Note: Descriptions are shown in the official language in which they were submitted.
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TASTE MASKED PHARMACEUTICAL COMPOSITIONS COMPRISING BITTER
DRUG AND pH SENSITIVE POLYMER
Field of Invention
The present invention relates to taste masked compositions comprising a bitter
drug
and a pH sensitive polymer and methods for preparing the same. The present
invention also
relates to a process for the preparation of a taste masked pharmaceutical
composition
comprising bitter drug and a pH sensitive polymer.
Background of invention:
Although a variety of delivery systems are being developed for different
routes of
administration like the oral, parenteral, nasal and transdermal, the oral
route remains
attractive for drug delivery because this mode of administration is an easy,
convenient,
noninvasive and familiar method of drug delivery. The majority of prescribed
drugs are
designed for oral application since they can be self administered by the
patient without
hospitalization. Oral dosage forms are designed according to the nature of the
drug, the
nature of application and the need for any special effects. The common oral
dosage forms
include: liquid mixtures like solutions, suspensions, solid dosage forms like
tablets and
capsules and liquid filled capsules etc. The solid dosage forms are further
modified
depending on the therapeutic action desired, like controlled, extended or
delayed release.
However, patients at the extremes of age, such as children and the elderly,
often experience
difficulty in swallowing solid oral dosages forms. For these patients the
drugs are mostly
provided in liquid dosage forms such as solutions, emulsions and suspensions.
These dosage
forms usually lead to perceptible exposure of the active drug ingredient to
the taste buds,
which is a very serious problem when the drug has an extremely unpleasant or
bitter taste.
The bitter taste of the drugs, which are orally administered, is
disadvantageous in
several aspects. Taste is an important parameter governing the compliance. The
disagreeable
taste of drugs causes difficulties in swallowing or causes patients to avoid
their medication
thereby resulting in low compliance of patients. Conventional taste masking
techniques such
as use of sweeteners, amino acids, flavoring agents are often unsuccessful in
masking the
taste of the highly bitter drugs like quinine, barberin, etoricoxib,
antibiotics like levofloxacin,
ofloxacin, sparfloxacin, ciprofloxacin, cefuroxime axetil, erythromycin and
clarithromycin.
Thus taste-masking technologies axe considered important and developed by many
researchers.
Taste masking is a major problem when the drugs axe extremely unpleasant and
bitter
and this problem is not restricted to the liquid oral compositions like
solutions, dry syrup and
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suspensions but may also be encountered during the formulation of chewable
tablets or
dispersible tablets wherein these dosage forms usually lead to perceptible
exposure of active
ingredient to taste buds. Depending on the type of dosage form, various
methods have been
employed to overcome the unpleasant taste and bitterness of the drug.
Patent Application WO 03/13470 discloses the use of ammonium glycyrrhyzinate
to
taste-mask the formulation comprising of a dry blend of paroxetine and a
glycyrrhyzinate
formulated as a dispersible powder or moulded into a dispersible or chewable
tablet. Patent
Application WO 03/I 1227 discloses a taste masked composition for the delivery
of ibuprofen
which causes a throat catch in the form of chewable ibuprofen tablets with the
polymer,
carbomer 934. European Patent EP 1219291 discloses chewable tablets and
texture masked
particles of the active ingredient, acetaminophen which is coated by a taste
masking polymer
ethyl cellulose and a film forming polymer and a texture masking coating
solution of
hydroxypropyl methyl cellulose and polyethylene glycol 800 and acesulfame
potassium.
Tn yet another patent application JP 2002363066 the taste masked
pharmaceutical or
food composition is disclosed which is suitable for formulation as granule,
tablet or a
chewable tablet. The taste masked fine granule is obtained by using polymers
such as ethyl
cellulose, hydroxy propyl cellulose. European patent EP 1166777 discloses yet
another
chewable tablet made from taste masked particles. The active ingredient
ibuprofen was
coated by the enteric polymer HPMCP and an insoluble film forming agent
cellulose acetate
and chewable tablets with no throat burn were prepared from the coated
particles by blending
with aspartame, acesulfame potassium, citric acid, granular mannitol, fumaric
acid,
microcrystalline cellulose, and flavor.
Taste masking techniques are extended to the dispersible dosage forms and
rapidly
disintegrating tablets, too. The patent application WO 01/58449 discloses the
water
dispersible powder and tablets of paroxetine for the immediate release of the
drug and a taste-
masking agent comprising of the methacrylic acid copolymer. The taste-masked
composition
was obtained by spray drying of paroxetine and the polymer.
Patent Application WO 02/64119 discloses quickly disintegrating tablets in the
oral
cavity providing masking of the unpleasant taste and the fast absorption of
the active from the
tablets in the digestive tract. The disclosure is limited to the drug, which
is hardly soluble in
water under neutral or alkaline conditions but highly soluble in water under
acidic conditions
giving an unpleasant taste. The physicochemical properties of different drug
molecules are
different and so such systems would not be suitable for the drugs, which are
water soluble.
Patent Application WO 01/52848 discloses a taste masked oral formulation of
linezolid
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which can be formulated as a suspension, a fast-disintegrating, effervescent
or chewable
tablet, by microencapsulating the antibiotic by solvent coacervation of ethyl
cellulose with an
optional seal coat of shellac and further coating the particles by functional
polymer Eudragit
L30 D. The formulated microcapsules can be suspended in an aqueous medium
prior to oral
administration to pediatric and geriatric patients, who are unwilling and / or
find it difficult to
swallow the tablets, else, fast-disintegrating tablets can be formulated which
rapidly disperse
into taste masked granules in the mouth.
Various methods for taste masking have been tried earlier, which include use
of ion
exchange resins, complexation of bitter drugs with pharmaceutically acceptable
excipients
and coating of drugs by lipids and various polymeric materials. Of these, the
coating is the
most widely used technique for taste masking. Coating of the active ingredient
can be done
by any of the techniques known in the art like microencapsulation, hot melt
granulation, Fluid
bed coating, and spray drying.
One of the approaches for taste masking is the use of ion exchange resins.
Various
anionic resins like Duolite AP143/1083 (cholestyramine resin USP), Cationic
resin like
Amberlite IRP 64 (copolymer of methacrylic acid crosslinked with
divinylbenzene) and
Dowex (based on polystyrenesulfonic acid crossliked with divinylbenzene) are
used. US
patent 6514492, discloses the use of ion exchange resin AMBERLITE® IRP 69
for taste
masking of quinolone derivatives thereby eliminating the extreme bitterness of
the
quinolones in oral liquid formulation.
Patent Application WO 01/70194 discloses a fast dissolving orally consumable
film
adapted to adhere to and dissolve in the mouth of the consumer. The film is
composed of an
ion exchange resin, amberlite and a water soluble polymer pullulan as taste
masking agent for
the bitter drug, dextromethorphan. The film adheres to the oral cavity and
dissolves to deliver
the active ingredient. The use of the water soluble polymer in the formulation
would restrict
the use of such delivery system if the taste masking was desired for liquid
oral preparation.
Further such delivery systems may not be well accepted in case of pediatric
and geriatric
preparations where patient compliance is very important. US Patent 6,001,392
discloses a
controlled, release syrup suspension for the oral administration containing
dextromethorphan
adsorbed on to a polystyrene sulfonate ion exchange resin. The drug polymer
complex is
coated by a mixture of ethyl cellulose or ethyl cellulose latexes with
plasticizers and water
dispersible polymers such as SURELEASE. For the drugs where immediate release
is
required for rapid action, the controlled release of the active ingredient may
not be favored
and a delay in release may also be of concern for drugs having a limited
absorption window.
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The use of ion exchange resin to adsorb drugs containing amino groups for
taste
masking has found limited applicability in masking the taste of highly bitter
drugs and also
where the drug is to be dispersed in a liquid oral composition for long
duration of time.
