U.S. patent application number 14/165887 was filed with the patent office on 2014-05-22 for pharmaceutical suspension composition.
This patent application is currently assigned to Wyeth LLC. The applicant listed for this patent is Wyeth LLC. Invention is credited to Amanda Alley, Jay Dickerson, David Jaeger, William Mark, Annabelle Trimmer.
Application Number | 20140142187 14/165887 |
Document ID | / |
Family ID | 35425554 |
Filed Date | 2014-05-22 |
United States Patent
Application |
20140142187 |
Kind Code |
A1 |
Dickerson; Jay ; et
al. |
May 22, 2014 |
Pharmaceutical Suspension Composition
Abstract
An aqueous oral liquid pharmaceutical composition system with
reduced propensity for agglomeration and phase separation which is
particularly amendable to the suspension of one or more
pharmaceutical actives that are substantially insoluble in water.
The oral liquid pharmaceutical composition may further comprise
pharmaceutical actives that are soluble in water and dissolve in
the aqueous medium. In the composition of the invention both
suspended and any dissolved active agents are distributed
homogeneously.
Inventors: |
Dickerson; Jay; (Midlothian,
VA) ; Mark; William; (Glen Allen, VA) ;
Trimmer; Annabelle; (Manakin-Sabot, VA) ; Jaeger;
David; (Chester, VA) ; Alley; Amanda;
(Midlothian, VA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Wyeth LLC |
New York |
NY |
US |
|
|
Assignee: |
Wyeth LLC
New York
NY
|
Family ID: |
35425554 |
Appl. No.: |
14/165887 |
Filed: |
January 28, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12403081 |
Mar 12, 2009 |
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14165887 |
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10852946 |
May 25, 2004 |
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12403081 |
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Current U.S.
Class: |
514/570 |
Current CPC
Class: |
A61K 31/137 20130101;
A61K 47/10 20130101; A61K 47/36 20130101; A61K 9/0053 20130101;
A61K 45/06 20130101; A61K 47/38 20130101; A61K 31/00 20130101; A61K
31/4402 20130101; A61K 9/10 20130101; A61K 47/12 20130101; A61K
31/192 20130101; A61K 9/0095 20130101; A61K 47/26 20130101 |
Class at
Publication: |
514/570 |
International
Class: |
A61K 9/10 20060101
A61K009/10; A61K 47/36 20060101 A61K047/36; A61K 47/38 20060101
A61K047/38; A61K 31/192 20060101 A61K031/192 |
Claims
1. An oral liquid pharmaceutical composition comprising: a. a
suspending system comprising an an aqueous medium, about 0.1 g/100
mL to about 0.5 g/100 mL xanthan gum and about 0.5 g/100 mL to
about 3.0 g/100 mL microcrystalline
cellulose/carboxymethylcellulose sodium; b. Ibuprofen; c. at least
one density adjusting agent consisting of sorbitol, glycerin,
propylene glycol, or a mixture thereof; d. wherein said composition
is sugar free; and e. wherein said composition optionally includes
one or more soluble pharmaceutical active ingredients dissolved in
the aqueous medium.
2. (canceled)
3. (canceled)
4. (canceled)
5. The pharmaceutical composition of claim 1 wherein the density
adjusting agent comprises 10 g/100 mL to about 50 g/100 mL glycerin
and about 10 g/100 mL to about 50 g/100 mL sorbitol.
6. The pharmaceutical composition of claim 1 further comprising
about 0.1 g/100 mL to about 1.5 g/100 mL of a surface modifying
agent.
7. (canceled)
8. (canceled)
9. (canceled)
10. (canceled)
11. (canceled)
12. The pharmaceutical composition of claim 6 wherein the surface
modifying agent is a polysorbate.
13. (canceled)
14. (canceled)
15. (canceled)
16. (canceled)
17. (canceled)
18. (canceled)
19. (canceled)
20. (canceled)
21. (canceled)
22. (canceled)
23. (canceled)
24. A method for treatment of pain and discomfort associated with
at least one of headache, body ache, cold symptoms, flu symptoms,
and allergy symptoms in humans comprising the administration to a
human of a safe and effective amount of the pharmaceutical
composition of claim 7.
