U.S. patent application number 11/119827 was filed with the patent office on 2005-09-08 for liquid pharmaceutical composition.
This patent application is currently assigned to Reliant Pharmaceuticals Inc.. Invention is credited to Bobotas, George, Fawzy, Abdel A..
Application Number | 20050196417 11/119827 |
Document ID | / |
Family ID | 30443093 |
Filed Date | 2005-09-08 |
United States Patent
Application |
20050196417 |
Kind Code |
A1 |
Bobotas, George ; et
al. |
September 8, 2005 |
Liquid pharmaceutical composition
Abstract
This invention relates to new pharmaceutical compositions and
methods for their preparation, and in particular it relates to
taste-masked liquid compositions comprising a solution of a
histamine H.sub.2-antagonist complexed with an alginate and also
containing a humectant. The solution is buffered to a pH of between
about 6 to 7. The inventive solution may be flavored and sweetened
and preserved.
Inventors: |
Bobotas, George; (Tarpon
Springs, FL) ; Fawzy, Abdel A.; (Dracut, MA) |
Correspondence
Address: |
ARENT FOX PLLC
1050 CONNECTICUT AVENUE, N.W.
SUITE 400
WASHINGTON
DC
20036
US
|
Assignee: |
Reliant Pharmaceuticals
Inc.
|
Family ID: |
30443093 |
Appl. No.: |
11/119827 |
Filed: |
May 3, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11119827 |
May 3, 2005 |
|
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10198271 |
Jul 17, 2002 |
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Current U.S.
Class: |
424/400 ;
514/365 |
Current CPC
Class: |
A61K 31/4164 20130101;
A61K 31/341 20130101; A61K 31/426 20130101; Y10S 514/974 20130101;
A61K 31/00 20130101; A61K 47/61 20170801; A61K 9/0095 20130101 |
Class at
Publication: |
424/400 ;
514/365 |
International
Class: |
A61K 031/426; A61K
009/00 |
Claims
We claim:
1. A liquid pharmaceutical composition for the oral administration
of a therapeutically effective amount of nizatidine, said
composition comprising a solution of nizatidine or a
pharmaceutically acceptable salt thereof and a taste-masking agent
capable of forming a complex with the nizatidine wherein said
taste-masking agent comprises alginate and wherein said composition
exhibits a non-bitter taste.
2. The pharmaceutical composition according to claim 1, wherein the
alginate taste-masking agent comprises sodium alginate.
3. The pharmaceutical composition according to claim 1, wherein the
nizatidine is in the form of a pharmaceutically acceptable
salt.
4. The pharmaceutical composition according to claim 1, wherein the
nizatidine is in the form of a free base.
5. The pharmaceutical composition according to claim 1, wherein the
ratio of nizatidine to alginate taste-masking agent is from 1:0.1
to 1:0.6 weight:weight.
6. The pharmaceutical composition according to claim 1, wherein the
ratio of nizatidine to alginate is about 1:0.2 to about 1:0.4
weight:weight.
7. The pharmaceutical composition according to claim 1 further
comprising a flavoring agent selected from the groups consisting of
natural and artificial flavors and mints.
8. The pharmaceutical composition according to claim 1 further
comprising a sweetening agent selected from the group consisting of
water-soluble sweetening agents, water-soluble artificial
sweetening agents and mixtures thereof.
9. The pharmaceutical composition according to claim 8, wherein
said water-soluble natural sweetening agent is selected from the
group consisting of: xylose, ribose, glucose, mannose, galactose,
fructose, dextrose, sucrose, sugar, maltose, partially hydrolyzed
starch, corn syrup solids, sorbitol, xylitol, mannitol and mixtures
thereof.
10. The pharmaceutical composition according to claim 8, wherein
said artificial sweetening agent is L-aspartylphenylalanine methyl
ester.
11. The pharmaceutical composition according to claim 8, wherein
said water-soluble artificial sweetening agent is selected from the
group consisting of: sodium or calcium saccharin salts, cyclamate
salts, acesulfam-K, ammonium glycyrrhizinate, dipotassium
glycyrrhizinate, and the free acid form of saccharin.
