EXTENDED RELEASE SUSPENSION COMPOSITIONS
Field of the Invention
The present invention relates to extended release suspension compositions of an
active ingredient. Said extended release suspension compositions comprise multiple
coated cores of t e active ingredient and a suspension base, wherein t e suspension base
generates a hypertonic condition such that there is no substantial change in the in-vitro
dissolution release profile of the extended release suspension compositions upon storage
for at least seven days. The invention also relates to processes for the preparation of said
extended release suspension compositions.
Background of the Invention
Extended release solid compositions are preferred dosage forms over immediate
release solid compositions, especially for active ingredients showing fluctuations in the
plasma concentration and for active ingredients having short half-lives. Extended release
solid compositions can be in the form of tablets or capsules, wherein the release of the
active ingredient is controlled by using a reservoir or a matrix system. However, extended
release solid compositions suffer from certain drawbacks such as difficulty in swallowing,
particularly for certain groups of patients, e.g., pediatrics and geriatrics, resulting in poor
patient compliance. Further, high doses of active ingredient lead to large-sized
compositions which aggravates this problem. Also, there remains a tendency to divide
extended release solid compositions such as tablets into small pieces in order to facilitate
administration, which may ultimately lead to inaccurate dosing and/or dose dumping. In
view of all this, extended release liquid compositions provide the best alternative over
extended release solid compositions. Extended release liquid compositions are easy to
administer, thereby leading to enhanced patient compliance. Additionally, extended
release liquid compositions provide a unique advantage of having a flexible dosing
regimen.
Although extended release liquid compositions are advantageous, there remain
some complexities involved in formulating such compositions. The important prerequisite
of these compositions is to provide the desired extended release of the active ingredient
throughout its shelf life, as irregular release may lead to sub-therapeutic or toxic effects.
The key hurdle remains to avoid the release of the active ingredient into the suspension
base during storage, and to allow release only when the suspension enters the stomach.
The prior art discloses various approaches for the preparation of extended release
liquid compositions.
U.S. Patent No. 6,156,340 discloses a controlled release suspension comprising
inert cores coated with an active ingredient, which were further coated with two layers of
polymers with increased permeability to water.
U.S. Patent No. 7,906,145 discloses a sustained release suspension of
microcapsules in an aqueous liquid phase, wherein each microcapsule comprises a core of
an active ingredient and a film coating applied to the core which controls the modified
release of the active ingredient in gastrointestinal fluids, comprising a film-forming
polymer, a nitrogen-containing polymer, a plasticizer, and a surfactant/lubricant.
PCT Publication No. WO 201 1/107855 discloses a ready to use sustained release
oral suspension comprising inert pellets surrounded by a seal coating, an active ingredient
layer surrounding the seal coated inert pellets, and a coating layer comprising a ratecontrolling
polymer surrounding the active ingredient layer.
PCT Publication No. WO 201 1/07745 1 discloses a controlled release suspension
comprising an active ingredient loaded core and a polymer dispersion comprising a
controlled-release polymer, wherein said suspension has a duration of therapeutic effect
for at least about 6 hours to about 30 hours after oral administration.
PCT Publication No. WO 2008/122993 discloses a suspension of an active
ingredient containing microparticles with at least one coat of a pH-independent polymer.
PCT Publication No. WO 2012/063257 and U.S. Publication No. 2008/01 18570
disclose controlled release suspensions employing ion-exchange resins.
In the formulations disclosed in the prior art, there is a possibility of leaching of
t e active ingredients from the coated units into the media during storage. Further,
although ion-exchange resin systems provide the desired extended release without
significant leaching during storage, these systems require chemical binding of the active
ingredient to the resin, which is complicated and not suitable for many active ingredients.
There remains a need in the art to formulate extended release liquid compositions
of active ingredients which are based on a simplified technology and which provide the
desired extended release throughout the shelf life of the compositions. The present
invention provides such compositions and improves patient compliance by reducing
dosing frequency for pediatric as well as geriatric patients.
The extended release suspension compositions of the present invention are
relatively simple, easy to manufacture, and functionally reproducible. The extended
release suspension compositions provide the desired extended release throughout the shelf
life of the compositions. The scientists of the present invention have surprisingly
discovered that a hypertonic condition generated in the suspension base affects t e
leaching of the active ingredient from t e extended release coated cores into the
suspension base. This hypertonic condition minimizes the leaching problem and thus
provides substantially similar in-vitro extended release of the active ingredient throughout
the shelf life of the compositions. This consistent in-vitro release then ensures a steady
plasma concentration with no fluctuations throughout the shelf life of the compositions.
Additionally, the extended release suspension compositions of the present invention are
able to incorporate two or more active ingredients with different release profiles or two or
more incompatible active ingredients in a single composition.
Summary of the Invention
The present invention relates to extended release suspension compositions of an
active ingredient. Said extended release suspension compositions comprise multiple
coated cores of the active ingredient and a suspension base, wherein the suspension base
generates a hypertonic condition such that such that there is no substantial change in the
in-vitro dissolution release profile of the extended release suspension compositions upon
storage for at least seven days. The invention also relates to processes for the preparation
of said extended release suspension compositions.
The extended release suspension compositions of the present invention are easy to
administer, thereby leading to enhanced patient compliance. Further, said extended
release suspension compositions provide better dose flexibility depending on the age and
body weight of the patient. Also, said extended release suspension compositions are
stable, easy to commercially manufacture, and provide reproducible bioavailability.
Additionally, said extended release suspension compositions provide a pleasant mouth
feel, thereby further enhancing patient compliance.
Brief Description of the Drawings
Figure 1 shows the in-vitro dissolution release on day 0, day 30, and day 66 of the
extended release suspension composition prepared according to Example 4 upon storage at
room temperature. This figure also shows the in-vitro dissolution release on day 0, day
36, and day 66 of the extended release suspension composition (at room temperature)
formed after reconstituting the powder stored for one month at accelerated conditions.
Figure 2 shows the in-vitro dissolution release on day 0 and day 30 of the extended
release suspension composition prepared according to Example 5 upon storage at room
temperature. This figure also shows the in-vitro dissolution release on day 0 and day 32 of
the extended release suspension composition (at room temperature) formed after
reconstituting t e powder stored for three months and six months at accelerated
conditions.
Figure 3 shows the in-vitro dissolution release on day 0 and day 30 of the extended
release suspension composition prepared according to Example 6 upon storage at room
temperature. This figure also shows the in-vitro dissolution release on day 0 and day 30 of
the extended release suspension composition (at room temperature) formed after
reconstituting the powder stored for one month at accelerated conditions.
Detailed Description of the Invention
A first aspect of the present invention provides an extended release suspension
composition comprising:
(a) multiple coated cores comprising:
(i) a core comprising an active ingredient; and
(ii) a coating layer over said core comprising one or more releasecontrolling
polymers;
(b) a suspension base, wherein the suspension base generates a hypertonic
condition such that there is no substantial change in the in-vitro dissolution release
profile of the extended release suspension compositions upon storage for at least
seven days.
A second aspect of the present invention provides an extended release suspension
composition comprising:
(a) multiple coated cores comprising:
(i) a core comprising an active ingredient; and
(ii) a coating layer over said core comprising one or more releasecontrolling
polymers;
(b) a suspension base, wherein the composition is characterized by having an
osmolality ratio of at least about 1„ and wherein there is no substantial change in
the in-vitro dissolution release profile of the extended release suspension
compositions upon storage for at least seven days.
