Note: Descriptions are shown in the official language in which they were submitted.
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FLAVORING SYSTEMS FOR PHARMACEUTICAL COMPOSITIONS AND
METHODS OF MAKING SUCH COMPOSITIONS
Field of the Invention
This invention relates to flavoring systems for pharmaceutical compositions,
pharmaceutical compositions containing such flavoring systems, and methods of
making such
compositions. In particular, this invention is related to flavoring systems
for liquid
pharmaceutical compositions containing ritonavir or derivatives thereof,
lopinavir or
derivatives thereof, and mixtures of any of the above. The invention is also
directed toward
pharmaceutical compositions containing the flavoring systems of the invention
and toward
methods of making these pharmaceutical compositions.
Background of the Invention
The pharmaceutically active agents lopinavir and ritonavir are well known
inhibitors
of the Human Immunodeficiency Virus (HIV), which is the causative organism of
Acquired
Immunodeficiency Syndrome (AIDS). Both ritonavir and lopinavir inhibit HIV by
inhibiting
HIV proteases. Proteases are enzymes that cleave proteins at specific peptide
bonds, and
many significant biological functions are controlled or mediated by proteases
and their
inhibitors. By administering pharmaceutically active agents that inhibit HIV
proteases, the
replication of HIV in humans can be controlled or ceased.
Although much progress has been made toward treating AIDS, none of the current
treatments have proven to be totally effective in reversing the disease. In
addition, many of
the pharmaceutically active agents useful in treating AIDS have a bitter taste
that discourages
patients from complying with their drug taking regimen. Therefore, improving
the taste of
liquid compositions containing pharmaceutically active agents, such as
lopinavir and
ritonavir, is important in the fight against AIDS.
Flavoring agents for liquid pharmaceuticals are well known. For example, U.S.
Patent 5,484,801, which issued on January 16, 1996, discloses the use of such
flavoring
agents as wild cherry flavor, banana flavor, strawberry flavor, sodium
saccharin, citric acid,
chocolate mint, and other flavor enhancers in pharmaceutical compositions
containing
ritonavir. However, there remains a need for improved flavoring systems for
liquid
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pharmaceutical compositions containing pharmaceutically active agents, such as
ritonavir
and/or lopinavir, which are practically insoluble in water and tend to have a
bitter taste.
Summary of the Invention
In general, Applicants have discovered that by increasing the number and type
of
ingredients in flavoring systems for liquid pharmaceutical compositions
containing
pharmaceutically active agents, such as lopinavir and ritonavir, the taste of
pharmaceutical
compositions containing these agents is improved. Flavoring systems of the
invention
generally contain two or more flavored ingredients, one or more sweetening
agents, and one
or more flavor modifiers selected from the group consisting of sodium citrate,
sodium
chloride, citric acid and mixtures thereof. Preferably two or more and most
preferably all of
the ingredients identified in the previous sentence are included as flavor
modifiers in
flavoring systems of the invention. The total amount of flavor modifiers
included in
flavoring systems of the invention is at least about 0.10% by weight and not
greater than
about 1 ~0% by weight based upon the total pharmaceutical composition
containing such
flavoring system. Most preferably, all of these flavor modifiers are included
in the flavoring
system in the following amounts by weight: sodium citrate in an amount of
about 0.20%,
sodium chloride in an amount of about 0.35%,.and citric acid in an amount of
about 0.11%
based upon the total weight of the pharmaceutical composition. Unless
otherwise stated
herein, all weights are based upon the total weight of the pharmaceutical
composition.
Flavoring systems of the invention also include at least two flavored
ingredients
having a vanilla, menthol, cotton candy, and/or peppermint flavor. More
preferred flavoring
systems of the invention include at least three of these flavored ingredients,
and most
preferred flavoring systems of the invention include all four of these
flavored ingredients.
The most preferred menthol flavored ingredient is menthol crystals, and the
most preferred
peppermint flavored ingredient is peppermint oil. The total amount by weight
of flavored
ingredients in pharmaceutical compositions containing flavoring systems of the
invention is
at least about 1.4% by weight and not greater than about 3.5% by weight. More
preferably,
the total amount of flavored ingredients in pharmaceutical compositions
containing flavoring
systems of the invention is at least about 2.4% by weight and not greater than
about 2.8% by
weight. Most preferably the total amount of flavored ingredients in
pharmaceutical
compositions containing flavoring systems of the invention is about 2.6% by
weight. In
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preferred embodiments, the following flavored ingredients are included in
compositions of
the invention in the following amounts by weight: a cotton candy flavored
ingredient in an
amount of at least about 0.55% and not greater than about 1.10%; a peppermint
flavored
ingredient in an amount of at least about 0.15% and not greater than about
0.60%; a menthol
flavored ingredient in an amount of at least about 0.03% and'not greater than
about 0.25%;
and a vanilla flavored ingredient in an amount of at least about 0.70% and not
greater than
about 1.5%. In most preferred embodiments of pharmaceutical compositions of
the
invention, the following flavored ingredients are included in such
compositions in the
following amounts by weight: cotton candy flavor in an amount of about 1:00%;
peppermint
oil in an amount of about 0.30%; vanilla flavor in an amount of about 1.25%;
and menthol
crystals in an amount of about 0.05%.
At least one sweetening agent and preferably at least two sweetening agents
are
included in flavoring systems of the invention. More preferably, at least
three sweetening
agents, and most preferably at least four sweetening agents are included in
flavoring systems
of the invention. High fructose corn syrup, glycerin, saccharin sodium,
monoammonium
glycyrrhizinate, and acesulfame potassium are most preferred sweetening
agents. Preferably,
sweetening agents are included in flavoring systems of the invention in a
total amount of at
least about 20% by weight of the total weight of the pharmaceutical
composition and not
more than about 67% by weight. More preferably, sweetening agents are included
in
flavoring systems of the invention in a total amount of at least about 22% by
weight and not
greater than about 27.5% by weight. Most preferred flavoring systems of the
invention
comprise the following sweetening agents: high fructose corn syrup in an
amount of about
16.6% by weight, glycerin in an amount of about 5.5% to about 8.5% by weight,
monoammonium glycyrrhizinate in an amount of about 0.58% by weight, saccharin
sodium
in an amount of about 0.40% by weight; and acesulfame potassium in an amount
of about
0.40% by weight. As used herein the terms "comprise(s)", "comprising",
"contain(s)",
"containing", "include(s)" and "including" when referencing ingredients of
pharmaceutical
compositions of the invention, shall refer to: (1) ingredients added
individually or
simultaneously with other ingredients to pharmaceutical compositions of the
invention; or (2)
ingredients that may be formed during preparation of pharmaceutical
compositions of the
invention.
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The invention is also directed toward liquid, preferably orally dosed,
pharmaceutical
compositions comprising: (a) a flavoring system of the invention; (b) one or
more
pharmaceutically active agents, such as lopinavir, ritonavir, or mixtures
thereof; (c) and a
solvent system. Optionally, pharmaceutical compositions of the invention may
also include
one or more thickening agents, such as polyvinylpyrrolidone, one or more
bioavailability
enhancing agents, such as a castor oil derivative, one or more antioxidants,
and/or
preservatives.