25. A method of preparing an oral liquid pharmaceutical composition
comprising: a. preparing a suspending system, comprising xantham
gum, microcrystalline cellulose, carboxymethylcellulose sodium, or
combinations thereof in an aqueous medium; b. optionally dissolving
additional sugar free excipients in an aqueous medium; c. preparing
a homogeneous composition by mixing the optional additional
excipients into the suspending system; d. uniformly dispersing at
least one substantially insoluble first pharmaceutical active
selected from ibuprofen, ketoprofen, naproxen and pharmaceutically
acceptable salts thereof in a solution comprising polyols; and e.
mixing the uniformly dispersed first pharmaceutical active in a
solution comprising polyols with the homogeneous composition to
form a suspension; wherein the polyols are used at a concentration
that creates a solution with a specific gravity matching the true
density of the at least one substantially insoluble first
pharmaceutical active; f. optionally adding to the suspension at
least one soluble additional pharmaceutical active dissolved in a
water/polyol mixture.
26. The method of claim 25 further comprising de-aerating the
composition by subjecting it to vacuum.
27. (canceled)
28. The method of claim 26 further comprising adding a surface
modifying agent to the pharmaceutical composition.
29. A method for treatment of pain and discomfort associated with
at least one of headache, body ache, cold symptoms, flu symptoms,
and allergy symptoms in humans comprising the administration to a
human of a safe and effective amount of the pharmaceutical
composition of claim 25.
30. A method for treatment of pain and discomfort associated with
at least one of headache, body ache, cold symptoms, flu symptoms,
and allergy symptoms in humans comprising the administration to a
human of a safe and effective amount of the pharmaceutical
composition of claim 26.
Description
FIELD OF INVENTION
Background of Invention
[0001] This is a divisional application of copending application
Ser. No. 10/852,946 filed on May 25, 2004 the entire disclosure of
which is hereby incorporated by reference.
[0002] Orally administered pharmaceutical compositions are provided
to patients in many dosage forms, including solid forms such as
capsules, caplets or tablets and liquid forms such as solutions,
emulsions or suspensions. Pharmaceutical compositions administered
in solid form are usually intended to be swallowed whole. Children,
older persons and many other persons including disabled or
incapacitated patients often have trouble swallowing tablets or
capsules. For many such patients, including pediatric and geriatric
patients, a liquid dose form is preferable because of the ease with
which it may be swallowed.
[0003] Pharmaceutically acceptable liquid excipient suspension
systems have been described in the literature. For example, in U.S.
Pat. No. 5,759,579, Singh et al. describe a xanthan gum and
hydroxypropylmethylcellulose liquid excipient for suspending solid
pharmaceutically active compounds. Blase et al. in U.S. Pat. Nos.
5,272,137 and 5,409,907 describe and claim a liquid suspension
system for the substantially water soluble pharmaceutical active,
acetaminophen.
[0004] Although such suspensions are known, the known systems
frequently manifest the undesirable properties of irreversible
agglomeration and/or phase separation particularly if a
pharmaceutical active with a limited solubility in water is used.
Hence, it would be desirable to have a liquid excipient suspension
system with reduced propensity for occurrence of irreversible
agglomeration and/or phase separation that is suitable for the
suspension of pharmaceutical actives substantially insoluble in
water.
SUMMARY OF THE INVENTION
[0005] The invention is directed to an oral liquid pharmaceutical
composition comprising a suspending system which comprises in a
preferred embodiment an aqueous composition, which includes about
0.1 g/100 mL to about 1.0 g/100 mL xanthan gum and about 0.5 g/100
mL to about 3.0 g/100 mL microcrystalline
cellulose/carboxymethylcellulose sodium in an aqueous base (or
"aqueous medium") and at least one pharmaceutical active (also
referred to herein as "at least one pharmaceutical active compound"
or "at least one first pharmaceutical active"), that is
substantially insoluble in water (or the aqueous base). The
suspending system is also referred to herein as an "aqueous based
suspending system" or an "aqueous composition".
[0006] The pharmaceutical active is suspended in the aqueous
composition and a density adjusting agent is employed to balance or
match the true density of the suspended ingredients (typically the
pharmaceutical active) with the specific gravity of the suspending
medium. In an exemplary embodiment, the density adjusting agent
comprises about 10 g/100 mL to about 50 g/100 mL glycerin and about
10 g/100 mL to about 50 g/100 mL sorbitol. Alternatively,
conventional sugars and/or other polyols may be used for density
adjusting. However, in some embodiments it is preferable to prepare
a sugar free composition, avoiding the use of conventional sugars.
Optionally, about 0.1 g/100 mL to about 1.5 g/100 mL of a surface
modifying agent such as a surfactant may be included in the liquid
pharmaceutical composition. The pharmaceutical active that is
substantially insoluble in the aqueous composition may comprise
ibuprofen, naproxen, ketoprofen or loratadine, or a mixture thereof
for example.