According to another embodiment of the above aspect, the suspension base has an
osmolality of not less than about 1 osmol/kg of the suspension base, and in particular not
less than about 2 osmol/kg of the suspension base. In another aspect, the suspension base
comprises an osmogent.
According to another embodiment of the above aspect, the extended release
suspension composition is in the form of a suspension or a reconstituted powder for
suspension.
According to another embodiment of the above aspect, the release-controlling
polymer is selected from t e group comprising a pH-dependent polymer, a pHindependent
polymer, or mixtures thereof.
According to another embodiment of the above aspect, the core is in the form of a
bead, a pellet, a granule, a spheroid, or the like.
According to another embodiment of the above aspect, the active ingredient is
layered onto an inert particle to form the core.
A third aspect of the present invention provides a process for the preparation of an
extended release suspension composition, wherein the process comprises the steps of:
(i) preparing cores comprising an active ingredient and one or more
pharmaceutically acceptable excipients;
(ii) dissolving/dispersing a release-controlling polymer and one or more
pharmaceutically acceptable coating additives in a suitable solvent;
(iii) applying the coating composition of step (ii) over the cores of step (i);
(iv) dissolving one or more osmogents and pharmaceutically acceptable excipients
into a pharmaceutically acceptable vehicle to form a suspension base; and
(v) dispersing the coated cores of step (iii) in the suspension base of step (iv) to
obtain the extended release suspension composition.
A fourth aspect of the present invention provides a process for the preparation of
an extended release suspension composition, wherein the process comprises the steps of:
(A) preparing a powder for suspension comprising the steps of:
(i) preparing cores comprising an active ingredient and one or more
pharmaceutically acceptable excipients;
(ii) dissolving/dispersing a release-controlling polymer and one or more
pharmaceutically acceptable coating additives in a suitable solvent;
(iii) applying the coating composition of step (ii) over the cores of step (i);
(iv) mixing one or more pharmaceutically acceptable excipients with the
coated cores of step (iii) to obtain the powder for suspension;
(B) preparing a suspension base by dissolving/dispersing one or more
osmogents and pharmaceutically acceptable excipients into a pharmaceutically
acceptable vehicle; and
(C) reconstituting the powder for suspension of step (A) with a suspension base
of step (B) to obtain the extended release suspension composition.
A fifth aspect of the present invention provides a process for t e preparation of an
extended release suspension composition, wherein the process comprises the steps of:
(A) preparing a powder for suspension comprising the steps of:
(i) preparing cores comprising an active ingredient and one or more
pharmaceutically acceptable excipients;
(ii) dissolving/dispersing a release-controlling polymer and one or more
pharmaceutically acceptable coating additives in a suitable solvent;
(iii) applying t e coating composition of step (ii) over the cores of step (i);
(iv) mixing one or more osmogents and one or more pharmaceutically
acceptable excipients with the coated cores of step (iii) to obtain the
powder for suspension; and
(B) reconstituting the powder for suspension of step (A) with a
pharmaceutically acceptable vehicle to obtain the extended release suspension
composition.
A sixth aspect of the present invention provides the use of a suspension base for
the preparation of an extended release suspension composition comprising multiple cores
of active ingredient coated with a release-controlling polymer, wherein the suspension
base generates a hypertonic condition such that there is no substantial change in the invitro
dissolution release profile of the extended release suspension compositions upon
storage for at least seven days.
A seventh aspect of the present invention provides the use of a suspension base for
the preparation of an extended release suspension composition comprising multiple cores
of active ingredient coated with a release-controlling polymer, wherein the composition is
characterized by having an osmolality ratio of at least about 1, and wherein there is no
substantial change in the in-vitro dissolution release profile of the extended release
suspension compositions upon storage for at least seven days.
According to one embodiment of the above aspects, the suspension base comprises
an osmogent.
According to another embodiment of the above aspects, the composition is a
suspension or a reconstituted powder for suspension.
The term "extended release," as used herein, refers to the release profile of the
active ingredient over an extended period of time, e.g., over a period of 4, 6, 8, 12, 24
hours, or more.
The term "hypertonic condition," as used herein, means the suspension base has
higher solute concentration which helps to generate high osmotic pressure such that there
is no leaching of active ingredient from t e coated cores into the suspension base. In the
present invention, the solutes are osmogents i . e., pharmaceutically acceptable inert watersoluble
compounds that contribute towards generating hypertonic conditions in the
suspension base.
The term "osmolality ratio," as used herein, means the ratio of the osmolality of
the external phase to the osmolality of the internal phase. The external phase herein means
the suspension base without multiple coated cores of the active ingredient. The internal
phase herein means the coated cores of the active ingredient. As the direct measurement of
the osmolality of the internal phase i . e., coated cores is difficult, the osmolality of the
internal phase herein, is represented as the osmolality of a solution which prevents
significant leaching of the active ingredient from the coated cores into the solution. The
leaching of the active ingredient from the coated cores is determined by the difference in
the osmolalities across the coating layer and the absence of any significant leaching from
the coated cores directs that the osmolality of the solution has become equal to the
osmolality of the coated cores. The osmolality ratio of the extended release suspension
compositions of present invention is at least about 1.
The term "osmolality," as used herein, is expressed as number of moles of any
water-soluble compound per kg of a liquid phase. The liquid phase can be a suspension
base or a solution. In the present invention, the osmolality may be measured according to
known methods, such as using a vapor pressure osmometer, a colloid osmometer, or a
freezing point depression osmometer such as Osmomat 030-D or Osmomat 3000, in
particular by a freezing point depression osmometer.
The osmolality of the suspension base of the extended release suspension
compositions of the present invention remains equivalent upon storage for at least seven
days. Particularly, the osmolality of the suspension base measured after one month
remains equivalent to the osmolality of the suspension base measured as soon as
practicable after preparation of the extended release suspension compositions. More
particularly, the osmolality of the suspension base measured after three months or six
months remains equivalent to the osmolality of the suspension base measured as soon as
practicable after preparation of the extended release suspension compositions. The
equivalent osmolality of the suspension base ensures that there is no leaching of the active
ingredient from the coated cores into the suspension base.
The term "stable," as used herein, refers to chemical stability, wherein not more
than 5% w/w of total related substances are formed on storage at 40°C and 75% relative
humidity (R.H.) or at 25°C and 60% R.H. for a period of at least three months to t e extent
necessary for the sale and use of the composition.
The term "inert particle," as used herein, refers to a particle made from a sugar
sphere also known as a non-pareil seed, a microcrystalline cellulose sphere, a dibasic
calcium phosphate bead, a mannitol bead, a silica bead, a tartaric acid pellet, a wax based
pellet, and the like.
The term "about," as used herein, refers to any value which lies within the range
defined by a variation of up to ±10% of the value.
The term "equivalent" as used herein, refers to any value which lies within the
range defined by a variation of up to ±30% of the value.
The term "significant leaching," as used herein means more than 20% of the active
ingredient is leached out from the coated cores into the solution.
The in-vitro dissolution release profile of the extended release suspension
compositions of the present invention upon storage for at least seven days remains
substantially similar to the initial in-vitro dissolution release profile obtained as soon as
practicable after preparation of the extended release suspension compositions.