Because, pharmaceutically active agents, such as lopinavir and ritonavir are
practically insoluble in water, particular types of pharmaceutically
acceptable solubilizing
agents (i.e., solvents) should be included in the solvent system. These
particular types of
solubilizing agents include, but are not limited to: water, pharmaceutically
acceptable alkyl
alcohols, and pharmaceutically acceptable alkylene glycols. At least two of
these particular
types of solubilizing agents should be included in the solvent system, and
most preferably all
three of these types of agents should be included. At least about 32% by
weight and not more
. than about 69% by weight of pharmaceutical compositions of the invention. is
the solvent
system. More preferably, the solvent system comprises at least about 53% by
weight of
pharmaceutical compositions of the invention and not greater than about 60% by
weight.
These total amounts for the solvent system and the amounts for each of the
individual
solubilizing agents included in solvent systems of the invention exclude any
additional
amounts of solubilizing agents: (a) that are a part of other ingredients
(e.g., flavored
ingredients or sweetening agents) included in the composition; (b) that axe
used to rinse the
vessel in which the pharmaceutical compositions of the invention are made as
described in
the "Preparation of the Pharmaceutical Compositions" section herein below; and
(c) that are
used to bring the final pharmaceutical composition up to batch volume as
described in the
"Addition of Any Bioavailabilty Enhancer and Any Additional Ingredients"
section below.
It is also noted that the total amounts disclosed herein for the flavoring
system and for
each of the individual ingredients included in the flavoring system generally
include, unless
otherwise noted, any solvents or solubilizing agents that are incorporated
into such individual
ingredients. For example, high fructose corn syrup is a preferred sweetening
agent that can
be included in flavoring systems of the invention, and high fructose corn
syrup usually
contains a significant amount of water. The weight of the water that is
included in the
amounts for high fructose corn syrup is included in~the total weight amounts
disclosed herein
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for sweetening agents and flavoring systems. The amount of water included in
the high
fructose corn. syrup is not included in the amounts disclosed herein for
solubilizing agents or
for the solvent system.
Preferred solubilizing agents include water, ethanol, propylene glycol,
polyethylene
5 glycol, and mixtures thereof. The most preferred alkyl alcohol is ethanol,
and the most
preferred alkylene glycol is propylene glycol.
Flavoring systems of the invention are generally included in an amount of at
least
about 20% by weight of pharmaceutical compositions of the invention and not
more than
about 70% by weight. More preferably, flavoring systems of the invention are
included in an
amount of at least about 22% by weight and not greater than about 68% by
weight of the
pharmaceutical compositions of the invention. Most preferably, flavoring
systems of the
invention are included in pharmaceutical compositions of the invention in an
amount of
about 27% by weight to about 29.5% by weight.
Other ingredients, such as thickening agents and agents that enhance the
bioavailability of the pharmaceutically active agents may also be included in
pharmaceutical
compositions of the invention. The most preferred thickening agent is
polyvinylpyrrolidone.
The most preferred bioavailability enhancer is a castor oil derivative, such
as polyoxy1,40
hydrogenated castor oil, which is commercially available as Cremophor RH40. In
preferred
embodiments of the invention, one or more thickening agents is included in
pharmaceutical
. compositions of the invention in a total amount of at least about 2.5% by
weight and not
greater than about 5% by weight, and one or more bioavailability enhancers are
included in a
total amount of at least about 0.01 % by weight and not greater than about 3%
by weight.
Most preferably, polyvinylpyrrolidone is included in pharmaceutical
compositions of the
invention in an amount of about 3% by weight, and the castor oil derivative is
included in an
amount of about 1 % by weight.
Ritonavir or derivatives thereof, lopinavir or derivatives thereof, and
mixtures thereof
are preferably the pharmaceutically active agents included in the invention.
More preferably,
both ritonavir or one or more of its derivatives and lopinavir or one or more
of its derivatives
are included in the compositions of the invention. If both ritonavir or one or
more of its
derivatives and lopinavir or one or more of its derivatives are included in
compositions of the
invention, then most preferably, the weight ratio of the amount of lopinavir
or one or more of
its derivatives to ritonavir or one or more of its derivaties is about 4:1.
Preferably, at least
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about 4% by weight of the pharmaceutical composition is one or more
pharmaceutically
active agents, and more preferably the amount of pharmaceutically active
agents) in the
composition is not greater than about 10% by weight of the pharmaceutical
composition. If
both lopinavir or one or more of its derivatives and ritonavir or one or more
of its derivatives
are both included in compositions of the invention, then preferably, ritonavir
or one or more
of its derivatives is included in the composition in an amount of at least
about 1.30% by
weight and not greater than about 2.10% by weight; and preferably, lopinavir
or one or more
of its derivatives is included in the composition in an amount of at least
about 2.5% by weight
and not greater than about 8% by weight. Most preferably, ritonavir or one or
more of its
derivatives is included in compositions of the invention in an amount of about
2% by weight,
and lopinavir or one or more of its derivatives is included in compositions of
the invention in
an amount of about 8% .by weight.
The invention is also directed toward methods of making pharmaceutical
compositions of the invention. Methods of the invention include: (a) charging
a vessel with
at least a portion of the solvent system; (b) dissolving the one or more
pharmaceutically
active agents, such as ritonavir or its derivatives, lopinavir or its
derivatives, or mixtures
thereof in the vessel with at least a portion of the solvent system; (c)
dissolving the flavor
modifiers (excluding any flavor modifiers in liquid form) and any non-liquid
sweetening
agents in water in a separate vessel to form a side mixture; (d) and combining
the side
mixture with the at least a portion of the solvent system containing the one
or more dissolved
pharmaceutically active agents, any one or more liquid sweetening agents, any
liquid flavor
modifiers, the flavored ingredients, and any remaining portion of the solvent
system.
Methods of the invention also include combining all of the ingredients in the
vessel as stated
in the previous sentence without preparing a separate side mixture.
Preferably, if a castor oil
derivative is included in the composition, it is heated prior to being added
to the vessel. If
menthol crystals are used in the composition, then preferably, they are
dissolved in the at
least a portion of the solvent system prior to dissolution of the one or more
pharmaceutically
active agents in the solvent system. Preferably, the vessel has mixing means
to mix the vessel
contents during the process. Most preferably, a thickening agent, such as
polyvinylpyrrolidone, is added to the vessel and mixed with other ingredients
in the
pharmaceutical composition.
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Detailed Description of the Invention
Generally, liquid pharmaceutical compositions of the invention include a
flavoring
system, at least one pharmaceutically active agent, a solvent system and
optionally other
additives useful in enhancing the bioavailability of and/or increasing the
viscosity and/or
stability of pharmaceutical compositions. Flavoring systems of the invention
include at least
one sweetening agent, and at least two flavored ingredients selected from the
group
consisting of a menthol flavored ingredient, a peppermint flavored ingredient,
a vanilla
flavored ingredient, a cotton candy flavored ingredient, and mixtures thereof.
Flavoring
systems of the invention also include at least one flavor modifier selected
from the group
consisting of sodium citrate, sodium chloride, citric acid, and mixtures
thereof. A solvent
system in which each of the pharmaceutically active agents can dissolve is
also included in
pharmaceutical compositions of the invention.