[0007] In one embodiment the pharmaceutical composition may further
comprise at least one second pharmaceutical active which is soluble
in the aqueous composition and whereby the at least one second
pharmaceutical active remains in solution in the aqueous medium.
The second pharmaceutical active may include one or more of
pseudoephedrine, chlorpheniramine, dextromethorphan,
brompheniramine, guaifenesin and diphenhydramine, for example.
[0008] The invention provides a method of preparing an oral liquid
pharmaceutical composition comprising: preparing a suspending
system, suspending at least one substantially insoluble
pharmaceutical active in the suspending system and matching the
true density of the substantially insoluble pharmaceutical active
with the specific gravity of the aqueous medium. The suspending
system may comprise an aqueous composition which includes about 0.1
g/100 mL to about 0.5 g/100 mL xanthan gum and about 0.5 g/100 mL
to about 3.0 g/10 mL microcrystalline
cellulose/carboxymethylcellulose sodium and an aqueous medium. In
some embodiments the method may further comprise dissolving at
least one soluble pharmaceutical active in the aqueous medium
and/or adding a surface modifying agent to the pharmaceutical
composition.
DETAILED DESCRIPTION OF THE INVENTION
[0009] The invention provides an oral (and aqueous) liquid
pharmaceutical composition system with reduced propensity for
irreversible agglomeration and phase separation and is particularly
amenable to the suspension of one or more pharmaceutical actives
that are substantially insoluble in water. The oral liquid
pharmaceutical composition may further comprise pharmaceutical
actives that are soluble in water and which dissolve in the aqueous
medium. In the composition of the invention both suspended and any
dissolved components of the composition are distributed
substantially homogeneously. The pharmaceutical composition
comprises a suspending system, one or more suspended pharmaceutical
actives and a density adjusting agent. The suspending system is
based on a thixotropic gum system in an aqueous medium where
sufficient shear (upon shaking) permits mobility of the suspension.
In one preferred embodiment, the suspending system comprises
xanthan gum and microcrystalline cellulose/carboxymethylcellulose
sodium in an aqueous base. This combination yields thixotropic
properties such that the viscosity of the undisturbed base
increases over time. Such increase in viscosity is believed to
facilitate minimization of the migration of the suspended active
(or actives) upon storage over time. Upon shear (shaking), the
viscosity decreases to allow easy dispensing of the drug
product.
[0010] Additionally, the invention further offers the advantage
that it is preferably formulated using polyols. The inventors
believe, without wishing to be bound to the theory, that the use of
polyols facilitates stability in the suspension by equilibrating
the true density of the suspended ingredients with the specific
gravity of the suspending medium. This is believed to minimize the
migration of suspended pharmaceutical active over time. The
preferred polyols for use in the practice of the invention are a
mixture of glycerin and sorbitol. The sorbitol may be in pure form
or a sorbitol solution, such as a 70% sorbitol in water solution,
for example. Likewise pure glycerin, or a glycerin in water
solution, such as 96% glycerin in water may be used. Conventional
sugars, such as cane sugar or sucrose, fructose, or corn syrup
alone or in combination with other sugars and/or polyols may be
used as the density adjusting agent. However, in embodiments
intended for administration to a young child or diabetic geriatric
patient, avoidance of conventional sugars is preferable.
[0011] In some embodiments surface modifying agents, such as a
surfactant, are used in the pharmaceutical composition to modify
the surface of the suspended components. Such surface modification
is believed to facilitate diminished irreversible aggregation of
the suspended particles.
[0012] The aqueous-based suspending system may be used to suspend
one or more pharmaceutically active compounds which are
substantially insoluble in water or the aqueous medium. In some
embodiments the aqueous suspending system may suspend one or more
substantially insoluble pharmaceutical active compounds and further
comprise one or more other pharmaceutically active compounds which
are soluble in water and which are dissolved in the aqueous medium.
In the pharmaceutical composition of the invention the
pharmaceutical active compounds (i.e., active ingredients), both
the suspended substantially insoluble active ingredients and any
soluble active ingredients dissolved in the aqueous medium, are
distributed to form a substantially homogeneous distribution of
active ingredients in the pharmaceutical composition.
