U.S. patent application number 14/643441 was filed with the patent office on 2015-07-02 for chewable tablet containing phenylephrine.
The applicant listed for this patent is Wyeth. Invention is credited to Manish Agrawal, Amanda Alley, Aaron Lewis Durr, Josephine Fubara, Mark Mabry, Angela Taylor.
Application Number | 20150182478 14/643441 |
Document ID | / |
Family ID | 38617929 |
Filed Date | 2015-07-02 |
United States Patent
Application |
20150182478 |
Kind Code |
A1 |
Fubara; Josephine ; et
al. |
July 2, 2015 |
CHEWABLE TABLET CONTAINING PHENYLEPHRINE
Abstract
A chewable pharmaceutical composition comprising phenylephrine,
artificial sweetener, and a substantially aldehyde-free matrix is
provided. The composition has phenylephrine stability suitable for
a typical commercial product with a two year shelf life. A method
of manufacture of the composition and a method of use are also
provided.
Inventors: |
Fubara; Josephine;
(Richmond, VA) ; Mabry; Mark; (Chesterfield,
VA) ; Durr; Aaron Lewis; (Glen Allen, VA) ;
Agrawal; Manish; (Richmond, VA) ; Alley; Amanda;
(Midlothian, VA) ; Taylor; Angela; (Chester,
VA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Wyeth |
Madison |
NJ |
US |
|
|
Family ID: |
38617929 |
Appl. No.: |
14/643441 |
Filed: |
March 10, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11492656 |
Jul 25, 2006 |
9005652 |
|
|
14643441 |
|
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Current U.S.
Class: |
514/357 ;
514/653 |
Current CPC
Class: |
A61K 31/137 20130101;
A61K 31/4402 20130101; A61P 37/08 20180101; A61K 9/0056 20130101;
A61P 31/12 20180101; A61P 25/04 20180101; A61P 31/16 20180101 |
International
Class: |
A61K 31/137 20060101
A61K031/137; A61K 31/4402 20060101 A61K031/4402; A61K 9/00 20060101
A61K009/00 |
Claims
1-38. (canceled)
39. A chewable composition comprising: a). phenylephrine; b). an
artificial sweetener; and c). a matrix comprising substantially
aldehyde-free excipients and an aldehyde-free flavorant.
40. The composition of claim 39 wherein the composition further
comprises less than 2.5% wt/wt total isoquinolines and maintains
said level of isoquinolines for at least 24 months.
41. The composition of claim 39, wherein the composition further
comprises less than 1.5% wt/wt total isoquinolines and maintains
said level of isoquinolines for at least 24 months.
42. The composition of claim 39, further comprising at least one
second pharmaceutical active.
43. The composition of claim 42, wherein the at least one second
active agent is selected from the group consisting of analgesics,
decongestants, expectorants, antitussives, antipyretics,
anti-inflammatory agents, cough suppressants and
antihistamines.
44. The composition of claim 43, wherein the at least one second
active agent is selected from the group consisting of ibuprofen,
naproxen, ketoprofen, flurbiprofen, fenoprofen, suprofen,
fluprofen, fenbufen, tolmetin sodium, zomepirac, sulindac,
indomethacin, mefenamic acid, meclofenamate sodium, diflunisal,
flufenisal, oxicams, piroxicam, sudoxicam, isoxicam,
chlorpheniramine, brompheniramine, dexchlorpheniramine,
dexbrompheniramine, triprolidine, chlorcyclizine, diphenhydramine,
doxylamine succinate, tripelenamine, cyproheptatine,
bromodiphenhydramine, phenindamine, pyrilamine, azatadine,
acrivastine, astemizole, azelastine, cetirizine, ebastine,
fexofenadine, ketotifen, carbinoxamine, desloratadine, loratadine,
pheniramine, thonzylamine, mizolastine, terfenadine,
chlophendianol, caramiphen, dextromethorphan, diphenhydramine,
codeine, hydrocodone, pseudoephedrine, ephedrine, phenylephrine,
phenylpropenolamine, terpin hydrate, guaifenesin, potassium,
potassium guaicolsulfonate, Celecoxib, Rofecoxib, Valdecoxib,
aspirin, acetaminophen, phenacetin, salicylate salts and
combinations thereof.