12. The pharmaceutical composition according to claim 7, wherein
said flavoring agent is present in from about 0.01% to about 1% by
weight/volume of the final composition.
13. The pharmaceutical composition according to claim 7, wherein
said flavoring agent is one or more members selected from the group
consisting of: peppermint, menthol, artificial vanilla, cinnamon,
lemon, lime, orange, menthol, strawberry, bubblegum, and mixtures
thereof.
14. The pharmaceutical composition according to claim 1, further
comprising a humectant.
15. The pharmaceutical composition according to claim 14, wherein
the humectant is present in an amount from 8 to 15 percent w/v of
the final composition.
16. The pharmaceutical composition according to claim 14, wherein
the humectant is selected from the group consisting of glycerol,
propylene glycol and mixtures thereof.
17. The pharmaceutical composition according to claim 1, wherein
the liquid is adjusted to a pH of 6.0 to 7.0.
18. The pharmaceutical composition according to claim 1, wherein
the liquid is adjusted to a pH of 6.0 to 6.9.
19. The pharmaceutical composition according to claim 1, wherein
the liquid is adjusted to a pH of 6.25 to 6.75.
20. The pharmaceutical composition according to claim 1, further
comprising an artificial sweetness enhancer in from about 0.05 to
about 1.5 percent w/v of the final composition.
21. The pharmaceutical composition according to claim 1, further
comprising EDTA in an amount from about 0.05% w/v to about 0.1%
w/v.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention relates to new pharmaceutical compositions
and methods for their preparation, and in particular it relates to
taste-masked liquid compositions comprising a solution of a
histamine H.sub.2-antagonist complexed with an alginate.
[0003] 2. Description of Related Art
[0004] The histamine H.sub.2-receptor antagonists are a highly
successful class of drugs. These compounds are widely prescribed to
treat gastrointestinal disorders and are usually administered
orally. Unfortunately, most members of this class have the drawback
of having an extremely disagreeable taste. The art has recognized
this problem and has applied many different approaches to trying to
solve this problem.
[0005] U.S. Pat. No. 4,996,222 describes a pharmaceutical
suspension of cimetidine having a pH of at least 7 wherein
substantially all of the cimetidine is in the polymorph B
crystalline form. The composition will contain a suspending agent.
The composition may contain alginate as a thickening agent.
Examples of suspending agents include xanthan gum,
hydroxypropylmethylcellulose, methylcellulose, carageenan, sodium
carboxymethyl cellulose, and sodium carboxymethyl
cellulose/microcrystall- ine cellulose mixtures, particularly
sodium carboxymethyl cellulose/microcrystalline cellulose
mixtures.
[0006] Thus, in U.S. Pat. No. 5,576,344,a process for reducing the
adverse taste and malodor associated with H.sub.2-receptor
antagonist nizatidine is described. The process involves formning
an aqueous solution of the compound and subjecting the solution to
elevated temperatures sufficient for a period sufficient to cause a
reduction in the adverse taste and/or malodor.
[0007] U.S. Pat. No. 5,622,980 describes a solid composition for
oral administration of an H.sub.2-receptor antagonist which
composition includes a silicate taste-masking agent capable of
forming an adsorbate complex with the H.sub.2-antagonist wherein
the complex exhibits a non-bitter taste. The complex inhibits the
release of the H.sub.2-antagonist in the oral cavity.
[0008] Chewable tablets containing unpleasant tasting medicaments
such as cimetidine are disclosed in U.S. Pat. No. 5,275,823. The
palatability of the tablets is improved by including certain
hygroscopic water-insoluble substances as extragranular excipients.
Such excipients include cellulose derivatives, sodium starch
glycolate and cross-linked polyvinylpyrrolidine.