Complexation is yet another method for taste masking of bitter drugs. US
Patent
4,808,411 discloses a taste masked composition comprising 75-95 % of
erythromycin and
about 5 to 75 % of carbomer where the drug and carbomer are held together by
ionic
interactions between erythromycin and carbomer. The complex is further coated
with a
functional polymer, hydroxy propyl methylcellulose phthalate to make the
preparation
palatable. Erythromycin is released slowly from the complex to avoid a
significant perception
of bitterness in the mouth. It is clear that slow release, not fast release of
bitter medicament is
critical as disclosed in the patent. But complexing alone is not sufficient
enough to mask
taste. Coating with functional polymers is required to attain desired
palatability and further
proper selection of complexing agent is vital since drug release should not be
compromised.
Coating of drugs is another method but this alone may prove effective, only
for
moderately bitter drugs or in products where coated particles are formulated
as aqueous
preparations just before administration or are formulated in non-aqueous
medium.
Patent Application WO 02/092106 discloses a taste-masked composition
comprising
polycarbophil and a macrolide antibiotic, clarithromycin. The complex is
further coated with
an acid resistant polymer Eudragit L100 55, releasing the drug in the
intestine. For certain
drugs the bioavailability may not be altered by the use of enteric coating
where the drug is
released in the small intestine, but for the drugs with a narrow absorption
window restricted
to the upper gastric region, the use of enteric coating may alter the
bioavailability. European
Patent Application EP 0409254 discloses an oral particulate preparation with
unpleasant taste
being masked using ethyl cellulose and a water swelling agent where the active
is released
rapidly from the said formulation. US Patent 5,635,200 discloses a taste-
masked preparation
of bitter drug ranitidine by a lipid coating and dispersion of these coated
particles in the non-
aqueous medium. US Patent Application 2003-028025 discloses taste-masked
composition of
gatifloxacin suitable for use in oral dosage forms, particularly for pediatric
formulations. A
crystalline co-precipitate of gatifloxacin and one or both of stearic acid and
palmitic acid is
used to effectively mask the bitter taste of gatifloxacin in the mouth and in
aqueous
suspension through a full dosage cycle of fourteen days.
Patent Application WO 02/72111 discloses a taste masked pharmaceutical
suspension
of telithromycin. Four different coating agents Novata AB, Eudragit E100,
glycerol
monostearate and talc M10 are employed and at least three successive layers of
coating are
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essential to taste mask telithromycin. The coated granules as disclosed could
further be
formulated as dry syrup, which is reconstituted as a suspension. US Patent
4,865,851
discloses yet another method for taste masking highly bitter 1 acetoxy ethyl
ester of
cefuroxime in particulate form being coated with an integral coating of lipid
or a mixture of
lipids, which serves to mask the taste.
The taste masking coatings, using lipids requires that the melting point of
the lipid
should be sufficiently high to prevent melting in the mouth and should not be
so high that
active ingredient itself melts or is chemically degraded. Cefuroxime axetil in
a substantially
amorphous form with maximum bioavailability has a low melting point of about
70 degree C
and the difference in the melting of the lipid and drug is very marginal and
also the
temperature at which the mixture is atomized is higher than the melting point
of the lipid. The
lipid based microencapsulation requires a highly sophisticated hot melt
granulation process
for producing fine particles without adversely affecting the drug molecule.
British Patent 2081092 also discloses a lipid coating for the purpose of taste
masking.
It was however found that wax coating resulted in poor dissolution of the
active ingredients
in the alimentary tract. Further the Patent discloses a technique to overcome
this problem by
mixing the waxes with a water swellable polymer. Again the use of the water
swellable
polymer referred to in the patent makes it less appropriate for the liquid
orals like suspensions
and dry syrup. US Patent 5,286,489 describes a porous drug polymer matrix
formed by
admixing a bitter tasting active ingredient and a methacrylic ester copolymer
in at least a 1:1
weight ratio of active ingredient to copolymer, effective to mask the taste of
the drug. None
of the examples described in the patent disclose the effect of these polymers
on the release of
the drug from the matrix. It is observed that the drug release is retarded
from the matrix
described herein.
Patent Application WO 00/56266 discloses the use of a high viscosity swellable
polymer carbomer, in combination with film forming polymethacrylates and
channelising
agents for taste masking of bitter drugs. The addition of the water swellable
polymer aids in
the fast release of the active ingredient in the gastric media. In yet another
Patent application
WO 00/76479 a taste masking composition, using a combination of two enteric
polymers
comprising methacrylic acid copolymer and a phthalate polymer is disclosed.
The patent
discloses the use of the channelising agents which comprise the water soluble
or water
swellable materials to aid the release of the active ingredient .The enteric
polymers as
disclosed in the patent are known to release the active ingredient in the
alkaline pH where the
polymers are soluble. Release of active ingredient will be delayed due to the
use of the
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enteric polymers and in case of the medicaments having a narrow absorption
window
restricted to upper gastrointestinal tract; such system would be of limited
use.
Microencapsulation of highly bitter drug cefuroxime axetil for taste masking
is
disclosed by M.Cuna et.al (M. Cuna, M.L. Lorenzo, J.L. Vila Jato, D. Torres,
M.J. Alonso,
Acta Technologiae et Legis Medicamenti. volume VII, N.3, 1996) using different
polymeric
materials like cellulose acetate trimellitate, HPMCP-50, HPMCP-55 with the
final aim to
mask the taste and assuring its release in the intestinal cavity.
In yet another publication by Alonso (M. J. Alonso, M.L Lorenzo-Lamosa,
M.Cuna,
J. L. Vila-Jato and D. Torres, Journal of Microencapsulation, 1997, Volume 14,
No.S, 607-
616) the encapsulation of cefuroxime axetil, a highly bitter drug, in pH
sensitive acrylic
microspheres in order to formulate a suspension dosage from is described. The
acrylic
polymers used were eudragit E, eudragit RL 100, eudragit L100-SS.The cationic
Polymer
eudragit E showed a negative interaction with cefuroxime axetil. The enteric
polymer
eudragit L100 -55 showed a favorable release in alkaline pH.
In the above disclosures the release of cefuroxime axetil was studied in the
basic
media whereas Dantzig et al (Anne H. Dantzig, Dale C. Duckworth, Linda B.
Tabas,
Biochimica et Biophysica Acta 1191, 1994, 7-13) showed that cefuroxime axetil
is
hydrolyzed to cefuroxime in the intestinal lumen by the esterases reducing the
cefuroxime
axetil concentration in the lumen and resulting in reduced absorption, leading
to low
bioavailability of Cefuroxime axetil in humans. Cefuroxime axetil already has
a low
bioavailability of 32-50 % and hence further reduction in the bioavailability
due to the
formulation aspects should be minimized.
The taste masking formulations should be so designed that the bioavailability
of the
drugs is not compromised and the use of certain polymers like the enteric
coatings should not
affect the time to peak. Further the drug should be sufficiently absorbed to
ensure effective
therapeutic concentration in the plasma. Vogelman et al (B. Vogelman, William
A. Craig
Journal of Pediatric 1986, 108 (5, pt2) 835-40, ~c B. Vogelman, William A.
Craig, S. Ebert,
S. Gudmundsson, J. Leggett, Journal of Infectious Diseases 1988,158(4), 831-
47) have
established that bactericidal killing is rapid, intensive and increases
proportionately to the
concentration. In the presence of high concentration of the drug, the killing
is complete and
almost instantaneous. In some drugs rapid and complete absorption and high
systemic
concentration are important to elicit the desired therapeutic effect.