As used herein, the terms below have the following meanings. The term
"flavored
ingredient" shall mean any compound or composition that: (a) is
pharmaceutically
15. acceptable, (b) is not a sweetening agent, and (c) imparts a known and
readily identifiable
blend of taste and/or smell sensations to pharmaceutical compositions of the
invention.
Examples of flavored ingredients include, but are not limited to: wild cherry
flavor,
strawberry flavor, banana flavor, peppermint flavor, peppermint oil, menthol
flavor, menthol
crystals, cotton candy flavor, vanilla flavor, mixed fruit flavor, and
chocolate flavor. As used
herein, the term "pharmaceutically acceptable" refers to a compound or
composition that is
currently or becomes in the future accepted by: (1) the United States Food and
Drug
Administration as useable in pharmaceutical compositions made and/or sold in
the United
States; or (2) any pharmaceutical regulatory agency outside of the United
States as useable in
pharmaceutical compositions made and/or sold in the jurisdiction governed by
such
regulatory agency.
The term "lopinavir" as used herein shall mean a pharmaceutically active agent
represented by the chemical name [1S-[1R*,(R*),3R*,4R*]]-N-[4-[[(2,6-
dimethylphenoxy)acetyl] amino]-3 -hydroxy-5-phenyl-1-
(phenylmethyl)pentyl]tetrahydro-
alpha-(1-methylethyl)-2-oxo-(2H)-pyrimidine acetamide. The term
"derivative(s)" as used
herein when referring to lopinavir shall mean the pharmaceutically acceptable
salts, esters,
pharmaceutical derivatives, and pharmaceutical analogs of lopinavir as
described in U.S.
Patent 5,914,332, which issued on June 22, 1999 and is hereby incorporated by
reference.
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8.
The term "ritonavir" as used herein shall mean a pharmaceutically active agent
represented by
the chemical name [SS-(SR*, 8R*, lOR*, 11R*)] -10 -Hydroxy-2-methyl-5-(1-
methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-
bis(phenylmethyl)-2,4,7,12-
tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester. The term
"derivative(s)" as used herein
when referring to ritonavir shall mean the pharmaceutically acceptable salts,
esters,
pharmaceutical derivatives, and pharmaceutical analogs of ritonavir as
described in U.S.
Patents: (a) 5,541,206, which issued on July 30, 1996; and (b) 5,648,497,
which issued on
July 15, 1997 and both of which are hereby incorporated by reference.
The term "sweetening agent" shall mean any pharmaceutically acceptable liquid
or
solid compound or composition that is not a flavored ingredient and that has
or imparts to
pharmaceutical compositions a sugar-like or sugar-based taste. Examples of
sweetening
agents include, but are not limited to, glycerin, saccharin sodium, acesulfame
potassium,
monoammonium glycyrrhizinate, and high fructose corn syrup. The term "flavor
modifier(s)" as used herein shall mean pharmaceutically acceptable ingredients
that are not
15' sweetening agents and not flavored ingredients that enhance the flavor of
pharmaceutical
compositions. Examples of flavor modifiers include, but are not limited to:
sodium citrate,
citric acid, and sodium chloride.
Flavoring Systems
Generally, pharmaceutical compositions with the best flavor profiles have when
tasted: (1) an immediate impact of an identifiable flavor; (2) rapid
development of a balanced
and full flavor; (3) compatible mouthfeel factors (i.e., the composition is
texturally
satisfactory); (4) no "off notes" or unexpected flavors; (5) and a short
aftertaste. Applicants'
goal in developing the flavoring systems of the invention was to insure that
compositions
containing lopinavir or its derivatives, ritonavir or its derivatives, and
mixtures thereof would
exhibit most, if not all of these characteristics.
In general, there are four distinct basic taste types in a flavor profile:
bitter, sweet,
sour, and salty. These four basic taste types are used to describe tastes of
orally ingested
compositions while they are in the mouth and to describe the aftertaste
associated with these
compositions. Lopinavir and its derivatives and ritonavir and its derivatives
tend to have a
flavor profile that is undesirably high in the bitter basic taste, and these
pharmaceutically
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active agents also have a lingering aftertaste. Because these drugs without a
flavoring system
or with an unsatisfactory flavoring system have an undesirable flavor profile,
patients are less
likely to take the drug in compliance with their daily dosage regimen.
Therefore, Applicants
have developed a flavoring system that counteracts the undesirable aftertaste
and the bitter
basic taste in these drugs' flavor profiles. In addition, the flavoring system
is compatible with
the particular types of solvent systems required for these two drugs.
Because lopinavir and ritonavir are practically insoluble in water at room
temperature
and pressure (i.e., approximately 25° C and 1 atmosphere of pressure),
these drugs must be
dissolved and maintained in a particular type of solvent system, and flavoring
systems of the
invention are compatible with such solvent systems. Generally, flavoring
systems of the
invention include at least two flavored ingredients, at least one sweetening
agent, and at least
two flavor modifiers.
Flavored Ingredients
The flavored ingredients in flavoring systems of the invention minimize the
unpleasant aftertaste and counteract the bitter basic taste in the lopinavir
and ritonavir (and
their respective derivatives) flavor profiles. A variety of flavored
ingredients can be used to
improve these drugs' flavor profiles; however, Applicants have optimized these
drugs' flavor
profiles by including at least two flavored ingredients in their flavoring
systems. Preferably,
at least three flavored ingredients are included, and most preferably at least
four flavored
ingredients are included in flavoring systems of the invention. Applicants
have found that
combinations of the following flavors axe particularly useful in flavoring
systems for
pharmaceutical compositions containing ritonavir or one or more of its
derivatives, lopinavir
or one or more of its derivatives, and mixtures thereof: vanilla, cotton
candy, menthol, and
peppermint. However, other flavors may also be used. For example, green apple,
licorice,
chocolate, chocolate mint, strawberry, banana, mixed fruit, and cherry may be
used alone or
in combination with the previously identified flavors that are useful in the
invention.
Generally, flavored ingredients axe included in pharmaceutical compositions of
the
invention in a total amount of at least about 1.4% by weight and not greater
than about 3.5%
by weight. Preferably, flavored ingredients are included in pharmaceutical
compositions of
the invention in a total amount of at Ieast about 1.45% by weight and not
greater than about
3% by weight, and more preferably in an amount of at least about 2.4% by
weight and not
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greater than about 2.8% by weight. Most preferably, flavored ingredients are
included in
pharmaceutical compositions of the invention in an amount of about 2.6% by
weight. Most
preferred flavoring systems of the invention comprise menthol, peppermint,
vanilla, and
cotton candy flavored ingredients.
The menthol flavored ingredient is included in most preferred flavoring
systems of the
invention in any form (i.e., liquid or solid). For example, menthol crystals
(i.e., in solid form)
may be incorporated into compositions of the invention, or menthol crystals
may be dissolved
into a pharmaceutically acceptable solvent (e.g., propylene glycol) and the
dissolved crystals
in the solvent may be included in compositions of the invention. Preferably,
the amount of
10 menthol flavored ingredient included in most preferred flavoring systems of
the invention is
at least about 0.03% by weight and not greater than about 0.25% by weight.