45. The composition of claim 44, wherein the at least one second
active agent is selected from the group consisting of
chlorpheniramine, brompheniramine, dextromethorphan, guaifenesin,
acetaminophen, chlophendianol, diphenhydramine, loratadine,
aspirin, and doxylamine succinate
46. The composition of claim 39, wherein the artificial sweetener
is selected from the group consisting of sucralose, saccharine
salts, cyclamates, acesulfame K, aspartame and mixtures
thereof.
47. The composition of claim 46, wherein the artificial sweetener
comprises sucralose.
48. The composition of claim 39, wherein the substantially
aldehyde-free flavorant is selected from the group consisting of
mints, menthol, chocolate, artificial chocolate, bubblegum,
artificial fruit flavors, natural fruit flavors, debittering
flavors and combinations thereof.
49. The composition of claim 39, wherein the matrix comprises an
antioxidant.
50. The composition of claim 49, wherein the antioxidant is propyl
gallate.
51. The composition of claim 39, wherein the matrix comprises
mannitol.
52. A chewable tablet comprising: a). phenylephrine; b). an
artificial sweetener; c). a matrix comprising substantially
aldehyde-free excipients; and d.) optionally aldehyde-free
flavorant.
53. The chewable tablet of claim 52, wherein the tablet further
comprises a.) less than 2.5 % wt/wt total isoquinolines and
maintains said level of isoquinolines for at least 24 months; and
b.) wherein the tablet is formed in the absence of liquid water at
substantially ambient temperature.
54. The chewable tablet of claim 52, further comprising at least
one second pharmaceutical active.
55. The chewable tablet of claim 54, wherein the at least one
second active agent is selected from the group consisting of
analgesics, decongestants, expectorants, anti-tussives,
antipyretics, anti-inflammatory agents, cough suppressants and
antihistamines.
56. The chewable tablet of claim 55, wherein the at least one
second active agent is selected from the group consisting of
ibuprofen, naproxen, ketoprofen, flurbiprofen, fenoprofen,
suprofen, fluprofen, fehbufen, tolmetin sodium, zomepirac,
sulindac, indomethacin, mefenamic acid, meclofenamate. sodium,
diflunisal, flufenisal, oxicams, piroxicam, sudoxicam, isoxicam,
chlorpheniramine, brompheniramine, dexchlorpheniramine,
dexbrompheniramine, triprolidine, chlorcyclizine, diphenhydramine,
doxylamine, tripelenamine, cyproheptatine, romodiphenhydramine,
phenindamine, pyrilamine, azatadine, acrivastine, astemizole,
azelastine, cetirizine, ebastine; fexofenadine, ketotifen,
carbinoxamine, desloratadine, loratadine, pheniramine,
thonzylamine, mizolastine, terfenadine, chlophendianol, caramiphen,
dextromethorphan, diphenhydramine, codeine, hydrocodone,
pseudoephedrine, ephedrine, phenylephrine, phenylpropenolamine,
terpin hydrate, guaifenesin, potassium, potassium guaicolsulfonate,
Celecoxib, Rofecoxib, Valdecoxib, aspirin; acetaminophen,
phenacetin, salicylate salts and combinations thereof.
57. The chewable tablet of claim 56, wherein the at least one
second active agent is selected from the group consisting of
chlorpheniramine, brompheniramine, dextromethorphan, guaifenesin,
acetaminophen, chlophendianol, diphenhydramine, loratadine,
aspirin, and doxylamine succinate
58. The chewable tablet of claim 52, wherein the artificial
sweetener is selected from the group consisting of sucralose,
saccharine salts, cyclamates, acesulfame K, aspartame and mixtures
thereof.
59. The tablet of claim 52, wherein the matrix comprises an
antioxidant.
