Note: Descriptions are shown in the official language in which they were submitted.
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TABLET COMPOSITION
FIELD
The present invention relates to a tablet composition comprising a drug
active.
BACKGROUND
Orally administered compositions are given to the patient in many forms,
such as liquid solutions including gels, emulsions, and suspensions;, or in
solid
forms such as powders, granules, and tablets. Compositions administered in
~5 solid form, especially tablets, are usually intended to be swallowed whole
or
chewed.
Many consumers, particularly those who have difficulty swallowing a tablet
(e.g., the aged or children), prefer tablets which can be readily ingested by
chewing. Such people desire tablets which dissolve immediately during chewing
2o in the mouth.
However, conventional tablets tend to produce an unacceptable mouthfeel
(i.e., overall sensation of the product in the mouth) for the user. Product
attributes which tend to contribute to an unacceptable mouthfeel include
bitterness (typically caused by the drug active contained in the table) and
25 grittiness (i.e., the textural aspects of the granules making up the
tablet, as
sensed by the tongue and/or upper palate). Such unacceptable mouthfeel
properties tend to make the tablet {in chewed or unchewed form) difficult for
the
user to swallow.
Some of activve ingredients which tend to exhibit the undesirable
3o characteristic of bitter taste after oral administration by e.g.,
swallowing and/or
chewing, include e.g., acetaminophen, ampicillin, azithromycin,
chlorpheniramine, cimetidine, dextromethorphan, diphenhydramine,
erythromycin, ibuprofen, penicillin, phenylbutazone, psuedoephedrine,
ranitidine,
spironolactone, and theophylline for pharmaceutical compositions. See Keating
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2
U.S. Patent 2,990,332, Koff U.S. Patent 3,138,525, Raghunathan U.S. Patent
4,221,778, and Kelleher U.S. Patent 4,996,047.
Various formulation approaches for have been taken to address the issues
of bitterness and/or grittiness For example, U.S. Patent 3,138,525 (Koff,
issued
s June 23, 1964); U.S. Patent 4,221,778 (Raghunathan, September 9, 1980); and
U.S. Patent 4,996,047 (Kelleher et al, February 26, 1991).
Based on the foregoing, there is a need for a drug delivery tablet
composition which has improved mouthfeel properties andlor is easier for the
user to swallow.
SUMMARY
The present invention is directed to a composition comprising a drug
active; a thickening agent; and a sugar agent; wherein the composition is in
solid
form, and wherein the ratio of the thickening agent to the sugar agent causes
the
composition to become a paste when contacted with saliva.
These and other features, aspects, and advantages of the present
invention will become better understood from a reading of the following
description, and appended claims.
2o DETAILED DESCRIPTION
llVhite the specification concludes with claims particularly pointing out and
distinctly claiming the invention, it is believed that the present invention
will be
better understood from the following description.
All percentages and ratios used hereinafter are by weight of total
composfion, unless otherwise indicated.
Ail measurements referred to herein are made at 25°C unless
otherwise
specified.
All percentages, ratios, and levels of ingredients referred to herein are
based on the actual amount of the ingredient, and do not include solvents,
fillers,
or other materials with which the ingredient may be combined as a commercially
available product, unless otherwise indicated.
All publications, patent applications, and issued patents mentioned herein
are hereby incorporated in their entirety by reference. Citation of any
reference
is not an admission regarding any determination as to its availability as
prior art
to the claimed invention.
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3
Herein, "comprising" means that other steps and other components which
do not affect the end result can be added. This term encompasses the terms
"consisting of and "consisting essentially of."
Herein, "solid tablet" means a material which has a hard shape and is
made by compressing granules pre-mixed into a predetermined shape or direct
compression of ingredients contained, which includes, e.g., pills, lozenges,
and
troches.
Herein, "paste" means a material which is in smooth liquid form having
higher or lower viscosity, e.g., gel form and cream form. .
1o The present invention relates to a composition comprising a drug active; a
thickening agent; and a sugar agent; wherein the composition is in solid form,
and wherein the ratio of the thickening agent to the sugar agent causes the
. composition to become a paste when contacted with saliva. It is believed
that
tablets, when wetted with water; start penetration of water, swelling its
structure,
~5 dissolving and destroying its shape, thereby the tablets change the
structure into
paste.
The aspects and embodiments at the present invention set forth in. this
document have many advantages, including improved mouthfeel and/or
improved dissolution in the mouth. For example, in one aspect of the present
2o invention, the tablet composition converts into a paste when contacted with
saliva
in the mouth. Such a paste facilitates the user's swallowing the composition.