[0013] As used in this description and the appended claims, a
pharmaceutical active that is substantially insoluble in the
aqueous composition includes Ibuprofen, Ketoprofen, Naproxen,
Celecoxib, Rofecoxib, Valdecoxib, Nabumetone, Glimepiride,
Diclofenac, Piroxicam and Meloxican. For pharmaceutical actives not
specified on this list a pharmaceutical active substantially
insoluble in the aqueous composition means a pharmaceutical active
designated as relatively insoluble or insoluble in water by the
Merck Index.
[0014] A pharmaceutical active designated to be soluble in the
aqueous composition includes Fexofenadine (HCl), Chlorpheniramine
(maleate), Brompheniramine (maleate), Diphenhydramine (HCl,
Citrate), Cetirizine (HCl), Carbinoxamine (maleate), Loratadine,
Desloratadine, Guaifenesin. Pseudoephedrine (HCL, Sulfate),
Phenylpropanolamine (HCl), Ephedrine (HCl, Sulfate),
Dextromethorphan (HBr), Codine (Phosphate) and Hydrocodone
(bitartrate). For pharmaceutical actives not specified on this
list, soluble pharmaceutical active means a pharmaceutical active
indicated to be soluble in water by the Merck Index.
[0015] Unless otherwise specified, amounts designated in g/100 mL
means grams per 100 milliliters of the pharmaceutical composition.
For example, 10 g/100 mL ibuprofen means 10 g of ibuprofen in 100
mL of the oral liquid pharmaceutical composition. A designation of
mg/5 mL means milligrams per 5 milliliters of the pharmaceutical
composition. For example, a designation of 10 mg/5 mL ibuprofen
means 10 mg of ibuprofen would be found in 5 milliliters of the
composition. The preferred dosage unit is 5 mL, to be administered
to the patient as a single dosage unit or multiples thereof, based
on age and weight.
[0016] The term "medium density matching" (or "density matching")
means balancing the true density of the suspended components
(ingredients) in the composition with the specific gravity of the
suspending medium. Density matching is accomplished using a
"density adjusting agent" which may be comprised of one or more
components. Typically, the desired amount of suspended component
and its density is determined and the amount of density adjustment
agent needed to adjust the specific gravity of the medium to match
the density of the suspended compound is determined by calculation.
Calculations of density and specific gravity are well known to
those skilled in the art. In some instances it is desirable to make
density and specific gravity measurements, which are familiar to
those skilled in the art, and use the information obtained to
experimentally correct the amounts of components in the density
adjusting agent and/or amount of water to account for deviation
between theoretical amounts calculated and actual properties
manifested by the composition.
[0017] In one exemplary embodiment the density matching is
accomplished using the density adjusting agent of sorbitol, or a
sorbitol/water solution, and glycerin, or a glycerin/water
solution, in combination with adjusting the amount of water in the
composition. For a representative example in which ibuprofen was
the substantially insoluble pharmaceutically active agent, the
desired density matching was achieved using a ratio of
water:sorbitol (70% solution in water):glycerin (96% in water) of
about 5.6:2:3.
[0018] In some embodiments propylene glycol may be used in
combination with sorbitol and/or glycerin for density balancing.
Although polyols other than conventional sugars are preferred in
some embodiments of the invention, conventional sugars, mixtures of
sugars or mixtures of sugars with other polyols may be used in the
invention. The "density adjusting agent" comprises the component or
components (typically one or more polyols), excluding water, added
to achieve density matching.
[0019] "Microcrystalline cellulose/carboxymethylcellulose sodium"
means a dried coprecipitated microcrystalline of cellulose and
sodium carboxymethylcellulose. Microcrystalline
cellulose/carboxymethylcellulose sodium is a typical example of a
coprecipitate in microcrystalline cellulose which may be used in
the practice of the invention.
[0020] The suspending system of the invention is an aqueous based
system including xanthan gum and/or microcrystalline
cellulose/carboxymethylcellulose sodium incorporated therein. While
either xanthan gum or microcrystalline
cellulose/carboxymethylcellulose sodium may be used alone in the
practice of the invention, in a preferred embodiment the
combination is used. Xanthan gums suitable for use in the present
invention are high molecular weight polysaccharides such as the
xanthan gum produced by Xanthamonas capestris, for example. Xanthan
gum is an article of commerce and is available, for example, from
manufacturers such as: Rhodia, Inc. under the brand name
Rhodigel.TM. and from Kelco.TM., a division of Merck. Rhodigel.TM.
80 Pharm Grade is exemplary of one specific commercial product
suitable for use in the practice of the invention.
