Note: Descriptions are shown in the official language in which they were submitted.
2143439
.
W094/05260 PCT/US92/07513
TA8T~-MA8RING PHARMAC~UTICAh CO~PO8ITION8 AND
METHOD~ FOR MA~lN~ T~E 8AME
Field of the Invention
This invention relates to techniques for taste-
masking pharmaceutical drugs. More specifically, theinvention relates to compositions comprising a drug having its
taste masked by a lipid coating contained within an aqueous
polymer system for oral administration which provides an
improved taste for the drug.
Backqround of th~ Invention
It is well known that many medicaments intended for
oral administration are highly unpalatable because of their
bitter taste. Sweeteners have been added to these medicaments
in order to mask the unpleasant taste, however, sweeteners
alone are insufficient to entirely mask the bitter taste of
many drugs.
A more recent and convenient means of preparing
these drugs is in a granule lipid format which avoids the
storing of the drug in an aqueous solution which solution
could destroy the lipid coating. The granules are usually
suspended in an aqueous solution immediately prior to oral
administration and, in this manner, the drug is not dissolved
in the mouth of the patient, but rather passes on to the
gastro-intestinal tract where it is dissolved by stomach
fluids. By storing the drug within an integral coating of a
lipid a granule format, the drug can be maintained in its
flavor masked form for at least 14 days and maybe longer.
Lipid coatings for masking the bitter taste of
W094/05260 PCT/US92/07513
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- certain drugs have been beneficially employed as is shown in
U.S. Patent No. 4,865,851 to James et al and U.S. Patent No.
4,764,375 to Paradissis. However, these references describe
processes which require producing granules of the lipid coated
drug, which processes require special processing equipment to
produce the granules. The James et al. reference describes
the use of providing a lipid coating onto cefuroxime axetil
by use of a spray drying tec-hnique. Such a technique for
coating the drug requires specific spray drying equipment and
is relatively an expensive and intricate process. The drug
used in James necessitated an integral lipid coating and
storage in the granule state because the drug would gel in an
aqueous carrier solution. The Paradissis reference describes
the use of a lipid coating to coat potassium chloride. Again,
the drug is stored in the granule state which requires
assorted equipment to accomplish that process. The potassium
chloride is highly water soluble and therefore must be kept
in the granule state because the drug and integral lipid
taste-masking coating break down within minutes in an aqueous
state.
A need therefore exists to provide a drug
composition and a method for preparing the same in which a
drug which has an unpalatable taste is presented in a taste-
masked form wherein the drug composition is in a readied state
for oral administration, can be stored in such a stable state,
and does not require additional formulation immediately prior
to oral administration.
8umm~rY of the Invention
A method of producing a stable drug composition
which masks the flavor of a drug in need of flavor masking is
provided which is broadly defined by the following steps. A
drug in particulate form is mixed with a lipid at a
temperature below that where significant drug degradation
occurs, preferably below about 50C. To this drug and lipid
mixture is added an emulsifier, a polymer solution, and a
~ W094/05260 2 1 ~ 3 ~ 3 9 PCT/US92/07513
dilution solution to form the stable taste-masked drug
composition.
In an alternative embodiment, the method proceeds
as follows. A mixture of a lipid and an emulsifier are heated
until that mixture is brought into a molten state. The lipid
and emulsifier mixture temperature is then adjusted to a
temperature below that where significant drug degradation
occurs, preferably below about 50-C. To this cooled mixture
is then admixed the drug, in particulate form, which thereby
forms a flavor masked drug/lipid dispersion. To this drug
dispersion is supplied a polymer solution to form a
concentrated drug composition. Finally, a dilution solution,
preferably comprising a sweetening agent, is added to form the
final drug composition.
Preferably, the drug is selected from the group
consisting of cimetidine, ranitidine, ibuprofen,
acetaminophen, and erythromycin. The method of the present
invention provides a stable dispersion of the drug, in a
flavor masked state, which dispersion has an extended shelf
life of several months.
Certain preferred particular embodiments of the
invention are also disclosed. The drug to lipid weight ratio
ranges from about 1:0.25 to about 1:2. Also, the drug is
preferably added in amount up to about 800 milligrams per 10
milliliters (10 cc) of the drug composition. In another
preferred embodiment of the invention, the polymer is supplied
as a polymer solution which contains the polymer in an aqueous
solution and preferably contains carboxymethylcellulose and
xanthan gum.
The invention also provides for the drug
compositions produced by the inventive methods.
