present invention refer to uncoated tablets.
Additional coatings can be added as required.
[0726] Embodiments of the present invention will now be described
by way of example only.
EXAMPLE 1
TABLE-US-00001 [0727] Tablet 1: Naproxen Ingredient mg/tablet %
Weight Naproxen Sodium 110.0 mg 73.33% Microcrystalline Cellulose
34.45 mg 22.96% Povidone 4.50 mg 3.0% Mg Stearate 1.05 mg 0.7%
Total Tablet 150.0 mg 100.0%
TABLE-US-00002 Tablet 2: Immediate/Sustained Release
Dextromethorphan and Guaifenesin Ingredient mg/tablet % Weight
Guaifenesin 600.0 mg 76.41% Hypromellose 50.00 mg 6.37% MCC 87.52
mg 11.15% Dextromethorphan HBr 30.0 mg 3.82% Carbomer 7.50 mg 0.96%
Sodium Starch Glycolate 3.98 mg 0.51% Colourant 0.20 mg 0.025% Mg
Stearate 6.0 mg 0.76% Total Tablet 785.2 mg 100.0%
EXAMPLE 2
TABLE-US-00003 [0728] Tablet 1: Naproxen Ingredient mg/tablet %
Weight Naproxen Sodium 110.0 mg 51.16% Microcrystalline Cellulose
81.00 mg 37.67% Crospovidone 7.50 mg 3.49% Croscarmellose sodium
15.00 mg 6.98% Mg Stearate 1.50 mg 0.7% Total Tablet 215.0 mg
100.0%
TABLE-US-00004 Tablet 2: Immediate/Sustained Release
Dextromethorphan and Guaifenesin Ingredient mg/tablet % Weight
Guaifenesin 600.0 mg 74.77% Hypromellose 19.00 mg 2.37% MCC 129.40
mg 16.12% Dextromethorphan HBr 30.0 mg 3.74% Povidone 7.00 mg 0.87%
Croscarmellose Sodium 6.00 mg 0.74% Hydroxy ethyl cellulose 9.00 mg
1.12% Colourant 0.20 mg 0.025% Mg Stearate 1.9 mg 0.24% Total Layer
802.5 mg 100.0%
EXAMPLE 3
TABLE-US-00005 [0729] Tablet 1: Naproxen Ingredient mg/tablet %
Weight Naproxen Sodium 110.0 mg 73.33% Microcrystalline Cellulose
14.55 mg 9.7% Lactose 12.65 mg 8.4% Povidone 4.65 mg 3.1%
Croscarmellose sodium 7.15 mg 4.8% Mg Stearate 1 mg 0.7% Total
Tablet 150.0 mg 100.0%
TABLE-US-00006 Tablet 2: Immediate/Modified Release
Dextromethorphan and Guaifenesin Immediate Release Layer Ingredient
mg/tablet % Weight Guaifenesin 200 mg 63.77% Dextromethorphan HBr
10 mg 3.19% Microcrystalline Cellulose 85 mg 27.10% Povidone 10 mg
3.19% Croscarmellose Sodium 8.5 mg 2.71% Mg Stearate 0.15 mg 0.05%
Total Layer 313.65 mg 100.00%
TABLE-US-00007 Modified Release Layer Ingredient mg/tablet % Weight
Guaifenesin 400 mg 84.54% Dextromethorphan HBr 20 mg 4.23%
Hypromellose (K100M) 24.5 mg 5.18% Hydroxyethylcellulose 12.25 mg
2.59% Microcrystalline Cellulose 14.75 mg 3.12% Colourant 0.1 mg
0.02% Mg Stearate 1.55 mg 0.33% Total Layer 473.15 mg 100.00% Total
Tablet 786.8 mg 100.0%
EXAMPLE 4
TABLE-US-00008 [0730] Tablet 1: Naproxen Ingredient mg/tablet %
Weight Naproxen Sodium 110 mg 73.33% Microcrystalline Cellulose 6
mg 4.00% Lactose 5 mg 3.33% Povidone 3 mg 2.00% Sodium lauryl
sulfate 25 mg 16.67% Mg Stearate 1 mg 0.67% Total Tablet 150.0 mg
100.0%
TABLE-US-00009 Tablet 2: Immediate/Modified Release
Dextromethorphan and Guaifenesin Immediate Release Layer Ingredient