[0021] The xanthan gum is present in the liquid pharmaceutical
composition in an amount of about 0.1 g/100 mL to about 1.0 g/100
mL. More preferably the xanthan gum is present in an amount of
about 0.1 g/100 mL to about 0.3 g/100 mL and most preferably about
0.2 g/100 mL xanthan gum is used. It is preferable that the gum be
dispersed in glycerin and hydrated in water prior to the addition
of other components to the gum system.
[0022] A microcrystalline cellulose/carboxymethylcellulose sodium
suitable for use in the practice of the invention is a
coprecipitated microcrystalline cellulose and sodium
carboxymethylcellulose. It is preferable that the microcrystalline
cellulose/carboxymethylcellulose sodium comprises sodium
carboxymethylcellulose in the range of from about 8 weight percent
to about 19 weight percent and more preferably about 8 to about 15
weight percent sodium carboxymethylcellulose.
Microcrystallinecellulose/carboxymethylcellulose sodium is
commercially available, e.g., from FMC under the trademark
Avicel.TM.. Suitable Avicels.TM. include but are not limited to
Avicel.TM. CL-611; Avicel.TM. RC-581; and Avicel.TM. RC-591.
Avicel.TM. CL-611 is the preferred Avicel.TM. for use in the
suspending system.
[0023] The oral pharmaceutical composition preferably comprises
about 0.5 g/100 mL to about 3.0 g/100 mL, more preferably about 1
g/100 mL to about 2 g/100 mL, and most preferably about 1.5 g/100
mL microcrystalline cellulose/carboxymethylcellulose sodium. When
used in combination with xanthan gum, it is preferable that the
weight of microcrystalline cellulose/carboxymethylcellulose sodium
used be about 5 to about 10 times that of the weight of xanthan gum
used and more preferable that the weight of microcrystalline
cellulose/carboxymethylcellulose sodium be about 7.5 times that of
the weight of xanthan gum when used in combination.
[0024] The pharmaceutically active compounds useful in the practice
of the present invention include non-steroidal anti-inflammatory
drugs (NSAIDS), antihistamines, decongestants, antitussives,
expectorants and analgesic drugs such as acetaminophen and
phencetin. Amounts of pharmaceutically active compounds
incorporated are conventional dosages known to those skilled in the
art. Further, for pharmaceutical compositions intended for use in
the United States, amounts of pharmaceutical actives are preferably
in compliance with applicable FDA regulation regarding dosage of
such compounds.
[0025] Non-steroidal anti-inflammatory drugs (NSAIDS) which may be
used in the practice of the invention include, but are not limited
to: propionic acid derivatives such as ibuprofen, naproxen,
ketoprofen, flurbiprofen, fenoprofen, suprofen, fluprofen and
fenbufen; acetic acid derivatives such as tolmetin sodium,
zomepirac, sulindac, and indomethacin; fenamic acid derivatives
such as mefenamic acid and meclofenamate sodium; biphenyl
carboxylic acid derivatives such as diflunisal and flufenisal and
oxicams such as piroxicam, sudoxicam and isoxicam.
[0026] Antihistamines useful in the practice of the present
invention (along with their preferred salt form) include, but are
not limited to, chlorpheniramine (maleate), brompheniramine
(maleate); dexchlorpheniramine (maleate), dexbrompheniramine
(maleate), triprolidine (HCl), diphenhydramine (HCl), doxylamine
(succinate), tripelenamine (HCl), cyproheptatine (HC),
bromodiphenhydramine (HCl), phenindamine (tartrate), pyrilamine
(maleate, tannate), azatadine (maleate); acrivastine, astemizole,
azelastine, cetirizine, ebastine, fexofenadine, ketotifen,
carbinoxamine (maleate), desloratadine, loratadine, mizolastine and
terfenadine.
[0027] Antitussives useful in the practice of the present invention
(along with their preferred salt form) include, but are not limited
to, caramiphen (ediylate), dextromethorphan (HBr), codeine
(phosphate, sulfate) and Hydrocodone.
[0028] Decongestants useful in the practice of the invention (along
with their preferred salt form) include, but are not limited to,
pseudoephedrine (HCl), Ephedrine (HCl, Sulfate), phenylephrine
(ditartarate, tannate, HBr, HCl, and phenylpropenolamine (HCl).
[0029] Expectorants which may be used in the practice of the
invention (along with their preferred salt form) include but are
not limited to terpin hydrate, guaifenesin (glycerol, guaiacolate),
potassium (iodide, citrate) and potassium guaicolsulfonate.