[0009] A chewable dosage form containing a histamine
H.sub.2-receptor antagonist in an amount which is effective to
treat a gastrointestinal disorder is provided in a palatably
acceptable form in U.S. Pat. No. 6,270,807. The dosage form
comprises granules containing the histamine H2-receptor antagonist,
which are provided with a taste-masking coating comprising a
water-insoluble, water-permeable methacrylate ester copolymer in
which the coating is applied to the granules in an amount which
provides a taste-masking effect for a relatively short period
during which the composition is being chewed by a patient, but
which allows substantially immediate release of the histamine
H.sub.2-receptor antagonist after the composition has been chewed
and ingested.
[0010] U.S. Pat. No. 6,197,348 discloses a taste-masked
pharmaceutical composition. There is provided a taste masked oral
pharmaceutical composition including: a pharmaceutically active
ingredient having a pH-dependent solubility; a polymer
encapsulating said pharmaceutically active ingredient, said polymer
having a quaternary ammonium functionality; a suspending medium for
suspending the encapsulated pharmaceutically active ingredient,
said medium adjusted to a predetermined pH at which the
pharmaceutically active ingredient remains substantially insoluble;
and wherein the pharmaceutically active ingredient is taste masked
by the combination of the polymer and suspending medium.
[0011] Taste masked immediate release micromatrix powders are
described in U.S. Pat. No. 6,153,220. Taste masked immediate
release micromatrix powders can be formed by spray drying the drug
and cationic copolymer whereas sustained release micromatrix
powders can be formed by granulating controlled release powders,
which can be made by spray drying the drug with a retarding
polymer, with the cationic copolymer. These powders containing
drugs with poor organoleptic properties can be incorporated into
conventional oral dosage forms such as sprinkles, suspension, fast
melt tablets, chewable tablets or effervescent tablets.
BRIEF SUMMARY OF THE INVENTION
[0012] This invention relates to new pharmaceutical compositions
and methods for their preparation, and in particular it relates to
taste-masked liquid compositions comprising a solution of a
histamine H.sub.2-antagonist complexed with an alginate and also
containing a humectant. The solution is buffered to a pH of between
about 6 to 7. The inventive solution may be flavored and sweetened
and preserved.
DETAILED DESCRIPTION OF THE INVENTION
[0013] Histamine H.sub.2-antagonists have been used for a number of
years in the treatment of duodenal and benign gastric ulceration,
recurrent and stomal ulceration, esophageal reflux disease and
other conditions where reduction of gastric acid has been shown to
be beneficial, for example persistent dyspeptic symptoms with or
without ulceration. The members of this class of medicines have a
very bitter taste and palatability of oral compositions is a major
consideration and has been a major problem in the preparation of
liquid oral compositions. Although the inclusion of a bitter
tasting medicine in a coated tablet or within a capsule overcomes
the problem of offensive taste, many adults and many children that
have difficulty swallowing tablets or capsules cannot benefit from
these dosage forms.
[0014] Solutions of histamine H.sub.2-antagonists have been found
to be unpalatable. We have found that by preparing a solution of
H.sub.2-antagonists with an alginate, a taste-masked composition is
formed. The taste-masking is believed to result a complex being
formed between the H.sub.2-antagonist and the alginate. The taste
masking effect is augmented by the addition of sweetener, flavor,
artificial sweetener enhancer and a humectant.
[0015] It is clear that there has been a need for compositions of
histamine H.sub.2 antagonists which are liquid based and are
palatable. Histamine H.sub.2-antagonists are believed to be
absorbed almost exclusively in the small intestine and liquid-based
compositions offer the possibility that they could be absorbed more
quickly and more efficiently than tablet compositions, particularly
tablet compositions which have been coated to minimize unpleasant
tastes.
[0016] The composition of the present invention can be prepared by
mixing an alginate dispersion in a humectant and preservative
solution with a buffered solution of histamine H.sub.2 antagonist
then adding the sweetener, artificial sweetener enhancer (optional)
and flavor then adjusting the pH to about 6.5.+-.0.5 and adding
sufficient purified water to bring the solution to its final
volume.