Most preferably,
the menthol flavored ingredient is included in the pharmaceutical composition
in an amount
of about 0.05% by weight. These weight percentages exclude the weight of any
solvent in
which any menthol in solid form may be dissolved. Most preferably, the menthol
flavored
ingredient is menthol crystals. Menthol crystals that are useful in the
invention are L-
Menthol Crystals USP available from Takasago of Rockleigh, NJ, U.S.A.
The vanilla flavored ingredient can be included in most preferred flavoring
systems of
the invention in any form (i.e., liquid or solid). For example, extracts from
vanilla beans (i.e.,
vanilla bean extract) may be included in compositions of the invention with or
without a
pharmaceutically acceptable solvent. Preferably, the amount of vanilla
flavored ingredient
(including any solvent in which vanilla been extract, for example, may be
dissolved)
included in most preferred flavoring systems of the invention is at least
about 0.70% by
weight and not greater than about 1.50% by weight, and more preferably the
amount of
vanilla flavored ingredient is at least about 1.15% by weight and not greater
than about
1.35% by weight. Most preferably, the vanilla flavored ingredient is included
in the
composition in an amount of about 1.25% by weight, and most preferably,
vanilla flavor is
included in the pharmaceutical composition as the vanilla flavored ingredient.
Two vanilla
flavors that are useful in the invention are commercially available from Bush
Boake & Allen,
Inc. of Chicago, IL as Artificial Vanilla Cream Flavor and as Natural and
Artificial Vanilla
Flavor (#33869, Yarnalla) .
The cotton candy flavored ingredient can be included in most preferred
flavoring
systems of the invention in any form (i.e., liquid or solid); however,
Applicants are currently
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not aware of a solid form of a cotton candy flavored ingredient, and the
liquid form is
preferred. Preferably, the amount of cotton candy flavored ingredient included
in most
preferred flavoring systems of the invention is at least about 0.55% by weight
and not greater
than about 1.10% by weight, and more preferably the amount of cotton candy
flavored
ingredient is at least about 0.95% by weight and not greater than about 1.05%
by weight.
Most preferably, the cotton candy flavored ingredient is included in the
pharmaceutical
composition in an amount of about 1.00% by weight, and most preferably, the
cotton candy
flavored ingredient is cotton candy flavor. A cotton candy flavor that is
useful in the
invention is commercially available from E.A. Weber & Co. of Wheeling, IL as
Artificial
Cotton Candy Flavor #30-92-0011.
The peppermint flavored ingredient can be included in most preferred flavoring
systems of the invention in any form (i.e., liquid or solid). Preferably, the
amount of
peppermint flavored ingredient included in most preferred flavoring systems of
the invention
is at least about 0.15% by weight and not greater than about 0.60% by weight,
and more
preferably the amount of peppermint flavored ingredient is at least about
0.25% by weight
and not greater than about 0.35% by weight. Most preferably, the peppermint
flavored
ingredient is included in the pharmaceutical composition in an amount of about
0.30% by
weight, and most preferably the peppermint flavored ingredient is peppermint
oil. One
peppermint oil that is useful in the invention is commercially available from
A.M. Todd Co.
of Kalamazoo, MI as Peppermint Oil NF Type 102-130.
It is noted that many flavored ingredients axe commercially available in two
forms:
solids and liquids and that the liquids are available in various potencies. It
is also noted that
both forms of these ingredients may be diluted with starches, maltodextrin,
gums, and other
diluents known in the flavoring agent art and that the flavored ingredients in
liquid form may
also be diluted with pharmaceutically acceptable solvents. The weight
percentages associated
with the flavored ingredients herein pertain to flavored ingredients ~n a dry
or liquid form,
unless otherwise noted, having a potency that is pharmaceutically equivalent
to the potency
of the pharmaceutically acceptable commercially available flavored ingredients
cited herein.
Sweetening Agents
In order to improve the flavor profile of pharmaceutical compositions
containing
pharmaceutically active agents, such as ritonavir or its derivatives and
lopinavir or its
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derivatives, at least one sweetening agent should be included in the
composition and
preferably at least two sweetening agents should be included. More preferably,
at least three
or four sweetening agents should be included and most preferably at least five
sweetening
agents should be included in flavoring systems of the invention. Examples of
useful
sweetening agents include, but are not limited to: glycerin, monoammonium
glycyrrhizinate,
high fructose corn syrup, saccharin sodium, acesulfame potassium, maltitol,
sucrose, sorbitol,
hydrogenated starch hydrolysate, mannitol, xylitol, erythritol, maltose,
dextrose, and fructose,
and mixtures thereof. Sweetening agents useful in the invention can be
included in
compositions of the invention in any form (i.e., liquid or solid).
Preferably, the total amount of sweetening agents) included in compositions of
the
invention is at least about 20% by weight and not greater than about 67% by
weight. More
preferably at least about 22% by weight and not greater than about 28% by
weight of the
pharmaceutical compositions is sweetening agent(s). In most preferred
flavoring systems of
the invention, the total amount of sweetening agents is at least about 23% by
weight and not
greater than about 27% by weight. It is noted that the sweetening agent weight
percentages
detailed herein exclude any sweetening agents used as solvents in any one or
more flavored
ingredients.
In most preferred flavoring systems of the invention, the at least five
sweetening
agents included in the composition are glycerin, high fructose corn syrup,
monoammonium
glycyrrhizinate, acesulfame potassium, and saccharin sodium. Preferably, the
amount . of
glycerin included in most preferred flavoring systems of the invention is at
least about 5% by
weight and not greater than about 30% by weight, and more preferably the
amount of
glycerin is at least about 5.25% by weight and not greater than about 28.5% by
weight. Most
preferably, glycerin is included in pharmaceutical compositions of the
invention in an amount
of at least about 5.85% by weight and not greater than about 8.5% by weight.
Two glycerin
products that are useful in the invention are commercially available from Dial
of
Montgomery, IL, U.S.A and Witco of Memphis, TN, U.S.A. as Glycerin USP and
Kemstrene
99.7% USP respectively.
High fructose corn syrup is preferably included in most preferred flavoring
systems of
the invention in an amount of at least about 14.5% by weight and not greater
than about
33.6% by weight, and more preferably in an amount of at least about 15.7% by
weight and
not greater than about 17.4% by weight. Most preferably, high fructose corn
syrup is
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included in pharmaceutical compositions of the invention in an amount of about
16.6% by
weight. A high fructose corn syrup that is useful in the invention is
commercially available
as Hi-Sweet 55 Code 3S2 from Roquette of Keokuk, IA, U.S.A.
Preferably, the amount of acesulfame potassium included in most preferred
flavoring
systems of the invention is at least about 0.35% by weight and not greater
than about 0.85%
by weight, and more preferably at least about 0.35% by weight and not greater
than about
0.45% by weight. Most preferably, acesulfame potassium is added to the
pharmaceutical
composition in an amount of about 0.40% by weight. An acesulfame potassium
product that
is useful in the invention is commercially available from Nutrinova Inc. of
Somerset, NJ as
Sunett pharmaceutical grade acesulfame potassium , FCC.