[0030] Cox 2 inhibitors which may be used in the practice of the
invention include Celecoxib, Rofecoxib and Valdecoxib.
[0031] Other Pharmaceutical actives which are substantially
insoluble and may be suspended in the suspending system of the
invention include nabumetone, glimepiride, diclofenac, piroxicam
and meloxican.
[0032] Of the pharmaceutically active compounds described above,
those which are particularly preferred are set forth below along
with preferred ranges for their inclusion into the claimed
pharmaceutical composition.
[0033] Ibuprofen may be used in amounts of up to about 3 grams per
100 mL. Preferably ibuprofen is present in amounts of between about
1 g/100 mL and about 3 g/100 mL. Most preferably, ibuprofen is
present in amounts of about 2 g/100 mL of the pharmaceutical
composition.
[0034] Naproxen may be used in amounts of about 1 g/100 mL to about
5 g/100 mL of the pharmaceutical composition. Preferably naproxen,
when used in the pharmaceutical composition, is present in amounts
of between about 2 g/100 mL and about 3 g/100 mL of the
pharmaceutical composition.
[0035] Chlorpheniramine may be used in the pharmaceutical
composition in amounts between about 0.01 g/100 mL and about 0.05
g/100 mL. Preferably chlorpheniramine, when used in the
pharmaceutical composition, is present in the amount of about 0.01
g/100 mL to 0.03 g/100 mL.
[0036] Pseudoephedrine may be used in the pharmaceutical
composition in amounts between about 0.1 g/100 mL and about 0.6
g/100 mL of the suspension. Preferably, pseudoephedrine, when used
in the composition, is present in amounts of about 0.2 g/100 mL to
about 0.4 g/100 mL of the pharmaceutical composition.
[0037] Chlorpheniramine maleate may be used in the pharmaceutical
composition, preferably in the amount of about 0.01 g/100 mL to
about 0.03 g/100 mL.
[0038] Brompheniramine maleate may be used in the pharmaceutical
composition, preferably in the amount of about 0.01 g/100 mL to
about 0.03 g/100 mL.
[0039] Dextromethorphan HBr may be used in the pharmaceutical
composition, preferably in the amount of about 0.05 g/100 mL to
about 0.250 g/100 mL.
[0040] Diphenhydramine may be used in the pharmaceutical
composition, preferably in an amount of about 0.10 g/100 mL to
about 0.40 g/100 mL.
[0041] The pharmaceutically active compounds are preferably of N.F.
(National Formulary) or U.S.P. (United States Pharmacopeia)
grade.
[0042] Excipients known by those skilled in the art may be useful
in the practice of the present invention. Such excipients may
include but are not limited to humectants such as glycerin and
propylene glycol, defoaming agents, buffers, electrolytes,
preservatives such as sodium benzoate and disodium edetate,
sweeteners, taste masking agents and various flavoring and coloring
agents. It is preferable to use "non-sugar" sweeteners, e.g.
avoidance of the use of conventional sugars such as cane sugar or
sucrose, and corn syrup, or fructose is preferred. Preferred
sweeteners include sucralose, acesulfame K, saccharin sodium, and
sorbitol. To the extent that polyols are intended for use as
excipients, this use should be accounted for in the density
matching e.g., addition of polyols not accounted for in the medium
density matching is typically not desirable.
[0043] Examples of suitable flavoring agents include, but are not
limited to, natural and artificial flavors such as mints (i.e.,
peppermint, etc.), menthol, cinnamon, vanilla, artificial vanilla,
chocolate, artificial chocolate, bubblegum, both artificial and
natural fruit flavors (i.e., cherry, grape, orange, strawberry,
etc.) and combinations of two or more thereof. Flavoring agents are
generally provided as a minor component of the suspension in
amounts effective to provide palatable flavor to the compositions.
Typically, flavoring agents are present in amounts in the range of
about 0 grams to about 5 grams per 100 ml of the composition.
[0044] Preservatives useful in the present invention include but
are not limited to sodium benzoate, potassium sorbate, salts of
edetate (also known as salts of ethylenediaminetetraacetic acid or
EDTA, such as disodium edetate) benzaldionium chloride and parabens
(such as methyl, ethyl, propyl, and butyl p-hydroxybenzoic acid
esters). Preservatives listed above are exemplary, but each
preservative must be evaluated on an experimental basis, in each
formulation to assure compatibility and efficacy of the
preservative. Methods for evaluating the efficacy of preservatives
in pharmaceutical formulations are known to those skilled in the
art. Sodium benzoate and disodium edetate are the presently
preferred preservative ingredients.