EXAMPLE OF SWEETENERS INCLUDE
[0017] A. Water-soluble sweetening agents such as monosaccharides,
disaccharides and polysaccharides such as xylose, ribose, glucose,
mannose, galactose, fructose, dextrose, sucrose, sugar, maltose,
partially hydrolyzed starch, or corn syrup solids and sugar
alcohols such as sorbitol, xylitol, mannitol and mixtures
thereof.
[0018] B. Water-soluble artificial sweeteners such as the soluble
saccharin salts, i.e., sodium, or calcium saccharin salts,
cyclamate salts, acesulfam-K, ammonium glycyrrhizinate, dipotassium
glycyrrhizinate and the like, and the free acid form of
saccharin.
[0019] C. Dipeptide based sweeteners such as
L-aspartylphenylalanine methyl ester and materials described in
U.S. Pat. No. 3,492,131 and the like.
[0020] A water soluble sweetener (A.) will usually be present in an
amount corresponding to about 20 to 50% w/v of the total
composition, the amount depending in part upon whether other
sweetener ingredients are present and the level of sweetness
desired.
[0021] When sugar is used as the sweetener, typically it is present
from about 20% to about 50% w/v of the composition. It will be
appreciated that combinations of sweeteners can be used.
[0022] The sweetening agents when used, may also be used alone or
in combination with each other.
[0023] Humectants such as glycerol and propylene glycol are present
in the composition. Typically the total quantity of humectant
present is in the range of about 8 to 15% w/v. Thus, for example,
propylene glycol and glycerol can each be present individually or
in combination.
[0024] An artificial sweetness enhancer may optionally be utilized
in the present invention. When an artificial sweetness enhancer is
utilized, it may be present in an amount from about 0.05% to about
1.5% w/v of the final composition. Preferably, the artificial
sweetness enhancer will be present in an amount from about 0.1% to
about 1% w/v of the final composition. Typical artificial sweetness
enhancer would be Pro Sweet.RTM. manufactured by the Virginia Dare
company and Sweet AM.RTM. from Flavors of North America.
[0025] It is preferred that the liquid compositions of the present
invention contain preservatives to prevent microbial contamination.
Examples of preservatives are the alkylparabens, particularly
methylparaben, propylparaben and butylparaben. The amount of
preservative generally utilized will vary depending upon the
preservative selected and may for example range from about 0.05% to
about 1.5% w/v of the final composition. Preferably, the
preservative will be present in an amount from about 0.01% to about
0.1% w/v of the final composition.
[0026] Suitable flavorings include both natural and artificial
flavors, and mints such as peppermint, menthol, artificial vanilla,
cinnamon, various fruit flavors, both individual and mixed, and the
like are contemplated. The flavorings are generally utilized in
amounts that will vary depending upon the individual flavor, and
may, for example, range in amounts of about 0.01% to about 1% by
weight/volume of the final composition. Preferably, the flavorants
will be present in an amount ofabout 0.01% to about 0.1% w/v of the
final composition. The flavorants include synthetic flavorants or
natural flavorants, such as lemon, lime, orange, menthol,
strawberry, bubblegum, and the like.
[0027] The optional colorants useful in the present invention,
include the pigments such as titanium dioxide, that may be
incorporated in amounts of up to about 1% by weight/volume, and
preferably up to about 0.6% by weight/volume. Also, the colorants
may include other dies suitable for food, drug and cosmetic
applications, and known as F.D. & C. dyes and the like. The
materials acceptable for the foregoing spectrum of use are
preferably water-soluble. Illustrative examples include indigoid
die, known as F.D. & C. Blue No. 2, which is the disodium salt
of 5,5'-indigotindisulfonic acid. Similarly, the dye known as F.D.
& C. Green No. 1, comprises a triphenylmethane dye and is the
monosodium salt of
4-[4-Nethyl-p-sulfobenzylamino)diphenylmethylene]-[1-(N-ethyl-N-p-sulf-
oniumbenzyl)-2,5-cyclohexadienimine]. A full recitation of all F.D.
