TASTE MASKED DISPERSIBLE TABLETS
Field of the Invention
The present invention relates to a taste-masked dispersible tablet comprising a
drug, a cation exchange resin, and other pharmaceutically acceptable excipients, such that
the said drug and the said cation exchange resin are present in an un-complexed form in
the tablet. It further relates to a process for the preparation of the same.
Background of the Invention
It is well known that oral administration constitutes a preferred route of
administration for a majority of drugs. However, a drug having an inherently bitter taste
constitutes a disadvantage with certain types of oral preparations, particularly when
intended for use in the pediatric population. Unpleasant taste leads to poor adherence in
children which in turn causes treatment failure. Therefore, taste-masking can prove to be
an essential tool to improve patient compliance, especially of pediatric patients, by
increasing the palatability of such bitter-tasting drugs. This assumes more importance for
drugs that are used for a long-term cure and where treatment adherence is an important
requisite.
Several methods are known in the prior art for taste-masking. To some extent, the
bitter taste may be masked by the use of sweetening and/or flavoring agents. However,
this method is not always satisfactory and an unpleasant taste may remain in the mouth.
Additionally, there may be circumstances in which it is undesirable to use a sweetening
agent and/or flavoring agent. Use of ion-exchange resins is an alternatively known
method to mask the bitter taste in such cases.
U.S. Publication No. 2004/0067216 relates to a complex comprising a cation
exchange resin and an HIV protease inhibitor and formulation of this drug-resin complex
into a capsule dosage form.
U.S. Publication No. 2002/0032245 relates to a rapid-release resinate composition
comprising an ion exchange resin loaded with an active substance, wherein the said active
substance is anisotropically distributed throughout said ion exchange resin particle.
In the prior art, the drug-resin complexes are generally formed by mixing a drug
with an aqueous suspension of a resin, after which the complex is filtered, washed, and
dried. All these usual complexation steps are time-consuming and increase the cost of
manufacturing. Further, this method is not suitable for drugs which are prone to
hydrolysis and show poor stability in a solution form. The inventors have now developed
a taste-masked dispersible tablet comprising a drug and a cation exchange resin which can
be prepared by a simple procedure, does not involve the usual time consuming and costly
steps of filtering, washing, drying, etc., and is suitable for drugs which are prone to
hydrolysis. The inventors have also surprisingly found that the dispersible tablets wherein
the drug-resin complex is formed in situ exhibit better stability than the dispersible tablets
comprising the drug-resin complexes prepared by the usual complexation methods.
Summary of the Invention
In one general aspect, the present invention relates to a taste-masked dispersible
tablet comprising a drug, a cation exchange resin, and other pharmaceutically acceptable
excipients, such that the said drug and the said cation exchange resin are present in an uncomplexed
form in the tablet.
In one embodiment of the above aspect, the said drug and the said cation exchange
resin form a complex within 30 seconds to 15 minutes of dispersing the taste-masked
dispersible tablet in water.
In another embodiment of the above aspect, the cation exchange resin may be
Amberlite® IRP64.
In the above aspect and embodiments, the other pharmaceutically acceptable
excipients may be selected from diluents, binders, lubricants/glidants, disintegrants,
flavoring agents, sweetening agents, coloring agents, or combinations thereof.
In another general aspect, the invention relates to a process for the preparation of a
taste-masked dispersible tablet comprising a drug, a cation exchange resin, and other
pharmaceutically acceptable excipients, such that the said drug and the said cation
exchange resin are present in an un-complexed form in the tablet, wherein the process
comprises the steps of direct compression, dry granulation, or wet granulation.
In an embodiment of the above aspect, the process comprises the steps of:
a) sifting all the ingredients, i.e., the drug, the cation exchange resin, and other
pharmaceutically acceptable excipients separately through suitable sieves;
b) blending the sifted ingredients in a blender for a suitable time;
c) compressing the resultant blend into a dispersible tablet using appropriate
tooling.
In another embodiment of the above aspect, the process comprises the steps of:
a) sifting the ingredients, i.e., the drug, the cation exchange resin, and other
pharmaceutically acceptable excipients through suitable sieves;
b) blending the sifted ingredients in a blender for a suitable time;
c) granulating the resultant blend with a binder solution;
d) drying the granules;
e) mixing the granules with the extragranular excipient(s); and
f) compressing the resultant blend into a dispersible tablet using appropriate
tooling.
In another general aspect, the present invention relates to a method of orally
administering to a human a taste-masked dispersible tablet comprising a drug, a cation
exchange resin, and other pharmaceutically acceptable excipients in water, such that the
said drug and the said cation exchange resin are present in an un-complexed form in the
tablet, wherein the method comprises dispersing said tablet in a sufficient quantity of
water prior to administration.