mg/tablet % Weight Guaifenesin 200 mg 63.77% Dextromethorphan HBr
10 mg 3.19% Microcrystalline Cellulose 85 mg 27.10% Povidone 10 mg
3.19% Croscarmellose Sodium 8.5 mg 2.71% Mg Stearate 0.15 mg 0.05%
Total Layer 313.65 mg 100.00%
TABLE-US-00010 Modified Release Layer Ingredient mg/tablet % Weight
Guaifenesin 400 mg 84.54% Dextromethorphan HBr 20 mg 4.23%
Hypromellose (K100M) 24.5 mg 5.18% Hydroxyethylcellulose 12.25 mg
2.59% Microcrystalline Cellulose 14.75 mg 3.12% Colourant 0.1 mg
0.02% Mg Stearate 1.55 mg 0.33% Total Layer 473.15 mg 100.00% Total
Tablet 786.8 mg 100.0%
EXAMPLE 5
TABLE-US-00011 [0731] Tablet 1: Naproxen Ingredient mg/tablet %
Weight Naproxen Sodium 110.0 mg 73.33% Microcrystalline Cellulose
14.55 mg 9.7% Lactose 12.65 mg 8.4% Povidone 4.65 mg 3.1%
Croscarmellose sodium 7.15 mg 4.8% Mg Stearate 1 mg 0.7% Total
Tablet 150.0 mg 100.0%
TABLE-US-00012 Tablet 2: Immediate/Modified Release
Dextromethorphan and Guaifenesin Immediate Release Layer Ingredient
mg/tablet % Weight Guaifenesin 130 mg 54.83% Dextromethorphan HBr
7.00 mg 2.95% Microcrystalline Cellulose 85.00 mg 35.85% Povidone
8.00 mg 3.37% Croscarmellose Sodium 7.00 mg 2.95% Mg Stearate 0.10
mg 0.04% Total Layer 237.10 mg 100.00%
TABLE-US-00013 Modified Release Layer Ingredient mg/tablet % Weight
Guaifenesin 470 mg 86.35% Dextromethorphan HBr 23 mg 4.23%
Hypromellose (K100M) 17 mg 3.12% Hydroxyethylcellulose 17 mg 3.12%
Microcrystalline Cellulose 15.5 mg 2.85% Colourant 0.1 mg 0.02% Mg
Stearate 1.7 mg 0.31% Total Layer 544.3 mg 100.00% Total Tablet
781.40 mg 100.0%
EXAMPLE 6
TABLE-US-00014 [0732] Tablet 1: Naproxen Ingredient mg/tablet %
Weight Naproxen Sodium 110 mg 73.33% Microcrystalline Cellulose 6
mg 4.00% Lactose 5 mg 3.33% Povidone 3 mg 2.00% Sodium lauryl
sulfate 25 mg 16.67% Mg Stearate 1 mg 0.67% Total Tablet 150.0 mg
100.0%
TABLE-US-00015 Tablet 2: Immediate/Modified Release
Dextromethorphan and Guaifenesin Immediate Release Layer Ingredient
mg/tablet % Weight Guaifenesin 130 mg 54.83% Dextromethorphan HBr
7.00 mg 2.95% Microcrystalline Cellulose 85.00 mg 35.85% Povidone
8.00 mg 3.37% Croscarmellose Sodium 7.0 mg 2.95% Mg Stearate 0.10
mg 0.04% Total Layer 237.10 mg 100.00%
TABLE-US-00016 Modified Release Layer Ingredient mg/tablet % Weight
Guaifenesin 470 mg 86.35% Dextromethorphan HBr 23 mg 4.23%
Hypromellose (K100M) 17 mg 3.12% Hydroxyethylcellulose 17 mg 3.12%
Microcrystalline Cellulose 15.5 mg 2.85% Colourant 0.1 mg 0.02% Mg
Stearate 1.7 mg 0.31% Total Layer 544.3 mg 100.00% Total Tablet
781.40 mg 100.0%
EXAMPLE 7
TABLE-US-00017 [0733] Tablet 1: Naproxen Ingredient mg/tablet %
Weight Naproxen Sodium 110 mg 73.33% Microcrystalline Cellulose
34.45 mg 22.97% Povidone 4.5 mg 3.00% Mg Stearate 1.05 mg 0.7%
Total Tablet 150.0 mg 100.0%
TABLE-US-00018 Tablet 2: Immediate/Modified Release
Dextromethorphan and Guaifenesin Immediate Release Layer Ingredient