60. The tablet of claim 59, wherein the antioxidant is propyl
gallate.
61. The tablet of claim 53, wherein the matrix comprises
mannitol.
62. A method of treating an mammal in need of treatment comprising
providing an effective amount of a chewable composition comprising
phenylephrine, artificial sweetener, and a matrix comprising
substantially aldehyde-free excipients and optionally aldehyde-free
flavorant, wherein the composition further comprises less than 2.5%
wt/wt total isoquinolines and maintains said level of isoquinolines
for at least 24 months.
Description
FIELD OF THE INVENTION
[0001] A chewable pharmaceutical composition comprising
phenylephrine is provided. The composition is particularly well
suited for the relief of cold, cough, flu, fever, headache, pain,
body ache, migraine, and allergy symptoms.
BACKGROUND OF THE INVENTION
[0002] Many commercially available over-the-counter oral cold,
cough, flu, fever, and/or allergy preparations contain
pseudoephedrine as an active agent. Although such preparations have
been useful, misuse of such products as a starting material for
synthesis of illicit substances has lead to the desire to find
alternatives that are not suitable for such illicit synthesis.
Phenylephrine is a potential alternative active. However,
phenylephrine is susceptible to degradation. The degradation is
typically facilitated in excipient compositions of the type
typically used with pseudoephedrine.
[0003] 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,
suspensions and liquid fill for capsules. For many patients
including young children, older persons and incapacitated persons,
a chewable dosage form is preferable because of the ease with which
it may be ingested.
[0004] Accordingly, it would be desirable to have a palatable,
chewable dosage form comprising phenylephrine with reduced
propensity for degradation of phenylephrine.
SUMMARY OF THE INVENTION
[0005] The pharmaceutical composition described herein is a
chewable oral pharmaceutical composition comprising phenylephrine,
an artificial sweetener, and a substantially aldehyde free matrix.
The composition has less than 2.5 wt/wt % total isoquinolines and
maintains said level of isoquinolines for at least 24 months.
[0006] The composition may further comprise one or more second
active agents selected from analgesics, decongestants,
expectorants, anti-tussives, antipyretics, anti-inflammatory
agents, cough suppressants and antihistamines.
[0007] In one embodiment mannitol may be used as a diluent.
[0008] The composition may be formed in the absence of liquid water
at ambient temperatures.
DETAILED DESCRIPTION OF THE INVENTION
[0009] The invention provides an oral chewable pharmaceutical
composition comprising the pharmaceutical active phenylephrine. The
composition is palatable and has improved phenylephrine stability.
The inventors believe with out wishing to be bound to the theory
that the selection of substantially aldehyde-free excipients and
avoidance of liquid water and/or heat in the manufacturing process
enhance phenylephrine stability. The composition comprises
phenylephrine, an artificial sweetener, and a substantially
aldehyde free matrix. Roller compaction is exemplary of a suitable
method of tableting the composition that avoids use of liquid water
with the composition in the manufacturing process and may be
accomplished without adding heat (e.g. at ambient temperature).
[0010] Prior to the invention, solid compositions comprising
phenylephrine HCl were found to be susceptible to the formation of
significant levels of isoquinoline degradants (often observed in
amounts >4%). Phenylephrine containing solid compositions are
typically more susceptible to the formation of isoquinoline
degradants than phenylephrine HCl containing liquid oral dosage
forms. The solid phenylephrine comprising composition described
herein comprises less than 2.5% wt/wt total isoquinolines and
maintains said isoquinolines level for at least 24 months. More
preferably the composition comprises less than 1.5% wt/wt total
isoquinolines and maintains said isoquinoline level for at least 24
months.
[0011] Phenylephrine HCl has several degradation pathways that form
isoquinolines. The inventors believe without wishing to be bound to
the theory that a primary pathway for the formation of
isoquinloline degradants in prior phenylephrine HCl compositions is
the interaction of Phenylephrine HCl with aldehydes present from
flavors and other excitipients used in the prior compositions. The
aldehydes may be an added component as in the case of some flavors,
for example, or may be the result of impurities in or degradation
products of one or more excipients. Moisture, and in some cases the
presence of a reducing sugar, also appear to facilitate the
formation of isoquinolines Additionally, heat may facilitate
degradation by oxidative pathways.
