Description:FIELD OF INVENTION
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The present invention relates to a taste-masked stable pharmaceutical composition
comprising of Drug Resin complex wherein the drug is Mefenamic acid, and
wherein the resin includes atleast one ion exchange resin. The present invention
relates to a Taste Masked Stable Orally Dispersible Tablet composition comprising
of a Drug Resin complex wherein the drug includes an effective amount of
Mefenamic acid, and wherein the resin includes atleast one ion exchange resin. The
present invention particularly relates to an immediate release Taste Masked Stable
Orally Dispersible Tablet composition comprising of effective amount of
Mefenamic acid with atleast one ion exchange Resin, and at least one
pharmaceutically acceptable excipient. The invention also relates to a process for the
preparation of the Taste Masked Stable Orally Dispersible Tablet composition
comprising an effective amount of Mefenamic acid and Drug Resin complex.
BACKGROUND OF INVENTION
Oral drug administration is the most convenient and common way to take
pharmaceutical medications and various forms of oral administration which are
available that includes solid tablets and capsules, powders, granules, syrups,
suspensions and, more recently, chewable tablets and gummies. The oral route is the
most convenient and usually the safest and least expensive route which is almost
preferred. Even though oral formulations represent about 90% of the global market
share of all drug formulations, they have some drawbacks. Although most
individuals use oral medicines, active pharmaceutical ingredients (APIs) which have
a very bitter taste inhibits patient compliance. Patient compliance is closely related
to the acceptance of the medication. Many factors negatively impact patient
compliance, but one of the biggest and yet most often overlooked is the taste of the
medication. Bitterness reduction and inhibition are important characteristics of a
good oral dosage form. Taste plays an especially important role in pediatric
medications as well as adult compliance. With respect to over-the-counter (OTC)
preparations, such as cough and cold syrups, the bitterness of the preparation leads
to lack of patient compliance. Many of these bitter-tasting agents are
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pharmaceuticals which are found in liquid compositions (such as solutions and
syrups), solid compositions (such as capsules and tablets), and more recently,
dissolvable films. Hence, masking the bitter taste of drugs to make the oral
formulation acceptable to the patient is essential and efforts are made to provide a
patient-compliant product. Bitter drugs can often be delivered intravenously or
swallowed as a coated tablet, preventing stimulation of oral chemoreceptors so that
the bitterness is not perceived. Various techniques available for masking bitter taste
of drugs include taste masking with ingredients such as flavors, sweeteners, and
amino acids; taste masking by polymer coating; taste masking by conventional
granulation; taste masking by spray congealing with lipids; taste masking by
formation of inclusion complexes with cyclodextrins; taste masking by the
freeze‐drying process; taste masking by making multiple emulsions; and taste
masking with gelatin, gelatinized starch, liposomes, lecithin’s or lecithin‐like
substances, surfactants, salts, or polymeric membranes are available. Also, various
patent and non-patent literature available for taste masking bitter drug is Mefenamic
acid has been discussed.
IN202321043800 discloses about taste masked orally disintegrating tablet
pharmaceutical composition of dextromethorphan hydrobromide, chlorpheniramine
maleate, and phenylephrine hydrochloride.
IE990009A1 discloses the taste-masked pharmaceutical composition containing a
drug that is loaded onto an ion-exchange resin and subsequently coated by polymer.
IN1894/mum/2006 discloses about the pharmaceutical composition comprising a
bitter drug resin complex. Drugs and cation exchange resins of various grades are
complex in ratios ranging from 1:0.5 to 1:5 (drug: resin) to mask the bitter taste of
drugs. In which resin is selected from the group comprising methacrylic acid
polymer crosslinked with divinylbenzene, polyacrylic matrix type pharmaceutical
grade ion exchange resins with -COO functional group and weak acid cation
exchange resin with a cross-linked polyacrylic backbone. It is specifically related to
rizatriptan benzoate and levocetirizine hydrochloride.
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WO2012063257A2 discloses sustained release beads which comprise coated drug
resin complexes comprising drug-resin complexes of at least one active agent and at
least one ion exchange resin; coated with at least one release modifier.
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IN-DELNP-2008-08703A discloses a coated drug-ion exchange resin complex
comprising a core composed of a drug complexed with a pharmaceutically
acceptable ion-exchange resin. The drug-ion exchange resin complex is in admixture
with a release retardant. The coating contains a polyvinyl acetate polymer and a
plasticizer. Methods of making and products containing this coated complex are
described.
WO2009088385A1 provides methods for preparing pharmaceutical resin-complexed
granules which are taste-masked or capable of providing modified release of a
water-soluble drug comprising the steps of (a) dissolving a water-soluble drug in
water to form a solution; and (b) granulating the drug solution from step (a) in the
presence of a resin capable of complexing with the drug to form a drug-resin
complex.
The patent documents disclose different approaches wherein the bitter taste of drug
is masked by coating the drug resin complex and release of drug is modified to alter
its release on tongue. However, this process known in the art provides sustained
release of drugs prohibiting their interaction with taste buds and hence are palatable.
Moreover, the processes employed in taste masking are costly and have difficulty in
scale-up. Thus, considering the disclosures in the art, the inventors of the present
invention considered masking the bitter taste of drugs by a simple scalable process
wherein the drug is formulated in an orally dispersible tablet and orally
disintegrating tablet form. In spite of immediate release of bitter drugs from the
orally disintegrating tablet formulation, the inventors have been successful in
masking the bitter taste of drugs by novel drug resin complex formation and
providing a more patient-compliant product. Hence, the inventors of the present
invention formulated a stable taste-masked orally Disintegrating formulation
comprising of Drug resin complex wherein the drug comprises of an effective
amount of Mefenamic acid and resin which includes at least one ion exchange resin
by a simple scalable process that provides a product which is patient compliant. To
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summarize, the inventors of the present invention formulated a Taste Masked Stable
Pharmaceutical composition comprising of a Drug Resin complex wherein the drug
is Mefenamic acid, and wherein the resin includes atleast one ion exchange resin
with at least one pharmaceutically acceptable excipient which provides higher
loading of drug in drug resin complex, immediate release of drug and masks bitter
taste of drugs which improves patient compliance.