There are certain drugs which pose challenges during the formulation due to
their
physico-chemical characteristics like cefuroxime axetil, a second generation
cephalosporin
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antibiotic and celecoxib, from the class of COX 2 inhibitors. Both celecoxib
and cefuroxime
have relatively high dose requirement further increasing the difficulty in
administering the
therapeutically effective dose. Cefuroxime axetil exhibits the tendency to gel
in contact with
the aqueous media, necessitating that the dosage form disintegrates into
particles rapidly and
releases the drug at a faster rate before the gelling occurs ih vivo. Another
problem
associated with cefuroxime relates to extremely bitter taste of the drug
making it necessary to
formulate cefuroxime in a coated delivery system to make it palatable.
Celecoxib has an
extremely low aqueous solubility and is not readily dissolved and dispersed
for rapid
absorption in the gastrointestinal tract further the amorphous form of
celecoxib which is
known to increase its dissolution and also its bioavailability tends to
crystallize in contact
with the aqueous medium. Etoricoxib, another molecule from the COX 2 inhibitor
family is
also associated with extremely bitter taste. Such active molecules which pose
formulation
problems and are required to be administered as rapid release formulations to
overcome the
low bioavailability, need to have a protective polymer coating which releases
the active
ingredient at a rapid rate without compromising the bioavailability, and
masking the
unpleasant taste of the active ingredient.
Patent Application WO 02/43707 discloses oral pharmaceutical formulations for
cefuroxime axetil in tablet form such that the cefuroxime axetil is contained
in the tablet core,
coated with double layered film coat of hydroxypropyl Methyl cellulose and
shellac. The first
film coat as disclosed, serves to mask bitter taste of cefuroxime axetil and
second film coat
serves to delay the rupture time beyond 40 seconds. Since cefuroxime axetil is
associated
with gelling tendency in contact with aqueous media thereby reducing
bioavailability, the
rapid release of cefuroxime from the core of the dosage form is more
desirable.
US Patent 5,599,556, discloses liquid formulations where the active ingredient
is
coated with single outer polymeric coating derived from prolamine cereal grain
proteins and
plasticizing agent. The bitter drug clarithromycin cornixed with polyvinyl
pyrrolidone is
coated by prolamine to achieve taste masking and the coated particulate matter
is dispersed in
a suspending medium of pH greater than 6. The coatings are designed to rapidly
degrade once
the composition leaves the mouth and reaches the stomach. Most of the
pharmaceutical liquid
oral compositions are formulated at a pH of 3.5 - 5.5 (US Pharmacopoeia/
National
Formulary 23/NF 18,1995). Some drugs may not be stable at the higher pH and
some drugs
may not be stable in extreme acidic pH and would tend to degrade over
prolonged exposure.
US Patent 548,436 discloses chewable tablets made from a coated medicament
where
the coating is designed to be soluble at the lower pH of the stomach but
relatively water
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insoluble at the higher pH of the mouth. The coatings comprise a polymer blend
of
dimethylaminoethyl methacrylate and neutral methacrylic acid ester and a
cellulose ester. The
above mentioned "reverse enteric" coating method of taste masking oral
formulation is
disclosed in connection with chewable tablets.
Patent Application WO 02!096392 discloses taste masking of highly water
soluble
drug cetrizine hydrochloride. The polymers like hydroxy propyl methyl
cellulose, polyvinyl
pyrrolidone, ethyl cellulose are used which effectively mask the taste of
cetrizine in tablet
form and release the drug immediately under the acidic conditions prevalent in
stomach.
It is evident from the above disclosures, that taste masking can be achieved
by various
methods. Many natural and synthetic polymers, resins and waxes alone or in
combination
have been employed fox taste masking. The enteric polymers like eudragit L are
used for taste
masking but the pH of saliva is near 5.8 and these polymers solubilize at pH
beyond 5.5 so
there is a possibility of drug being partially leached. It is understood that
there is a need for
the development of a taste masking polymer such that the bitter taste is
completely masked
by the polymer at the pH of saliva in mouth and in the reconstitution medium
as in case of the
liquid orals and further which is able to protect the drug in a biologically
active form, from
the moisture in the dosage form and releasing the drug rapidly in the stomach
without
affecting its absorption and bioavailability.
Whilst the use of polymer coats as mentioned in the above examples may be
effective
for retarding dissolution of the drug during the time in contact with saliva,
during the process
of swallowing, it has disadvantages in preparing taste masked liquid
formulations intended
for long term storage in contact with liquid medium. None of the references
described above
satisfactorily mask the bitter taste of the medicament in the pharmaceutical
compositions like
suspension, dry syrups where in the drug should not be leached in the
suspension media up to
14 days, the normal reconstitution period and yet should be released in the
gastric cavity
immediately after ingestion without affecting the bioavailability. Regardless
of the numerous
techniques and pharmaceutical adjuncts known in the art to mask the taste of
bitter-tasting
medicaments, there remains the need to find an effective technique, adjunct or
combination
thereof fox specific agents.
Objects of the invention
It is the object of the present invention to provide an oral taste masked
composition
which can deliver a substantial amount of the bitter active immediately with
improved
palatability by using the specially synthesized pH sensitive polymers which
solubilize or
swell in the acidic conditions of the stomach and are insoluble or de-swell in
the neutral or
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near neutral media and which can be applied in various pharmaceutical oral
dosage forms.
The term oral dosage form as used herein means any pharmaceutical composition
intended to
be administered to an individual by delivering said composition to the gastro
intestinal tract
of an individual via mouth. Oral dosage forms include tablets like chewable
tablets,
dispersible tablets, coated tablets; liquids such as dry syrups and
suspensions.
The object of the present invention is to provide taste-masking compositions,
consisting of a pH sensitive polymer and further a method for the synthesis of
these polymers
and also the method of preparation of pharmaceutical composition containing
these polymers.
The other object of the present invention is to synthesize polymers, which
effectively
mask the unpleasant taste of the drug but do not compromise the dissolution
rate and
bioavailability of drug and further rapidly release the drug in the gastric
cavity.
Yet another object of the present invention is to develop a pH sensitive
polymer
suitable for taste masking the Liquid orals Like suspensions, dry syrups, and
solid dosage form
like chewable tablets, fast dispersible tablets and conventional tablets.
Yet another object of the present invention is to prevent the leaching of the
drug at the
pH of saliva and in the reconstitution medium, from the liquid and solid
dosage forms.
Yet another object of the present invention also aims at the coating of the
bitter drug
particle by various methods known in the art like microencapsulation, tray
drying, fluid bed
processing and spray drying etc.
A fiuther object of the present invention is to formulate the liquid oral
dosage forms
comprising the coated particles.
Summary of the invention
Accordingly the present invention provides for a taste masked pharmaceutical
composition comprising a pH sensitive polymer aired a bitter drug, and of the
formula P [A ~X~
B ~y~ C ~Z~]: D wherein P is the pH sensitive polymer comprising (A) a
hydrophobic monomer,
(B) a basic monomer and (C) a hydrophilic monomer and {D) a bitter dxug and
(x) = 30 -
95%, (y) = 5 - 70%, (z) = 0 - 60%, all expressed in terms of w/w and the ratio
of (P) to (D) is
in the range of 30:1 to 0.2:1 w/w.
In one embodiment of the invention the hydrophobic monomer (A) is a acrylic or
a
methacrylic acid ester selected from the group consisting of cyclohexyl
acrylate, dodecyl
acrylate, 2 ethyl hexyl acrylate, octyI acrylate, tertiary butyl acrylate,
phenyl acrylate, butyl
acrylate, methyl methacrylate, benzyl methacrylate, cyclohexyl methacrylate,
phenyl
methacrylate, tertiary butyl methacrylate, butyl methacrylate, 2 ethyl hexyl
methacrylate,
propyl methacrylate preferably butyl acrylate, methyl methacrylate and butyl
methaerylate.