Saccharin sodium is included in ~rriost preferred flavoring systems of the
invention in
an amount of at least about 0.05% by weight and not greater than about 0.85%
by weight, and
more preferably in an amount of at least about 0.35% by weight and not greater
than about
0.45% by weight. Most preferably, saccharin sodium is included in the
pharmaceutical
. composition in an amount of about 0.40% by weight. Saccharin sodium that is
useful in the
invention is commercially available from Syncal S of Cincinnati, OH, U.S.A. as
Sodium
Saccharin Powder USP/NF. As used herein the terms "USP" or "USP/NF" mean
United
States Pharmacopoeia and National Formulary, and the reference indicates that
the ingredient
meets the appropriate United States Pharmacopoeia and National Formulary
standards or
specifications.
Monoammonium glycyrrhizinate is included in most preferred flavoring systems
of
the invention in an amount of at least about 0.35% by weight and not greater
than about
0.65% by weight, and more preferably in an amount of at least. about 0.55% by
weight and
not greater than about 0.65% by weight. Most preferably, monoammonium
glycyrrhizinate is
included in the pharmaceutical composition in an amount of about 0.58% by
weight.
Monoammonium glycyrrhizinate can be included in compositions of the invention
in liquid
or solid form. One example of a useful commercially available liquid form of
monoammonium glycyrrhizinate are the magnasweet products, which are
commercially
available from MacAndrews & Forbes of Camden, NJ, U.S.A. One product that is
useful in
particular is Magnasweet 110 2X, which is monoammonium glycyrrhizinate
dissolved in
glycerin. This particular product is 20% by weight monoammonium
glycyrrhizinate and 80%
by weight glycerin based upon the total weight of the magnasweet composition.
If such a
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magnasweet product is used as a sweetening agent in compositions of the
invention, then
products that are 20% by weight monoammonium glycyrrhzinate should be included
in most
preferred flavoring systems of the invention in an amount of at least about
1.60% by weight
and not greater than about 3.10% by weight, and more preferably in an amount
of at least
about 2.75% by weight and not greater than about 3..10% by weight. Most
preferably, such a
magnasweet product is included in the pharmaceutical composition in an amount
of about
2.90% by weight.
Flavor Modifiers
At least one other ingredient should be included in flavoring systems of the
invention.
Generally, these ingredients are flavor modifiers. Generally, flavor modifiers
are included in
flavoring systems for pharmaceutical compositions in order to enhance, extend
or accentuate
flavored ingredients andlor sweetening agents. Flavor modifiers tend to
facilitate a higher
initial flavor impact, to extend the effect of flavors and sweeteners well
into the aftertaste,
and to combat the lingering effects of bitter and other undesirable aftertaste
characteristics
originating from the pharmaceutically active ingredients or solubilizing
agents included in the
pharmaceutical composition.
In order to improve the flavor profile of pharmaceutical compositions
containing
pharmaceutically active agents, such as ritonavir or its derivatives and
lopinavir or its
derivatives, at least one flavor modifier should be included in the
composition and preferably
at least two flavor modifiers should be included in compositions of the
invention. Most
preferably, at least three flavor modifiers are included in flavoring systems
of the invention.
Examples of useful flavor modifiers include, but are not limited to: sodium
citrate, sodium
chloride, citric acid, thaumatin, and mixtures thereof.
Preferably, flavor modifiers are included in compositions of the invention in
an
amount of at least about 0.10% by weight and not greater than about 1.00% by
weight. More
preferably flavor modifiers are included in compositions of the invention in
an amount of at
least about 0.60% by weight and not greater than about 0.70% by weight. Most
preferably,
flavor modifiers are included in compositions of the invention in an amount of
about 0.66%
by weight.
In most preferred flavoring systems of the invention, the at least three
flavor modifiers
included in the composition are citric acid, sodium chloride, and sodium
citrate. Preferably,
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the amount of sodium citrate included in most preferred flavoring systems of
the invention is
not greater than about 0.25% by weight, and more preferably at least about
0.15% by weight
and not greater than about 0.25% by weight. Most preferably, sodium citrate is
included in
the pharmaceutical composition in an amount of about 0.20% by weight. A sodium
citrate
5 product that is useful in the invention is Sodium Citrate Dihydrate USP FCC
commercially
available from ADM Southport of Southport, NC, U.S.A.
Sodium chloride is preferably included in most preferred flavoring systems of
the
invention in an amount of not greater than about 0.40% by weight, and more
preferably in an
amount of at least about 0.30% by weight and not greater than about 0.40% by
weight. Most
10 preferably, sodium chloride is included in pharmaceutical compositions of
the invention in an
amount of about 0.35% by weight. A sodium chloride product that is useful in
the invention
is commercially available from Morton Salt Company of Rittman, OH, U.S.A. as
Sodium
Chloride USP.
Preferably, the amount of citric acid included in most preferred flavoring
systems of
15 the invention is at least about 0.10% by weight and not greater than about
0.25% by weight,
and more preferably at least about 0.10% by weight and not greater than about
0.12% by
weight. Most preferably, citric acid is included in the pharmaceutical
composition in an
amount of about 0.11 % by weight. A citric acid product that is useful in the
invention is
Citric Acid USP Anhydrous Powder #0703064 commercially available from A.E.
Staley of
Dayton, OH, U.S.A.
Pharmaceutically Active Agents
Pharmaceutically active agents that are practically insoluble in water for
example,
ritonavir, derivatives of ritonavir, lopinavir, derivatives of lopinavir, or
mixtures thereof are
useful in compositions of the invention. Generally, pharmaceutical
compositions of the
invention are liquid in form, and preferably are orally dosed. At least one
pharmaceutically
active agent is included in compositions of the invention, and preferably two
pharmaceutically active agents are included.
Any pharmaceutically effective and pharmaceutically acceptable amount of the
pharmaceutically active agents or mixtures thereof can be included in
compositions of the
invention. In preferred embodiments, the total amount of pharmaceutically
active agents)
included in compositions of the invention is at least about 4% by weight and
not greater than
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16
about 10% by weight. More preferably, the total amount of pharmaceutically
active agents)
included in compositions of the invention is at least about 9.5% by weight and
not greater
than about 10% by weight. Most preferably, the total amount of
pharmaceutically active
agents) included in compositions of the invention is about 9.8% by weight.
Lopinavir,
ritonavir, and/or mixtures thereof are the most preferred pharmaceutically
active agents
included in compositions of the invention. However, derivatives of lopinavir,
derivatives of
ritonavir and/or mixtures thereof are also useful in compositions of the
invention. In most
preferred embodiments of the invention, the ratio of lopinavir or its
derivatives to ritonavir or
its derivatives in pharmaceutical compositions of the invention is about 4:1
based upon the
percent by weight of each agent in the composition.
If both lopinavir or its derivatives and ritonavir or its derivatives are
included in the
composition, then ritonavir or its derivatives are preferably included in an
amount of at least
about 1.30% by weight and not greater than about 2.10% by weight; and
lopinavir or its
derivatives are included in an amount of at least about 2.50% by weight and
not greater than
about 8.0%~by weight based upon the total weight of the pharmaceutical
composition.