[0012] Accordingly, the inventors have discovered that degradation
of phenylephrine including degradation to isoquinoline in solid
phenylephrine composition may be reduced by use of substantially
aldehyde-free excipients including substantially aldehyde-free
flavors and minimizing the degradation of excipients. The avoidance
of liquid water and heat in the manufacturing process facilitates
minimizing degradation products. The use of roller compaction as
the granulation process is exemplary of a suitable manufacturing
process.
[0013] Roller compaction is a dry granulation process involving the
compression of a blended powder between rollers to produce a solid
mass of material. After granulation, this material is milled to a
uniform particle distribution with an even distribution of active
ingredients. The lack of introduction of water and excess heat to
the blend during granulation minimizes any degradation from
moisture and heat while providing a consistent granulation
mixture.
[0014] In an exemplary embodiment, the oral chewable composition of
the invention comprises phenylephrine HCl as the active ingredient,
microcrystalline cellulose, a non-sugar based sweetening system and
substantially aldehyde-free diluent. The tablet granulation is
manufactured using a roller compaction process to minimize any
process related degradation.
[0015] The composition may contain one or more additional
pharmaceutical actives (also referred to as "active(s)", "active
agent(s)", "therapeutic agent(s)", "drug(s)"). Herein reference to
"first pharmaceutical active" means phenylephrine and reference to
"second pharmaceutical active" means any active other than
phenylephrine. Further, the term second pharmaceutical active may
refer to a single species of active or a plurality of species of
actives other than phenylephrine (e.g., the total number of actives
in the compositions may be greater than 2.)
[0016] "Substantially aldehyde-free" means no components with known
aldehyde functionality or components which have aldehyde impurity
levels greater than 1% or components which are know to readily
degrade to aldehydes in the presence of the tablet matrix disclosed
herein are included in the composition. The impurity level may be
achieved by section of highly pure ingredients and/or removal of
aldehydes.
[0017] "Matrix" means all components of the composition other than
the active agent(s) and the artificial sweetener including, but not
limited to, flavorants, colorants, fillers, binders, disintegrants,
preservatives, buffers, natural sweeteners, lubricants, milling
agents, glidants, anti-adherents, dispersants, thickeners,
solubilizing agents and diluents.
[0018] A "chewable tablet" means a tablet that is formulated to be
masticable by a mammal. Such tablets typically have a hardness of
about 3-20 KPa, but hardness may vary depending on size and shape
of the tablet and the propensity of the components to solubilize in
saliva. Such dosage forms may be administered without water and are
particularly useful for administration to pediatric patients.
[0019] Unless specified otherwise amounts are provided in
milligrams per dosage unit which is abbreviated as mg/du.
Percentages unless otherwise indicated are in weight percent.
[0020] Preferably the phenylephrine is in a salt form. Suitable
salt forms include, but are not limited to, phenylephrine
hydrochloride (HCl), hydrobromide (H Br), bitartarate and tannate
salts. Phenylephrine may be used in an amount of about 0.5 to about
30.0 mg/dosage unit. Preferably, phenylephrine is used in an amount
of about 2.5 to about 5.0 mg/dosage unit.
[0021] An artificial sweetener is provided to improve palatability.
An artificial sweetener is preferred for use as a sweetener to the
use of conventional sugar sweeteners as the inventors believe,
without wishing to be held to the theory, that conventional
reducing sugars may contribute to the degradation of phenylephrine.
Suitable artificial sweeteners, include but are not limited to
sucralose, saccharine salts, cyclamates, acesulfame K, dipeptide
based sweeteners, aspartame and mixtures thereof. Sucralose, which
is a high intensity sweetener, is particularly well suited for use
in the composition. Sucralose may be used in an amount of about 1%
wt/wt to about 10% wt/wt, for example. The appropriate amount of
artificial sweetener depends on properties and sweetness intensity
of the artificial sweetener and target organoleptic properties of
the composition. One skilled in the art is familiar with the
characteristics of sweeteners and methods for determining amount of
sweetener to be used.