mg/tablet % Weight Guaifenesin 85.5 mg 47.50% Dextromethorphan HBr
6.75 mg 3.75% Microcrystalline Cellulose 78.77 mg 43.76%
Hypromellose 4.50 mg 2.50% Sodium Starch Glycolate 3.58 mg 1.99% Mg
Stearate 0.90 mg 0.50% Total Layer 180.00 mg 100.00%
TABLE-US-00019 Modified Release Layer Ingredient mg/tablet % Weight
Guaifenesin 514.50 mg 88.83% Dextromethorphan HBr 23.25 mg 4.03%
Hypromellose 27.50 mg 4.75% Carbomer 8.25 mg 1.42% Colourant 0.22
mg 0.04% Mg Stearate 5.50 mg 0.95% Total Layer 579.22 mg 100.00%
Total Tablet 759.22 mg 100.0%
EXAMPLE 8
TABLE-US-00020 [0734] Tablet 1: Naproxen Ingredient mg/tablet %
Weight Naproxen Sodium 110 mg 73.33% Microcrystalline Cellulose
34.45 mg 22.97% Povidone 4.5 mg 3.00% Mg Stearate 1.05 mg 0.7%
Total Tablet 150.0 mg 100.0%
TABLE-US-00021 Tablet 2: Immediate/Modified Release
Dextromethorphan and Guaifenesin Immediate Release Layer Ingredient
mg/tablet % Weight Guaifenesin 76.00 mg 47.50% Dextromethorphan HBr
6.00 mg 3.75% Microcrystalline Cellulose 70.02 mg 43.76%
Hypromellose 4.00 mg 2.50% Sodium Starch Glycolate 3.18 mg 1.99% Mg
Stearate 0.80 mg 0.50% Total Layer 160.00 mg 100.00%
TABLE-US-00022 Modified Release Layer Ingredient mg/tablet % Weight
Guaifenesin 424.00 mg 91.74% Dextromethorphan HBr 24.00 mg 5.19%
Carbomer 9.90 mg 2.14% Colourant 0.26 mg 0.06% Mg Stearate 4.00 mg
0.87% Total Layer 462.16 mg 100.00% Total Tablet 622.16 mg
100.0%
EXAMPLE 9
TABLE-US-00023 [0735] Tablet 1: Naproxen Ingredient mg/tablet %
Weight Naproxen Sodium 110 mg 73.33% Microcrystalline Cellulose
14.5 mg 9.67% Povidone 4.75 mg 3.17% Mg Stearate 0.75 mg 0.7%
Lactose 10.00 mg 6.67% Croscarmellose Sodium 10.00 mg 6.67% Total
Tablet 150.0 mg 100.0%
TABLE-US-00024 Tablet 2: Immediate/Modified Release
Dextromethorphan and Guaifenesin Immediate Release Layer Ingredient
mg/tablet % Weight Guaifenesin 85.5 mg 47.50% Dextromethorphan HBr
6.75 mg 3.75% Microcrystalline Cellulose 78.77 mg 43.76%
Hypromellose 4.50 mg 2.50% Sodium Starch Glycolate 3.58 mg 1.99% Mg
Stearate 0.90 mg 0.50% Total Layer 180.00 mg 100.00%
TABLE-US-00025 Modified Release Layer Ingredient mg/tablet % Weight
Guaifenesin 514.50 mg 88.83% Dextromethorphan HBr 23.25 mg 4.03%
Hypromellose 27.50 mg 4.75% Carbomer 8.25 mg 1.42% Colourant 0.22
mg 0.04% Mg Stearate 5.50 mg 0.95% Total Layer 579.22 mg 100.00%
Total Tablet 759.22 mg 100.0%
EXAMPLE 10
TABLE-US-00026 [0736] Tablet 1: Naproxen Ingredient mg/tablet %
Weight Naproxen Sodium 110 mg 73.33% Microcrystalline Cellulose
14.5 mg 9.67% Povidone 4.75 mg 3.17% Mg Stearate 0.75 mg 0.7%
Lactose 10.00 mg 6.67% Croscarmellose Sodium 10.00 mg 6.67% Total
Tablet 150.0 mg 100.0%
TABLE-US-00027 Tablet 2: Immediate/Modified Release
Dextromethorphan and Guaifenesin Immediate Release Layer Ingredient
mg/tablet % Weight Guaifenesin 76.00 mg 47.50% Dextromethorphan HBr