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~De~ailed DescriPtion of the Invention
The present invention broadly relates to a novel and
economical method of preparing a stable pharmaceutical
composition which contains a drug, which is characterized by
having an unpleasant taste, wherein the drug is provided in
a flavor masked form in a dispersion system. The invention
provides for the effective flavor masked en~capsulation of the
drug in a lipid material and for the suspension of this
drug/lipid component in an aqueous phase with the aid of
emulsifiers and suspending agents. The drug composition
produced also contains an aqueous phase comprising a polymer
system and additive agents such as sweeteners and flavor
~nhAnç~r5. The final drug composition is a dispersion which
is believed to be stable indefinitely. Stability has been
demonstrated from as short as a day up to as long as 3 months
in its flavor masked state. The drug composition is generally
stored at a temperature range of from about 4-C to about 40'C,
preferably at about 15-25-C, and most preferably at room
temperature.
The methods by which the pharmaceutical compositions
are produced are described as follows. In one embodiment, the
drug, which is in particulate form, is mixed by conventional
methods with the lipid at a temperature below where
degradation of the drug can significantly occur. This
degradation is evidenced by a substantial inactivation of the
drug and is readily determined. The temperature is typically
kept below about 50C to avoid the degradation of the drug at
higher temperatures for most drugs. The lower temperature
limit of the lipid is governed by the ability to thoroughly
mix the drug in the lipid. The lipid can be either a paste
or a liquid and it is preferred that the lipid be in a liquid
state to aid in the drug admixing. An emulsifier, a polymer
solution and a dilution solution are then mixed with the
drug/lipid mixture to form a the final stable taste-masked
drug composition. This final drug composition contains the
drug, partially coated with the lipid and effectively taste-
masked by the lipid, suspended in the polymer solution. It
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21~3~3~
- 5 -
is preferred that the emulsifier be thoroughly admixed first,
followed by the addition of the polymer solution, and the
final drug volume achieved by addition of the dilution
solution. However, these three components can be admixed
together with the drug/lipid mixture. The final drug
composition is in a form which can be administered to a
patient orally.
The inventive method can also be carried out by a
different method. First, a mixture of a lipid and an
emulsifier is heated and mixed by conventional methods until
a molten homoge~ous state is reached. Preferably, the
temperature of the molten lipid will be at least about 20C
above the melting point of the lipid and typically will be in
the range of from about 50C - 100C. The temperature of this
lipid and emulsifier mixture is then adjusted to a temperature
below where significant drug degradation can occur, typically
below about 50C, in order to accept the drug without
degrading the integrity of the drug. A drug in need of taste
masking, in particulate form, is added to the lipid and
emulsifier mixture which can be in the form of a semi-solid
paste or a liquid. Then, a polymer is admixed to this
dispersion. Finally, a dilution solution, preferably an
aqueous solution containing, for example, sweetening agents
and/or flavoring agents and/or coloring agents is added to the
mixture to produce the final drug composition.
In order to produce the taste-masking pharmaceutical
compositions suitable for oral administration, the melting
point of the lipid should be sufficiently high to prevent
melting of the substantially coated particles during the short
period of time they are contacted with the mouth. Such
melting would release the unpleasant taste. There potentially
is no upper limit to the melting point of the lipid. The
lipids will conveniently have a melting point of from about
30C to about 95C. It is preferred to select a lipid which
allows for an effective amount of the drug to be released upon
digestion, and most preferably to select a lipid which does
not affect the bioavailability of the drug.
W O 94/05260 PC~r/US92/07~13
2~43~3~ - 6 -
The lipids which can be employed in the practice of
the present invention include triglycerides, for example a
glycerol ester of a high molecular weight (C1030) aliphatic
acid; fatty acids or monohydric alcohols thereof, fixed oils,
fats, waxes, sterols, phospholipids and glycolipids. The
lipid may also, for example, be a high molecular weight
straight chain (C1030) saturated or unsaturated aliphatic acid,
hydrogenated and partially hydrogenated oils such as cotton
seed oil, castrol oil, and coconut oil: waxes, for example,
bees wax or carnauba wax; mixtures of high molecular weight
fatty acids such as mixtures of stearic and palmitic acids,
and mixtures of high molecular weight straight chain aliphatic
alcohols. A preferred lipid is a partially hydrogenated
coconut oil sold by Karlshams Company under the trade name
PURECO 92.