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In another embodiment of the invention the basic monomer (B) is selected from
the
group consisting of amino alkyl acrylic acid and methacrylic acid esters
selected from the
group consisting of dimethyl amino ethyl methacrylate, dimethyl amino ethyl
acrylate,
diethyl amino ethyl methacrylate, diethyl amino ethyl acrylate, piperidine
ethyl methacrylate,
2 tert- butyl amino ethyl methacrylate, preferably dimethyl amino ethyl
methacrylate and
diethyl amino ethyl acrylate
In still another embodiment of the invention the basic monomer (B) is an
alkenyl
pyridine selected from the group consisting of 2-vinyl pyridine, 3- vinyl
pyridine, 4-vinyl
pyridine and 5- vinyl 2 picoline, 2-vinyl 4 picoline, 2 isopropenyl pyridine,
iso propenyl
pyridine, preferably 4- vinyl pyridine.
In still another embodiment of the invention the basic monomer (B) is selected
from
vinyl quinolines, aminoalkyl vinyl ethers, amino ethyl styrenes and allylic
amines, preferably
allylic amines.
In yet another embodiment of the invention the hydrophilic monomer (C) is an
acrylic
or methacrylic acid ester selected from the group consisting of hydroxy ethyl
methacrylate,
hydroxy propyl methacrylate, hydroxy ethyl ethyl methacrylate, hydroxy ethyl
acrylate,
hydroxy propyl acrylate, hydroxy ethyl ethyl acrylate preferably hydroxy ethyl
methacrylate
and hydroxy ethyl ethyl methacrylate.
In one embodiment of the invention the drug comprises a macrolide antibiotic
selected from the group consisting of erythromycin, azithromycin and
clarithromycin,
fluroquinolones selected from the group consisting of ciprofloxacin,
enrofloxacin, ofloxacin,
gatifloxacin, levofloxacin and norfloxacin, cephalosporins selected from the
group consisting
of cefuroxime, cephalexin, cephadroxil, cepfodoxime proxetil, nonsteoroidal,
and anti-
inflammatory and analgesic drugs selected from the group consisting of
ibuprofen and
diclofenac sodium and COX 2 inhibitors selected from the group consisting of
etoricoxib and
celecoxib, antihistamic drugs selected from the group consisting of
chlorpheniramine
maleate, oxazolidinones selected from the group consisting of linezolid and
other drug like
dextromethorphan.
In another embodiment of the invention, the total polymer to drug ratio for
optimal
taste masking bitter drug in the range 30:1 to 0.2:1 by weight. More
preferably the ratio of
the polymer to drug is 5:1 to 0.4:1 by weight.
In still another embodiment of the invention the pH sensitive polymer
solubilizes or
swells in the acidic pH <3 as found in stomach and remains insoluble or de
swelled in the pH
> 3.5.
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In yet another embodiment of the invention the drug itself or its
pharmaceutically
acceptable salt or ester or amide is used.
In another embodiment of the invention the drug is in the form of
microparticles
dispersed within or coated with the polymer matrix.
In yet another embodiment of the invention the pharmaceutical dosage forms
which
could be prepared using the composition of the present invention may be liquid
orals; such as
dry syrup or suspension and chewable or dispersible tablets.
In still another embodiment of the invention the pharmaceutical composition
comprising the microparticles by themselves or in a pharmaceutically
acceptable dosage
form, release a minimal amount of drug at pH of saliva from the oral dosage
form but rapidly
release substantial amount of the drug immediately at pH <3 found in the
stomach.
In the preferred embodiment the microparticles are formulated as aqueous
suspension
or are reconstituted in liquid medium for a normal storage period.
In yet another embodinnent the pharmaceutical composition is obtained by
dispersion
or coating of the bitter drug in the matrix of pH sensitive polymer by any of
the known
techniques, preferably by microencapsulation, spray drying, fluid bed
processing, co
precipitation in a non solvent or by tray drying method.
In yet another embodiment the taste masked drug polymer matrix in particulate
form
is suspended using the reconstitution medium of pH 4.5 comprising of sucrose,
tutti- frutti
flavor, citric acid and polyvinyl pyrrolidone.
The present invention also relates to a process for the preparation of a a
taste masked
pharmaceutical composition comprising a pH sensitive polymer and a bitter
drug, and of the
formula P [A fix) B (y, C ~Z~]: D wherein P is the pH sensitive polymer
comprising (A) a
hydrophobic monomer, (B) a basic monomer and (C) a hydrophilic monomer and (D)
a bitter
drug and (x) = 30 - 95%, (y) = 5 - 70%, (z) = 0 - 60%, a.11 expressed in terms
of w/w and the
ratio of (P) to (D) is in the range of 30:1 to 0.2:1 w/w.
In one embodiment of the invention the hydrophobic monomer (A) is a acrylic or
a
methacrylic acid ester selected from the group consisting of cyclohexyl
acrylate, dodecyl
acrylate, 2 ethyl hexyl acrylate, octyl acrylate, tertiary butyl acrylate,
phenyl acrylate, butyl
acrylate, methyl methacrylate, benzyl methacrylate, cyclohexyl methacrylate,
phenyl
methacrylate, tertiary butyl methacrylate, butyl methacrylate, 2 ethyl hexyl
methacrylate,
propyl methacrylate preferably butyl acrylate, methyl methacrylate and butyl
methacrylate.
In another embodiment of the invention the basic monomer (B) is selected from
the
group consisting of amino alkyl acrylic acid and methacrylic acid esters
selected from the
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WO 2005/055987 PCT/IN2003/000392
group consisting of dimethyl amino ethyl methacrylate, dimethyl amino ethyl
acrylate,
diethyl amino ethyl methacrylate, diethyl amino ethyl acrylate, piperidine
ethyl methacrylate,
2 tert- butyl amino ethyl methacrylate, preferably dimethyl amino ethyl
methacrylate and
diethyl amino ethyl acrylate
In still another embodiment of the invention the basic monomer (B) is an
alkenyl
pyridine selected from the group consisting of 2-vinyl pyridine, 3- vinyl
pyridine, 4-vinyl
pyridine and 5- vinyl 2 picoline, 2-vinyl 4 picoline, 2 isopropenyl pyridine,
iso propenyl
pyridine, preferably 4- vinyl pyridine.
In still another embodiment of the invention the basic monomer (B) is selected
from
vinyl quinolines, aminoalkyl vinyl ethers, amino ethyl styrenes and allylic
amines, preferably
allylic amines.
In yet another embodiment of the invention the hydrophilic monomer (C) is an
acrylic
or methacrylic acid ester selected from the group consisting of hydroxy ethyl
methacrylate,
hydroxy propyl methacrylate, hydroxy ethyl ethyl methacrylate, hydroxy ethyl
acrylate,
hydroxy propyl acrylate, hydroxy ethyl ethyl acrylate preferably hydroxy ethyl
methacrylate
and hydroxy ethyl ethyl methacrylate.
In one embodiment of the invention the drug comprises a macrolide antibiotic
selected from the group consisting of erythromycin, azithromycin and
clarithromycin,
fluroquinolones selected from the group consisting of ciprofloxacin,
enrofloxacin, ofloxacin,
gatifloxacin, levofloxacin and norfloxacin, cephalosporins selected from the
group consisting
of cefuroxime, cephalexin, cephadroxil, cepfodoxime proxetil, nonsteoroidal,
and anti-
inflammatory and analgesic drugs selected from the group consisting of
ibuprofen and
diclofenac sodium and CO~ 2 inhibitors selected from the group consisting of
etoricoxib and
celecoxib, antihistamic drugs selected from the group consisting of
chlorpheniramine
maleate, oxazolidinones selected from the group consisting of linezolid and
other drug like
dextromethorphan.
In yet another embodiment of the invention the drug itself or its
pharmaceutically
acceptable salt or ester or amide is used.
In another embodiment of the invention, the total polymer to drug ratio for
optimal
taste masking bitter drug in the range 30:1 to 0.2:1 by weight. More
preferably the ratio of
the polymer to drug is 5:1 to 0.4:1 by weight.