Particularly, the in-vitro dissolution release profile of the extended release suspension
compositions of the present invention upon storage for at least one month remains
substantially similar to initial in-vitro dissolution release profile obtained as soon as
practicable after preparation of the extended release suspension compositions. More
particularly, the in-vitro dissolution release profile of the extended release suspension
compositions of the present invention upon storage for at least three months remains
substantially similar to initial in-vitro dissolution release profile obtained as soon as
practicable after preparation of the extended release suspension compositions. More
particularly, the in-vitro dissolution release profile of the extended release suspension
compositions of the present invention upon storage for at least six months remains
substantially similar to initial in-vitro dissolution release profile obtained as soon as
practicable after preparation of the extended release suspension compositions. In the
present invention, wide ranges of dissolution methodologies can be utilized for different
active ingredients. These methodologies can be adopted to vary in hydrodynamic
mechanism to simulate in-vivo conditions by using different dissolution apparatuses,
volume of media, pH of media ranging from 1.0 to 7.5, any standard USP buffers with
standard molarity, addition of surfactants, and or enzymes.
The extended release suspension composition of the present invention provides the
consistent in-vivo release which ensures steady and predictable active ingredient release
with minimal inter and intra subject variation throughout the shelf life of the composition.
The term "substantial," as used herein refers to any value which lies within the
range as defined by a variation of up to ±15 from the average value.
The extended release suspension composition of the present invention may be in
t e form of a suspension or a reconstituted powder for suspension. The powder for
suspension may comprise of coated cores of active ingredient or a mixture of coated cores
of active ingredient with a one or more osmogents, and pharmaceutically acceptable
excipients. This powder for suspension may be reconstituted with a pharmaceutically
acceptable vehicle or a suspension base to form an extended release suspension
composition.
The term "suspension base," as used herein, refers to a medium which is used to
suspend the coated cores of the active ingredient or to reconstitute the extended release
powder for suspension of the active ingredient. The suspension base comprises a
pharmaceutically acceptable vehicle, one or more osmogents, and pharmaceutically
acceptable excipients.
The pharmaceutically acceptable vehicle as used herein means an aqueous vehicle.
The diameter of the coated cores of the present invention ranges from about 10 m i
to about 2000 m i, particularly from about 50 m i to about 1000 m i, and more particularly
from about 150 m i to about 500 m i. The finer sizes of the coated cores help in avoiding
grittiness in the mouth and are therefore are more acceptable. The cores of the present
invention may comprise one or more pharmaceutically acceptable excipients such as a
binder, and optionally one more osmogents.
The active ingredient of the present invention includes any active ingredient
belonging to a therapeutic category, including but not limited to antidiabetic, antibiotic,
antimicrobial, analgesic, antiallergic, antianxiety, antiasthmatic, anticancer, antidepressant,
antiemetic, antiinflammatory, anti-Parkinson's, antiepileptic, antitussive, antiviral,
immunosuppressant, diuretic, antimigraine, antihypertensive, hypolipidemics, ant i
arrhythmics, vasodilators, anti-anginals, sympathomimetic, cholinomemetic, adrenergic,
antimuscarinic, neuroleptics, antispasmodic, skeletal muscle relaxants, expectorants, and
drugs for treating attention deficit hyperactive disorder. The active ingredient of the
present invention can be present in the form of a free base or in t e form of
pharmaceutically acceptable salts. Specific examples of active ingredients include but are
not limited to t e group comprising metformin, acarbose, miglitol, voglibose, repaglinide,
nateglinide, glibenclamide, glimepride, glipizide, gliclazide, chloropropamide,
tolbutamide, phenformin, aloglitin, sitagliptin, linagliptin, saxagliptin, rosiglitazone,
pioglitazone, troglitazone, faraglitazar, englitazone, darglitazone, isaglitazone,
zorglitazone, liraglutide, muraglitazar, peliglitazar, tesaglitazar, canagliflozin,
dapagliflozin, remogliflozin, sergliflozin, verapamil, albuterol, salmeterol, acebutolol,
sotalol, penicillamine, norfloxacin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin,
trovafloxacin, gatifloxacin, cefixime, cefdinir, cefprozil, cefadroxil, cefuroxime,
cefpodoxime, tetracycline, demeclocycline hydrochloride, amoxicillin, clavulanate
potassium, azithromycin, losartan, irbesartan, eprosartan, valsartan, irbesartan, diltiazem,
isosorbide mononitrate, ranolazine, propafenone, hydroxyurea, hydrocodone, delavirdine,
pentosan polysulfate, abacavir, amantadine, acyclovir, ganciclovir, valacyclovir,
valganciclovir, saquinavir, indinavir, nelfinavir, lamivudine, didanosine, zidovudine,
nabumetone, celecoxib, mefenamic acid, naproxen, propoxyphene, cimetidine, ranitidine,
albendazole, mebendazole, thiobendazole, pyrazinamide, praziquantel, chlorpromazine,
sumatriptan, bupropion, aminobenzoate, pyridostigmine bromide, potassium chloride,
niacin, tocainide, quetiapine, fexofenadine, sertraline, chlorpheniramine, rifampin,
methenamine, nefazodone, modafinil, metaxalone, morphine, sevelamer, lithium
carbonate, flecainide acetate, simethicone, methyldopa, chlorthiazide, metyrosine,
procainamide, entacapone, metoprolol, propanolol hydrochloride, chlorzoxazone,
tolmetin, tramadol, bepridil, phenytoin, gabapentin, fluconazole, terbinafine, atorvastatin,
doxepine, rifabutin, mesalamine, etidronate, nitrofurantoin, choline magnesium
trisalicylate, theophylline, nizatidine, methocarbamol, mycophenolate mofetil, tolcapone,
ticlopidine, capecitabine, orlistat, colsevelam, meperidine, hydroxychloroquine,
guaifenesin, guanfacine, amiodarone, quinidine, atomoxetine, felbamate, pseudoephedrine,
carisoprodol, venlafaxine, etodolac, chondrotin, lansoprazole, pantoprazole,
esomeprazole, dexlansoprazole, dexmethylphenidate, methylphenidate, sodium oxybate,
or isotretinoin. The dose of any active ingredient depends upon the individual active
ingredient used in the extended release suspension compositions of the present invention.
Further, the extended release suspension compositions of the present invention permit
ready dose titration, i .e., adjusting the dose of the active ingredient based on recommended
dose range and frequency until the desired therapeutic effect is achieved. In particular, the
active ingredients used in t e present invention are active ingredients with a high dose.
The extended release suspension compositions of the present invention may further
include an immediate release component of the active ingredient to have a biphasic or
pulsatile type of release. The immediate release component may be present in the form of
a powder, a pellet, a bead, a spheroid, or a granule. Alternatively, the immediate release
component may be present in the form of an immediate release coating over the coated
cores. The immediate release component may help in providing an immediate therapeutic
effect which could be subsequently followed by an extended therapeutic effect over a
longer duration of time. Depending upon the type of polymer and percentage weight gain
of the coating, the lag between the two phases can be adjusted to get the desired release
profile.
The extended release suspension composition of the present invention may
comprise two or more different active ingredients with different type of release profiles.
One of the active ingredients provides the extended release, whereas another active
ingredient may provide the immediate release or the extended release.
The extended release suspension composition of the present invention may further
comprise two or more incompatible active ingredients present in a single composition.
One of the active ingredients would be present in the form of coated cores providing the
extended release and another incompatible active ingredient may be present in the form of
a powder, a pellet, a bead, a spheroid, or a granule providing the immediate release or the
extended release.
The extended release suspension compositions of the present invention are
homogenous and deliver the desired dose of the active ingredient in every use without any
risk of overdosing or underdosing.
The extended release suspension composition of the present invention has a pH
ranging from about 2 to about 10.
The release-controlling polymers used to form the extended release coating are
selected from a group comprising a pH-dependent polymer, a pH-independent polymer, or
mixtures thereof.