[0022] Suitable additional or second active agents include
analgesics, decongestants, expectorants, anti-tussives,
antipyretics, anti-inflammatory agents, cough suppressants and
antihistamines.
[0023] 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, citrate),
doxylamine (succinate), tripelenamine (HCl), cyproheptatine (HCl),
chlorcyclizine (HCl), bromodiphenhydramine (HCl), phenindamine
(tartrate), pyrilamine (maleate, tannate), azatadine (maleate);
acrivastine, astemizole, azelastine, cetirizine, ebastine,
fexofenadine, ketotifen, carbinoxamine (maleate), desloratadine,
loratadine, pheniramine maleate, thonzylamine (HCl), mizolastine
and terfenadine.
[0024] Antitussives useful in the practice of the present invention
(along with their preferred salt form) include, but are not limited
to, chlophendianol, caramiphen (ediylate), dextromethorphan (HBr),
diphenhydramine (citrate, HCl), codeine (phosphate, sulfate) and
hydrocodone.
[0025] Decongestants useful in the practice of the invention (along
with their preferred salt form) include, but are not limited to,
pseudoephedrine (HCl, sulfate), Ephedrine (HCl, Sulfate),
phenylephrine (bitartarate, tannate, HBr, HCl), and
phenylpropenolamine (HCl).
[0026] 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.
[0027] 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.
[0028] Cox 2 inhibitors which may be used in the practice of the
invention include, but are not limited to, Celecoxib, Rofecoxib and
Valdecoxib.
[0029] Analgesics which may be used in the practice of the
invention include but are not limited to aspirin, acetominophen,
phenacetin and salicylate salts.
[0030] 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 regulations regarding dosage of such
compounds.
[0031] Of the pharmaceutically active compounds described above
which may be included in addition to phenylephrine in the
composition, those which are particularly preferred are set forth
below along with preferred ranges for their inclusion into the
claimed pharmaceutical composition.
[0032] Chlorpheniramine may be used in the pharmaceutical
composition in amounts between about 1 mg/du and about 8 mg/du.
Preferably chlorpheniramine, when used in the pharmaceutical
composition, is present in the amount of about 1 mg/du to about 4
mg/du.
[0033] Brompheniramine maleate may be used in the pharmaceutical
composition, preferably in the amount of about 1 mg/du to about 4
mg/du.
[0034] Dextromethorphan HBr may be used in the pharmaceutical
composition, in the amount of about 15 mg/du to about 30 mg/du.
[0035] Guaifenesin may be used in the composition in amounts of
about 25 mg/du to about 200 mg/du and preferably in amounts of
about 25 mg/du to about 100 mg/du.
[0036] Acetaminophen may be used in the composition in amounts of
about 60 mg/du to about 1000 mg/du and preferably in amounts of
about 60 mg/du about 325 mg/du.
[0037] Chlophedianol may be used in the composition in amounts of
about 10 mg/du to about 25 mg/du.
[0038] Diphenhydramine may be used in the composition in amounts of
about 5 mg/du to about 50 mg/du and preferably in amounts of about
5 mg/du to about 25 mg/du.
[0039] Loratadine may be used in the composition in amounts of
about 2.5 mg/du to about 10 mg/du and preferably in amounts of
about 2.5 mg/du to about 5.0 mg/du.
[0040] Aspirin may be used in the composition in amounts of about
160 mg/du to about 650 mg/du and preferably in amounts of about 160
mg/du to about 320 mg/du.
[0041] Doxylamine may be used in the composition in amounts of
about 3.7 mg/du to about 25 mg/du and preferably in amounts about
3.75 mg/du to about 12.5 mg/du.
[0042] The pharmaceutically active compounds are preferably of a
compendial grade such as, for example, of N.F. (National Formulary)
or U.S.P. (United States Pharmacopeia) grade.