OBJECTIVE OF INVENTION
An objective of the invention is to design and develop taste masked orally
Dispersible Tablet for bitter drug which is Mefenamic acid.
Yet another object of the present invention is to provide taste masked orally
Dispersible Tablet for bitter drug which is Mefenamic acid by Drug Resin
complexation process and method of preparation thereof.
Yet another object of the present invention is to provide taste-masked orally
Dispersible Tablet formulation for bitter drugs such as Mefenamic acid by forming a
complex with Ion exchange Resin which is stable with higher drug loading, simple
scalable process, provides immediate release, masks bitter taste, palatable which
help improve patient compliance.
SUMMARY OF THE INVENTION
The present invention relates to a Taste Masked Stable Pharmaceutical composition
comprising a Drug Resin complex.
The present invention relates to a Taste Masked Stable Orally Dispersible Tablet
composition comprising of a Drug Resin complex wherein the drug is Mefenamic
acid and at least one ion exchange resin.
The present invention relates to the Taste Masked Stable Orally Dispersible Tablet
composition comprising of a Drug Resin complex wherein the drug includes an
effective amount of Mefenamic acid and at least one ion exchange resin with at least
one pharmaceutically acceptable excipient.
The present invention particularly relates to an immediate release Taste Masked
Stable Orally Dispersible Tablet composition comprising of Drug Resin complex
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wherein the drug resin complex includes Mefenamic acid, with at least one ion
exchange resin and at least one pharmaceutically acceptable excipient.
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The invention also relates to the process for preparation of the Taste Masked Stable
Orally Dispersible Tablet composition comprising an effective amount of Drug
Resin complex.
The invention particularly relates to the process for the preparation of the Taste
Masked Stable Orally Dispersible Tablet composition comprising an effective
amount of Mefenamic acid with at least one ion exchange resin by the Drug ion
resin complexation process.
DESCRIPTION OF THE DRAWINGS
For a more complete understanding of the invention, reference should now be made
to the embodiments illustrated in greater detail in the accompanying drawings and
described by way of embodiments of the invention.
Figure 1: Illustrates the dissolution profile of taste-masked orally Dispersible Tablet
composition.
DETAILED DESCRIPTION OF THE INVENTION
In describing the embodiment of the invention, specific terminology is chosen for
the sake of clarity. However, it is not intended that the invention be limited to the
specific terms so selected and it is to be understood that such specific terms include
all technical equivalents that operate in a similar manner to accomplish a similar
purpose. As used herein, reference to an element by the indefinite article “a” or “an”
does not exclude the possibility that more than one of the elements is present, unless
the context clearly requires that there is one and only one of the elements. The
disclosure of numerical ranges should be understood as referring to each discrete
point within the range, inclusive of endpoints unless otherwise noted. The term
“about” as used in the disclosure of numerical ranges indicates that deviation from
the stated value is acceptable to the extent that the deviation is the result of
measurement variability and/or yields a product of the same or similar properties.
The terms “orally disintegrating tablet”, “orally dispersing tablet”, or “ODT” refer
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to a solid dosage form of the present invention, which disintegrates rapidly in the
oral cavity of a patient after administration, without chewing. The rate of
disintegration can vary, but is faster than the rate of disintegration of conventional
solid dosage forms or chewable solid dosage forms (i.e., tablets or capsules) which
are intended to be swallowed immediately after administration.
As used herein the term “taste masked” is defined as a perceived reduction of an
undesirable taste that would otherwise exist. Taste masking results in the formation
of a physical barrier between the drug particle and the taste bud which minimizes
the interaction and makes the bitter drug palatable. The embodiments of the present
invention directed for Orally disintegrable Tablet formulation are also applicable to
the Orally dispersible Tablet formulation.
"Pharmaceutical composition" of the present invention refers to Taste Masked
Stable Orally Disintegrating or Dispersible Tablet composition comprising a Drug
Resin complex. of dolasetron and salt thereof, a vehicle generally accepted in the art
for oral administration of the combination of drug compound to a mammal, e.g., a
human. Such a medium includes all pharmaceutically acceptable excipients. For the
purposes of this disclosure, the phrase "pharmaceutical composition" is
interchangeable with the phrase "pharmaceutical formulation".
The present invention relates to a taste Masked Stable Pharmaceutical composition
comprising a Drug Resin complex. The present invention relates to a Taste Masked
Stable Orally Disintegrating or Dispersible Tablet composition comprising a Drug
Resin complex.
According to an embodiment, the present invention relates to a Taste Masked Stable
Pharmaceutical composition comprising of a Drug Resin complex wherein the
composition is an orally dispersible tablet or orally disintegrating tablet. According
to an embodiment, the present invention relates to Taste Masked Stable
Pharmaceutical composition comprising of a Drug Resin complex wherein the drug
includes Mefenamic acid. According to a further embodiment, the present invention
relates to the Taste Masked Stable Orally Dispersible Tablet composition
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comprising of a Drug Resin complex wherein the drug is Mefenamic acid.
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According to a further embodiment, the present invention relates to the Taste
Masked Stable Orally Dispersible Tablet composition comprising of a Drug Resin
complex wherein the drug includes an effective amount of Mefenamic acid.
According to a further embodiment, the present invention relates to the Taste
Masked Stable Orally Dispersible Tablet composition comprising of a Drug Resin
complex wherein the drug includes an effective amount of Mefenamic acid with at
least one ion exchange resin and at least one pharmaceutically acceptable excipient.
According to a further embodiment, the present invention relates to the Taste
Masked Stable Orally Dispersible Tablet composition comprising of a Drug Resin
complex wherein the drug includes an effective amount of Mefenamic acid.
According to an embodiment, the Taste Masked Stable Orally Dispersible Tablet
composition of the present invention wherein the drug includes Mefenamic acid.