Suitable examples of pH-dependent polymers are selected from the group
comprising acrylic copolymers such as methacryiic acid and methyl methacrylate
copolymers, e.g., E d git L 100 a d Eudragit*' S 100, methaerylic acid and ethyl
acrylate copolymers, e.g., Eud gi L 100-55 and Eudragit L 30 D-55,
dimethylaminoethyl methacrylate and butyl methacrylate and methyl methacrylate
copolymers e.g., Eudragit* E 100, Eudragit* E PC), methyl acrylate and methacrylic acid
and octyl acrylate copolymers, styrene and acrylic acid copolymers, butyl acrylate and
styrene and acrylic acid copolymers, and ethylacrylate-methacrylic acid copolymer;
cellulose acetate phthalate; cellulose acetate succinates; hydroxyalkyl cellulose phthalates
such as hydroxypropylmethyl cellulose phthalate; hydroxyalkyl cellulose acetate
succinates such as hydroxypropylmethyl cellulose acetate succinate; vinyl acetate
phthalates; vinyl acetate succinate; cellulose acetate trimelliate; polyvinyl derivatives such
as polyvinyl acetate phthalate, polyvinyl alcohol phthalate, polyvinyl butylate phthalate,
and polyvinyl acetoacetal phthalate; zein; shellac; or mixtures thereof.
Suitable examples of pH-independent polymers are selected from the group
comprising cellulosic polymers such as ethyl cellulose, methyl cellulose, hydroxyethyl
cellulose, hydroxy-propyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylmethyl
cellulose, and carboxy methylcellulose; acrylic copolymers such as methacrylic acid
copolymers, e.g., Eudragit® RS, Eudragit® RL, Eudragit®NE 30 D; cellulose acetate;
polyethylene derivatives e.g., polyethylene glycol and polyethylene oxide; polyvinyl
alcohol; polyvinyl acetate; gums e.g., guar gum, locust bean gum, tragacanth, carrageenan,
alginic acid, gum acacia, gum arabic, gellan gum, and xanthan gum; triglycerides; waxes,
e.g., Lubritab®, and Gelucires*; lipids; fatty acids or their salts/derivatives; a
mixture of polyvinyl acetate and polyvinyl pyrrolidone, e.g., Kollidon SR; or mixtures
thereof.
The term "osmogent," as used herein, refers to all pharmaceutically acceptable
inert water-soluble compounds that can imbibe water and/or aqueous biological fluids.
Suitable examples of osmogents or pharmaceutically acceptable inert water-soluble
compounds are selected from the group comprising carbohydrates such as xylitol,
mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose,
sucrose, maltose, lactose, dextrose and raffinose; water-soluble salts of inorganic acids
such as magnesium chloride, magnesium sulfate, potassium sulfate, lithium chloride,
sodium chloride, potassium chloride, lithium hydrogen phosphate, sodium hydrogen
phosphate, potassium hydrogen phosphate, lithium dihydrogen phosphate, sodium
dihydrogen phosphate, potassium dihydrogen phosphate, and sodium phosphate tribasic;
water-soluble salts of organic acids such as sodium acetate, potassium acetate, magnesium
succinate, sodium benzoate, sodium citrate, and sodium ascorbate; water-soluble amino
acids such as glycine, leucine, alanine, methionine; urea or its derivatives; propylene
glycol; glycerin; polyethylene oxide; xanthan gum; hydroxypropylmethyl cellulose; or
mixtures thereof. Particularly, the osmogents used in the present invention are xylitol,
mannitol, glucose, lactose, sucrose, and sodium chloride. The term "pharmaceutically
acceptable excipients," as used herein, refers to excipients that are routinely used in
pharmaceutical compositions. The pharmaceutically acceptable excipients may comprise
glidants, sweeteners, suspending agents, anti-caking agents, wetting agents, preservatives,
buffering agents, flavoring agents, anti-oxidants, chelating agents, or combinations
thereof.
Suitable glidants are selected from the group comprising silica, calcium silicate,
magnesium silicate, colloidal silicon dioxide, cornstarch, talc, stearic acid, magnesium
stearate, calcium stearate, sodium stearyl fumarate, hydrogenated vegetable oil, or
mixtures thereof.
Suitable sweeteners are selected from the group comprising saccharine or its salts
such as sodium, potassium, or calcium, cyclamate or its salt, aspartame, alitame,
acesulfame or its salt, stevioside, glycyrrhizin or its derivatives, sucralose, or mixtures
thereof.
Suitable suspending agents are selected from the group comprising cellulose
derivatives such as co-processed spray dried forms of microcrystalline cellulose and
carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxyethyl cellulose,
hydroxypropylmethyl cellulose, methylcellulose, carboxymethyl cellulose and its
salts/derivatives, and microcrystalline cellulose; carbomers; gums such as locust bean
gum, xanthan gum, tragacanth gum, arabinogalactan gum, agar gum, gellan gum, guar
gum, apricot gum, karaya gum, sterculia gum, acacia gum, gum arabic, and carrageenan;
pectin; dextran; gelatin; polyethylene glycols; polyvinyl compounds such as polyvinyl
acetate, polyvinyl alcohol, and polyvinyl pyrrolidone; sugar alcohols such as xylitol and
mannitol; colloidal silica; or mixtures thereof. Co-processed spray dried forms of
microcrystalline cellulose and carboxymethyl cellulose sodium have been marketed under
the trade names Avicel® RC-501, Avicel® RC-581, Avicel® RC-591, and Avicel® CL-61 1.
Suitable anti-caking agents are selected from the group comprising colloidal
silicon dioxide, tribasic calcium phosphate, powdered cellulose, magnesium trisilicate,
starch, or mixtures thereof.
Suitable wetting agents are selected from the group comprising anionic, cationic,
nonionic, or zwitterionic surfactants, or combinations thereof. Suitable examples of
wetting agents are sodium lauryl sulphate; cetrimide; polyethylene glycols;
polyoxyethylene-polyoxypropylene block copolymers such as poloxamers; polyglycerin
fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate;
sorbitan fatty acid esters such as sorbitan monostearate; polyoxyethylene sorbitan fatty
acid esters such as polyoxyethylene sorbitan monooleate; polyethylene glycol fatty acid
esters such as polyoxyethylene monostearate; polyoxyethylene alkyl ethers such as
polyoxyethylene lauryl ether; polyoxyethylene castor oil; or mixtures thereof.
Suitable preservatives are selected from the group comprising parabens such as
methyl paraben and propyl paraben; sodium benzoate; or mixtures thereof.
Suitable buffering agents are selected from the group comprising citric acid,
sodium citrate, sodium phosphate, potassium citrate, acetate buffer, or mixtures thereof.
Suitable flavoring agents are selected from the group consisting of peppermint,
grapefruit, orange, lime, lemon, mandarin, pineapple, strawberry, raspberry, mango,
passion fruit, kiwi, apple, pear, peach, apricot, cherry, grape, banana, cranberry, blueberry,
black currant, red currant, gooseberry, lingon berries, cumin, thyme, basil, camille,
valerian, fennel, parsley, chamomile, tarragon, lavender, dill, bargamot, salvia, aloe vera
balsam, spearmint, eucalyptus, or combinations thereof.
Suitable anti-oxidants are selected from the group comprising butylated
hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium metabisulfite, ascorbic
acid, propyl gallate, thiourea, tocopherols, beta-carotene, or mixtures thereof.
Suitable chelating agents are selected from the group comprising ethylenediamine
tetraacetic acid or derivatives/salts thereof, e.g., disodium edetate; dihydroxyethyl glycine;
glucamine; acids, e.g., citric acid, tartaric acid, gluconic acid, and phosphoric acid; or
mixtures thereof.