Lopinavir or its derivatives are most preferably included in compositions of
the invention in
an amount of about 8% by weight, and ritonavir or its derivatives are most
preferably
included in an amount of about 2% by weight based upon the total weight of the
pharmaceutical composition.
Solvent Systems
The low aqueous solubilities and insufficient bioavailability of ritonavir and
lopinavir
in their solid forms create a formulation challenge for developing
pharmaceutical
compositions containing one or both of these drugs or their respective
derivatives, especially
in instances when the total daily dose is relatively high. In general,
lopinavir is adequately
soluble at room temperature (i..e., about 25 °C) in pharmaceutically
acceptable solvents, such
as propylene glycol and ethanol. However, ritonavir is only poorly or
moderately soluble in
these types of pharmaceutically acceptable solvents. Therefore, individual
solvents may not
provide sufficient solubility for pharmaceutical compositions containing both
of these
pharmaceutically active agents or their respective derivatives. Applicants
have found that the
solubilities of both ritonavir and lopinavir and their respective derivatives
are significantly
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17
improved in a co-solvent system, which indicates a synergistic effect when
more than one
solvent is used in the solvent system.
Applicants have discovered that at least two and preferably at least three
types of
pharmaceutically acceptable solubilizing agents are useful in solvent systems
included in
pharmaceutical compositions of the invention. These solubilizing agents are
pharmaceutically acceptable water, alkyl alcohols, and alkylene glycols. Other
types of
pharmaceutically acceptable solubilizing agents can be useful in solvent
systems of the
invention. Generally, any pharmaceutically acceptbale solubilizing agent that
is useful in
increasing the solubility of ritonavir and/or lopinavir and/or their
respective derivatives is
useful as a solubilizing. agent in solvent systems of the invention. Examples
of useful
solubilizing agents include, but are not limited to: ethanol, propylene
glycol, polyethylene
glycol, fractionated coconut oil, mixtures thereof, and all other
pharmaceutically acceptable
solvents disclosed in U.S. Patents 4,484,801 and 5,914,332, which are
incorporated herein by
reference.
Preferably, the solvent system is at least about 32% by weight and not greater
than
about 69% by weight of the total weight of the pharmaceutical composition.
More
preferably, at least about 53% by weight and not greater than about 60% by
weight of the
pharmaceutical composition is the solvent system.
In most preferred pharmaceutical compositions of the invention, the at least
three
solubilizing agents included in the pharmaceutical composition comprise water,
propylene
glycol, and ethanol. The amount of water included in most preferred solvent
systems of the
invention is not greater than about 8.5% by weight, and more preferably at
least about 6% by
weight and not greater than about 8% by weight. Most preferably, water is
included in the
most preferred pharmaceutical compositions in an amount of about 6.80% by
weight. These
weight percentages for water pertain only to the amount of water that is added
to the
composition and do not include any water that is generated during preparation
of the
pharmaceutical composition. Water that is useful in the invention is
pharmaceutically
acceptable purified and distilled water and any water that is generated during
preparation of
the pharmaceutical composition.
Any type of pharmaceutically acceptable alkyl alcohol can be included in
solvent
systems of the invention. Preferably, the one or more alkyl alcohols included
in
pharmaceutical compositions of the invention are included in an amount of at
least about 24%
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18
by weight and not greater than about 42% by weight, and more preferably in the
amount of at
least about 33% by weight and not greater than about 37% by weight. Most
preferably, one
or more alkyl alcohols are included in compositions of the invention in an
amount of about
35% by weight. Additional amounts of an alkyl alcohol, such as ethanol, can be
included in
compositions of the invention to obtain the proper dosage form. Ethanol is the
most preferred
alkyl alcohol for use in compositions of the invention. An ethanol that is
useful in the
invention is Alcohol, Dehydrated, USP 200 Proof (reagent grade, non-beverage)
commercially available from Equistar of Tuscola, IL, U.S.A. An alkyl alcohol
of 190 proof
may be used by proportionally reducing the amount of added water.
Although any type of pharmaceutically acceptable alkylene glycol can be
included in
preferred solvent systems of the invention, propylene glycol is most
preferred. Preferably
one or more pharmaceutically acceptable alkylene glycols are included in an
amount of at
least about 7.5% by weight and not greater than about 18% by weight, and more
preferably at
least about 14% by weight and not greater than about 16% by weight. Most
preferably, one
or more alkylene glycols are included in the pharmaceutical composition in an
amount of
about 15% by weight. Propylene glycol products that are useful in the
invention are
commercially available from Dow Chemical North America's Texas Operation in
Freeport,
TX, U.S.A. and the Lyondell Bayport Plant in Pasedena, TX as Propylene Glycol
USP.
Other Additives to the Pharmaceutical Compositions
Generally, other pharmaceutically acceptable additives, such as thickening
agents,
bioavailability enhancers, antioxidants, and/or preservatives, may be included
in
compositions of the invention. Preferably, a thickening agent is included in
compositions of
the invention in an amount of at least about 2.50% and not greater than about
5.0% by
weight. More preferably, the amount of thickening agent that is included in
compositions of
the invention is at least about 2.50% by weight and not greater than about
3.20% by weight,
and most preferably a thickening agent is included in the composition in an
amount of about
3.0% by weight.
Any type of pharmaceutically acceptable thickening agent is useful in the
invention.
These types of thickening agents include, but are not limited to:
polyvinylpyrrolidone,
carbomers, xanthan gum, hydrated magnesium aluminum silicates, and cellulose
derivatives,
such as carboxymethyl cellulose. Most preferably, polyvinylpyrrolidone is used
in the
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19
compositions of the invention. A useful polyvinylpyrrolidone is
polyvinylpyrrolidone USP,
which is commercially available from ISP Chemicals of Texas City, TX, U.S.A.
as Plasdone
K 29/32.
Preferably, a pharmaceutically acceptable bioavailability enhancer is included
in
compositions of the invention in an amount of not greater than about 3% by
weight. More
preferably, the amount of bioavailability enhancer included in the composition
is at least
about 0.95% and not greater than about 1.10%, and most preferably the
bioavailability
enhancer is included in the composition in an amount of about 1.0% by weight.
Any type of pharmaceutically acceptable bioavailability enhancer is useful in
the
invention. These types of bioavailability enhancers include, but are not
limited to:
polyoxyethyleneglycerol triricinoleate, castor oil derivatives, such as but
not limited to
polyoxyethylene glycol 40 hydrogenated castor oil, polyoxyethylene (20)
sorbitan
monooleate, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid
esters (i.e.,
polysorbate), and mixtures thereof. Most preferably, polyoxyl 40 hydrogenated
castoff oil
USP, which is commercially available as Cremophor RH40 from BASF of Mt. Olive,
NJ,
U.S.A. is used in compositions of the invention.
The following is the most preferred pharmaceutical composition of the
invention.