According to an embodiment, the Taste Masked Stable Orally Dispersible Tablet
composition of the present invention wherein the drug includes an effective amount
of Mefenamic acid. According to an embodiment, the Taste Masked Stable Orally
Dispersible Tablet composition of the present invention wherein the drug includes
Mefenamic acid with a concentration of at least 45-65%. According to an
embodiment, the Taste Masked Stable Orally Dispersible Tablet composition of the
present invention wherein the drug includes Mefenamic acid with a concentration of
at least 55%. According to an embodiment, the Taste Masked Stable Orally
Dispersible Tablet composition of the present invention wherein the drug includes
Mefenamic acid with a concentration of at least 50%. According to a further
embodiment, the present invention relates to the Taste Masked Stable Orally
Dispersible Tablet composition comprising of a Drug Resin complex wherein the
resin includes at least one ion exchange resin. According to a further embodiment,
the present invention relates to the Taste Masked Stable Orally Dispersible Tablet
composition comprising of a Drug Resin complex wherein the resin includes
Methacrylic acid divinyl benzene copolymer with hydrogen ions. However, those
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skilled in the art will appreciate that it is possible to utilize other resins without
departing from the scope of the present invention.
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According to a further embodiment, the present invention relates to the Taste
Masked Stable Orally Disintegrating Tablet composition comprising of a Drug
Resin complex wherein the resin includes Methacrylic acid divinyl benzene
copolymer with Hydrogen Ion, Polacrilin potassium, Calcium Polystyrene Sulphate,
and Sodium Polystyrene Sulphate. In a further embodiment, the present invention
relates to the Taste Masked Stable Orally Disintegrating Tablet composition
comprising of a Drug Resin complex wherein the resin particularly includes
Methacrylic acid divinyl benzene copolymer with hydrogen ion.
According to a further embodiment, the present invention relates to the Taste
Masked Stable Orally Dispersible Tablet composition comprising of a Drug Resin
complex wherein the resin is present in an effective amount. According to a further
embodiment, the present invention relates to the Taste Masked Stable Orally
Dispersible Tablet composition comprising of a Drug Resin complex wherein the
Drug Resin complex is uncoated. According to a further embodiment, the present
invention relates to the Taste Masked Stable Orally Dispersible Tablet composition
comprising of a Drug Resin complex wherein the ratio of drug resin is in the range
of 1:0.5. According to a further embodiment, the present invention relates to the
Taste Masked Stable Orally Dispersible Tablet composition comprising of a Drug
Resin complex wherein the ratio of drug resin is in the range of 1:0.3. According to
a further embodiment, the present invention relates to the Taste Masked Stable
Orally Dispersible Tablet composition comprising of a Drug Resin complex wherein
the ratio of drug resin is in the range of 1:0.4. According to a further embodiment,
the present invention relates to the Taste Masked Stable Orally Dispersible Tablet
composition comprising of a Drug Resin complex wherein the ratio of drug resin is
in the range of 1:0.2. According to a further embodiment, the present invention
relates to the Taste Masked Stable Orally Dispersible Tablet composition
comprising of a Drug Resin complex wherein the ratio of drug resin is in the range
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of 1:0.15. According to a further embodiment, the present invention relates to the
Taste Masked Stable Orally Dispersible Tablet composition comprising of a Drug
Resin complex wherein the ratio of drug resin is in the range of 1:0.4 According to a
further embodiment, the present invention relates to the Taste Masked Stable Orally
Dispersible Tablet composition comprising of a Drug Resin complex wherein the
ratio of drug resin particularly is in the range of about 1:0.5, 1:0.4 and 1:0.15.
According to another embodiment, the present invention relates to the Taste Masked
Stable Orally Dispersible Tablet composition comprising of a Drug Resin complex
wherein Methacrylic acid divinyl benzene copolymer with Hydrogen Ion resin
present in the concentration from 15% to 25% w/w. According to a further
embodiment, Methacrylic acid divinyl benzene copolymer with Hydrogen Ion resin
present in the concentration from 18% to 22% w/w. According to a further
embodiment, Methacrylic acid divinyl benzene copolymer with Hydrogen ion resin
present in a concentration of 19.5% w/w.
According to a further embodiment, the Taste Masked Stable Orally Dispersible
Tablet composition of the present invention further includes at least one
pharmaceutically acceptable excipients such as diluents, binders, super
disintegrants, disintegrant, sweeteners, flavouring agent, lubricant, vehicle,
colouring agent and glidant.
According to an embodiment, the disintegrant or super-disintegrant includes at least
one of Croscarmellose sodium, Crospovidone, and Sodium starch glycolate.
However, those skilled in the art will appreciate that it is possible to utilize other
disintegrants or super-disintegrants without departing from the scope of the present
invention.
According to an embodiment, the diluents include at least one of Lactose, Fructose,
Sorbitol powder and Mannitol. However, those skilled in the art will appreciate that
it is possible to utilize other diluents without departing from the scope of the present
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invention.
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According to an embodiment, the binders include at least one of
Polyvinylpyrrolidone K30, Maize Starch, Starch, Pregelatinized starch, propylene
glycol, Hydroxy Propyl Cellulose and Purified water. However, those skilled in the
art will appreciate that it is possible to utilize other binders without departing from
the scope of the present invention.
According to an embodiment, the flavorants or flavouring agents include at least
one of Mango flavour, orange flavour, Pineapple flavour, Banana flavour, Masking
flavour and Peppermint flavour. However, those skilled in the art will appreciate
that it is possible to utilize other flavorants or flavouring agents without departing
from the scope of the present invention.
According to an embodiment the sweeteners include atleast one of Aspartame,
Sucralose, Saccharine Sodium and Neotame. However, those skilled in the art will
appreciate that it is possible to utilize other sweeteners without departing from the
scope of the present invention.