In
another aspect of the present invention, the paste provides an improved
mouthfeel by, e.g., masking the bitter taste otherwise produced by the drug
active and/or reduang any gritty sensation otherwise experienced by the user.
25 In a preferred embodiment, the ratio of. the thickening agent to the, sugar
agent included in the composition is at least about 1:7. Such a ratio is
believed
to facilitate maintaining separation of individual particles of the thickening
agent,
(i.e., preventing their lumping together) when the composition is contacted
with
saliva in the mouth.
3o In yet another aspect of the present invention, the paste of the
composition prevents the user from experiencing the bitter taste of the drug
active. Without being bound by theory, it is believed the combination of the
thickening agent and sugar agent "suspends" the drug active in the paste form,
such that the drug active does not fully contact the bitter sensing taste buds
of
35 the mouth. While conventional formulations have, in some cases, resorted to
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4
coating the drug active (e.g., drug resin complex) to prevent such a bitter
taste
sensation, such a formulation step is not necessary in the composition of the
present invention. For example, an embodiment of the present invention
comprising an uncoated drug resin complex would also result in little or no
bitter
taste sensation to user.
In another aspect at the present invention, the composition can contain a
higher concentration of drug actives in comparison with those included in the
conventional tablets or lozenges. For example, the composition could contain
from about 2 to about 6 times or more of an uncoated drug resin active, versus
to conventional compositions containing an uncoated resin composition.
A. D~y9 active
The composition of the present invention includes a drug active. Herein,
"drug active" refers to an ingredient intended to be delivered (e.g., ingested
by)
~5 the user for therapeutic treatment. Preferably the drug active is a drug
resin
complex. The drug resin complex contains an active ingredient which is
conventionally used in pharmaceutical industries, in combination with an ionic
exchange resin (e.g., ration), thereby delaying the release of the active
ingredients during administration, for example, until the composition reaches
the
2o gastrointestinal tract.
Exemplary active ingredients which are suitable for the use in the drug
resin complex may be acidic, basic or amphoteric. Examples of acidic drugs
useful herein include, but are not limited to, dehydrocholic acid, diflunisal,
ethacrynic acid, fenoprofen, furosemide, gemfibrozil, ibuprofen, naproxen,
25 phenytoin, probenecid, suiindac, theophylline, salicylic acid and
acetylsalicylic
acid.
Exemplary active ingredients which are basic include, but are not limited
to, acetophenazine, amitriptyline, amphetamine, benztropine, biperiden,
bromodiphenhydramine, brompheniramine. carbinoxamine, chlorcyclizine,
3o chlorpheniramine, chiorphenoxamine, chlorpromazine, clemastine, clomiphene,
clonidine, codeine, cyclizine, cyclobenzapnne, cyproheptadine, desipramine,
dexbrompheniramine, dexchlorphen~ramine, dextroamphetamine,
dextromethorphan, dicyclomine, diphemarnl. diphenhydramine, doxepin,
doxylamine, ergotamine, fluphenazme. haloperidol, hydrocodone,
35 hydroxychloroquine, hydroxyzine, hyoscyamine. imipramine, levopropoxyphene,
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maprotiline, meclizine, mepenzolate, meperidine, mephentermine, mesoridazine,
methadone, methdilazine, methscopolamine, methysergide, metoprolol,
nortriptylene, noscapine, nylindrin, orphenadrine, papaverine, pentazocine,
phendimetrazine, phentermine, phenylpropanolamine, pyriiamine,
5 tripelennamine, triprolidine, promazine, propoxyphene, propanolol,
pseudoephedrine, quinidine, and scopolamine.
Exemplary amphoteric drugs useful herein include, but are not limited to,
aminocaproic acid, aminosaiicylic acid, hydromorphone, isoxsuprine,
levorphanol, melphalan, morphine, nalidixic acid, and paraaminosalicylic acid.
~o Preferred ion-exchange resins (hereinafter, "ion-exchanger") useful herein
are water-insoluble resins and consist of a pharmacologically inert organic or
inorganic matrix containing covalently bound functional groups that are ionic
or
capable of being ionized under the appropriate pH conditions. The organic
matrix may be synthetic (e.g., polymers or copolymers of acrylic acid,
methacryiic
~5 acid, sulfonated styrene, sulfonated divinylbenzene), or partially
synthetic (e.g.,
mod~ed cellulose and dextrans).