In still another embodiment of the invention the pH sensitive polymer
solubilizes or
swells in the acidic pH <3 as found in stomach and remains insoluble or de
swelled in the pH
> 3.5.
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In another embodiment of the invention the drug is in the form of
microparticles
dispersed within or coated with the polymer matrix.
Detailed description of the invention
The present invention provides oral pharmaceutical compositions, which
effectively
mask the bitter, unpleasant and otherwise undesirable taste of the active
ingredient. More
specifically the invention relates to the synthesis of the pH sensitive
polymers which can be
used in various pharmaceutical compositions providing taste masking and
substantial
immediate release and absorption of the bitter active ingredient, which is
generally desirable
in case of solid and liquid dosage forms like tablets; chewable or dispersible
and suspensions
or dry syrups. It also relates to the process for preparing such a
composition.
The composition of the present invention is in the form of a taste masked
formulation
providing a substantial immediate release of the bitter active compound due to
the
solubilization or swelling of the reverse enteric polymer in acidic pH of <3
and the
prevention of release of the drug in the pH range of > 3 .5 as found in saliva
and reconstitution
media over the complete period of storage of up to 14 days. The pH sensitive
polymer is
synthesized comprising of essentially of a hydrophobic monomer, a basic
monomer and
optionally a hydrophilic monomer.
An important feature of the present invention is that it provides taste-masked
microcapsules of bitter drugs, suitable for oral administration as a
suspension, a fast-
disintegrating, effervescent or chewable tablet, and more specifically relates
to such oral
dosage forms in which the bitter taste of drugs is masked by a functional
membrane coating
on said microcapsules by pH sensitive polymer. A taste-masked microcapsule
composition
for taste masking an orally effective bitter drug in accordance with the
present invention
comprises microcapsules of the drug in a polymeric coating matrix prepared by
emulsification, solvent evaporation or solvent extraction or by the spray
drying technique.
More specifically the present invention relates to the taste masked liquid
oral formulation like
the dry syrups intended for the pediatric use. It is likewise useful fox
preparations intended for
all patients who, as a result of physical challenge or preference, would
prefer a liquid
preparation. The taste-masked compositions of the invention are further
advantageous in that
the reconstituted liquid preparations made from them are stable over the
normal therapeutic
dosage schedule, typically up to fourteen days.
According to the basic feature of the present invention, taste masking of
bitter drug is
achieved by using a pH sensitive polymeric coating on the bitter drug, wherein
the polymer
essentially solubilizes or swells in the acidic condition of the stomach and
remains insoluble
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WO 2005/055987 PCT/IN2003/000392
or de-swelled at neutral or near neutral pH. The pH sensitive polymer when
applied to the
pharmaceutical dosage forms like, the liquid orals such as dry syrup or
suspension and
tablets; chewable or dispersible, releases the active ingredient in the acidic
pH of the stomach
but maintains the taste palatable, by preventing the leaching of the drug in
pH of saliva or
suspending media or in the near neutral aqueous environment. The said pH
sensitive
polymers are synthesized using monomers essentially from the class of
hydrophobic
monomer and basic monomers and optionally a hydrophilic monomer.
Another aspect of the present invention is to formulate a coated bitter drug
in the form
of suspensions and prevent leaching of the drug in suspending media during
reconstitution
period of up to 14 days, and also ensure substantial release of active drug in
the simulated
gastric fluid without compromising on bioavailability. pH sensitive polymers
of the present
invention inhibit the release of the active agent in the aqueous media of pH
>3 .5 such that the
leaching of bitter drug in the saliva and also in the reconstitution media, in
case of liquid orals
is inhibited and release the drug rapidly in the pH range of <3 as found in
the stomach.
The present invention also provides for the taste masking of bitter drugs like
macrolide antibiotics such as erythromycin, azithromycin and cl~,rithromycin,
fluroquinolones such as ciprofloxacin, enrofloxacin, ofloxacin, gatifloxacin,
levofloxacin and
norfloxacin, cephalosporins such as cefuroxime, cephalexin, cephadroxil,
cepfodoxime
proxetil, nonsteoroidal and anti-inflammatory and analgesic drugs such as
ibuprofen,
diclofenac sodium and COX 2 inhibitors like etoricoxib and eelecoxib,
antihistamic drugs
like chlorpheniramine maleate, oxazolidinones like Iinezolid and other drug
like
dextromethorphan. The drug itself or its pharmaceutically acceptable salt or
ester or amide
may be used in the present invention. The drugs preferred for the practice of
present
invention can be chosen from a wide range comprising cefuroxime axetil,
ciprofloxacin,
celecoxib and clarithromycin. The pharmaceutical composition described herein
has the total
polymer to drug ratio for optimal taste masking bitter drug in the range 30:1
to 0.2:1 by
weight. More preferably the ratio of the polymer to drug is 5:1 to 0.4:1 by
weight.
In particular, the invention comprises development of a formulation useful as
a stable
taste-masking liquid suspension capable of being ingested without producing
the unpleasant
taste associated with the active agent, while still providing immediate
bioavailability upon
exposure to the pH levels found in the stomach of a human.
In another feature the taste-masked particles obtained as described in the
invention are
optionally blended with other pharmaceutically acceptable excipients such as
flavors,
sweeteners, suspending agents and / or preservatives and formulated as dry
syrup or
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WO 2005/055987 PCT/IN2003/000392
compressed into fast disintegrating, effervescent or chewable tablets. Stable
aqueous
suspensions can be constituted from the dry syrup powder for oral
administration up to 14
days for pediatric and geriatric patients who are unwilling and / or find it
difficult to swallow
tablets. Fast disintegrating tablets rapidly disintegrate in the mouth and are
therefore suitable
for oral administration to patients who find it difficult to swallow tablets.
Such dosage forms
on oral administration should release not more than 10%, most preferably not
more than 5%,
at pH of reconstitution media up to 14 days but rapidly release at least 40-
60% within 15 min
and not less than 70 % in an hour at pH as found in the stomach.
The mean particle size of the microcapsules will be in the range of about 30
to 1000
microns, most preferably in the range of about 100 to 500 microns.
Examples of the bitter, unpleasant tasting drugs which may be used include,
but are
not limited to macrolide antibiotics such as erythromycin azithromycin and
clarithromycin,
fluroquinolones such as ciprofloxacin enrofloxacin, ofloxacin, gatifloxacin,
levofloxacin and
norfloxacin, cephalosporins such as cefuroxime, cephalexin, cephadroxil,
cepfodoxime
proxetil nonsteoroidal and anti-inflammatory and analgesic drugs such as
ibuprofen,
diclofenac sodium and COX 2 inhibitors like celecoxib and etoricoxib,
antihistamic drugs
like ' chlorpheniramine maleate, oxazolidinones like linezolid and other drug
like
dextromethorphan.
Various derivatives of polymethacrylates and cellulose polymers have been used
in
the past to coat antibiotic drug cefuroxime axetil. The release profile of the
drug from these
materials depends on the type of polymer being used for the coating. The
patent W00236126
discloses a sustained release of cefuroxime axetil from the composition
comprising of
eudragit L 30 D, eudragit RL 30 D and Eudragit RS 30D.The release of
cefuroxime axetil in
0.07N HCl for lhr and phosphate buffer of pH 6.8 is disclosed as follows:
Time : 60 min 120 min 180 min 240 min 3 60 min
release: 34.6 44.3 67.4 83.7 96.1
Alonso disclosed the release of cefuroxime axetil from the microparticles
obtained
using the polymeric coating of Eudragit E, Eudragit L100-55 and eudragit RL-
100. (M. J.