6.00 mg 3.75% Microcrystalline Cellulose 70.02 mg 43.76%
Hypromellose 4.00 mg 2.50% Sodium Starch Glycolate 3.18 mg 1.99% Mg
Stearate 0.80 mg 0.50% Total Layer 160.00 mg 100.00%
TABLE-US-00028 Modified Release Layer Ingredient mg/tablet % Weight
Guaifenesin 424.00 mg 91.74% Dextromethorphan HBr 24.00 mg 5.19%
Carbomer 9.90 mg 2.14% Colourant 0.26 mg 0.06% Mg Stearate 4.00 mg
0.87% Total Layer 462.16 mg 100.00% Total Tablet 622.16 mg
100.0%
EXAMPLE 11
TABLE-US-00029 [0737] Tablet 1: Naproxen Ingredient mg/tablet %
Weight Naproxen Sodium 110 mg 72.37% Microcrystalline Cellulose
9.25 mg 6.09% Povidone 4.75 mg 3.13% Mg Stearate 1.00 mg 0.66%
Sodium Lauryl Sulphate 25.00 mg 16.45% Croscarmellose Sodium 2.00
mg 1.32% Total Tablet 150.0 mg 100.0%
TABLE-US-00030 Tablet 2: Immediate/Modified Release
Dextromethorphan and Guaifenesin Immediate Release Layer Ingredient
mg/tablet % Weight Guaifenesin 85.5 mg 47.50% Dextromethorphan HBr
6.75 mg 3.75% Microcrystalline Cellulose 78.77 mg 43.76%
Hypromellose 4.50 mg 2.50% Sodium Starch Glycolate 3.58 mg 1.99% Mg
Stearate 0.90 mg 0.50% Total Layer 180.00 mg 100.00%
TABLE-US-00031 Modified Release Layer Ingredient mg/tablet % Weight
Guaifenesin 514.50 mg 88.83% Dextromethorphan HBr 23.25 mg 4.03%
Hypromellose 27.50 mg 4.75% Carbomer 8.25 mg 1.42% Colourant 0.22
mg 0.04% Mg Stearate 5.50 mg 0.95% Total Layer 579.22 mg 100.00%
Total Tablet 759.22 mg 100.0%
EXAMPLE 12
TABLE-US-00032 [0738] Tablet 1: Naproxen Ingredient mg/tablet %
Weight Naproxen Sodium 110 mg 72.37% Microcrystalline Cellulose
9.25 mg 6.09% Povidone 4.75 mg 3.13% Mg Stearate 1.00 mg 0.66%
Sodium Lauryl Sulphate 25.00 mg 16.45% Croscarmellose Sodium 2.00
mg 1.32% Total Tablet 150.0 mg 100.0%
TABLE-US-00033 Tablet 2: Immediate/Modified Release
Dextromethorphan and Guaifenesin Immediate Release Layer Ingredient
mg/tablet % Weight Guaifenesin 76.00 mg 47.50% Dextromethorphan HBr
6.00 mg 3.75% Microcrystalline Cellulose 70.02 mg 43.76%
Hypromellose 4.00 mg 2.50% Sodium Starch Glycolate 3.18 mg 1.99% Mg
Stearate 0.80 mg 0.50% Total Layer 160.00 mg 100.00%
TABLE-US-00034 Modified Release Layer Ingredient mg/tablet % Weight
Guaifenesin 424.00 mg 91.74% Dextromethorphan HBr 24.00 mg 5.19%
Carbomer 9.90 mg 2.14% Colourant 0.26 mg 0.06% Mg Stearate 4.00 mg
0.87% Total Layer 462.16 mg 100.00% Total Tablet 622.16 mg
100.0%
EXAMPLE 13
Composite Tablet
TABLE-US-00035 [0739] Immediate Release Layer Ingredient mg/tablet
% Weight Guaifenesin 140 mg 28.58% Dextromethorphan HBr 8 mg 1.63%
Naproxen Sodium 110 mg 22.45% Microcrystalline Cellulose 60 mg
12.24% Povidone 11 mg 2.25% Croscarmellose sodium 26 mg 5.31%
Crospovidone 9.8 mg 2.00% Sodium lauryl sulfate 25 mg 5.10%
Bicarbonate 100 mg 20.41% Mg Stearate 0.1 mg 0.02% Total Tablet
489.9 mg 100.0%
TABLE-US-00036 Modified Release Layer Ingredient mg/tablet % Weight