According to an embodiment, the lubricants include at least one of microcrystalline
cellulose, Colloidal silicon dioxide, Stearic Acid, Hydrogenated Castor Oil, Sodium
Stearyl Fumarate, Magnesium Fumarate or a combination thereof. In another
embodiment, the lubricants include a combination of microcrystalline cellulose and
Colloidal silicon dioxide e.g., PROSOLV® SMCC 90. However, those skilled in the
art will appreciate that it is possible to utilize other lubricants without departing
from the scope of the present invention.
According to a further embodiment, the disintegrating time of the drug from Taste
Masked Stable Orally Dispersible Tablet composition of the present invention
wherein at least 85%-92% of the drug is released within 5-10 minutes. According to
an embodiment, the Taste Masked Stable Orally Dispersible Tablet composition of
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the present invention provides an immediate release.
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According to an embodiment, the dissolution rate of the Taste Masked Stable Orally
Dispersible Tablet composition is measured with a Dissolution Test Apparatus
namely the USP Paddle Apparatus.
According to a further embodiment, the release of drug from Taste Masked Stable
Orally Dispersible Tablet composition of the present invention wherein at least
87.5% of the drug is dissolved within 5 minutes. According to a further
embodiment, the dissolution rate of the drug from Taste Masked Stable Orally
Dispersible Tablet composition of the present invention wherein at least 91.9% of
the drug is dissolved within 10 minutes. According to a further embodiment, the
dissolution rate of the drug from Taste Masked Stable Orally Disintegrating Tablet
composition of the present invention wherein at least 93.6% of the drug is dissolved
within 15 minutes. According to a further embodiment, the release of drug from
Taste Masked Stable Orally Dispersible Tablet composition of the present invention
wherein at least 94.6% of the drug is dissolved within 20 minutes. According to a
further embodiment, the dissolution rate of the drug from Taste Masked Stable
Orally Dispersible Tablet composition of the present invention wherein at least
92.9% of the drug is dissolved within 30 minutes. According to a further
embodiment, the dissolution rate of the drug from Taste Masked Stable Orally
Dispersible Tablet composition of the present invention wherein at least 91.8% of
the drug is dissolved within 45 minutes. According to a further embodiment, the
dissolution rate of drugs from Taste Masked Stable Orally Dispersible Tablet
composition of the present invention wherein at least 90.5% of the drug is dissolved
within 60 minutes.
According to an embodiment, the hardness of the Taste Masked Stable Orally
Dispersible Tablet composition of the present invention is in the range of 70N to
90N. According to an embodiment, the hardness of the Taste Masked Stable Orally
Disintegrating Tablet composition of the present invention is in the range of 75N to
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85N. The hardness is measured by using an Electrolab tablet hardness tester wherein
the crushing strengths of six randomly selected tablets were measured and expressed
in Newton units.
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According to an embodiment, the Taste Masked Stable Orally Dispersible Tablet
composition of the present invention masks the bitter taste of the drug and provides
a sweet taste. According to an embodiment, the Taste Masked Stable Orally
Dispersible Tablet composition of the present invention has at least about 40 percent
better mouth-feel. According to an embodiment, the Taste Masked Stable Orally
Dispersible Tablet composition of the present invention has at least about 50 percent
better mouth-feel. According to an embodiment, the Taste Masked Stable Orally
Dispersible Tablet composition of the present invention has at least about 70 percent
better mouth-feel. According to an embodiment, the Taste Masked Stable Orally
Dispersible Tablet composition of the present invention has at least about 80 percent
better mouth-feel. According to an embodiment, the Taste Masked Stable Orally
Dispersible Tablet composition of the present invention has at least about 90 percent
better mouth-feel. According to an embodiment, the Taste Masked Stable Orally
Dispersible Tablet composition of the present invention has at least about 95 percent
better mouth-feel.
According to a further embodiment, the present invention relates to the Taste
Masked Stable Orally Dispersible Tablet composition wherein the composition is
stable. The stability test was done as per ICH guidelines and the composition has
been tested at 30°C/75%RH and 40°C/75%RH for 6 months.
According to an embodiment, the present invention relates to the process for the
preparation of the Taste Masked Stable Orally Dispersible Tablet composition
comprising an effective amount of Drug Resin complex.
According to the further embodiment, the invention particularly relates to the
process for the preparation of the Taste Masked Stable Orally Dispersible Tablet
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composition comprising an effective amount of Mefenamic acid with an ion
exchange resin by Drug ion resin complexation process. According to an
embodiment, the present invention relates to a process of preparation of Taste
Masked Stable Orally Dispersible Tablet composition of the present invention
includes:
Step1: Sifting Mefenamic Acid, Methacrylic Acid Divinyl Benzene Copolymer with
Hydrogen Ion, and excipients such as disintegrant, binder, diluent, and glidant
through an appropriate sieve using sifter and transfer the sifted material to the High
Shear Mixer Granulator (RMG). Mix the sifted material of High Shear Mixer
Granulator for 10 minutes.
Step 2: Adding Binder under continuous stirring to purify water to get a clear
solution.
Step 3: Add the binder Solution of step 2 into the High Shear Mixer Granulator and
mix for 5 minutes at a slow speed. Further mix material in High Shear Mixer
Granulator and granulate till a wet mass of desired consistency is formed. Also, an
additional quantity of Purified Water is to be added to achieve the desired
consistency of wet mass.
Step 4: Dry the wet granules at 60°C (± 5°C) in a Fluid Bed Dryer to get LOD of
dried granules between 2.0% - 3.0%w/w.
Step 5: Sift the dried granules through an appropriate sieve using a vibratory sifter
and add flavour, masking flavour, and at least one lubricant to an octagonal blender
and mix for 5 minutes. Further, compress the lubricated granules to obtain the
capsule-shaped, biconvex uncoated Orally dispersible Tablet of the present
invention.