The inorganic matrix can also be, e.g., silica gel modified by the addition
of ionic groups. The covalently bound ionic groups may be strongly acidic
(e.g.,
suifonic acid), weakly acidic (~.g., carboxylic acid), strongly basic (e.g.,
2o quaternary ammonium), weakly basic (e.g., primary amine), or a combination
of
acidic and basic groups. In general, those types of ion-exchangers suitable
for
use in ion-exchange chromatography and for such applications as deionization
of
water are suitable for use in the compositions of the invention.
Examples of such ion-exchangers are described by H. F. Walton in
25 "Principles of Ion Exchange" (pp. 312-343) and 'Techniques and Applications
of
Ion-Exchange Chromatography" (pp. 344-361) in Chromatoqraohy. (E.
Heftmann, editor), Van Nostrand Reinhold Company, New York (1975).
Preferably, the particle size of the ion-exchangers is from about 40
microns to about 150 microns. Particle sizes substantially below the lower
limit
3o tend to be difficult to handle in all steps of the processing. Particle
sizes
substantially above the upper limit (e.g., commercially available ion-exchange
resins having a spherical shape and diameters up to about 1000 microns) tend
to
be gritty in solid dosage forms and have a greater tendency to fracture when
subjected to drying-hydrating cycles.
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6
Binding of drug ingredients and resins can be accomplished by any of the
methods known in the art, the selection depending upon the drug ingredient and
the ion-exchanger making up the desired drug resin complex. The concentration
of the drug ingredient and the resin can be also selected depending upon the
characteristic of the resultant drug resin complex necessary to meet the
requirement of the therapy.
The drug resin complex useful herein can be uncoated or coated.
Preferably the coating material comprises water permeable diffusion
. components. In a preferred embodiment, the drug active (e.g., drug resin
1o complex) is uncoated.
The drug resin complex preferably has an uncoated particle size of ftom
about 10 microns to about 150 microns. In coated drug active embodiments,
such a size range will increase, commensurate with the thickness of the
coating.
It is believed a higher particle size of drug resin complex may lead to an
~5 unacceptable gritty mouthfeel when the tablet is converted into the paste
form in
the mouth. The lower particle size tends to provide manufacturing loss and
result
in difficulty of handling during processing.
In a preferred embodiment, the drug active useful herein is present at a
level of from about 0.5 to about 16.0 %, preferably from about 1.0 to about
20 12.0%. These levels of drug resin complex without coating are up to 8 times
compared to those included in the conventional tablets.
B. Thickening aa_ent
The composition of the present invention also includes a thickening agent.
25 Herein, "thickening agent" refers to a material which provides a desirable
consistency when contacted with saliva and/or water in the mouth. Such
thickening agents in the composition have characteristics such as wetting
quickly
and absorbing fluid when contacted with water and/or saliva, thereby swelling
and converting into a paste. It is believed that water is absorbed into the
3o structure of the composition maintaining cohesiveness of the composition
structure. When more and more water enters the composition structure, more
swelling takes place and a paste is formed.
Nonlimiting examples of thickening agents useful herein include:
pregelatinized starch; gums such as agars, locust bean gums, guar gums, and
35 tare gums; carrageenan; alginate; xanthan; dextran; and cellulose
derivatives
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7
such as sodium carboxymethyi cellulose and sodium carboxymethyi hydroxyethyl
cellulose. Natural gums such as gum karaya, gum arabic, and gum tragacanth
can also be used. Synthetic silicates such as colloidal magnesium aluminum
silicate or finely divided silica can be used as part of the thickening agent
to
s further improve texture. The thickening agent is preferably present from
about
0.2% to about 5.5% by weight of the composition.
C. Sugar agent
The composition of the present invention also includes a sugar agent.
Herein, usugar agent" refers to a material which is used to enhance salivation
and
help in dissolution of the composition. The sugar agent presents in the
composition can provide sweetness to the formulation, and a desirable
dissolution property to the composition as well as aid in the processing of
the
composition into tablet form. The sugar agent is believed to keep the
individual
15 particles of the thickening agent separated and prevent their lumping when
contacted with saliva and/or water.
Preferably, the sugar agent useful herein is a sugar, sugar alcohol, or
mixture thereof. Nonlimiting examples of sugars useful herein include lactose,
glucose, maltodextrins, and sucrose. Sugar alcohols useful herein include
2o sorbitol, xylitol, mannitol and mamtol.
The total amount of sugar agent is selected depending upon its
compatibility with the other ingredients, especially drug actives, and the
desired
characteristic of the composition such as dissolution and mouthfeel, e.g.,
bitterness and gritthness of the tablet. The sugar agent is present at an
effective
25 level, preferably at a level of from about 20% to about 80°~, more
preferably from
about 20% to about 85% by weight.