Guaifenesin 460 mg 84.73% Dextromethorphan HBr 22 mg 4.05%
Hypromellose 28 mg 5.16% Hydroxy ethyl cellulose 14 mg 2.58%
Microcrystalline Cellulose 17 mg 3.13% Colourant 0.1 mg 0.02% Mg
Stearate 1.8 mg 0.33% Total Layer 542.9 mg 100.0%
EXAMPLE 14
Composite Tablet
TABLE-US-00037 [0740] Immediate Release Layer Ingredient mg/tablet
% Weight Guaifenesin 200 mg 45.25% Dextromethorphan HBr 10 mg 2.26%
Naproxen Sodium 110 mg 24.89% Microcrystalline Cellulose 45 mg
10.18% Povidone 11 mg 2.49% Crospovidone 65 mg 14.71% Mg Stearate 1
mg 0.23% Total Tablet 442 mg 100.0%
TABLE-US-00038 Modified Release Layer Ingredient mg/tablet % Weight
Guaifenesin 400 mg 84.54% Dextromethorphan HBr 20 mg 4.23%
Hypromellose 24.5 mg 5.18% Hydroxy ethyl cellulose 12.25 mg 2.59%
Microcrystalline Cellulose 14.75 mg 3.12% Colourant 0.1 mg 0.02% Mg
Stearate 1.55 mg 0.33% Total Layer 473.15 mg 100.0%
EXAMPLE 15
Composite Tablet
TABLE-US-00039 [0741] Immediate Release Layer Ingredient mg/tablet
% Weight Guaifenesin 95 mg 24.26% Dextromethorphan HBr 7.5 mg 1.92%
Naproxen Sodium 110 mg 28.09% Microcrystalline Cellulose 60 mg
15.32% Povidone 11 mg 2.81% Croscarmellose sodium 15 mg 3.83%
Crospovidone 8.00 mg 2.00% Sodium Lauryl Sulfate 25 mg 5.10% Sodium
Bicarbonate 60 mg 20.41% Mg Stearate 0.1 mg 0.03% Total Layer 391.6
mg 100.0%
TABLE-US-00040 Modified Release Layer Ingredient mg/tablet % Weight
Guaifenesin 505 mg 89.35% Dextromethorphan HBr 22.5 mg 3.98%
Hypromellose 25 mg 4.42% Carbomer 7.5 mg 1.33% Colourant 0.2 mg
0.04% Mg Stearate 5.0 mg 0.88% Total Layer 565.2 mg 100.0%
EXAMPLE 16
Composite Tablet
TABLE-US-00041 [0742] Immediate Release Layer Ingredient mg/tablet
% Weight Guaifenesin 95 mg 27.34% Dextromethorphan HBr 7.5 mg 2.16%
Naproxen Sodium 110 mg 31.65% Microcrystalline Cellulose 75 mg
21.58% Povidone 11 mg 3.17% Croscarmellose sodium 40 mg 11.51%
Crospovidone 8.00 mg 2.30% Mg Stearate 1 mg 0.29% Total 347.5 mg
100.0%
Modified Release Layer
TABLE-US-00042 [0743] Modified Release Layer Ingredient mg/tablet %
Weight Guaifenesin 505 mg 89.35% Dextromethorphan HBr 22.5 mg 3.98%
Hypromellose 25 mg 4.42% Carbomer 7.5 mg 1.33% Colourant 0.2 mg
0.04% Mg Stearate 5.0 mg 0.88% Total Layer 565.2 mg 100.0%
EXAMPLE 17
Composite Tablet
TABLE-US-00043 [0744] Immediate Release Layer Ingredient mg/tablet
% Weight Guaifenesin 95 mg 24.32% Dextromethorphan HBr 7.5 mg 1.92%
Naproxen Sodium 110 mg 28.16% Microcrystalline Cellulose 60 mg
15.36% Povidone 11 mg 2.82% Croscarmellose sodium 22 mg 5.63%
Sodium Lauryl Sulphate 25.00 mg 6.40% Sodium Bicarbonate 60.00 mg
15.36% Mg Stearate 0.1 mg 0.03% Total 390.6 mg 100.0%
TABLE-US-00044 Modified Release Layer Ingredient mg/tablet % Weight
Guaifenesin 505 mg 89.35% Dextromethorphan HBr 22.5 mg 3.98%
Hypromellose 25 mg 4.42% Carbomer 7.5 mg 1.33% Colourant 0.2 mg
0.04% Mg Stearate 5.0 mg 0.88% Total Layer 565.2 mg 100.0%