In one embodiment of the above aspects, the said drug is tenofovir disoproxil
fiimarate.
Detailed Description of the Invention
The "cation exchange resin", as recited herein, can be, for example, a copolymer of
styrene or acrylic or methacrylic acid with a vinyl aromatic compound such as
divinylbenzene, and the resin may derive its exchange activity from either weakly or
strongly acidic groups such as carboxylic acid or sulphonic acid groups. Examples of
suitable resins are those that are copolymers of styrene and divinylbenzene which are
sulphonated, or copolymers of methacrylic acid and divinylbenzene, including those
available commercially as Dowex® resins or Amberlite® resins. The resin may be in acid
form or in the form of a salt with an alkali metal, (e.g., sodium or potassium). Particularly
preferred is Amberlite® which is an insoluble, weakly acidic, hydrogen form, cation
exchange resin supplied as dry, fine powder. It is derived from a porous copolymer of
methacrylic acid and divinylbenzene.
The "taste-masked dispersible tablet", as recited herein, means that the tablet is to
be dispersed in a sufficient quantity of water to form a taste-masked dispersion, prior to
administration. The underlying principle of this particular tablet is that the said drug and
the said cation exchange resin are present in an un-complexed form in the tablet. Upon
dispersing the tablet in water prior to administration, the said drug and the said cation
exchange resin form a complex within 30 seconds to 15 minutes of dispersing the said
tablet in water. This results in the desired taste-masking of the drug.
The taste-masked dispersible tablets may further comprise one or more of other
pharmaceutically acceptable excipients that are routinely used and may be selected from
diluents, binders, lubricants/glidants, disintegrants, flavoring agents, sweetening agents,
coloring agents, or combinations thereof
Suitable diluents that may be used include, but are not limited to, microcrystalline
cellulose, silicified microcrystalline cellulose, microfine cellulose, lactose, starch,
pregelatinized starch, calcium carbonate, calcium sulfate, sugar, mannitol, sorbitol,
dextrates, dextrin, maltodextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic
calcium phosphate, magnesium carbonate, magnesium oxide, or combinations thereof
Suitable binders that may be used include, but are not limited to, acacia, guar gum,
alginic acid, carbomer, dextrin, maltodextrin, methylcellulose, ethylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose,
carboxymethylcellulose sodium, magnesium aluminum silicate, polymethacrylates,
crospovidones, povidones, copovidones, gelatin, starch, or combinations thereof When a
wet granulation process is followed for the preparation of the tablets, the granulating fluid
can be either a solvent or a binder dissolved in a solvent. The solvents that may be used
include, but are not limited to, dichloromethane, ethyl alcohol, or isopropyl alcohol.
Suitable lubricants/glidants that that may be used include, but are not limited to,
magnesium stearate, zinc stearate, calcium stearate, stearic acid, colloidal silicon dioxide,
glyceryl palmitostearate, vegetable oils, polyethylene glycols, polyvinyl alcohols, talc,
sodium benzoate, sodium stearyl fiimarate, magnesium oxide, poloxamer, sodium lauryl
sulphate, polyoxyethylene monostearate, cocoa butter, hydrogenated vegetable oils,
mineral oil, polysaccharides, or combinations thereof
Suitable disintegrants that may be used include, but are not limited to, cross linked
calcium or sodium carboxy methyl cellulose, starch, sodium starch glycolate,
pregelatinized starch, crosslinked polyvinyl pyrrolidone, low-substituted hydroxypropyl
cellulose, microcrystalline cellulose, ion exchange resin, cross-linked polyacrylic acid,
alginates, colloidal magnesium-aluminum silicate, calcium silicate, or combinations
thereof
Additional taste-masking agents that may be used include flavoring agents and
sweetening agents. Flavoring agents may be chosen from natural and synthetic flavor
liquids and include, but are not limited to, volatile oils, synthetic flavor oils, flavoring
aromatics, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits,
stems, or combinations thereof. The sweetening agents may be chosen from the following
non-limiting list: sucrose, dextrose, invert sugar, fructose, and mixtures thereof; saccharin,
aspartame, acesulfame, sucralose; or sugar alcohols such as sorbitol, mannitol and xylitol.
Suitable coloring agents that may be used include, but are not limited to, titanium
dioxide pigments, lake colors, and iron oxide pigments.
The taste-masked dispersible tablets, as defined herein, may be manufactured using
conventional tabletting techniques like direct compression, dry granulation, or wet
granulation.
Preferred taste-masked dispersible tablets of the present invention may take the
form of several different embodiments.
In one embodiment, the present invention relates to a taste-masked dispersible
tablet comprising a drug, the cation exchange resin Amberiite® IRP64, and other
pharmaceutically acceptable excipients.