[0043] 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, flavorants, colorants, fillers,
binders, disintegrants, preservatives, pH adjustment agents,
natural sweeteners, lubricants, milling agents, glidants,
anti-adherents, dispersants, thickeners, solubilizing agents,
diluents, preservatives, antioxidants, and taste masking
agents.
[0044] Diluents useful in the practice include polyols such as
mannitol. Diluents with aldehyde functionality, aldehyde
impurities, or a propensity to form aldehyde degradants are
preferably avoided. For the materials tested, the inventors found
tablets made with mannitol, to be less susceptible to degradation
than tablets made with sorbitol or xylitol. It is not known if this
is due to inherently superior properties of mannitol or whether
this is due to specific features of the lots of material
tested.
[0045] Anti-oxidants may be included in the composition. Propyl
gallate is exemplary of an antioxidant that is suitable for use in
the composition.
[0046] Dicarboxylic and tricarboxylic organic acids may be used as
pH adjustment agents Fumaric acid and citric acid are exemplary of
suitable pH adjustment agents. It is preferable to adjust the
composition to maintain the pH less than about 6 when placed in
water.
[0047] 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
composition. Suitable coloring agents are well known to those
skilled in the art.
[0048] A binder may be included in the composition. Exemplary
binders include, but are not limited to, polyethylene oxide,
hydroxypropylmethyl cellulose (i.e., HPMC or hypromellose), and
povidone.
[0049] Lubricants suitable for use in the composition include, but
are not limited to stearic acid, magnesium stearate, and glyceryl
behenate.
[0050] Microcrystalline cellulose is exemplary of a filler suitable
for use in the practice of the invention. Microcrystalline
cellulose is commercially available from suppliers such as FMC
(1735 Market Street, Philadelphia, Pa. 19103) under the trade name
Avicel.TM.
[0051] Typically, addition of a flavorant is desirable in a
chewable tablet to enhance palatability. The flavorant should be
substantially free of aldehyde functionality. Accordingly, it is
desirable that to both avoid flavors with aldehyde functionality
and flavors provided in a medium that contains aldehydes. Addition
of a flavorant is desirable in a chewable tablet. Examples of
suitable flavorants include, but are not limited to, natural and
artificial flavors such as mints (i.e., peppermint, etc.), menthol,
chocolate, artificial chocolate, bubblegum, both artificial and
natural fruit flavors (i.e., cherry, grape, orange, strawberry,
etc.), debittering flavors and combinations of two or more thereof.
Flavoring agents are generally provided in the composition 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 grams of the
composition.
[0052] Agents which adjust "mouth feel" (e.g. organoleptic
properties) may be included in the composition. Glycine and kappa
caragenen are exemplary of agents which adjust "mouth feel".
Glycine may be used in amounts of about 2 to about 20 mg/du, for
example
[0053] Glidants may be included in the composition. Silicon dioxide
is exemplary of a suitable glidant.
[0054] Optionally, preservatives may be included in the
composition. Preservatives useful in the present invention include
but are not limited to sodium benzoate, sorbates, such as 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.
[0055] Excipients should be selected and amounts adjusted such that
the composition exhibits good flow properties under gravity flow
conditions, have cohesive properties and be compressible. For
example, addition of a binder and/or adjustment of the amount of
binder may be used to facilitate compressibility.
[0056] In an exemplary embodiment, the active agent(s) is
pre-blended with a diluent, binder and other excipients in a mixing
vessel such as, for example, a V-Blender. Upon mixing, the
resulting blend, may be fed, typically by gravity, to the hopper of
a roller compactor.
[0057] In a typical roller compaction process, a vertical feed
screw (i.e., a "VFS") facilitates feeding the blend into the
compactor by deareating the blend and forcing it between the rolls.
A horizontal feed screw (i.e., a "HVS") within the hopper feeds the
material to VFS. The feed screw speeds (rpm) of the VFS and HFS may
be adjusted to optimize the amount of blend going into the roll nip
region of the roller compactor. In one exemplary embodiment the
ratio of VFS:HFS speed is about 3:1.