The inventors of the present invention found that the Taste is masked orally
Dispersible Tablet composition of the present invention helps mask the bitter taste
of drugs by drug resin ion exchange complexation. The inventors of the present
invention masked the bitter taste of the drug with the help of the Drug-Resin
complex wherein the drug resin complex is uncoated and the drug is Mefenamic
acid. In spite of the immediate release of drugs from the Taste masked Orally
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Dispersible Tablet composition of the present invention, the taste of the drugs was
not bitter and thus added to patient compliance. Thus, the Taste masked Orally
Dispersible Tablet composition of the present invention provides a simple scalable
process, industry feasible, immediate release, high drug loading, reduced dose
frequency, masks bitter taste with a pleasant mouth feel making it palatable and
patient compliant. Other embodiments of the present disclosure will be apparent to
those skilled in the art from consideration of the specification and practice of the
disclosed embodiments.
The following examples should be considered as exemplary only, with a true scope
and spirit of the present disclosure being indicated by the claims. It will be
understood that particular embodiments described herein are shown by way of
illustration and not as limitations of the invention. The principal features of this
invention can be employed in various embodiments without departing from the
scope of the invention. Those skilled in the art will recognize, or be able to ascertain
using no more than routine experimentation, numerous equivalents to the specific
procedures described herein. Such equivalents are considered to be within the scope
of this invention and are covered by the claims. While the compositions and
methods of this invention have been described in terms of embodiments, it will be
apparent to those of skill in the art that variations may be applied to the
compositions and/or methods and in the steps or in the sequence of steps of the
method described herein without departing from the concept, spirit and scope of the
invention. More specifically, it will be apparent that certain agents which are both
chemically and physiologically related may be Substituted for the agents described
herein while the same or similar results would be achieved. All such similar
substitutes and modifications apparent to those skilled in the art are deemed to be
within the spirit, scope and concept of the invention as defined by the appended
claims.
Preparatory Examples:
Specific preferred embodiments of the invention will now be described with
reference to the following examples which should be regarded in an illustrative
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rather than a restrictive sense.
Table 1
INGREDIENTS Ex. 1

Ex. 2

Ex. 3

Ex. 4

Ex. 5

Ex. 6

Ex. 7

A) Dry Mixing
1) Mefenamic acid 250.00 250.00 250.00 250.00 250.00 250.00 250.00
2) Methacrylic Acid
Divinyl Benzene
Copolymer with
Hydrogen Ion
97.50

50.00 83.00 80.00 80.00 101.50
3) Mannitol - 110.50 53.00 - - - -
4) Crospovidone XL-10 - - 20.00 20.00 20.00 20.00
5) Croscarmellose Sodium - 5.00 - - - - -
6) Colloidal silicon
dioxide
3.00
2.50
2.50 2.50 2.50 2.50 3.00
7) Microcrystalline
Cellulose - - - - - - 30.00
8) PROSOLV® SMCC 90 30.00 - - - - - -
9) Sucralose 8.00 8.00 4.00 4.00 4.00 4.00 6.00
10) HPC-LH-11 - - - - - 10.00 -
11) Sodium Lauryl
Sulphate
7.00

2.00 2.00 5.00
12) Citric Acid anhydrous - 2.00 - - - - -
B) Binder Addition
13) P/W q.s. q.s. q.s. q.s. q.s. q.s. q.s.
14) PVP K-30 4.00 2.00 - 10.00 4.00
15) Starch 25.00 15.00 15.00 25.00
16) Propylene glycol 6.00 3.00 6.00 6.00 6.00 6.00 6.00
17) Sodium Lauryl
Sulphate -
2.00 - - - - -
18) Colour Tartrazine 0.30 0.30 0.30 0.30 0.30 0.30 0.30
C) Lubrication: - -
20.00
19) Croscarmellose
Sodium
20) Crospovidone XL-10 -
35.00
25.00
30.00 -
50.00
30.00 - -
21) Colloidal silicon
dioxide
30.00
4.00
4.20
4.20
4.20
4.20
4.20
35.00
4.00
22) Flavour Capsaroma
Mango DC 217 PH -
8.00
8.00
8.00
8.00
8.00 -
23) Flavour Powdarome
peppermint - - - - - -
24) Powdarome Peppermint 5.00
2.00
5.00
25) Masking Flavour
599399
2.50
2.50
2.50
2.50
26) Magnesium Stearate
3.20
2.50
2.50
2.50
2.50
2.50
2.00
27) Microcrystalline
Cellulose (Directly
Compressible)
3.20 - - - - - -
20.00
28) PROSOLV® SMCC 90 20.00 - - - -
Average Weight of Tablets
(mg) -
500
420
450
450
420 -
420
Example 1 is prepared as follows:
1. Sifting of materials:
5
500
Sift the Mefenamic Acid, Methacrylic Acid Divinyl Benzene Copolymer
with Hydrogen Ion, Sodium Lauryl Sulphate, Sucralose, Colloidal silicon
dioxide, PROSOLV® SMCC 90 through 40# S.S sieves
2. Preparation of binder solution:
Take Purified Water in S.S. Vessel. Add slowly Polyvinylpyrrolidone-K30
under continuous stirring till to get clear solution.
10
3. Dry & wet mixing:
Mix the sifted material of High Shear Mixer Granulator for 10 minutes at
17
5
10
15
20
25
30
slow speed of impeller with chopper ‘OFF’. Add the Binder Solution into
High Shear Mixer Granulator and mix for 5 minutes at slow speed. After the
addition of binder mix material in High Shear Mixer Granulator and
granulate till wet mass of desired consistency is formed. Additional quantity
of Purified Water to be add to achieve the desired consistency of wet mass.
4. Drying:
Dry the wet granules at 60°C (± 5°C) in Fluid Bed Dryer to get LOD of
dried granules between 2.0% - 3.0%w/w.
5. Sizing:
Sift the dried granules completely through 40# SS sieve using vibratory
sifter.