Preferably, the sugar agent of the present invention is a combination of
sugar and sugar alcohol, more preferably the ratio of sugar of such
combination
is lower than the ratio of sugar alcohol. A preferred combination is sucrose
30 (sugar) with a higher ratio of mannitol (sugar alcohol). It is believed the
combination of sugar and sugar alcohol as the sugar agent improves the
pleasant dissolution provided by the combination of the sugar agent with
thickening agent. inclusion of mannitol slows the dissolution speed of the
composition as compared to inclusion of sugar only. Without being bound by
35 theory, it is believed that dissolution of a sugar agent having a faster
dissolving
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8
speed may cause the formation of a thick film around the individual particles
of
thickening agents, undissolved sugar agents, and other particles included in
the
composition. Such a thick film tends to prevent further penetration of water
into
the composition structures and particles which have not dissolved yet; thereby
preventing complete and/or even dissolution of the composition as a whole.
Preferably, the composition includes from about 1.0 to about 50% of sugar
and from about 20 to about 80% of sugar alcohol by weight of the composition.
In one embodiment, the sugar agent may further include a binding agent.
Inclusion of the binding agent is particularly useful when a sugar agent, such
as
mannitol, may have a limited ability to bind the components used for the
composition. It is believed that insufficiencies in binding ability tend to
cause
tablets to break off, e.g., into two pieces along the length of the tablet
during the
manufacturing process. This splitting of the tablet is commonly referred to as
"capping." The levels and types of binding agent are selected depending upon
~5 the character of the carriers, compatibility with other components, and
desired
characteristic of the final product.
In addition, when the composition is in tablet form, it is recognized that
some sugar agent of the present invention may also have properties as a
binding
agent for making tablets. Most of the sugar agents herein, preferably sugar,
may
2o be useful for providing improved binding properties of the composition in
tablet
form to prevent the tablet from breaking into two pieces.
Examples of useful binding agents, other than the previously described
sugar agents, include starches such as starch paste and pregelatinized starch;
polyvinylpyrrolidone; cellulose derivatives; gelatin; gums; and mixtures
thereof.
25 In certain embodiments, the binding agent and the tableting carrier may be
made
of the same material. Alternatively, the binding agent and the sugar agent may
be altogether different. The binding agent is present in an effective amount,
preferably from about 0.1 % to about 5% by weight, more preferably from about
0.5°~ to about 3%.
D. Water insoluble diluent
The composition of the present invention can further include a water
insoluble diluent. Herein, "water insoluble diluent" means a material which
improves the disintegration or dispersion property of the tablet composi5on.
Without being bound by theory, it is believed that the water insoluble diluent
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tends to provide a desired porosity to the composition. Such porosity is
believed
to provide channels for water into the tablet structure, thereby allowing
penetration of, and more exposure of the composition surface area to, the
water.
The water insoluble diluent useful herein is any material which is insoluble
in
water which improves the dissolution of the composition, versus a composition
that does not contain the material. The water insoluble diluent useful herein
includes, but is not limited to, calcium carbonate, calcium phosphate, and the
like. Preferably, the water insoluble diluent is present at an effective
level,
preferably at a level of from about 0.5% to about 70% of the tablet
composition.
E. Tabletin9 carrier
The composition of the present invention can further include a tableting
carrier. Herein, °tableting carrier" means one or more compatible solid
or liquid
substances, preferably in solid form, which are suitable for. oraf
administration to
~5 a human and commonly used for making tablets. The tableting carrier must be
of
sufficiently high purity and sufficiently low toxicity to render the tablet
suitable for
administration to human beings. Examples of useful tableting carriers include
the
water insoluble diiuent, a tableting aid, a coloring agent, a flavoring agent,
the
granulating fluid, and mixtures thereof. Preferably, the tableting carrier is
present
20 from about 10 to about 80%, more preferably from about 30 to about 80% by
weight.
1. Tabletins aid
Herein, "tableting aid" refers to an ingredient that is added in small
quantities to the composition to provide flowability during manufacturing, to
25 reduce friction, and/or to ease removal of the tablets from the tableting
machine.
The tableting aids useful herein include, for example, magnesium stearate,
stearic acid, aerosol, talc, and mixtures thereof. Preferably, the tableting
aid is
present in an amount sufficient to prevent the tablet from breaking into two
pieces, preferably from about 2% to about 8%, by weight.
s0 2. Colo,-,~ agent
The tablet composition of the present invention may further include a
coloring agent. Preferably, the coloring agent is added with the granulating
fluid
to facilitate uniform distribution and mixing. The coloring agent is present
at an
effective level, preferably from about l0ppm to about 500ppm, more preferably
35 from about 20ppm to about 250ppm by weight.