Ingredient % By Weight
Menthol Crystals 0.05
Peppermint Oil 0.30
Vanilla Flavor 1.25
Cotton Candy Flavor 1.00
Sodium Chloride 0.35
Sodium Citrate 0.20
Citric Acid 0.11
Water (excluding generated water) 6.80
Ethanol 35.00
Propylene Glycol 15.00
Saccharin Sodium 0.40
Acesulfame Potassium 0.40
High Fructose Corn Syrup 16.57
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Glycerin 8.17
Monoammonium Glycyrrhizinate 0.58
Polyoxyl 40 Hydrogenated Castor Oil 1.00
Ritonavir I .97
5 Lopinavir 7.86
Polyvinylpyrrolidone 3.00
10 Preparation of the Pharmaceutical Compositions
Generally, pharmaceutical compositions of the invention may be prepared in any
pharmaceutically acceptable manner in which all ingredients are satisfactorily
dissolved in
the composition. In general, Applicants have found that for the most efficient
production any
15 one or more solubilizing agents included in the solvent system should be
added to the mixing
vessel first and any one or more heated semi-solids or heated viscous liquids,
such as any
castor oil derivatives, should be the ingredients added last or at least near
the end of the
process. In addition, the most insoluble solids included in the composition,
such as any
menthol crystals andlor the pharmaceutically active agents (e.g., ritonavir
and/or lopinavir),
20 should be added to the vessel just after any one or more solubilizing
agents; and any one or
more flavored ingredients in a non-solid form should be added to the mixing
vessel just
before any of the heated semi-solids or heated viscous liquids. Applicants
have also found
that continuous mixing between the addition of ingredients facilitates
complete dissolution of
all the ingredients included in the composition.
In preferred methods, Applicants have found that pharmaceutical compositions
of the
invention can be prepared by: (1) charging a vessel with at least a portion of
the solvent
system; (2) dissolving any menthol crystals or any other menthol in solid form
in the portion
of the solvent system that is in the vessel; (3) dissolving the
pharmaceutically active agents)
in the vessel containing the solvent system; (4) dissolving any thickening
agent in the vessel
containing the solvent system and pharmaceutically active agent(s); (5)
dissolving the water
soluble non-liquid flavoxing system ingredients, excluding the flavored
ingredients, in watex
to form a side mixture; (6) adding the side mixture, any one or more liquid
sweetening
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21
agents) and other liquid flavoring system ingredients, the flavored
ingredients, and any
remaining excipients to the mixing vessel containing the dissolved
pharmaceutically active
agent(s).
Charging a Vessel with Solubilizing Agents
Any one or more solubilizing agents included in the solvent system should
first be
added to a mixing vessel. Preferably, the mixing vessel is a jacketed
stainless steel pressure
rated vessel having the ability to continuously mix the composition during the
preparation
process. Mixing is preferably performed at one or more speeds of 100 - 320
revolutions per
minute ("rpm") with two hydrofoil impellers that are secured to the mixing
vessel.
Preferably, the mixing vessel is capable of being purged with Nitrogen, NF, to
minimize any
explosion or fire hazards. More preferably, a continuous flow of nitrogen is
applied to the
vessel during the preparation of compositions of the invention. After all the
ingredients are
added to the vessel as fully described below, the vessel should be sealed and
a nitrogen head
pressure of at least 1 psig should be maintained after the vessel is sealed.
Examples of
mixing vessels that can be used to make pharmaceutical compositions of the
invention are:
an 800L stainless steel tank available from Northern Stainless, Inc. of
Tomahawk, WI; and a
1900L stainless steel tank available from Brighton Corp. of Cincinnati, OH.
Any one or more solubilizing agents used in the composition should be added to
the
vessel first so that the remaining ingredients can be dissolved in these
agents. Preferably,
water, an alkyl alcohol (e.g., ethanol), and an alkylene glycol (e.g.,
propylene glycol) are
solubilizing agents that are first added to the vessel with continuous mixing
at a speed of 100
- 320 rpm and continuous nitrogen flow as described above. The solubilizing
agents should
be added to the mixing vessel at a temperature of about 25°C, and
should be mixed until there
is no visible separation of the solvent system in the vessel.
Dissolution of Any Menthol in Solid Form
Because any menthol in solid form (e.g., crystals) has low solubility in
water, it
preferably is added to the mixing vessel and dissolved in the solvent system
just after the
solubilizing agents are mixed in the vessel. After any menthol is added to the
vessel at a
temperature of about 25°C, the contents of the vessel should be mixed
until the menthol is
dissolved. Typically, the menthol and solubilizing agents should be mixed for
at least about
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22
minutes prior to adding the pharmaceutically active agents to the vessel. Any
menthol
included in the composition of the invention in liquid from may be added to
the vessel with
the flavored ingredients as described herein below.
5 Dissolution of the Pharmaceutically Active Agents)
Prior to adding any one or more pharmaceutically active agents, the mixing
vessel
temperature must be set at about 25°C, and the temperature of the
vessel's contents should be
at least about 18°C and not greater than about 30°C. This
temperature range should be
maintained throughout the remainder of the preparation process. Preferably, if
both ritonavir
or its derivatives and lopinavir or its derivatives are included in the
composition, then
ritonavir or its derivatives should be slowly and steadily added to the mixing
vessel and
mixed, and then lopinavir or its derivatives should be added to the vessel in
the same manner.
In order to facilitate dispersion and dissolution of these pharmaceutically
active agents, the
vessel contents should be mixed continuously at a speed of about 200 - 320 rpm
so that a
vortex is maintained in the vessel. Generally, after any thickening agents are
added to the
vessel, as described below, the mixing speed may be lowered without causing
any significant
amount of the pharmaceutically active agents to settle on the bottom of the
vessel.
Preferably, after the pharmaceutically active agents are added to the vessel,
the vessel
walls and any hopper or port through which the pharmaceutically active agents
were added
are rinsed with a pharmaceutically acceptable alkyl alcohol, such as ethanol,
to insure that all
the pharmaceutically active agents) is washed into and dissolved in the
vessel. To equalize
the solution compositions for each batch size, an alcohol rinse of 5.0% by
weight per unit
volume of the pharmaceutical composition for an 800 liter batch size and an
alcohol rinse of
about 14.4% by weight per unit volume of the composition for a 2000 liter
batch size should
be used to rinse the walls and any hopper or ports of the mixing vessel.
Preferably, after the
walls and hopper or any port through which any one or more pharmaceutically
active agents
were delivered are rinsed, each batch contains about 31 % by weight per unit
volume of the
composition of an alkyl alcohol, such as ethanol. Continuous mixing and re-
circulation of the
vessel contents help to insure that a minimal amount of solids settle to the
bottom of the
vessel and that the dissolution of the pharmaceutically active agents is
complete. Once
dissolution of the pharmaceutically active agents is confirmed by visual
inspection and/or
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23
sampling from the vessel's bottom, then any thickening agents) and other solid
low- or non-
water soluble ingredients should be added to the vessel.
Dissolution of Any Thickening Agents) and Other Dry Solids
Any remaining dry solid low- or non-water soluble ingredients, such as any
thickening agents, should be added to and uniformly mixed in the vessel after
the
pharmaceutically active agent(s). Any thickening agents) or other low-or non-
soluble
ingredients included in the composition should be added slowly and steadily to
the vessel to
facilitate its complete dispersion and dissolution. A directional funnel can
be used during the
addition of these ingredients (e.g., any thickening agent) to minimize any
clumping,
agglomeration and adherence to the vessel walls. The vessel contents should be
mixed until
the ingredients are uniformly mixed.