6. Lubrication:
Sift ProSolve SMCC 90, Flavour Powdarome Peppermint Premium,
Masking Flavour, Sucralose 40# SS Sieve Separately. Mix Crospovidone &
Colloidal Silicon Dioxide & sift through 40# SS sieve. Sift Magnesium
Stearate through 100# SS sieve. Transfer dried and sized granules, sifted
lubricants to Octagonal blender and mix for 20 minutes at 8 RPM. Add
sifted Magnesium Stearate to octagonal blender and mix for 5 minutes at 8
RPM.
Example 2 to 7 are prepared as per the process mentioned in Example 1. The
Example 1 are divided into three batches and tested for stability as per ICH
guidelines and the data for the same is mentioned in Table 3-5. Also, physical
properties of samples prepared such as hardness, tablet weight, friability were tested
and mentioned in Table 2. The bitter taste of ODT formulation were tested on
volunteers and the taste of drug was determined on their response which is as
presented in the Table 6 to 8. The dissolution test of formulation of the present
invention exemplified in examples 1 were evaluated by USP paddle method in 0.05
M Tris Buffer PH 9.0 +1% SLS with 900 ml volume and 50 RPM as dissolution
media at 5, 10, 15, 20, 30, 45 and 60 minutes respectively. The dissolution data at
different time intervals in presented in Table 9.
Table 2: Physical Parameters of Tablet:
18
Observations
Parameters
Ex 1
Ex 2
Ex. 3
Ex 4
Ex 5
Appearance
Ex 6
Ex 7
*Complies *Complies *Complies *Complies *Complies *Complies *Complies
500.0
Weight of
Tablets (mg)
420.0
450.0
450.0
Thickness
(mm)
5.20-5.60
4.40-4.45
4.60-4.70
420.0
420.0
500.0
4.55-4.65
Hardness (N)
70-90
55-65
70-80
70-80
4.80-4.85
60-70
3.60-3.65
60-70
5.50-5.60
Disintegratio
n Time (Sec)
65-75
20-25 sec.
110-125
sec.
40-50 sec.
3-4 min
Friability
(%w/w)
0.03
0.28
0.23
100-110
sec.
35-40 sec. 30-40 sec.
0.18
Uniformity of
Dispersion
Complies
Complies
Complies
0.20
0.34
0.16
Not
Complies
Complies
Not
Complies
*Pale yellow colored, capsule shaped, elongated, uncoated dispersible tablet plain
on both sides.
5
Stability Data:
Table 3: Batch 1:
TESTS
30°C/75%RH
40°C/75%RH
Complies
Limit
Initial
3M
6M
3M
*Description
6M
Complies
Complies Complies Complies Complies
Complies
Hardness
TBD
90-120N
100
110N
90-105N
Disintegratio
n Time
NMT 3
Min
15-20sec
95-105N
90-100 N
15-20sec 15-20sec 15-20sec
UOD
To Comply Complies Complies Complies Complies
15-20sec
% Assay
Complies
90.0% to
110.0%
Mefenamic
Acid
100.63
98.95
98.40
99.16
98.35
19
20


Table 4: Batch 2:

Table 5: Batch 3:
% Dissolution
Mefenamic
Acid
NL
T
80%
Avg. 99.1 99.3 98.7 98.8 99.0
Max 101.3 103.1 100.4 99.8 101.1
Min 97.3 96.5 98.3 98.2 97.5
TESTS
30°C/75%RH 40°C/75%RH
Limit Initial 3M 6M 3M 6M
*Description Complies Complies Complies Complies Complies Complies
Hardness TBD 100-115N 100-115N 90-105 N 100-110N 90-105 N
Disintegration
Time
NMT 3 Min 15-20sec 15-20sec 15-20sec 15-20sec 15-20sec
UOD To Comply Complies Complies Complies Complies Complies
% Assay
Mefenamic
Acid
90.0% to
110.0%
100.50 99.03 98.76 99.61 98.56
% Dissolution
Mefenamic
Acid
NLT
80%
Avg 99.4 99.5 99.2 98.7 99.1
Max 100.7 102.5 101.2 99.8 100.0
Min 98.2 96.2 97.2 98.0 99.2
TESTS
30°C/75%RH 40°C/75%RH
Limit Initial 3M 6M 3M 6M
*Description Complies Complies Complies Complies Complies Complies
Hardness 100±30N 100-115N 100-105N 90-100 N 95-105N 80-100 N
Disintegration
Time
NMT 3 Min 15-20sec 15-20sec 15-20sec 15-20sec 15-20sec
UOD To Comply Complies Complies Complies Complies Complies
% Assay
90.0% to
110.0%
Mefenamic
Acid
100.20
99.24
99.10
% Dissolution
98.9
98.7
Avg
99.2
99.9
99.3
Mefenamic
Acid
NLT
80%
Max
101.3
102.5
98.3
99.4
100.4
Min
99.4
97.6
98.9
101.3
98.6
98.0
99.2
Thus, the data indicated in Table 3 demonstrates that the composition of the present
invention is stable.
5
10
15
Moreover, the inventors of the present invention further demonstrated the bitter taste
of drugs of different formulations on Taste Panel members which were chosen
among male and female candidates for their ability to distinguish flavours,
sweetness and mouth feel and were trained in how to score different characteristics.
Approx. 2 ml of each Test sample is consumed in interval of 5 minutes and a pinch
of coffee followed by water is consumed between 2 testing intervals to diminish the
taste effect of a previous test sample. The volunteers determined the score on their
taste and the data of same is mentioned in Table 6 to 8. The scoring criteria are as
mentioned below:
Scoring Criteria: Procedure: Approx. 2 ml sample of each Test sample consumed
in interval of 5 minutes. A pinch of Coffee followed by Water is consumed between
2 testing intervals to diminish the taste effect of a previous Test sample.