[0045] Preservatives are generally present in amounts of up to one
gram per 100 ml of the pharmaceutical composition. Preferably the
preservatives are present in amounts in the range of from about 0.1
g/100 mL to about 0.4 g/100 mL of the composition. Typically, the
preservative sodium benzoate would be present in the range of about
0.2 g/100 mL to about 0.3 g/1001 mL of the composition. Sodium
benzoate is typically used in a concentration of about 0.25 g/100
ml of the composition.
[0046] Coloring agents may also be incorporated in the
pharmaceutical composition to provide an appealing color to the
composition. The coloring agents should be selected to avoid
chemical incompatibilities with other ingredients in the
suspension. Suitable coloring agents are well known to those
skilled in the art.
[0047] Typically, water is added in the process of making the
pharmaceutical composition in portions with various components.
During the process of preparation of the pharmaceutical
composition, amounts of added water are believed to be particularly
important in three instances. Sufficient water should be available
when soluble active ingredient(s) and soluble salts are added to
permit them to dissolve, a sufficient amount of water should be
available in combination with the density adjusting agent to
achieve medium density matching, and sufficient water should be
available to hydrate the water soluble/dispersible gums.
[0048] Preferably, the specific gravity of the liquid portion
(i.e., the suspending medium) of the suspension should be balanced
with the true density of the suspended actives. This may be
accomplished by adding a density adjusting agent. For a typical
example, a density adjusting agent comprising about 10 g/100 mL to
about 50 g/100 mL glycerin and about 10 g/100 mL to about 50 g/100
mL sorbitol may be added to the pharmaceutical composition to
achieve the desired density balance. In an exemplary embodiment
containing ibuprofen as a substantially insoluble active, the
desired balance was achieved using about 30 g/100 mL glycerin (96%
in water) and 20 g/100 mL sorbitol (70% solution in water). The use
of the polyol, sorbitol, is preferred in some embodiments as it
also offers the additional advantage of sweetening the
composition.
[0049] It will be understood by those skilled in the art that as
liquids other than water are included in the liquid portion of the
pharmaceutical composition, the amounts of the components including
water used to balance the specific gravity of the liquid portion
with the true density may need to be adjusted to achieve the
desired balance.
[0050] Optionally about 0.1 g/100 mL to 1.5 g/100 mL surfactant may
be added to the suspending system to further stabilize the
pharmaceutical composition. The inventors believe, without wishing
to be bound to the theory, that the surfactant modifies the surface
of suspended actives and facilitates diminished irreversible
aggregation of the suspended particles. The surfactant may be an
ionic or non-ionic surfactant or mixtures thereof. Exemplary
surfactants include but are not limited to polysorbates (tweens),
Spans.TM., togats, lecithin, polyoxyethylene-polyoxypropylene block
copolymers and medium chain mono/di-glycerides. In an exemplary
embodiment in which ibuprofen was the active agent, polysorbate 80
was used in an amount of about 0.3 g/100 mL.
[0051] For an exemplary embodiment of the pharmaceutical
composition, the pH is about 3.5 to about 4.5 and the disturbed
viscosity (e.g. viscosity measured after mixing under specified
conditions) at 25.degree. C. will be about 1500 to about 4500
cps.
Example 1
[0052] The following Example discloses a pharmaceutical composition
(which is a suspension) comprising ibuprofen as a substantially
insoluble active and a process for manufacturing this composition.
The composition of the suspension of Example 1 is provided in Table
1 below:
TABLE-US-00001 TABLE 1 Component g/100 mL Ibuprofen USP (40 micron
particle size) 2.00 Pseudoephedrine HC1HCl USP 0.300
Chlorpheniramine Maleate USP 0.0200 Xanthan Gum NF (Rhodigel 80
Pharma Grade) 0.200 Microcrystalline
Cellulose/Carboxymethylcellulose 1.50 Sodium NF (Avicel Type CL
611) Polysorbate 80 NF 0.300 Glycerin 96% USP 30.0 Sorbitol
Solution USP 70% 20.0 Micronized Sucralose Powder NF 0.200 Sodium
Citrate USP/FCC 0.550 Sodium Benzoate NF 0.250 Edetate Disodium USP
0.0500 Citric Acid Hydrous USP 0.750 Flavor 0.360 Color 0.0025
Purified Water USP Qs 100 mL
[0053] As indicated in the header of Table 1, amounts are stated in
grams per 100 milliliter aliquot of the final composition. Density
matching was accomplished by first calculating theoretical amounts
of components of density adjusting agent based on the density of
the insoluble active and specific gravity of the aqueous based
medicine, preparing the composition based on calculated amounts,
then making experimental measurements on the composition, and
making final adjustment of component amounts of density matching
agents for desired matching of specific gravity of the medium with
the true density of suspended component based on experimental
measurements. Amounts of density matching agent components for the
Example disclosed in Table 1 were determined using this approach
prior to manufacture of the composition.