Alonso, M.L Lorenzo-Lamosa, M.Cuna, J. L. Vila-Jato and D. Torres, Journal of
Microencapsulation, 1997, Volume 14, No.S, 607-616)..The release of cefuroxime
axetil was
almost complete from eudragit E microspheres in 0.07 N HCl in 20 -30 min.. The
release
from the eudragit E microsphere in Sorensens buffer pH 7 was found to be slow
as compared
to the 0.07 N HCI. The release data are summarized below
CA 02549572 2006-06-14
WO 2005/055987 PCT/IN2003/000392
Media 0.07 N HCL
Time : IO min to 20 min
release: upto 80 to 100
Media pH 5.8 Sorensens buffer
Time : 10 min 20 min 30 min 40 min 50 min 60 min
release: upto 20 30 40 45 50 60
The cationic Polymer eudragit E however showed a negative interaction with
cefuroxime axetil showing a significant degradation in presence of Eudragit E.
The
microspheres using eudragit L 55 and RL showed a release of < 9 % in 2 hrs in
pH 5.2 and a
significant amount of 75% released in 30min at pH 6Ø
M.Cuna et.al discloses the coating of cefuroxime axetil for taste masking (M.
Cuna,
M.L. Lorenzo, J.L. Vila Jato, D. Torres, M.J. Alonso, Acta Technologiae et
Legis
Medicaments. volume VII, N.3, 1996) using different polymeric materials like
cellulose
acetate trimellitate, HPMCP-S0, HPMCP-55. The release data:are summarized
below
(microspheres with HPMCP-55) At pH 5.2
Time : 15 min to 60 min
release: less than 25%
(microspheres with HPMCP-55) At pH 6.0
Time : 15 min 3 0 min
% release: 50 -75 75- 100
In the above disclosures the release of cefuroxime axetil was studied in the
basic
media whereas Dantzig et al (Anne H. Dantzig, Dale C. Duckworth, Linda B.
Tabas,
Biochsmica et Biophysica Acta 1191, 1994, 7-13) showed that cefuroxime axetil
is
hydrolyzed to cefuroxime in the intestinal lumen by the esterases reducing the
cefuroxime
axetil concentration in the lumen and resulting in reduced absorption, leading
to low
bioavailability of Cefuroxsme axetil in humans.
The drug molecules like cefuroxiine axetsl tend to gel in presence of the
aqueous
media. Also if the tablets are not protected from moisture during storage,
they result in poor
dissolution and lower drug bioavailability. So the liquid oral preparation of
cefuroxime axetil
needs to protect the drug during the reconstitution period from the aqueous
environment.
Cefuroxime axetil has a limited absorption region in the gastrointestinal
tract as the enzyme
esterases, hydrolyses it to cefuroxime, which cannot be absorbed across the
tract thereby
reducing its bioavailability. Cefuroxime axetil is also associated with an
extremely bitter
taste. The pharmaceutical compositions of cefuroxime axetil are therefore
required to be taste
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WO 2005/055987 PCT/IN2003/000392
masked. The use of water soluble and enteric coating polymers for Cefuroxime
axetil are
therefore of limited use. Tn the preferred embodiment of the present invention
the bitter drugs
used for taste masking include cefuroxime axetil, ciprofloxacin hydrochloride
and
clarithromycin. One of the feature of the present invention is fast swelling
and / or dissolution
of the polymer in acidic pH, with rapid release of drug, like cefuroxime
axetil which have a
low bioavailability of 32-50 %, from the polymer coating and thus should not
cause any delay
in the absorption and alter the bioavailability. The release of the drugs form
the polymers
used in the present invention is disclosed in the examples.
In another feature of the present invention the pharmaceutical composition may
be
obtained by coating of the drug using of pH sensitive polymer either by
microencapsulation,
spray drying, fluid bed processing, co-precipitation in a non solvent or by
tray drying method.
The drug is dispersed within the polymer matrix.
In still another feature the taste masking, compositions are made by
microencapsulation of the drug in the polymer matrix. The microencapsulation
of the bitter
drugs can be obtained by emulsification, solvent evaporation or solvent
extraction and spray
drying of the drug polymer solution or dispersion of drug in polymer solution.
If the drug is
not soluble in the polymer solution then it is dispersed in the polymer
solution uniformly with
the help of the dispersing agents like the surfactants. The preferred
surfactants are the
nonionic surfactants belonging to the class of SPAN and TWEEN. Preferably the
solvent is
selected such that the drug and the polymer are both soluble in the solvent.
In the preferred
embodiment of the present invention the solvents chosen for the solubilization
of the drug
and polymer are alcohols like methanol, ethanol, isopropanol, butanol,
chlorinated
hydrocarbons like dichloromethane, chloroform, ketones like methyl ethyl
ketone, methyl
iso-butyl ketone and acetone. Preferably the solvents used to dissolve the
drug and polymers
are methanol, acetone and dichloromethane. The preferred solvent to dissolve
the drug and
polymer is acetone or a mixture of methanol and dichloromethane, in the ratio
1:1 to 1: 1.5.
The taste-masked microcapsules of the bitter drug can be obtained by
micro~encapsulation by emulsification solvent evaporation technique. The
dispersed phase is
the organic solvent containing the drug and polymer and the dispersion medium
is the liquid
paraffin. The pH sensitive polymer synthesized is dissolved in the organic
solvent (acetone,
methanol, dichloromethane or a mixture of methanol and dichloromethane in the
ratio 1:1 to
1: 1.5.) The drug is added to the polymer solution resulting in a solution or
a homogeneous
dispersion. The organic phase is then added into the light liquid paraffin-
containing span 85
(0.1 to 1 % w/w). A constant mechanical stirring rate of 1000 rpm and at room
temperature is
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WO 2005/055987 PCT/IN2003/000392
maintained fox a 3-4 hours. The solvent is allowed to evaporate and the
microspheres so
obtained are separated by filtration, washed by petroleum ether or by n hexane
and dried
under vacuum for up to 24 hours.
The taste-masked microcapsules of the bitter drag can be further obtained by
S microencapsulation by emulsification solvent extraction technique. The
dispersed phase is the
organic solvent containing the drug and polymer and the dispersion medium is
the liquid
paraffin. The pH sensitive polymer synthesized is dissolved in the organic
solvent (acetone,
methanol, dichloromethane or a mixture of methanol and dichloromethane in the
ratio 1:1 to
1: 1.5.). The drug is added to the polymer solution resulting in a solution or
a homogeneous
dispersion. The organic phase is then added into the light liquid paraffin-
containing span 85
(0.1 to 1 % w/w). A constant mechanical stirring rate of 500 rpm and 25
° G is maintained for
30 min and 40 ml of n hexane or cyclohexane is added at a rate of 5 mI /min,
followed by
another 40 ml n hexane or cyclohexane being added rapidly. The agitation is
maintained for
another 10 - 15 min then the microparticles are separated by filtration and
washed by
petroleum ether or by n hexane and dried at 27°G under vacuum for up to
24 hours.
Alternately the taste masked micro particles can be obtained by spray drying.
The
drug - polymer solution or dispersion in the organic solvent is spray dried to
obtain the taste
masked micro particles. The drying gas can be an inert gas such as nitrogen,
argon and
carbon dioxide or air. The preferred gas in the present invention is air. The
gas inlet
, temperature to the spray dryer depends on the choice of the solvent used but
may be in the
range of 35 - 150°C preferably 40 -60°C. The gas outlet
temperature is similarly dependant
on the solvent but may be in the range of 25 to 50, preferably 25 to
40°C. The polymer is
solubilized in methanol or a mixture of methanol and dichloromethane 1: 1 and
the drug is
either solubilized or dispersed in the polymer solution. The resulting mixture
is spray dried to
obtain the taste masked micro particles.
The taste masked particles and granules obtained may be mixed with the
flavoring
agents such as natural or artificial flavors, citric and tartaric acids,
sweeteners such as
sucrose, saccharin and aspartame, and other pharmaceutically acceptable
excipients to be
formulated as conventional whole, chewable or dispersible tablets, dry syrups,
suspensions,
sachets or any other suitable oral dosage form.