Overall Taste and Scale
Flavor and Scale
Unpalatable:
Sweetness and Scale
0.0-0.5
Unpleasant: 0.0-0.5
Bitter:
Palatable:
0.0-0.5
0.6-1.9
Mild:
0.6-1.9
Palatable:
Good:
0.6-1.9
2.0-2.5
Pleasant:
2.0-2.5
Moderately
Sweet:
Excellent:
2.6-3.0
Excellent:
2.6-3.0
2.0-2.5
Sweet:
2.6-3.0
21
22

Table 6: Taste evaluation data
Volunteer’s
Details
Sweetness
Ex 1 Ex 2 Ex 3 Ex 4 Ex 5 Ex 6 Ex 7
YGA (M) 2.3 0.46 0.7 1.8 1.7 1.8 2.3
ALC (M) 2.5 0.5 0.8 2.0 1.9 2.0 2.5
AKP (M) 2.4 0.48 0.7 1.9 1.8 1.9 2.4
DRD (M) 2.6 0.52 0.8 2.1 2.0 2.0 2.6
ASA (M) 2.4 0.48 0.7 1.9 1.8 1.9 2.4
KVD (F) 2.4 0.48 0.7 1.9 1.8 1.9 2.4
SRD (M) 2.6 0.52 0.8 2.1 2.0 2.0 2.6
DVJ (M) 2.7 0.54 0.8 2.2 2.0 2.1 2.7
AKL (M) 2.5 0.5 0.8 2.0 1.9 2.0 2.5
NVT (M) 2.5 0.5 0.8 2.0 1.9 2.0 2.5
VUB (M) 2.6 0.52 0.8 2.1 2.0 2.0 2.6
MDN (M) 2.6 0.52 0.8 2.1 2.0 2.0 2.6
KR (M) 2.7 0.54 0.8 2.2 2.0 2.1 2.7
SSP (F) 2.6 0.52 0.8 2.1 2.0 2.0 2.6
Total score 35.4 7.08 10.6 28.3 26.6 27.6 35.8
Final Avg. score 2.5 0.5 0.8 2.0 1.9 2.0 2.5
Abbreviations: M: Male, F: Female
Table 7: Taste evaluation data
Volunteer’s
Details
Flavour
Ex 1 Ex 2 Ex 3 Ex 4 Ex 5 Ex 6 Ex 7
YGA (M) 2.7 0.5 0.8 2.2 2.0 2.1 2.7
ALC (M) 2.7 0.5 0.8 2.2 2.0 2.1 2.7
AKP (M) 2.6 0.5 0.8 2.1 2.0 2.0 2.6
DRD (M) 2.5 0.5 0.8 2.0 1.9 2.0 2.5
ASA (M) 2.7 0.5 0.8 2.2 2.0 2.1 2.7
KVD (F) 2.6 0.5 0.8 2.1 2.0 2.0 2.6
SRD (M) 2.6 0.5 0.8 2.1 2.0 2.0 2.6
23

DVJ (M) 2.5 0.5 0.8 2.0 1.9 2.0 2.5
AKL (M) 2.8 0.6 0.8 2.2 2.1 2.2 2.8
NVT (M) 2.7 0.5 0.8 2.2 2.0 2.1 2.7
VUB (M) 2.5 0.5 0.8 2.0 1.9 2.0 2.5
MDN (M) 2.4 0.5 0.7 1.9 1.8 1.9 2.4
KR (M) 2.4 0.5 0.7 1.9 1.8 1.9 2.4
SSP (F) 2.5 0.5 0.8 2.0 1.9 2.0 2.5
Total score 36.2 7.2 10.9 29.0 27.2 28.2 36.6
Final Avg. score 2.58 0.5 0.8 2.1 1.9 2.0 2.6
Abbreviations: M: Male, F: Female
Table 8: Taste evaluation data
Volunteer’s
Details
Overall Taste
Ex 1 Ex 2 Ex 3 Ex 4 Ex 5 Ex 6 Ex 7
YGA (M) 2.6 0.5 0.8 2.1 2.0 2.0 2.6
ALC (M) 2.7 0.5 0.8 2.2 2.0 2.1 2.7
AKP (M) 2.5 0.5 0.8 2.0 1.9 2.0 2.5
DRD (M) 2.7 0.5 0.8 2.2 2.0 2.1 2.7
ASA (M) 2.7 0.5 0.8 2.2 2.0 2.1 2.7
KVD (F) 2.6 0.5 0.8 2.1 2.0 2.0 2.6
SRD (M) 2.4 0.5 0.7 1.9 1.8 1.9 2.4
DVJ (M) 2.6 0.5 0.8 2.1 2.0 2.0 2.6
AKL (M) 2.6 0.5 0.8 2.1 2.0 2.0 2.6
NVT (M) 2.8 0.6 0.8 2.2 2.1 2.2 2.8
VUB (M) 2.4 0.5 0.7 1.9 1.8 1.9 2.4
MDN (M) 2.5 0.5 0.8 2.0 1.9 2.0 2.5
KR (M) 2.6 0.5 0.8 2.1 2.0 2.0 2.6
SSP (F) 2.8 0.6 0.8 2.2 2.1 2.2 2.8
Total score 36.5 7.3 11.0 29.2 27.4 28.5 36.9
Final Avg. score 2.6 0.5 0.8 2.1 2.0 2.0 2.6
Abbreviations: M: Male, F: Female
Thus, data indicated in Tables 6, 7 and 8 indicates that the composition of the
present invention has an overall excellent taste than other experimental batch's
compositions in spite of the immediate release of drugs from the formulation.
5
10
15
20
Dissolution Profile
Dissolution studies were carried out using USP Paddle Apparatus and 0.05 M Tris
Buffer PH 9.0 +1% SLS with 900 ml volume and 50 RPM.
Table 9: Dissolution Profile of Mefenamic Acid Dispersible Tablets
Time
% Dissolution
5 min
10 min
87.5%
91.9 %
15 min
93.6 %
20 min
30 min.
94.6 %
92.9 %
45 min.
91.8 %
60 min.
90.5%
Technical Advancements:
The present disclosure described herein above has several technical advantages
including, but not limited to, the realization of:
 Mask bitter taste
 Immediate drug release
 Drug resin complex is uncoated
 Scalable process
 Patient compliant , Claims:we claim:
1. A taste-masked Orally Dispersible Tablet pharmaceutical composition
comprising: a drug-resin complex; wherein
the drug includes mefenamic acid; and
resin includes atleast one ion exchange resin.