[0054] The composition of Example 1 was prepared by placing a
portion of the glycerin in a first stainless steel mixing vessel
equipped with variable speed mixer and gradually adding the xanthan
gum with mixing to thoroughly disperse the xanthan gum. An aliquot
of water (an amount less than the final amount of water) was added
to a second stainless steel mixing vessel (main vessel) equipped
with a variable speed mixer and the microcrystalline
cellulose/carboxymethyl cellulose sodium was added with mixing to
hydrate the microcrystalline cellulose/carboxymethyl cellulose
sodium. The thoroughly mixed glycerin/xanthan gum and
microcrystalline cellulose/carboxymethyl cellulose sodium/water
dispersions were then combined in the main vessel with mixing.
Edetate disodium was then added and mixing was continued until the
composition was uniform.
[0055] Sorbitol solution (70% sorbitol in water) was placed in a
third stainless steel vessel equipped with a mixer. Polysorbate 80
was added to the sorbitol solution and mixed thoroughly. Ibuprofen
was then added to the sorbitol/polysorbate 80 solution and mixed
thoroughly to uniformly disperse the ibuprofen.
[0056] Sodium benzoate, sodium citrate, sucralose micronized powder
and coloring agents were dissolved in an aliquot of purified water
and then added to the contents of the main vessel with mixing.
[0057] Following the addition of the sodium benzoate, sodium
citrate, sucralose and coloring agent mixture, the
sorbitol/polysorbate 80/ibuprofen dispersion was added to the
contents of the main vessel with mixing.
[0058] Upon completion of transfer of the sorbitol/polysorbate
80/ibuprofen dispersion to the main vessel and mixing of the
resulting composition, a citric acid solution in purified water was
prepared and added to the contents of the main vessel.
[0059] Soluble actives, pseudoephedrine HCl and chlorpheniramine
maleate in this example, were dissolved in a water/glycerin mixture
and then added to the contents of the main vessel with mixing.
Assembly of the composition of Example 1 was completed by adding
flavor to the contents of the main vessel and adding sufficient
purified water to adjust batch volume to the final batch size.
[0060] After the final addition of components, mixing was continued
for an additional 30 minutes with the composition being
re-circulated through a 40-mesh filter. The composition was
de-aerated by subjecting it to a vacuum prior to packaging and/or
storage.
Example 2
[0061] The composition of Example 2 is provided in Table 2
below:
TABLE-US-00002 TABLE 2 Component g/100 mL Ibuprofen USP (40 micron
particle size) 2.00 Pseudoephedrine HCl USP 0.300 Dextromethorphan
HBr USP 0.150 Xanthan Gum NF (Rhodigel 80 Pharma Grade) 0.200
Microcrystalline Cellulose/Carboxymethyl- 1.50 cellulose Sodium NF
(Avicel Type CL 611) Propyl Gallate NF (Progallin P-Drum) 0.00500
Polysorbate 80 NF 0.300 Glycerin 96% USP 30.0 Sorbitol Solution USP
70% 20.0 Micronized Sucralose Powder NF 0.200 Sodium Citrate
USP/FCC 0.550 Sodium Benzoate NF 0.250 Edetate Disodium USP 0.0500
Citric Acid Hydrous USP 0.750 Flavor 0.334 Color 0.0300 Purified
Water USP Qs 100 mL
[0062] Example 2 is prepared in a manner similar to Example 1. The
propyl gallate is dispersed in glycerin prior to addition of water,
then combined with the soluble actives prior to addition to the
main vessel. After the addition of the soluble actives and propyl
gallate to the main vessel, flavor is then added followed by the
adjustment of the final volume with water.
[0063] Although the foregoing invention has been described in some
detail by way of illustration and examples for purposes of clarity
of understanding, it will be obvious that certain changes and
modifications, may be practiced within the scope of the appended
claims. Modifications of the above-described modes of practicing
the invention that are obvious to persons of skill in the art are
intended to be included within the scope of the following
claims.
* * * * *