In another embodiment, the drug is tenofovir disoproxil fiimarate, the cation
exchange resin is Amberiite® IRP64, and the other pharmaceutically acceptable excipients
are sucralose, flavor, croscarmellose sodium, mannitol, magnesium stearate, and colloidal
silicon dioxide.
In another embodiment, the drug is tenofovir disoproxil fumarate, the cation
exchange resin is Amberiite® IRP64, and the other pharmaceutically acceptable excipients
are microcrystalline cellulose, sucralose, flavor, corscarmellose sodium, ethylcellulose,
mannitol, xylitol, and magnesium stearate.
In another embodiment, the drug is tenofovir disoproxil fumarate, the cation
exchange resin is Amberlite® IRP64, and the other pharmaceutically acceptable excipients
are microcrystalline cellulose, sucralose, flavor, croscarmellose sodium, ethylcellulose,
crospovidone, mannitol, xylitol, and magnesium stearate.
In another embodiment, the present invention relates to a process for the
preparation of a taste-masked dispersible tablet comprising tenofovir disoproxil fumarate,
Amberlite® IRP64, and other pharmaceutically acceptable excipients, wherein the process
comprises the steps of:
a) sifting the ingredients, i.e., tenofovir disoproxil fumarate, Amberlite® IRP64,
and other pharmaceutically acceptable excipients separately through suitable
sieves;
b) blending the sifted ingredients in a blender for a suitable time;
c) compressing the resultant blend into a dispersible tablet using appropriate
tooling.
In another embodiment, the present invention relates to a process for the
preparation of a taste-masked dispersible tablet comprising tenofovir disoproxil fumarate,
Amberlite® IRP64, and other pharmaceutically acceptable excipients, wherein the process
comprises the steps of:
a) sifting the ingredients, i.e., tenofovir disoproxil fumarate, Amberlite® IRP64,
and other pharmaceutically acceptable excipients through suitable sieves;
b) blending the sifted ingredients in a blender for a suitable time;
c) granulating the resultant blend with a binder solution;
d) drying the granules;
e) mixing the granules with the extragranular excipient(s); and
f) compressing the resultant blend into a dispersible tablet using appropriate
tooling.
In another embodiment, the present invention relates to a method of orally
administering to a human, a taste-masked dispersible tablet as described in the above
embodiments, wherein the method comprises dispersing the tablet in a sufficient quantity
of water prior to administration so that tenofovir disoproxil fumarate and Amberlite®
IRP64 form a complex within 30 seconds to 15 minutes of dispersing the said tastemasked
dispersible tablet in water. The sufficient quantity of water may be from 1 mL to
200 mL or a quantity of water comfortably consumed by the human, such as a glass of
water routinely consumed.
From the above, it is apparent that various modifications and combinations of the
dispersible tablets detailed in the text may be made without departing from the spirit and
scope of the invention. The invention, as described herein, may be illustrated by the
following examples but is not to be construed to be limited by them.
EXAMPLES
Examples 1-4:
S. No.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Ingredients
Tenofovir disoproxil
fumarate
Amberlite®IRP64
Povidone
Microcrystalline cellulose
Ethylcellulose
Hydroxypropyl cellulose
Sucralose
Flavor
Croscarmellose sodium
Crospovidone
Mannitol
Xylitol
Magnesium stearate
Colloidal silicon dioxide
Dichloromethane
Total Weight
Quantity (mg/tablet)
Example 1
70.0
210.0
-
-
-
-
70.0
15.0
20.0
-
109.0
-
2.0
4.0
-
500.0
Example 2
150.0
450.0
-
-
-
-
150.0
15.0
20.0
-
110.0
-
2.5
4.5
-
902.0
Example 3
100.0
45.0
3.0
100.0
7.0
50.0
75.0
20.0
60.0
-
305.0
125.0
10.0
-
q.s.*
900.0
Example 4
100.0
45.0
10.0
205.0
14.0
75.0
15.0
60.0
25.0
266.0
125.0
10.0
-
q.s.*
950.0
Procedures:
Examples 1-2:
a) All the above ingredients were sifted separately through suitable sieves;
b) The sifted ingredients were blended in a blender for a suitable time; and
c) The resultant blend was compressed into dispersible tablet using appropriate tooling.