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3. Flavoring anent
Flavoring agents may also be added to the tablet composition of the
present invention: Examples of flavoring agents useful herein include oil of
peppermint, oil of sassafras, clove bud oil, peppermint, menthol, anethole,
5 thymol, methyl salicylate, eucalyptol, cassia, 1-menthyl acetate, sage,
eugenol,
parsley oil, oxanone, oil of wintergreen, alpha-irisone, oil of spearmint,
marjoram,
lemon, orange, propenyl guaethol, cinnamon, and mixtures thereof. Flavoring
agents are generally used in the tablet composition at levels of from about
0.01
to about 5% by weight.
1o The tablet composition in accordance with the present invention may
further, optionally, include other known compounds having the capability to
enhance substantivity of a sweetener, if desired. These compounds is added to
increase the overall sweetness impact. Such compounds include, but are not
limited to, saccharine, aspartame, acesulfame K, and glycyrrhizin.
F. ~ ~ ~ ' ~t;~l~
The composition of the present invention in tablet form can be produced
by any method useful for forming conventional tablets known in the art. These
conventional methods include granulating methods: either wet or dry
granulating
2o method, preferably wet granulating. Depending on the properties of the
ingredients (e.g., drug resin complexes, thickening agents, pharmaceutical
acceptable carriers, flavors, coloring agents, and the like) to be formulated
into
granules, one method may provide a more favorable end product over the other
method. The wet granulation method is widely used and usually produces the
most satisfactory results in tablets. See, for example, E.J. de Jong; 'The
preparaflon of microgranulates, an improved tabieting technique,"
Pharmaceutical Weekblad, 104(23), pages 469-474, 1989 and E.J. de Jong, U.S.
Patent 3,266,992.
Direct compression may also be chosen for the present composition, as
long as producing non-gritty tablets does not cause capping. See, for example,
Blaaze, T. Palermo, et al., U.S. Patent 3,384,546.
In one embodiment, a method for making a composition in tablets form of
the present invention comprises: (1 ) adding drug actives, sugar agents and
any
of additional ingredients which are stable in the proceeding process (e.g.,
coloring agent), if needed, to make granules; (2) passing the granules through
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#10 mesh; (3j drying the sieved granules through conventional drying
techniques; (4) sieving again the dried granules through #14 mesh; (5) mixing
the
granules of step (4) with a thickening agent and any additional ingredients
(e.g.,
sweetening agent, flavour, tableting aids); and (6) compressing the mixture of
step (5) to form tablets by conventional method.
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EXAMPLES
The following examples further describe and demonstrate embodiments
within the scope of the present invention. The examples are given solely for
the
purpose of illustration and are not to be construed as limitations of the
present
invention, as many variations thereof are possible without departing from the
spirit and scope of the invention.
The components shown below can be prepared by any conventional
method known in the art. Suitable methods and formulations are as follows:
F~camoles 1 -2
%w/w
In redient Ex. 1 Ex.2
Pseudoephedrine-IRP 69 Com lex *' 11.12 -
Dextrometho han-Dow XYS40010 Com lex - 3.32
*2
Mannitoi 37.29 70.20
Su ar 8.00 4.15
Calcium Carbonate 34.94 -
dicaicium hos hate . - 12.50
As artame 0.35 0.28
Xanthan Gum 1.25 0.10
Carbo meth I cellulose 2.15 0.15
Synthetic silicate 0.20 4.60
Ma nesium stearate 2.00 2.00
Talc 2.50 2.50
Flavour 0.19 0.19
Color 0.01 0.01
-~ rseuaoephedrine-IRP 69 Complex: a drug-resin complex containing
35.69°~w/w pseudoephedrine without coating, supplied by Rohm & Haas
*2 Dextromethorphan-Dow XYS40010 Complex: drug -resin complex
containing 56.2 %wlw of dextromethorphan without any coating, provided by
t5 HCRC-PSG, US
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13
The tablet having Example 1 formulation is made by the method described
in °Method for making tablets" section.
The tablet having Example 2 formulation is made by the method described
in "Method for making tablets" section, except the drug actives are added at
step
5 during mixing of the granules, rather than at step 1.
The embodiments disclosed and represented by the previous examples
have many advantages. For example, they become a paste when contacted with
saliva, and thereby provide a desirable dissolution property and a pleasant
mouthfeel such as non-bitter taste.
It is understood that examples and embodiments described herein are for
illustrative purpose only and that various modifications or changes in right
thereof
will be suggested to one skill the art and are to be included in the spirit
and
purview of this application and scope of the appended claims.