& C. and D. & C. and their corresponding chemical
structures may be found in the Kirk Otlimer Encyclopedia of
Chemical Technology, in Volume 5, at Pages 857-884, which text is
accordingly incorporated herein by reference.
[0028] The liquid compositions of the present invention may
optionally contain ingredients which improve its taste, such as
sodium chloride and natural and artificial flavour enhancers such
as monosodium glutamate, soy sauce and the like.
[0029] The liquid compositions of the present invention contain
from about 0.5 to 5% w/v histamine H.sub.2-antagonist. Preferably,
the histamine H.sub.2-antagonist will be present in an amount of
about 0.01% to about 0.1% w/v of the final composition. The
histamine H.sub.2 antagonist is selected from the group consisting
of nizatidine, famotidine, ranitidine, and cimetidine.
[0030] The ratio of histamine H.sub.2-antagonist to alginate is
about 1:0.1 to about 1:0.6 w/w and preferably about 1:02 to about
1:04 w/w.
[0031] Alginates are a hydrophilic, colloidal polysaccharide in the
form of salts such as sodium, calcium, magnesium and other bases.
The preferred form of alginate is an alkali metal salt most
preferably the sodium salt. Alginatc is present in an amount of
about 20% to about 40% w/w of the histamine H.sub.2-antagonist.
[0032] Buffers: The buffer comprises acids and their base salts for
example, citric acid (e.g., citric acid anhydrous), tartaric acid,
malic acid, phosphoric acid and the like and their respective
salts.
[0033] Obviously, numerous modifications and variations of the
present invention are possible in light of the above teachings and
the invention is not limited to the example herein. It is therefore
understood that within the scope of the appended claims, the
invention may be practiced otherwise than as specifically described
herein.
[0034] In one preferred embodiment of the invention there is
provided a composition containing 0.5 to 2.5% w/v of histamine
H.sub.2-antagonist. In another preferred embodiment, the histamine
H.sub.2-antagonist is nizatidine.
EXAMPLE
[0035] A Sample Nizatidine Formulation:
1 Component per 100 ml. % w/v Nizatidine 0.5 to 2.5 Humectant 8 to
15 Sodium alginate 0.1 to 1.5 Sodium chloride 0.1 to 0.5 Artificial
sweetener 0.1 to 0.5 Buffer 0.5 to 1.5 Preservative 0.05 to 0.5
Natural sweetener 20 to 50 Flavor 0.01 to 1.0 Artificial sweetness
enhancer 0.1 to 0.9 Water to 100% v/v QS
[0036] Process
[0037] Premix 1:
[0038] Add with mixing the preservative(s) to the humectant which
is contained in a suitable vessel and has been preheated to about
60.degree. C..+-.5.degree. C. and continue mixing until dissolved.
Cool the solution to about 50.degree. C..+-.5.degree. C. then
slowly add the alginate with continued mixing to uniformly disperse
the alginate in the liquid.
[0039] In a second vessel, add an amount of purified water equal to
about 64% of the final batch volume. Add the following ingredients
in the order listed below, with continuous mixing and not adding
the next ingredient until the current added ingredient is
completely dissolved.
[0040] 1. Flavor enhancer (salt)
[0041] 2. Artificial sweetener
[0042] 3. Buffering agent (basic portion first if a two component
buffer)
[0043] 4. Buffering agent (acidic portion if applicable)
[0044] 5. Histamine H sub 2 antagonist
[0045] 6. Premix 1
[0046] 7. Sweetener
[0047] 8. Artificial sweetener enhancer
[0048] 9. Flavor
[0049] 10. EDTA (optional)
[0050] Stop mixing and pre qs to 95% of the final batch volume then
mix until the solution is uniform. Measure the pH (use temperature
compensation to RT) and adjust the pH if necessary to 6.5. If the
pH is greater than 6.5, adjust by adding citric acid solution 20%
and mix well. If the pH is less than 6.5, adjust by adding sodium
hydroxide 1N and mix well. Discontinue mixing and qs to the final
batch volume with purified water.
* * * * *