Examples 3-4:
a) Tenofovir disoproxil fumarate, microcrystalline cellulose (first portion; Example 4),
and Amberlite® IRP64 were sifted through a suitable mesh;
b) The sifted ingredients of step a) were transferred into a rapid mixer granulator and
dry mixed for a suitable time;
c) Ethylcellulose and povidone were dissolved in dichloromethane, and the solution
thus formed was used to granulate the mixture of step b) in the rapid mixer
granulator;
d) The resultant granules were dried in a fluid bed dryer and sifted through a suitable
mesh to get uniform size granules;
e) Mannitol, sucralose, xylitol, croscarmellose sodium, microcrystalline cellulose
(second portion; Example 4), and crospovidone (Example 4) were sifted through a
suitable mesh;
f) The sifted extragranular ingredients of step e) were mixed with the dried granules of
step d) in a suitable blender;
g) Flavor and magnesium stearate were sifted through a suitable mesh and mixed with
the blend of step f); and
h) The resultant blend was compressed into dispersible tablets using appropriate
tooling.
A taste-masked dispersible tablet comprising a drug-resin complex was prepared as
per the usual complexation method for comparison and is described in Table 1 below:
Table 1: Comparative Example of a taste-masked dispersible tablet comprising the
drug resin-complex prepared as per the usual complexation method
Ingredients
Tenofovir + Amberlite® IRP64 resin complex
Polyplasdone® XL
Aspartame
Acesulfame Potassium
Lactose
Magnesium stearate
Mint flavor
Total weight
Quantity in mg/tablet
280.00
20.00
15.00
7.00
22.00
3.00
3.00
350.00
Procedure for the Comparative Example:
(I) Drug-Resin Complex Preparation Process
a) A required quantity of Amberlite® IRP64 was added to distilled water to make
about 10% w/w slurry;
b) The slurry was stirred for a sufficient time to get a uniform/lump free dispersion;
c) A specified quantity of tenofovir disoproxil fumarate was added slowly under
stirring to the above dispersion to make a drug:resin ratio of 1:3;
d) The entire mixture was stirred for about 4 hours and the dispersion was kept
aside for setting;
e) The solid resin was separated by filtration and subsequently dried to get the
desired tenofovir disoproxil fumarate-Amberlite® IRP64 complex.
(II) Tablet Preparation Process
a) The drug-resin complex prepared as per the above process, magnesium stearate,
and all other excipients were separately sifted through suitable sieves;
b) The above sifted ingredients were mixed for a sufficient time to get a uniform
blend;
c) The resultant blend was compressed into a dispersible tablet using appropriate
tooling.
A comparative stability analysis was performed by subjecting the tablets prepared
as per the above Example I and tablets prepared as per the Comparative Example to an
accelerated stability testing at 40°C/75% relative humidity. The assay values are
summarized in Table 2 below.
10
Table 2: Assay results of tenofovir disoproxil fumarate in taste-masked dispersible
tablets prepared as per the above Example 1 and the Comparative
Example when stored at 40*'C/75% relative humidity
S.No.
1.
2.
3.
4.
Stability Condition
Initial
1 month 40°C/75% RH
2 month 40°C/75% RH
3 month 40°C/75% RH
Assay Results
Example 1
94.0%
94.0%
95.4%
94.5%
Comparative Example
89.3%
78.6%
Not performed
Not performed
The assay results clearly indicate that the tablets in which the drug-resin complex
is formed in situ exhibit better stability than the tablets comprising the drug-resin complex
prepared by the usual complexation method.
11

WE CLAIM: V-
1. A taste-masked dispersible tablet comprising a drug, a cation exchange resin, and
other pharmaceutically acceptable excipients, such that the said drug and the said
cation exchange resin are present in an un-complexed form in the tablet.
2. The taste-masked dispersible tablet according to claim 1, wherein the said drug and
the said cation exchange resin form a complex within 30 seconds to 15 minutes of
dispersing the taste-masked dispersible tablet in water.
3. The taste-masked dispersible tablet according to claim 1, wherein the cation
exchange resin is Amberlite® IRP64.
4. The taste-masked dispersible tablet according to claim 1, wherein the other
pharmaceutically acceptable excipients are selected from diluents, binders,
lubricants/glidants, disintegrants, flavoring agents, sweetening agents, coloring
agents, and combinations thereof
5. A process for the preparation of a taste-masked dispersible tablet according to claim
1, wherein the process comprises the steps of direct compression, dry granulation, or
wet granulation.
6. A method of orally administering to a human a taste-masked dispersible tablet
comprising a drug, a cation exchange resin, and other pharmaceutically acceptable
excipients, such that the said drug and the said cation exchange resin are present in
an un-complexed form in the tablet, wherein the method comprises dispersing the
said tablet in a sufficient quantity of water prior to administration.
7. A taste-masked dispersible tablet comprising tenofovir disoproxil flimarate, a cation
exchange resin, and other pharmaceutically acceptable excipients, such that tenofovir
disoproxil fumarate and the cation exchange resin are present in an un-complexed
form in the tablet.
8. The taste-masked dispersible tablet according to claim 7, wherein the cation
exchange resin is Amberlite® IRP64.