The emulsifiers, or surfactants, which are useful
in the practice of the present invention maybe of the anionic
or nonionic type. The emulsifier of the present invention can
be a mixture of several emulsifiers. A mixture of an anionic
and a nonionic emulsifier is preferred as the emulsifying
agent. Examples of emulsifiers include acids, for example,
stearic acid, lauric acid, palmitic acid, etc.; glyceryl
behenate, and monooleates, such as sorbitan monooleate and
polyoxyethylene sorbitan monooleate. Preferred emulsifiers
include anionic surfactant such as a diacetyl tartaric acid
monoglyceride, for example, those sold under the trade name
PANOD~N 205 and SDK by the Grinsted Company. Also, a
preferred nonionic surfactant is glycerol stearate, for
example, LIPOGMS 470 manufactured by Lipo Chemical Co~rAny.
Drugs in need of taste masking are those drugs which
have an unpleasant taste when orally administered and include
cimetidine,ranitidine,ibuprofen,acetaminophen,erythromycin
and the like. Cimetidine is conveniently preferred. The
method of the invention provides a highly convenient and
economical method of taste-masking certain unpleasant tasting
drugs. However, the drug is believed to be substantially
coated but not entirely coated by the lipid. Thus certain
W094/05260 2 1 ~ 3 4 ~ 9 PCT/US92/07513
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drugs, such as cifuroxime axetil which tend to gel upon
contact with an aqueous medium are not suitable for use in the
invention. The drug is supplied in particulate form, and
preferably has a weight average particle size below about 300
microns, most preferably below about 200 microns in order to
avoid a gritty taste upon consumption. The drug preferably
has a low water solubility and the pH of the composition can
be adjusted to ~hAnse this aspect of the invention.
The polymers which are useful in the present
invention are added to keep the lipid encapsulated drug in
suspension and for thickening and include cellulose
derivatives such as sodium carboxymethylcellulose as well as
xanthan gum. One particular sodium carboxymethylcellulose for
use in the present invention is a low molecular weight AQUALON
7LF PH manufactured by the Aqualon Company. It is preferred
to provide the polymer in an aqueous solution. It is also
preferred to add a substance to aid in the dissolution of the
polymer in the aqueous solution, such as glycerin.
The dilution solution is preferably an aqueous
solution and functions to dilute the concentrated drug
emulsion to an acceptable level for oral administration.
Various sweeteners, flavoring agents, and coloring agents can
also be added to the dilution solution. Basically, the
dilution solution is a sugar solution in a concentrated form,
for example, above about 50% by weight of sweetener. The
various sweeteners include sucrose, sodium cyclamate, sodium
saccharinate, aspartame and ammonium glycyrrhizinate. Typical
flavoring agents include peppermint oil flavor and artificial
pineapple flavor. Examples of coloring agents include
titanium dioxide pigments, lake colors and iron oxide
pigments.
Other suitable additives are included within the
scope of the invention, such as an antacid to a cimetidine
preparation.
The pharmaceutical drug composition of the present
invention can be formulated in any desired quantities. In
order to more fully describe the present invention, a basis
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of 10 cc of the final stable taste-masked drug composition can
be used to define weight and volume ratios. Typical oral
administration volumes range from about 5 cc to 15 cc. The
amount of the drug to be added to a 10 cc solution of ~he drug
composition of the present invention is from about 100 to 800
milligrams of the drug. Once the amount of drug to be added
has been determined, the amount of lipid to be used can
readily be determined. Typically, the amount of lipid ranges
from 25-200% by weight of the amou~t of drug employed. In a
preferred embodiment, the ratio of drug to lipid is 1:1.
However, the maximum amount of lipid to be added to a 10 cc
solution of the drug composition is about 800 milligrams. The
amount of emulsifier to be used in the present invention
varies depending upon the type of emulsifier utilized. An
effective amount of emulsifier is needed however to provide
a drug composition which exhibits extended shelf life. In a
preferred embodiment, the amount of emulsifier is generally
from about 0.3-3% by weight of the drug composition. The
amount of polymer to be added to a 10 cc solution of the drug
composition of the present invention generally ranges from
about 30 milligrams to about 120 milligrams. The dilution
sweetening agent solution (containing also the flavoring and
coloring agents) generally is added in an amount to bring the
volume of the drug composition to the 10 cc quantity.
In a more detailed embodiment of the invention, the
method for producing the drug composition of the present
invention comprises five broad steps. In the first step, the
weighed amount of lipid and emulsifier are mixed together and
heated into a molten solution up to about 20OC above the
melting point of the lipid. It is preferred that the
temperature of the molten solution be from about 85-95 C. The
lipid and emulsifier are mixed until a homogenous liquid phase
is formed.