Suitable binders are selected from the group comprising polyvinyl pyrrolidone,
starch, pregelatinized starch, hydroxypropylmethyl cellulose, hydroxyethyl cellulose,
methyl cellulose, sodium carboxymethyl cellulose, gums, acrylate polymers, or mixtures
thereof.
The cores of the present invention comprising the active ingredient can be prepared
by any method known in the art, e.g., extrusion-spheronoization, wet granulation, dry
granulation, hot-melt extrusion granulation, spray drying, and spray congealing.
Alternatively, the active ingredient can be layered onto an inert particle to form the core.
Further, the active ingredient particles can be directly coated with a releasecontrolling
polymer to form the microparticles or microcapsules. The microparticles or
microcapsules can be prepared by a process of homogenization, solvent evaporation,
coacervation phase separation, spray drying, spray congealing, polymer precipitation, or
supercritical fluid extraction.
The extended release suspension compositions of the present invention may further
comprise one or more seal coating layers which may be applied before and/or after the
functional coating layer. The seal coating layer may comprise of one or more film forming
polymers and coating additives.
Examples of film-forming polymers include ethylcellulose, hydroxypropyl
methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethyl cellulose,
hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropyl
methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes
such as polyethylene glycol; methacrylic acid polymers such as Eudragit®. Alternatively,
commercially available coating compositions comprising film-forming polymers marketed
under various trade names, such as Opadry® may also be used.
The coating additives used in the present invention are selected from the group
comprising plasticizers, opacifiers, anti-tacking agents, coloring agents, or combinations
thereof.
Suitable plasticizers are selected from the group comprising triethyl citrate,
dibutylsebacate, triacetin, acetylated triacetin, tributyl citrate, glyceryl tributyrate,
diacetylated monoglyceride, rapeseed oil, olive oil, sesame oil, acetyl tributyl citrate,
acetyl triethyl citrate, glycerin, sorbitol, diethyl oxalate, diethyl phthalate, diethyl malate,
diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, or combinations
thereof.
Suitable opacifiers are selected from the group comprising titanium dioxide,
manganese dioxide, iron oxide, silicon dioxide, or combinations thereof.
Suitable anti-tacking agents are selected from the group comprising talc,
magnesium stearate, calcium stearate, stearic acid, silica, glyceryl monostearate, or
combinations thereof.
Suitable coloring agents are selected from the group consisting of FD&C (Federal
Food, Drug and Cosmetic Act) approved coloring agents; natural coloring agents; natural
juice concentrates; pigments such as iron oxide, titanium dioxide, and zinc oxide; or
combinations thereof.
Coating may be performed by applying the coating composition as a
solution/suspension/blend using any conventional coating technique known in the art such
as spray coating in a conventional coating pan, fluidized bed processor, dip coating, or
compression coating. The percentage of the coating build-up shall be varied depending on
the required extended release.
Suitable solvents used for granulation or for forming a solution or dispersion for
coating are selected from the group consisting of water, ethanol, methylene chloride,
isopropyl alcohol, acetone, methanol, or combinations thereof.
The extended release suspension compositions of the present invention may be
packaged in a suitable package such as a bottle. The powder for suspension may be
packaged in a suitable package such as a bottle or a sachet. Further, the sachet can be
filled as a unit dose or a multidose sachet. The present invention further includes a copackage
or a kit comprising two components, wherein one package or one component
comprises a powder for suspension and another package or another component comprises
a suspension base or a pharmaceutically acceptable vehicle.
The invention may be further illustrated by the following examples, which are for
illustrative purposes only and should not be construed as limiting the scope of the
invention in any way.
EXAMPLES
Example 1
Ingredients Quantity (mg/niL)
Core
Metformin hydrochloride 100.00
Microcrystalline cellulose spheres 90.00
Hydroxypropylmethyl cellulose 5.00
Purified water q.s.
Extended Release Coating
Ethyl cellulose 61.42
Dibutyl sebacate 6.82
Acetone q.s.
Purified water q.s.
Total Weight of Extended Release Beads 263.24 mg
Xylitol 450.00
Xanthan gum 1.500
Microcrystalline cellulose - sodium
20.00
carboxymethyl cellulose (Avicel® CL 611)
Strawberry flavor 1.50
Vehicle
Purified water q.s. to 1mL
Procedure:
1. Metformin hydrochloride and hydroxypropylmethyl cellulose were dissolved in
purified water.
2 . Microcrystalline cellulose spheres were coated with the solution of step 1.
3. Ethyl cellulose and dibutyl sebacate were dispersed in a mixture of acetone and
purified water.
4 . The beads of step 2 were coated with the coating dispersion of step 3 .
5. Xylitol, xanthan gum, microcrystalline cellulose - sodium carboxymethyl cellulose,
and strawberry flavor were mixed with t e coated beads of step 4 .
6. The mixture of step 5 was dispersed in required amount of purified water to obtain the
extended release suspension composition.
In-Vitro Studies
In-vitro release of metformin from the extended release suspension composition
prepared as per Example 1 was determined by the dissolution for metformin using USP
type II apparatus at 100 rpm, in 1000 mL of phosphate buffer with pH 6.8 at 37°C. The
results of the release studies are represented in Table 1.
Table 1: Percentage (%) of the In-Vitro Metformin Release in USP Type II
Apparatus (Media: Phosphate Buffer, pH 6.8, 1000 mL, and 100 rpm)
From the above data, it is clear that the extended release suspension composition
prepared according to Example 1 provides substantially similar in-vitro metformin release
for 30 days.
Example 2
Procedure:
1. Metformin hydrochloride and hydroxypropylmethyl cellulose were dissolved in
purified water.
2 . Microcrystalline cellulose spheres were coated with the solution of step 1.
3. Ethyl cellulose and dibutyl sebacate were dispersed in a mixture of acetone and
purified water.
4 . The beads of step 2 were coated with the coating dispersion of step 3 .
5. Xylitol, xanthan gum, microcrystalline cellulose - sodium carboxymethyl cellulose,
and strawberry flavor were mixed with the coated beads of step 4 to obtain a powder
for suspension.
6. The powder for suspension as per step 5 is reconstituted with required amount of
purified water when required to obtain the extended release suspension composition.
Example 3
Procedure:
1. Metformin hydrochloride, microcrystalline cellulose, and hydroxypropylmethyl
cellulose were sifted and mixed to obtain a blend.
2 . The blend of step 1 was mixed with purified water to obtain a wet mass.
3. The wet mass of step 2 was extruded through an extruder.
4 . The extrudates of step 3 were spherionized through a spherionizer to obtain beads.
5. The beads of step 4 were dried.
6. Ethyl cellulose and dibutyl sebacate were dispersed in a mixture of acetone and
purified water.
7. The dried beads of step 5 were coated with the coating dispersion of step 6 to obtain a
powder for suspension.
8. Xyltiol, xanthan gum, microcrystalline cellulose - sodium carboxymethyl cellulose,
and strawberry flavor were dispersed in purified water to obtain the vehicle.
9. The powder for suspension of step 7 is reconstituted with the vehicle of step 8 when
required to obtain the extended release suspension composition.
Example 4
Procedure:
1. Metformin hydrochloride and hydroxypropylmethyl cellulose were dissolved in
purified water.
2 . Microcrystalline cellulose spheres were coated with the solution of step 1.
3. Ethyl cellulose and dibutyl sebacate were dispersed in a mixture of acetone and
purified water.