[0058] The blend is densified and granulated, as it passes between
two high-pressure rolls that compress the blend. Controlling and
monitoring roll speed (which impacts dwell time for the material to
be compacted by the rolls), roll pressure (which is the pressure
applied to the rolls) and/or roll gap (which is a function of the
pressure applied to the rolls and the material passing between
them) facilitates maintaining uniformity and batch-to-batch
reproducibility.
[0059] The compacted material is collected and passed thru a mill
for particle sizing. Once sized the compacted material may be
tableted directly or blended with additional ingredients and
tableted.
[0060] Roller compaction is exemplary of one method for preparing
the composition of the invention. Other dry granulation methods
such as slugging, for example, may be likewise suitable.
[0061] Typically, the composition is provided to a patient in need
of treatment in a dosage unit of 1-2 tablets per dosage units
although other dosage units may be likewise suitable. The dosage
unit may be provided as a single dosage unit or multiples thereof,
based on age, weight and other health parameters determined by a
physician to be relevant.
EXAMPLE 1
[0062] An exemplary composition comprising the single first
pharmaceutical active phenylephrine is provided in Table 1. This
composition is representative and one of many composition that are
within the scope of the invention. The exemplary embodiment is
provided for illustrative purposes.
TABLE-US-00001 TABLE 1 Amount Ingredient (mg/du) Phenylephrine HCl
2.50 Mannitol 175 Microcrystalline Cellulose (MCC) 75 Fumaric acid
21 Glycine 15 Color 1 Artificial Sweetener 5 Flavorant 10 Magnesium
stearate 2.5 Polyethylene oxide 17
[0063] The composition of Table 1 may be prepared by roller
compaction as described herein.
EXAMPLE 2
[0064] An exemplary composition comprising phenylephrine and a
second active Brompheniramine maleate is provided in Table 2. This
composition is representative and one of the many compositions that
are within the scope of the invention. The exemplary embodiment is
provided for illustrative purposes.
TABLE-US-00002 TABLE 2 Amount Ingredient (mg/du) Phenylephrine HCl
2.5 Brompheniramine Maleate 1 Mannitol 175 Microcrystalline
Cellulose 75 Fumaric acid 21 Glycine 15 Colorant 1 Artificial
flavor 10 Magnesium stearate 2.5 Polyethylene oxide 17
[0065] The composition of Table 2 may be prepared by roller
compaction as described herein.
EXAMPLE 3
[0066] Table 3 provides degradation data for an exemplary
embodiment of the composition of the invention comprising
substantially aldehyde-free excipients and a similar composition
comprising an aldehyde containing flavorant.
TABLE-US-00003 TABLE 3 Condition (Temperature .degree. C./%
relative Time % Sample humidity) point (week) Degradants
Substantially Ambient Initial 0.071 Aldehyde Free 40/75 2 .089
composition 40/75 4 .070 40/75 8 .100 40/75 12 0.339 40/75 16 0.284
Composition Ambient Initial 0.524 with Aldehyde 40/75 2 1.705
containing flavorant 40/75 4 2.392 (vanilla) 40/75 8 3.253 40/75 12
4.831 40/75 16 4.159
EXAMPLE 4
[0067] Table 4 provides degradation data for an exemplary
embodiment of the composition of the invention comprising
substantially aldehyde-free excipients prepared by roller
compaction and a similar composition prepared by wt granulation
methods.
TABLE-US-00004 TABLE 4 Condition (Temperature .degree. C./%
relative Time % Sample humidity) point (week) Degradants
Composition Ambient Initial 0.071 prepared by Roller 40/75 2 .089
Compaction 40/75 4 .070 40/75 8 .100 40/75 12 0.339 40/75 16 0.284
Composition 40/75 16 1.039 prepared by Wet Granulation
[0068] Although the foregoing invention has been described in some
detail by way of illustrations 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.
* * * * *