The present invention is more directed towards the taste masking of the liquid
oral
compositions suitable for the pediatric patients or those, who have a
difficulty in swallowing
the solid dosage form. The taste masked pharmaceutical composition is prepared
by
reconstitution of the polymer coated drug particles in a liquid vehicle
comprising sucrose,
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WO 2005/055987 PCT/IN2003/000392
flavor and citric acid and a suspending agent like cellulose derivatives or
polyvinyl
pyrrolidone or xanthan gum etc. The taste masked pharmaceutical composition of
the present
invention is prepared by using the reconstitution medium of pH 4.5 comprising
of sucrose,
tutti- frutti flavor, citric acid and polyvinyl pyrrolidone.
The taste masked pharmaceutical compositions as exemplified in the examples 1
to 12
given below were tested for the drug release with respect to time. Cefuroxime
axetil release
from the taste masked particles was determined in 900 ml of 0.07 N
hydrochloric acid, at 37
+ 0.5 °C, using USP type II apparatus rotated at 100 rpm. The samples
were withdrawn at 15,
30, 4S, 60 and 90 min. The amount withdrawn each time was replaced with fresh
media to
maintain the sink conditions.
Ciprofloxacin hydrochloride release from the taste masked particles was
determined
in 900 ml of 0.1 N hydrochloric acid buffer, at 37 + 0.5°C, using USP
type IT apparatus
rotated at 100 rpm. The samples were withdrawn at 15, 30, 45, and 60, min. The
amount
withdrawn each time was replaced with fresh media to maintain the sink
conditions.
Clarithromycin release from the taste masked particles was determined in 900
ml of
acetate buffer pH 2.8, at 37 + 0.5°C, using USP type II apparatus
rotated at 100 rpm. The
samples were withdrawn at 15, 30, 45 and 60 min. The amount withdrawn each
time was
replaced with fresh media to maintain the sink conditions.
Celecoxib release from taste masked particles was determined by placing
composition
consisting of celecoxib and polymer in 0.1 N HCl 100m1 for 30 min and then
addition of
900m1 of 0.1 N NaOH solution, at 37 + 0.5 °C, using USP type II
apparatus rotated at 100
rpm. Samples were withdrawn from 0.1 N NaOH solution at 1S, 30, 45 and 60 min.
Amount
withdrawn each time was replaced with fresh media to maintain sink conditions.
Taste making compositions and properties thereof are described below with
reference
to illustrative examples which should not be construed to limit the scope of
the present
invention in any manner.
Example 1
Taste masked microcapsules were obtained by emulsification solvent evaporation
technique. 3.50 g of ciprofloxacin was dispersed in polymer solution
containing 900 mg of
polymer in 45 ml of mixture of methanol and dichloromethane (1: 1). The
polymer has the
monomer composition Methyl methacrylate 60 % by weight Hydroxyethyl
methacrylate 25
by weight and Vinyl Pyridine 15% by weight. The nonionic surfactant Span 85
was added
0.5% w/w to facilitate the dispersion of ciprofloxacin in the polymer
solution. The dispersion
of ciprofloxacin was added dropwise to the bath of light liquid paraffin under
mechanical
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WO 2005/055987 PCT/IN2003/000392
stirring. A constant mechanical stirring rate of 1000 rpm and at room
temperature was
maintained for a 3-4 hours. Solvent was allowed to evaporate and the
microspheres so
obtained were separated by filtration, washed by petroleum ether and dried at
27 °C under
vacuum for 24 hours. Drug release pattern of the composition prepared was
studied and
results are tabulated in Table-1. Results in Table -1 show the immediate
release of the drug.
Table -1
Time min % Release
86.58
30 91.57
45 96.85
10 Example 2
Taste-masked microcapsules of the bitter drug were obtained by
microencapsulation
by emulsification solvent evaporation technique. 2.35 g of ciprofloxacin was
dispersed in
polymer solution containing 7.0 g of polymer in 40 ml of mixture of methanol
and
dichloromethane (1:1). The polymer has the monomer composition Methyl
methacrylate 60
15 % by weight Hydroxyethyl methacrylate 25 % by weight and Vinyl Pyridine 15%
by weight.
The microencapsulation of the ciprofloxacin with the pH sensitive polymer was
achieved
using the method similar as mentioned in the example 1.- The drug release
pattern of the
composition prepared was studied and the results are tabulated in Table-2
Table 2
y
Time min % Release
15 61.45
30 68.30
45 74. 56
60 81.42
Example 3
Taste masked microcapsules were obtained by microencapsulation by
emulsification
solvent evaporation technique. 2.0g of clarithromycin was dissolved in polymer
solution
containing 4.0g of polymer in 40m1 of mixture of methanol and dichloromethane
(1: 1). The
polymer has the monomer composition Methyl methacrylate 60% by wt Hydroxyethyl
methacrylate 25% by wt and Vinyl Pyridine 15% by wt. Microencapsulation of
clarithromycin with pH sensitive polymer was achieved using a method similar
to that of
example 1. Drug release pattern of composition prepared was studied and
results are
tabulated in Table 3.
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Table 3
Time min % Release
15 48.20
30 65.51.
45 72.80
60 82.59
Example 4
Taste masked microcapsules were obtained by microencapsulation by
emulsification
solvent evaporation technique. 2.0g of clarithromycin was dissolved in polymer
solution
containing 1.2g of polymer in 30m1 of mixture of methanol and dichloromethane
(l: 1). The
polymer has the monomer composition Methyl methacrylate 60% by wt,
Hydroxyethyl
methacrylate 25% by wt and Vinyl Pyridine 15% bywt. Microencapsulation of
clarithromycin with pH sensitive polymer was achieved using a method similar
to that of
example 1. Drug release pattern of composition prepared was studied and
results are
tabulated in Table 4
Table 4
Time min % Release
15 53.97
3 0 69.40
45 76.32
60 85.59
Example 5
Taste masked microcapsules of cephalosporin antibiotic cefuroxime axetil were
obtained by microencapsulation by emulsification solvent evaporation
technique. 2.0g of
cefuroxime axetil was dissolved in polymer solution containing 6.0g of polymer
in 40m1 of
mixture of methanol and dichloromethane (1: 1). The polymer has the monomer
composition
Methyl methacrylate 43% by wt Hydroxyethyl methacrylate 42% by wt and Vinyl
Pyridine
15% by wt. Microencapsulation of cefuroxime axetil with pH sensitive polymer
was achieved
using a method similar to that of example 1. Drug release pattern of
composition prepared
was studied and results are tabulated in Table-5
Table 5
Time min % Release
15 95.2
30 97.2
Taste masked pharmaceutical composition of microcapsules prepared in example 5
is
prepared for microparticles having drug equivalent to 4 doses by using
reconstitution medium
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WO 2005/055987 PCT/IN2003/000392
of pH 4.5 comprising of sucrose 85 % w/v, tutti- frutti flavor qs., citric
acid qs. and polyvinyl
pyrrolidone 2%. The drug release during the storage for 7 days is shown in the
table 6
Table 6
Da % Release
2 0.26
3 0.31
4 0.38
0.50
6 0.60
7 0.68
5 Example 6
Taste masked microcapsules of cefuroxime axetil were obtained by
microencapsulation by emulsification solvent evaporation technique. 2.0 g of
cefuroxime
axetil was dissolved in polymer solution containing 6.0 g of polymer in 40 ml
of mixture of
methanol and dichloromethane (l: 1). The polymer has the monomer composition
Methyl
methacrylate 60 % by weight, Hydroxyethyl methacrylate 25 % by weight and
Vinyl Pyridine
15% by weight. The microencapsulation of cefuroxime axetil with the pH
sensitive polymer
was achieved using the method similar as mentioned in the example 1. The drug