4 . The beads of step 2 were coated with the coating dispersion of step 3 .
5. Metformin hydrochloride, xylitol, microcrystalline cellulose - sodium carboxymethyl
cellulose, xanthan gum, strawberry flavor, sucralose, sodium benzoate, and colloidal
silicon dioxide were mixed.
6. The coated beads of step 4 were mixed with the mixture of step 5 to obtain a powder
for suspension.
7. The powder for suspension of step 6 is reconstituted with required amount of purified
water when required to form the extended release suspension composition.
In-Vitro Studies
The extended release suspension composition prepared according to Example 4
was stored at room temperature for 66 days. This extended release suspension was
analyzed for the in-vitro dissolution at 0, 30, and 66 days using USP type II apparatus at
100 rpm, in 1000 mL of phosphate buffer with pH 6.8 at 37°C. The results of t e release
studies are represented in Table 2 .
Table 2 : Percentage (%) of the In-Vitro Metformin Release in USP Type II
Apparatus (Media: Phosphate Buffer, pH 6.8, 1000 mL, and 100 rpm)
From the above data, it is clear that the extended release suspension composition
prepared according to Example 4 provides substantially similar in-vitro metformin release
for 66 days.
The powder for suspension prepared as per Example 4 (till step 6) was kept for one
month at accelerated conditions i.e., 40°C/75% R.H. After one month, the powder for
suspension was reconstituted with required amount of purified water and this extended
release suspension composition was kept for 66 days at room temperature. The in-vitro
dissolution was determined at 0, 36, and 66 days using USP type II apparatus at 100 rpm,
in 1000 mL of phosphate buffer with pH 6.8 at 37°C. The results of the release studies are
represented in Table 3.
Table 3 : Percentage (% of the In-Vitro Metformin Release in USP Type II
Apparatus (Media: Phosphate Buffer, pH 6.8, 1000 inL, and 100 rpm
From the above data, it is clear that the extended release powder prepared according
to Example 4 stored at accelerated conditions for one month, upon reconstitution and
storage for 66 days at room temperature provides substantially similar in-vitro metformin
release for 66 days. The results are shown in Figure 1.
Example 5
Ingredients Quantity (mg/mL)
Core
Metformin hydrochloride 80.00
Microcrystalline cellulose spheres 56.00
Hydroxypropylmethyl cellulose 4.00
Purified water q.s.
Extended Release Coating
Ethyl cellulose 50.40
Dibutyl sebacate 5.60
Acetone q.s.
Purified water q.s.
Total Weight of Extended Release Beads 196.00 mg
Metformin hydrochloride 20.00
Xylitol 450.00
Microcrystalline cellulose - sodium
20.00
carboxymethyl cellulose (Avicel® CL-611)
Xanthan gum 1.50
Strawberry flavor 2.00
Sucralose 0.50
Vehicle
Purified water q.s. to 1mL
Procedure:
1. Metformin hydrochloride and hydroxypropylmethyl cellulose were dissolved in
purified water.
2 . Microcrystalline cellulose spheres were coated with the solution of step 1.
3. Ethyl cellulose and dibutyl sebacate were dispersed in a mixture of acetone and
purified water.
4 . The beads of step 2 were coated with the coating dispersion of step 3 .
5. Metformin hydrochloride, xylitol, microcrystalline cellulose - sodium carboxymethyl
cellulose, xanthan gum, strawberry flavor, and sucralose were mixed.
6. The coated beads of step 4 were mixed with the mixture of step 5 to form a powder for
suspension.
7. The powder for suspension of step 6 is reconstituted with required amount of purified
water when required to form t e extended release suspension composition.
In-Vitro Studies
The extended release suspension composition prepared as per Example 5 was
stored at room temperature for 30 days. The in-vitro dissolution was determined at 0 and
30 days using USP type II apparatus at 100 rpm, in 1000 mL of phosphate buffer with pH
6.8 at 37°C. The results of the release studies are represented in Table 4 .
Table 4 : Percentage (%) of the In-Vitro Metformin Release in USP Type II
Apparatus (Media: Phosphate Buffer, pH 6.8, 1000 mL, and 100 rpm)
From the above data, it is clear that the extended release suspension composition
prepared according to Example 5 provides substantially similar in-vitro metformin release
for 30 days.
The powder for suspension prepared as per Example 5 (till step 6) was kept for
three months at accelerated conditions i.e., 40°C/75% R.H. After three months, t e powder
for suspension was reconstituted with required amount of purified water and this extended
release suspensions composition was kept for 32 days at room temperature. The in-vitro
dissolution was determined at 0 and 32 days using USP type II apparatus at 100 rpm, in
1000 mL of phosphate buffer with pH 6.8 at 37°C. The results of the release studies are
represented in Table 5.
Table 5 : Percentage (%) of the In-Vitro Metformin Release in USP Type II
Apparatus (Media: Phosphate Buffer, pH 6.8, 1000 mL, and 100 rpm)
The powder for suspension prepared as per Example 5 (till step 6) was kept for six
months at accelerated conditions i.e., 40°C/75% R.H. After six months, the powder for
suspension was reconstituted with required amount of purified water and this extended
release suspensions composition was kept for 32 days at room temperature. The in-vitro
dissolution was determined at 0 and 32 days using USP type II apparatus at 100 rpm, in
1000 mL of phosphate buffer with pH 6.8 at 37°C. The results of the release studies are
represented in Table 6 .
Table 6 : Percentage (%) of the In-Vitro Metformin Release in USP Type II
Apparatus (Media: Phosphate Buffer, pH 6.8, 1000 inL, and 100 rpm)
From the above data, it is clear that the extended release powder prepared according
to Example 5 stored at accelerated conditions for three or six months, upon reconstitution
and storage for 32 days at room temperature provides substantially similar in-vitro
metformin release for 32 days. The results are presented in Figure 2 .
Example 6
Procedure:
1. Metformin hydrochloride and hydroxypropylmethyl cellulose were dissolved in
purified water.
2 . Microcrystalline cellulose spheres were coated with the solution of step 1.
3. Ethyl cellulose and dibutyl sebacate were dispersed in a mixture of acetone and
purified water.
4 . The beads of step 2 were coated with the coating dispersion of step 3 .
5. Metformin hydrochloride, xylitol, microcrystalline cellulose - sodium carboxymethyl
cellulose, xanthan gum, strawberry flavor, sucralose, and colloidal silicon dioxide
were mixed.
6. The coated beads of step 4 were mixed with the mixture of step 5 to form a powder for
suspension.
7. The powder for suspension of step 6 is reconstituted with required amount of purified
water when required to form the extended release suspension composition.
In-Vitro Studies
The extended release suspension composition prepared as per Example 6 was
stored at room temperature for 30 days. The in-vitro dissolution was determined at 0 and
30 days using USP type II apparatus at 100 rpm, in 1000 mL of phosphate buffer with pH
6.8 at 37°C. The results of the release studies are represented in Table 7 .
Table 7: Percentage (%) of the In-Vitro Metformin Release in USP Type II
Apparatus (Media: Phosphate Buffer, pH 6.8, 1000 mL, and 100 rpm)
Number of Days 0 30
Percentage of Metformin
Time (hours) Re ease
0.5 20 22
1 27 28
2 59 64
3 77 80
4 84 89
5 88 93
6 92 95
8 95 99
10 97 101
12 98 103
From the above in-vitro release data, it is evident that the extended release
suspension composition prepared according to Example 6 provides t e substantially
similar in-vitro metformin release for 30 days.