The second step requires for the molten solution to
be cooled. It is preferred that the solution be cooled to at
least 50~C or below to avoid drug degradation, but such that
the mixture remains a liquid or a semi-solid paste.
~ W094/05260 2 1 ~ 3 4 3 ~ PCT/US92/07513
_ 9 _
In the next step, the weighed amount of the drug to
be used is added to this cooled lipid phase. The drug and
lipid phase are mixed thoroughly using any appropriate mixing
device. In this way, the drug particles are substantially
5 coated with the lipid material whereby a flavor masking effect
r is obt~; ne~ as at least a portion of the drug is contained
within the lipid phase and has its flavor masked by the lipid
phase.
To this drug/lipid phase is added an appropriate
lO amount of the polymer, i.e. an amount of polymer sufficient
to suspend the lipid coated particles and provide the desired
thickness. The polymer is preferably added as polymer
solution. This polymer solution is an aqueous solution in
which the polymer is dissolved. If a non-aqueous solution is
15 chosen it is to be compatible with the lipid. Preferably, the
polymer is present in the polymer solution in an amount of
from about 6% to about 10% by weight. This solution may also
contain glycerin in an amount of about 20~ by weight to aid
in the dissolution of the polymer. The polymer solution is
20 thoroughly mixed into the drug/lipid phase by the aid of
mechanical mixing devices.
In the last step, a sweetening dilution mixture is
slowly added to the drug composition to enhance the flavor of
that composition. Preferably, this sweetening solution is
25 added in a concentrated form and contains sweetening agents,
flavoring agents, and coloring agents. The sweetening
solution is an aqueous base solution and is added to the drug
composition until the final drug composition attains its
desired volume.
lNV~.~ ' V~ EXANPLE 1
70mg of Panodan 205, 50mg of Lipo GMS 470, and 400mg
of Pureco 92 were weighed into the same vessel, and heated to
about 90 degree centigrade until clear homogeneous liquid
phase was formed. This lipid phase was allowed to cool to
room temperature at which point it becomes a semisolid paste.
To this lipid phase was added cimetidine (400mg). This
W094/05260 PCT/US92/07513 ~~
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mixture was mixed until homogeneous. To this drug-lipid
mixture was added polymer solution (8%w/v 7LF PH, 20%w/v
Glycerin, 788 mg). This mixture so obtained was mixed until
homogeneous. To this mixture was added the sucrose solution
(65%w/w sucrose, 0.05%w/v methyl parabens; 10.560g), a
spearmint oil flavor (2.8mg), a peppermint oil flavor (lmg),
and the mixture was mixed until homogeneous. The product so
obtained was a viscous syrup with a pH of 7.7 containing 400mg
of cimetidine per approximately lOml of liquid. This product
has improved taste over the non-inventive formulation.
IN~ENTIV~ BXA~PLE 2
Panodan 205 (9Omg) and Pureco 92 (400mg) were mixed
and heated to about 90 degree centigrade until a homogeneous
liquid was formed. This lipid phase was allowed to cool to
room temperature. Cimetidine (400mg) was added to this lipid
phase. The mixture so obtained was mixed until homogeneous.
To this drug-lipid mixture was added polymer solution (8%w/v
CMC 7LF PH, 20%w/v Glycerin; 788mg). The mixture so obtained
was mixed until homogeneous. To this mixture was added the
sucrose solution (65%w/w sucrose; 10.75g), Methyl parabens
(5mg), artificial pineapple flavor (3mg) and color (5%w/v FD&C
yellow #5; 2.Smg). This composition has a pH of 7.4 and
contains approximately 400mg cimetidine in lOml of liquid.
l~.V~ V~ ~XANPLE 3
Lipo GMS 470 (lOOmg), stearic acid (lOOmg) and
Pureco 92 (400mg) were mixed and heated to 90 degree
centigrade until a homogeneous liquid was formed. The other
ingredients were mixed in the same amount and in the same way
described in inventive example 2. This composition has a pH
of 7.6 and contains about 400mg cimetidine in lOmg of liquid.
lN V~I. ~ l V ~ BXAMPLE
Lipo GMS 470 (20Omg) and Pureco 92 (40Omg) were
mixed and heated to 90 degree centigrade until a homogeneous
liquid phase was formed. The other ingredients were mixed in
21~343~
W094/05260 PCT/~S92/07513
the same amount and in the same way described in inventive
example 2, except that flavor and color were not added. This
composition has a pH of 8.1 and contains about 400mg
cimetidine in lOmg of liquid.