2. The taste-masked Orally Dispersible pharmaceutical composition as claimed
in claim 1, wherein the drug resin complex is uncoated.
3. The taste-masked Orally Dispersible pharmaceutical composition as claimed
in claim 1, wherein the drug resin ratio is about 1:0.5, particularly about
1:0.15, particularly about 1:0.2 and 1:0.4.
4. The taste-masked Orally Dispersible pharmaceutical composition as claimed
in claim 1, wherein resin includes Methacrylic acid divinyl benzene
copolymer with Hydrogen Ion, Polacrilin potassium, Calcium Polystyrene
Sulphate, Sodium Polystyrene Sulphate.
5. The taste-masked Orally Dispersible pharmaceutical composition as claimed
in claim 1, wherein resin particularly includes Methacrylic acid divinyl
benzene copolymer with Hydrogen ion.
6. The taste-masked Orally Dispersible pharmaceutical composition as claimed
in claim 1, wherein the drug resin complex includes mefenamic acid present
in a concentration of 45 to 65%.
7. The taste-masked Orally Dispersible pharmaceutical composition as claimed
in claim 1, wherein the drug resin complex includes Methacrylic acid divinyl
benzene copolymer with Hydrogen ion present in a concentration of at least
15-25%.
8. The taste-masked Orally Dispersible pharmaceutical composition as claimed
in claim 1, further includes at least one pharmaceutically acceptable
excipient.
9. The taste-masked Orally Dispersible pharmaceutical composition as claimed
in claim 1, wherein at least one pharmaceutically acceptable excipient
comprises at least one diluent, disintegrant, super-disintegrants, binders,
25
diluents, lubricants, flavouring agent, sweeteners, colorants, or combinations
and mixtures thereof.
5
10
15
20
25
30
10. The taste-masked Orally dispersible pharmaceutical composition as claimed
in claim 1, wherein disintegrants include at least one of Sodium starch
glycolate, Croscarmellose sodium, and Crospovidone.
11. The taste-masked Orally dispersible pharmaceutical composition as claimed
in claim 1, wherein diluents include at least one of Lactose, Fructose,
Sorbitol Powder, and Mannitol.
12. The taste-masked Orally dispersible pharmaceutical composition as claimed
in claim 1, wherein the binders include at least one of Polyvinylpyrrolidone
K90, Maize Starch, Pregelatinized starch, Starch, propylene glycol, Hydroxy
Propyl Cellulose, and Purified water.
13. The taste-masked Orally dispersible pharmaceutical composition as claimed
in claim 1, wherein flavorants or flavoring agents include at least one of
Mango Flavour, Orange Flavour, Pineapple Flavour, Banana Flavour,
Masking Flavour, and Peppermint Flavour.
14. The taste-masked Orally dispersible pharmaceutical composition as claimed
in claim 1, wherein the sweeteners include at least one of Aspartame,
Sucralose, Saccharine Sodium, and Neotame.
15. The taste-masked Orally dispersible pharmaceutical composition as claimed
in claim 1, wherein the lubricants include at least one of microcrystalline
cellulose, Colloidal silicon dioxide, Stearic Acid, Hydrogenated Castor Oil
and Sodium Stearyl Fumarate, Magnesium Fumarate or combination thereof.
16. The taste-masked Orally dispersible pharmaceutical composition as claimed
in claim 1, wherein the composition provides an immediate release.
17. The taste-masked Orally dispersible pharmaceutical composition as claimed
in claim 1, wherein the composition provides at least 87.5% release of drugs
in 5 minutes.
18. The taste-masked Orally dispersible pharmaceutical composition as claimed
in claim 1, wherein the composition comprises a disintegration time of about
20 seconds to about 25 seconds.
26
19. The taste-masked Orally dispersible pharmaceutical composition as claimed
in claim 1, wherein the composition comprises a hardness of between about
70 N to about 90N.
5
10
15
20
25
30
20. The taste-masked Orally dispersible pharmaceutical composition as claimed
in claim 1, wherein the composition has at least about 40 percent better
mouth-feel.
21. The taste-masked Orally dispersible pharmaceutical composition as claimed
in claim 1, wherein the composition effectively masks an unpalatable taste
associated with the immediate delivery of the drugs.
22. A process of preparing taste-masked Orally dispersible pharmaceutical
composition as claimed in claim 1, by Drug ion resin complexation process
includes:
Step 1: Sifting Mefenamic Acid, Methacrylic Acid Divinyl Benzene
Copolymer with Hydrogen Ion, and excipients such as disintegrant, binder,
diluent, and glidant through an appropriate sieve using a sifter and transfer
the sifted material to the High Shear Mixer Granulator (RMG). Mix the
sifted material of High Shear Mixer Granulator for 10 minutes.
Step 2: Adding Binder under continuous stirring to purify water to get a
clear solution.
Step 3: Add the binder Solution of step 2 to the High Shear Mixer
Granulator and mix for 5 minutes at a slow speed. Further mix material in
High Shear Mixer Granulator and granulate till a wet mass of desired
consistency is formed. Also, an additional quantity of Purified Water is to be
added to achieve the desired consistency of wet mass.
Step 4: Dry the wet granules at 60°C (± 5°C) in a Fluid Bed Dryer to get
LOD of dried granules between 2.0% - 3.0%w/w.
Step 5: Sift the dried granules through an appropriate sieve using a vibratory
sifter and add flavor, masking flavor, and at least one lubricant to the
octagonal blender and mix for 5 minutes. Further, compress the lubricated
granules to obtain the uncoated Orally dispersible Tablet.
27
23. The method of masking the bitter taste of drugs by taste-masked Orally
dispersible Tablet pharmaceutical composition comprising of a drug-resin
complex, wherein the drug includes mefenamic acid; and resin includes at
least one ion exchange resin as claimed in claim 1.