The powder for suspension prepared as per Example 6 (till step 6) was kept for one
month at accelerated conditions i.e., 40°C/75% R.H. After one month, the powder for
suspension was reconstituted with required amount of purified water and this extended
release suspension composition was kept for 30 days at room temperature. The in-vitro
dissolution was determined at 0 and 30 days using USP type II apparatus at 100 rpm, in
1000 mL of phosphate buffer with pH 6.8 at 37°C. The results of the release studies are
represented in Table 8.
Table 8 : Percentage (%) of the In-Vitro Metformin Release in USP Type II
Apparatus (Media: Phosphate Buffer, pH 6.8, 1000 mL, and 100 rpm)
From the above data, it is clear that the extended release powder prepared according
to Example 6 stored at accelerated condition for one month, upon reconstitution and
storage for 30 days at room temperature provides substantially similar in-vitro metformin
release for 30 days. The results are presented in Figure 3.
Osmolality Measurement of the Extended Release Suspension
The metformin extended release powder prepared according to the Example 6 (till
step 6) was reconstituted with required amount of purified water. This suspension was
shaken manually for at least 20 minutes. This suspension was then filtered and diluted
with purified water and the osmolality was measured using Osmomat 030-D.
The osmolality of the suspension base was found to be 4 .112 osmol/kg of the
suspension base on day 0 .
The osmolality of the suspension base was found to be 4.328 osmol/kg of the
suspension base on day 7 .
It is evident from the above data that the osmolality of t e suspension base of the
extended release suspension composition as per Example 6 remains equivalent for seven
days.
Osmolality Measurement of the External Phase
The metformin hydrochloride, xylitol, microcrystalline cellulose - sodium
carboxymethyl cellulose, xanthan gum, strawberry flavor, sucralose, and colloidal silicon
dioxide were mixed as per step 5 of Example 6 . This mixture was reconstituted with
required amount of purified water. This suspension was then filtered and diluted with
purified water, and the osmolality was measured using Osmomat 030-D.
The osmolality of the suspension base i.e., external phase was found to be 4.204
osmol/kg of the suspension base.
Osmolality Measurement of the Internal Phase
Various solutions having various concentrations of osmogent (sodium chloride)
were prepared as per Examples 6A-6F. The osmolalities of these solutions were measured
using Osmomat 030-D.
* Extrapolated using values of dilute solutions
The coated beads of step 4 were dispersed in different solutions as per Examples
6A-6F. These solutions were kept for seven days at room temperature. After seven days,
each solution was analyzed by HPLC for metformin content. The results are represented
in following Table 9 .
Table 9 : Effect of Osmolality on Metformin Leaching
Extrapolated using values of dilute solutions
From the above data, it is evident that the leaching of metformin from the coated
beads into the solution was decreasing as the osmolality of the solution was increasing
from Examples 6A-6F. The leaching is found to be significantly reduced from Example
6C onwards. The osmolality of Example 6C i.e., 3.574 is considered as osmolality of the
internal phase.
Osmolality Ratio 1.176
Dose Uniformity Data
The extended release suspension equivalent to 0 mL was prepared according to
formula given in Example 6 . This suspension was shaken manually for at least 20 minutes
and then ten 7.5 mL samples were taken with a graduated syringe. The metformin content
of each sample is determined by HPLC method [Inertsil ODS column (250 x 4.6 mm, 5
mih); mobile phase-buffer (pH 3.5):acetonitrile (95:5 v/v); flow rate of 1.5 mL/min; UV
detection at 233 nm] The results are shown in Table .
Table 0: Metformin Content %w/w For Each 7.5 mL of Suspension
Sample Metformin content (%) for each
Number 7.5 mL of suspension
1 98.6
2 97.9
3 96.6
4 97.2
5 99.7
6 96.4
7 95.9
8 97.3
9 98.8
10 96.9
Mean value 97.5
From the above data, it is evident that t e extended release suspension composition
prepared as per Example 6 is homogeneous.
Assay Data
The assay for the extended release suspension composition prepared as per
Example 6 was determined at 0 day and after storage at room temperature for 30 days. The
powder for suspension prepared as per Example 6 (till step 6) was kept for one month at
40°C/75% R.H. After one month, the powder for suspension was reconstituted with
required amount of purified water and then assay was determined at 0 day and after
storage at room temperature for 30 days.
The assay of metformin was determined by HPLC method [Inertsil ODS column (250 x
4.6 mm, 5 m i); mobile phase-buffer (pH 3.5):acetonitrile (95:5 v/v); flow rate of 1.5
mL/min; UV detection at 233 nm]. The results are shown in Table .
Table 11: Assay for Metformin
prepared as per Example 6 is stable.
Example 7
Preparation of Extended Release Beads
Ingredients Quantity (mg)
Core
Guanfacine hydrochloride 1.15
Microcrystalline cellulose spheres 4.00
Hydroxypropylmethyl cellulose 30.00
Mannitol 10.00
Purified Water q.s.
Extended Release Coating
Ethyl cellulose 14.22
Dibutyl sebacate 1.58
Acetone q.s.
Purified Water q.s.
Total Weight of Extended Release Beads 60.95 mg
Procedure:
1. Guanfacine hydrochloride and hydroxypropylmethyl cellulose were dissolved in
purified water.
2 . Microcrystalline cellulose spheres were coated with the solution of step 1.
3. Ethyl cellulose and dibutyl sebacate were dispersed in a mixture of acetone and
purified water.
4 . The beads of step 2 were coated with the coating dispersion of step 3 .
Various solutions having various concentrations of osmogent (sodium chloride)
were prepared as per Examples 7A-7D. The osmolalities of these solutions were measured
using Osmomat 030-D.
Extrapolated using values of dilute solutions
Sodium chloride was dissolved in purified water as per Examples7A-7D. The
osmolality of these solutions were measured using Osmomat 030-D.
The coated beads of step 4 were dispersed in different suspension bases as per
Examples7A-7D. These suspensions were kept for seven days at room temperature. After
seven days, each suspension was filtered and diluted with purified water. These were then
analyzed by using HPLC for guanfacine content. The results are represented in following
Table 12.
Table 12: Effect of Osmolality on Guanfacine Leaching
Example Osmolality (osmol/kg) of Guanfacine Content (%)
the solution
7A 0.910 69.80
7B 1.787 8.90
7C 3.574* 1.30
7D 5.361* 0.30
*Extrapo ated using values of dilute solutions
From the above data, it is evident that the leaching of guanfacine from t e coated
beads into t e solution was decreasing as the osmolality of the solution was increasing
from Examples 7A-7D.
Example 8
Procedure:
1. Valacyclovir hydrochloride and hydroxypropylmethyl cellulose are dissolved in
purified water.
2 . Microcrystalline cellulose spheres are coated with the solution of step 1.
3. Ethyl cellulose and dibutyl sebacate are dispersed in a mixture of acetone and purified
water.
4 . The beads of step 2 are coated with the coating dispersion of step 3 .
5. Xylitol, xanthan gum, microcrystalline cellulose - sodium carboxymethyl cellulose,
strawberry flavor are mixed.
6. The coated beads of step 4 are mixed with the mixture of step 5 to form a powder for
suspension.
7. The powder for suspension of step 6 is reconstituted with required amount of purified
water when required to form the extended release suspension composition.
Example 9
Procedure:
1. Amoxicillin and polyvinylpyrrolidone are dispersed in purified water.
2 . Microcrystalline cellulose spheres are coated with the solution of step 1.
3. Ethyl cellulose and dibutyl sebacate are dispersed in a mixture of acetone and purified
water.