EXAMPLE 18
Composite Tablet
TABLE-US-00045 [0745] Immediate Release Layer Ingredient mg/tablet
% Weight Guaifenesin 95 mg 27.98% Dextromethorphan HBr 7.5 mg 2.21%
Naproxen Sodium 110 mg 32.40% Microcrystalline Cellulose 75 mg
22.09% Povidone 11 mg 3.24% Croscarmellose sodium 40 mg 11.78% Mg
Stearate 1 mg 0.29% Total 339.5 mg 100.0%
TABLE-US-00046 Modified Release Layer Ingredient mg/tablet % Weight
Guaifenesin 505 mg 89.35% Dextromethorphan HBr 22.5 mg 3.98%
Hypromellose 25 mg 4.42% Carbomer 7.5 mg 1.33% Colourant 0.2 mg
0.04% Mg Stearate 5.0 mg 0.88% Total Layer 565.2 mg 100.0%
[0746] The tablets of the example embodiments of the present
invention can be made using standard tableting procedures
well-known to the person skilled in the art.
[0747] The bi-layer tablet may be manufactured according to any
method known to those of skill in the art. The resulting tablet may
comprise the two portions compressed against one another so that
the face of each portion is exposed as either the top or bottom of
the tablet, or the resulting tablet may comprise the sustained
release portion in the centre coated by the immediate release
portion so that only the immediate release portion is exposed. In a
preferred embodiment, a bi-layer tablet of the present invention
comprises the two portions compressed against one another so that
the face of each portion is exposed.
[0748] The final dosage form can be made by inserting both the
immediate-release naproxen tablet and the
immediate-release/sustained or modified release
guaifenesin/dextromethorphan tablet into a gelatin capsule which is
then sealed.
[0749] Furthermore, the composite tablets of Examples 3 and 4 are
final dosage forms and need not, though they can, be inserted into
a suitable capsule.
[0750] An advantage of the present invention is that there is
provided a composition that provides multi-symptom cough/cold/flu
relief for 12 hours. Currently, there are no other products that
offer all of these significant benefits to consumers.
[0751] A further advantage is that there is provided a composition
which comprises naproxen, guaifenesin and dextromethorphan in a
single dose yet avoids any impact on the dissolution rate of either
guaifenesin or dextromethorphan by naproxen.
[0752] The composition of the present invention also provides for
more consistent release of both guaifenesin and dextromethorphan
when compared to known products in various pH conditions and when
exposed to various agitation speeds. For example purposes only,
these novel formulations have been shown to improve the consistency
of dextromethorphan release after 6 hours by 29% and guaifenesin
release after 6 hours by 52% and 71%.
[0753] Further modifications and improvements can be made without
departing from the scope of the invention described herein.
* * * * *