release
pattern of the composition prepared was studied and the results axe tabulated
in Table-7
Table 7
Time min % Release
15 78.72
30 80.52
45 88.2
60 95.12
Taste masked pharmaceutical composition of microcapsules prepared in example 6
is
prepaxed for micropaxticles having drug equivalent to 4 doses by using
reconstitution medium
of pH 4.5 comprising of sucrose 85 % w/v, tutti- frutti flavor qs., citric
acid qs. and polyvinyl
pyrrolidone 2%. The drug release during the storage for 7 days is shown in the
table 8
Table 8
Day % Release
2 0.25
3 0.27
4 0.38
5 0.45
6 0.57
7 0.64
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Example 7
Taste masked microcapsules of the bitter cephalosporin antibiotic cefuroxime
axetil
were obtained by microencapsulation by emulsification solvent evaporation
technique. 2.0 g
of cefuroxime axetil was dissolved in polymer solution containing 6.0 g of
polymer in 40 ml
of mixture of methanol and dichloromethane (1: 1). The polymer has the monomer
composition Methyl methacrylate 70 % by weight and Vinyl Pyridine 30% by
weight. The
microencapsulation of the cefuroxime axetil with the pH sensitive polymer was
achieved
using the method similar as mentioned in the example 1. The drug release
pattern of the
composition prepared was studied and the results are tabulated in Table-9
Table 9
Time min % Release
15 92.7
30 96.2
45 97.3
Taste masked pharmaceutical composition of microcapsules prepared in example 7
is
prepared for microparticles having drug equivalent to 4 doses by using
reconstitution medium
of pH 4.5 comprising of sucrose 85 % w/v, tutti- frutti flavor qs., citric
acid qs. and polyvinyl
pyrrolidone 2%. The drug release during the storage for 7 days is shown in the
table 10
Table 10
Da % Release
2 0.76
3 1.32
4 1.71
5 1.73
6 2.10
7 2.14
Example 8
Taste masked microcapsules of the bitter cephalosporin antibiotic cefuroxime
axetil
were obtained by microencapsulation by emulsification solvent evaporation
technique. 2.0 g
of cefuroxime axetil was dissolved in polymer solution containing 6.0 g of
polymer in 40 ml
of mixture of methanol and dichloromethane (1: 1). The polymer has the monomer
composition Methyl methacrylate 35 % by weight, Hydroxyethyl methacrylate 35 %
by
weight and Vinyl Pyridine 30% by weight. The microencapsulation of the
cefuroxime axetil
with the pH sensitive polymer was achieved using the method similar as
mentioned in the
example 1. The drug release pattern of the composition prepared was studied
and the results
are tabulated in Table- 11
23
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Table 11
Time min % Release
15 91.85
30 95.38
45 97.53
Example 9
The cefuroxime axetil - polymer solution in the organic solvent was spray
dried to
obtain the taste masked micro particles. The polymer has the monomer
composition Methyl
methacrylate 60 % by weight Hydroxyethyl methacrylate 25 % by weight and 4
Vinyl
pyridine 15% by weight of polymer .The drying gas was air. The inlet air
temperature to the
spray dryer was in the range 40 - 70° C. The outlet air temperature was
in the range of 25 to
60 °C. The polymer weighing 2.4 g was solubilized in the mixture of
methanol and
dichloromethane 1; l and cefuroxime axetil weighing 4.8 g was added in the
polymer
solution. The atomization was in the range of 1 - 2 kg. The feed rate was 20
to 85 rpm .The
resulting solution was spray dried to obtain the taste masked micro particles.
The drug release
pattern of the composition prepared was studied and the results are tabulated
in Table-12
Table 12
Time min % Release
15 53.47
3 0 69.97
45 84.47
60 91.72
90 ~ 93.18
Taste masked pharmaceutical composition of microcapsules prepared in example 9
is
prepared for microparticles having drug equivalent to 5 doses by using
reconstitution medium
of pH 4.5 comprising of sucrose 85 % w/v, tutti- frutti flavor qs., citric
acid qs. and polyvinyl
pyrrolidone 2%. The drug release during the storage for 7 days is shown in the
table 13
Table 13
Da % Release
2 0.96
3 1.43
4 1.92
5 2.57
6 2.~8
3.44
24
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Example 10
The cefuroxime axetil - polymer solution in the organic solvent was spray
dried to
obtain the taste masked micro particles. The polymer has the monomer
composition Methyl
methacrylate 60 % by weight Hydroxyethyl methacrylate 25 % by weight and 4
Vinyl
pyridine 15% by weight of polymer .The solvent used was a mixture of methanol
and
dichloromethane l: 1. The drying gas was air. The inlet air temperature to the
spray dryer was
in the range 40 - 70° C. The outlet air temperature was in the range of
25 to 60 °C. The
polymer weighing 2.4 g was solubilized in the in the mixture of methanol and
dichloromethane l: 1 and cefuroxime axetil weighing 4.8 g was added in the
polymer
solution. The atomization was in the range of 1 - 2 kg. The feed rate was 20
to 85 rpm .The
resulting solution was spray dried to obtain the taste masked micro particles.
The drug release
pattern of the composition prepared was studied and the results are tabulated
in Table-14
Table 14 _
Time min % release
15 72.58
30 85.41
45 89.48
60 93.8
90 94.58
The taste masked pharmaceutical composition of the microcapsules prepared in
example 10 is prepared for microparticles having the drug equivalent to 5
doses by using the
reconstitution medium of pH 4.5 comprising of sucrose 85 % w/v, tutti- frutti
flavor qs., citric
acid qs. and polyvinyl pyrrolidone 2%. The drug release during the storage for
7 days is
shown in the table 15
Table 15
Da % Release
2 0.85
3 1.36
4 2.26
5 3.0
6 3.44
7 3.84
Example 11
The celecoxib - polymer solution in the organic solvent was spray dried to
obtain the
taste masked micro particles. The polymer has the monomer composition Methyl
methacrylate 60 % by weight Hydroxyethyl methacrylate 25 % by weight and 4
Vinyl
pyridine 15% by weight of polymer .The solvent used was a mixture of methanol
and
CA 02549572 2006-06-14
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dichloromethane (1.5: 1). The drying gas was air. The inlet air temperature to
the spray dryer
was in the range 40 - 70° C. The outlet air temperature was in the
range of 25 to 60 °C. The
polymer weighing 1.5 g was solubilized in mixture of methanol and
dichloromethane ( 1. 5 : 1 )
and celecoxib weighing 2.0 g was added in the polymer solution. The
atomization was in the
range of 1 - 2 kg. The feed rate was 20 to 85 rpm .The resulting solution was
spray dried to
obtain the taste masked micro particles. The drug release pattern of the
composition prepared
was studied and the results are tabulated in Table-16
Table 16
Time min % Release
15 86.8
30 94.0
Example 12
The celecoxib - polymer solution in the organic solvent was spray dried to
obtain the
taste masked micro particles. The polymer has the monomer composition Methyl
methacrylate 60 % by weight Hydroxyethyl methacrylate 25 % by weight and 4
Vinyl
pyridine 15% by weight of polymer .The solvent used was a mixture of methanol
and
dichloromethane (1.5: 1). The drying gas was air. The inlet air temperature to
the spray dryer
was in the range 40 - 70° C. The outlet air temperature was in the
range of 25 to 60 °C. The
polymer weighing 0.750 g was solubilized in the mixture of methanol and
dichloromethane
(1.5: 1) and celecoxib weighing 2.0 g was added in the polymer solution. The
atomization is
in the range of 1 - 2 kg. The feed rate was 20 to 85 rpm .The resulting
solution was spray
dried to obtain the taste masked micro particles. The drug release pattern of
the composition
prepared was studied and the results are tabulated in Table-17
Table 17
Time min % Release
15 73.45
3 0 93 .74
26