Addition of Any Liquid Sweetening Agents
Preferably, any one or more liquid sweetening agents are added to the vessel
after any
thickening agents or other low- or non-soluble ingredients. More preferably,
if both high
fructose corn syrup and glycerin are used in the composition, then the
glycerin is added to the
vessel before the high fructose corn syrup. After the addition of any
glycerin, the contents of
the vessel should be mixed until the contents are uniformly mixed, and then
any high fructose
corn syrup should be added to the vessel. Preferably, the high fructose corn
syrup is pumped
into the vessel and then mixed until the vessel contents are uniform.
Preparation and Addition of Any Side Mixture
While the vessel contents are being mixed, the water soluble powdered
ingredients,
except for any thickening agents, to be included in the composition preferably
are dissolved
in water in a separate vessel. Preferably, each of the individual water
soluble powdered
ingredients included in the separate vessel is less than about 3% by weight of
the total
pharmaceutical composition. Preferably, the separate vessel is a stainless
steel vessel having
continuous mixing means and the capability to mix its contents at a rate of
about 650 +/- 150
rpm. Any type of mixing means can be used as long as it can efficiently
dissolve the water
soluble ingredients in the separate vessel; however, an air mixer with one
propeller is most
preferred. The water soluble powdered ingredients to be included in any side
mixture are the
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24
non-liquid flavor modifiers and the non-liquid sweetening agents. In most
preferred
compositions of the invention, the dry forms of sodium chloride, sodium
citrate, saccharin
sodium, acesulfame potassium, and citric acid are dissolved in water and mixed
in the
separate vessel to form the side mixture. These ingredients can be added to
the separate
vessel in any order as long as each is uniformly mixed prior to the side
mixture being added
to the main mixing vessel. The side mixture is prepared at ambient temperature
(i.e., about
25°C) with constant mixing at a speed of 650 +/- 150 rpm. In general,
the vessel mix speeds
should be adjusted to insure that there is a minimal amount of splash in the
vessel.
Each of these powdered water soluble ingredients is preferably separately
added to
the side mixture and dissolved. Once the side mixture is prepared, it is
preferably pumped
into the main mixing vessel through the same port or transfer lines as was
pumped any one or
more liquid sweetening agents so that any remaining high fructose corn syrup
or other liquid
sweetening agents can be washed into the main mixing vessel and mixed.
Addition of the Flavored Ingredients
After the side mixture is added to the main mixing vessel, the flavored
ingredients
should be added to and mixed in the vessel. The flavored ingredients can
generally be added
in any order. In most preferred embodiments, peppermint oil, vanilla flavor,
and cotton candy
flavor are all added to the main mixing vessel separately and mixed in the
vessel. Ariy
menthol in liquid form or flavor modifiers in liquid form may also be added to
the vessel with
the flavored ingredients.
Addition of .Any Bioavailability Enhancer and Any Additional Ingredients
If a bioavailability enhancer is included in the composition, it is preferably
added to
the mixing vessel after the flavored ingredients. More preferably, any
bioavailability
enhancer is added to the mixing vessel in liquid form. Thus, if a
bioavailability enhancer,
such as a castor oil derivative is used, it preferably is heated prior to
being added to the
mixing vessel. In most preferred embodiments, Polyoxyl 40 Hydrogenated Castor
Oil, NF is
heated in a separate vessel to a temperature of about 40°C and melted
to form a viscous liquid
prior to being added to the mixing vessel. Melting any castor oil derivative
prior to adding it
to the mixing vessel facilitates efficient and complete dispersion and
dissolution of the castor
CA 02417258 2003-O1-24
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oil derivative (or any bioavailability enhancer in solid or semisolid form).
Once melted, any
bioavailability enhancer should be added to the main mixing vessel and mixed
until the
contents are uniform. Any bioavailability enhancer that does not need to be
heated (i.e., in
non-viscous liquid form) may be added with other non-viscous liquids earlier
in the
5 preparation process.
After any bioavailability enhancer is added to the mixing vessel and mixed,
any final
excipients can be added to the mixing vessel. Once all of the excipients are
added to the
vessel, then an additional quantity of a pharmaceutically acceptable alkyl
alcohol, such as
ethanol, can be added to the vessel in an amount of quantum sufficia (QS) to
manufacture the
10 final composition and batch volume. Once a sufficient amount of such an
alcohol is added,
the tank can be sealed and pressurized to at least 1 psig with Nitrogen, NF,
and the solution ,
can be stored at ambient temperature (i.e., about 25°C) with continuous
mixing at about 80 -
240 rpm.
It is appreciated that the above described steps can be performed in any order
that
15 allows each ingredient to be mixed and dissolved in the composition soon
after such
ingredient is added to the mixing vessel. For example, any one or more of the
solubilizing
agents can be added initially to the vessel followed by any one or more non-
liquid
ingredients, and then additional solubilizing agents can be added to the
vessel. In addition, a
side mixture does not have to be separately prepared as long as the water
soluble powdered
20 ingredients are added to the vessel in a pharmaceutically acceptable manner
to facilitate
complete dispersion and dissolution of these ingredients. By way of example,
the following
order of addition of the most preferred ingredients is useful to prepare
pharmaceutical
compositions of the invention as long as the vessel contents are continuously
mixed, and each
ingredient is uniformly mixed.
25 ~ Adding the water to the alkyl alcohol (e.g., ethanol) in the mixing
vessel
~ Adding any citric acid to the vessel
~ Adding any alkylene glycol, such as propylene glycol to the vessel
~ Adding a first pharmaceutically active agent, such as ritonavir, to the
mixing vessel
~ Adding any second pharmaceutically active agent, such as lopinavir, to the
mixing vessel
~ Adding a first liquid sweetening agent, such as high fructose corn syrup, to
the mixing
vessel
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26
~ Adding any menthol to the mixing vessel
~ Adding any acesulfame potassium to the mixing vessel
~ Adding any sodium chloride to the mixing vessel
~ Adding any sodium saccharin to the mixing vessel
~ Adding any sodium citrate to the mixing vessel
~ Adding any thickening agents, such as polyvinyl pyrrolidone, to the mixing
vessel
~ Adding monoammonium glycyrrhizinate to the mixing vessel
~ Adding peppermint oil to the mixing vessel -
~ Adding vanilla flavor to the mixing vessel
~ Adding cotton candy flavor to the mixing vessel
~ Adding any bioavailability enhancers, such as a castor oil derivative,
(preferably in liquid
form) to the mixing vessel
~ Adding any second liquid sweetening agent, such as glycerin; to the mixing
vessel
In most preferred embodiments of the invention, pharmaceutical compositions of
the
invention are filtered prior to being put into final package form. Preferably,
Buchner Filters
on the order of 10 - 60 microns are used to filter these compositions. Most
preferably, a 14
micron filter is used to filter these compositions.
The foregoing is merely illustrative of the invention and is not intended to
limit the
invention to the disclosed compounds, methods, and compositions. Variations
and changes
that are obvious to one skilled in the art are intended to be within the scope
and nature of the
invention, which is defined in the claims below.