IN~_.. lv~ E~ANPLB 5
Panodan 205 (47mg), Lipo GMS 470 (33mg) and Pureco
92 (267mg) were mixed and heated to about 90 degree centigrade
until a homogeneous liquid was formed. This lipid phase was
allowed to cool to room temperature. Cimetidine (267mg) was
added to this lipid phase. The mixture so obtained was mixed
until homogeneous. To this drug-lipid mixture was added a CMC
solution (8%w/v CMC 7LF PH, 20%w/v Glycerin; 788mg) and a
Xanthan Gum solution (Keltrol from Kelco 2%w/v, Glycerin
20%w/v; 150mg). The mixture so obtA~ was mixed until
homogeneous. To this mixture was added the sucrose solution
(65%w/w sucrose; 11.07g), Methyl parabens (5mg). This
composition has a pH of 7.7 and contains approximately 266mg
cimetidine in lOml of liquid.
l~.V~ V~ ~XAMPLB 6
Lipo G~S 470 (150mg), Cottonseed oil (338mg) and
glycerol behenate (112mg) were mixed and heated to about 90
degree centigrade until a homogeneous liquid was formed. This
lipid phase was allowed to cool to room temperature.
Cimetidine (400mg) was added to this lipid phase. This
mixture so obtained was mixed until homogeneous. To this
drug-lipid mixture was added a CMC solution (8%w/v CMC 7LF PH,
%w/v Glycerin; 788mg). The mixture so obtained was mixed
until homogeneous. To this mixture was added the sucrose
solution (65%w/w sucrose; 10.75g), Methyl parabens (5mg),
citric acid solution (10%w/v; 130mg), and artificial pineapple
flavor (4mg). This composition has a pH of 7.1 and contains
approximately 400mg cimetidine in lOml of liquid.
lNV~N-llV~ EXAMPLE 7
lOOul of Panodan SDK, 600ul of Nestle Choco-bake
were mixed and heated to about 90 degree centigrade until a
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- 12 -
clear homogeneous liquid phase was formed. This lipid phase
was allowed to cool to room temperature at which point it
becomes a semisolid paste. To this lipid phase was added
cimetidine (400mg). This mixture was mixed until homogeneous.
To this drug-lipid mixture was added a polymer solution (4%w/v
7LF PH, 10%w/v Glycerin; lOOOul). The mixture so obtained was
mixed until homogeneous. To this mixture was added the
sucrose solution (65%w/w sucrose, 0.05%w/v methyl parabens;
7.9ml) and a peppermint oil flavor (0.7ul), and the mixture
was mixed until homogeneous. The product so obtained was a
viscous syrup containing 400mg of cimetidine per approximately
lOml of liquid.
INVFNTIVE LXAMPLB 8
50ul of Panodan SDK, 50ul of stearic acid and 600ul
of Nestle Choco-bake were mixed and heated to about 90 degree
centigrade until a clear homogeneous liquid phase was formed.
The other ingredients were mixed in the same amount and in the
same way described in inventive example 7. The product so
obtained was a viscous syrup containing 400mg of cimetidine
per approximately lOml of liquid.
l~.V~. ~ lV~ EXAMPLB 9
Panodan 205 (32mg), Lipo GMS 470 (32mg) and Pureco
92 (200mg) were mixed and heated to about 90 degree centigrade
until a homogeneous liquid was formed. This lipid phase was
allowed to cool to room temperature. Acetaminophen (320mg)
was added to this lipid phase. The mixture so obtained was
mixed until homogeneous. To this drug-lipid mixture was added
polymer solution (8%w/v CMC 7LF PH, 20~w/v Glycerin; 788mg).
The mixture so obtained was mixed until homogeneous. To this
mixture was added the sucrose solution (65%w/w sucrose;
11.26g). Sodium benzoate (lOmg) and citric acid (40mg). This
composition has a pH of 3.8 containing approximately 320mg
acetaminophen in lOml of liquid.
~ W094/05260 2 1 ~ 3 4 3 9 PCT/US92/07S13
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INVENTIVB ~XANPLE lo
Panodan 205 (50mg), Lipo GMS 470 (50mg) and Pureco
92 (300mg) were mixed and heated to about so degree centigrade
until a homogeneous liquid was formed. The other ingredients
were mixed in the same amount and in the same way described
in inventive example 9, except that the amount of citric acid
was 50mg and of sucrose solution was 11.05g. This composition
contains approximately 320mg acetaminophen in lOml of liquid.