4 . The beads of step 2 are coated with the coating dispersion of step 3 .
5. Clavulanic acid, lemon flavor, xylitol, microcrystalline cellulose - sodium
carboxymethyl cellulose, strawberry flavor are mixed.
6. The coated beads of step 4 are mixed with the mixture of step 5 to form a powder for
suspension.
7. The powder for suspension of step 6 is reconstituted with required amount of purified
water when required to form the extended release suspension composition.
Example 10
Procedure:
Esomeprazole magnesium, hydroxypropyl cellulose, crospovidone are dispersed in
purified water and is stirred to get form a dispersion.
The non-pareil seeds are coated with dispersion of step 1.
The hydroxypropylmethyl cellulose, polyethylene glycol, and talc are dispersed in
purified water to get a dispersion.
The coated pellets of step 2 are coated with the dispersion of step 3.
The polyethylene glycol, methacrylic acid copolymer dispersion, talc, and titanium
dioxide are dispersed in purified water to get a dispersion.
The coated pellets of step 4 are coated with the dispersion of step 5.
The coated pellets of step 6 are lubricated with talc.
The lubricated pellets of step 7 are mixed with xylitol to obtain a powder for
suspension.
The powder for suspension of step 8 is reconstituted with required amount of purified
water when required to form the extended release suspension composition.
We claim:
1. An extended release suspension composition comprising:
(a) multiple coated cores comprising:
(i) a core comprising an active ingredient; and
(ii) a coating layer over said core comprising one or more release-controlling
polymers;
(b) a suspension base, wherein t e suspension base generates a hypertonic
condition such that there is no substantial change in the in-vitro dissolution
release profile of the extended release suspension compositions upon storage
for at least seven days.
2 . An extended release suspension composition comprising:
(a) multiple coated cores comprising:
(i) a core comprising an active ingredient; and
(ii) a coating layer over said core comprising one or more release-controlling
polymers;
(b) a suspension base, wherein the composition is characterized by having an
osmolality ratio of at least about 1, and wherein there is no substantial change
in the in-vitro dissolution release profile of the extended release suspension
compositions upon storage for at least seven days.
3. The extended release suspension composition of claims 1 or 2, wherein the
suspension base comprises an osmogent.
4 . The extended release suspension composition of claims 1 or 2, wherein the
composition is a suspension or a reconstituted powder for suspension.
5. The extended release suspension composition of claims 1 or 2, wherein the active
ingredient is layered onto an inert particle to form the core.
6 . The extended release suspension composition of claim 5, wherein the inert particle
is selected from the group comprising a non-pareil seed, a microcrystalline
cellulose sphere, a dibasic calcium phosphate bead, a mannitol bead, a silica bead,
a tartaric acid pellet, or a wax based pellet.
7 . The extended release suspension composition of claim 3, wherein the osmogent is
selected from the group comprising carbohydrates such as xylitol, mannitol,
sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose,
maltose, lactose, dextrose and raffinose; water-soluble salts of inorganic acids such
as magnesium chloride, magnesium sulfate, potassium sulfate, lithium chloride,
sodium chloride, potassium chloride, lithium hydrogen phosphate, sodium
hydrogen phosphate, potassium hydrogen phosphate, lithium dihydrogen
phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and
sodium phosphate tribasic; water-soluble salts of organic acids such as sodium
acetate, potassium acetate, magnesium succinate, sodium benzoate, sodium citrate,
and sodium ascorbate; water-soluble amino acids such as glycine, leucine, alanine,
methionine; urea or its derivatives; propylene glycol; glycerin; polyethylene oxide;
xanthan gum; hydroxypropylmethyl cellulose; or mixtures thereof.
8. The extended release suspension composition of claim 1, wherein the releasecontrolling
polymer is selected from t e group comprising a pH-dependent
polymer, a pH-independent polymer, or mixtures thereof.
9 . The extended release suspension composition of claim 8, wherein the pHdependent
polymer is selected from the group comprising acrylic copolymers such
as methacrylic acid and methyl methacrylate copolymers, e.g., Eudragit 8 L 100
and Eudragit ' S 00, methacrylic acid and ethyl acrylate copolymers, e.g.,
Eudragit® L 100-55 and Eudragit® L 30 D-55, dimethylaminoethyl methacrylate
and butyl methacrylate and methyl methacrylate copolymer e.g., Eudragit 1' E 100,
Eudragit* E PC), methyl acrylate and methacrylic acid and octyl acrylate
copolymers, styrene and acrylic acid copolymers, butyl acrylate and styrene and
acrylic acid copolymers, and ethylacrylate-methacrylic acid copolymer; cellulose
acetate phthalate; cellulose acetate succinates; hydroxyalkyl cellulose phthalates
such as hydroxypropylmethyl cellulose phthalate; hydroxyalkyl cellulose acetate
succinates such as hydroxypropylmethyl cellulose acetate succinate; vinyl acetate
phthalates; vinyl acetate succinate; cellulose acetate trimelliate; polyvinyl
derivatives such as polyvinyl acetate phthalate, polyvinyl alcohol phthalate,
polyvinyl butylate phthalate, and polyvinyl acetoacetal phthalate; zein; shellac; or
mixtures thereof.
10. The extended release suspension composition of claim 8, wherein the pHindependent
polymer is selected from the group comprising cellulosic polymers
such as ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, hydroxy ethylmethyl cellulose, hydroxypropylmethyl cellulose, and
carboxy methylcellulose; acrylic copolymers such as methacrylic acid copolymers,
e.g., Eudragit® RS, Eudragit® RL, Eudragit® NE 30 D; cellulose acetate;
polyethylene derivatives e.g., polyethylene glycol and polyethylene oxide;
polyvinyl alcohol; polyvinyl acetate; gums e.g., guar gum, locust bean gum,
tragacanth, carrageenan, alginic acid, gum acacia, gum arabic, gellan gum, and
xanthan gum; triglycerides; waxes, e.g., Compritol®, Lubritab*', and Gelucires' ;
lipids; fatty acids or their salts/derivatives; a mixture of polyvinyl acetate and
polyvinyl pyrrolidone, e.g., Kollidon* SR; or mixtures thereof.
11. The extended release suspension composition of claim 1, wherein the active
ingredient is selected from the group comprising metformin, acarbose, miglitol,
voglibose, repaglinide, nateglinide, glibenclamide, glimepride, glipizide,
gliclazide, chloropropamide, tolbutamide, phenformin, aloglitin, sitagliptin,
linagliptin, saxagliptin, rosiglitazone, pioglitazone, troglitazone, faraglitazar,
englitazone, darglitazone, isaglitazone, zorglitazone, liraglutide, muraglitazar,
peliglitazar, tesaglitazar, canagliflozin, dapagliflozin, remogliflozin, sergliflozin,
verapamil, albuterol, salmeterol, acebutolol, sotalol, penicillamine, norfloxacin,
ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, trovafloxacin, gatifloxacin,
cefixime, cefdinir, cefprozil, cefadroxil, cefuroxime, cefpodoxime, tetracycline,
demeclocycline hydrochloride, amoxicillin, clavulanate potassium, azithromycin,
losartan, irbesartan, eprosartan, valsartan, irbesartan, diltiazem, isosorbide
mononitrate, ranolazine, propafenone, hydroxyurea, hydrocodone, delavirdine,
pentosan polysulfate, abacavir, amantadine, acyclovir, ganciclovir, valacyclovir,
valganciclovir, saquinavir, indinavir, nelfinavir, lamivudine, didanosine,
zidovudine, nabumetone, celecoxib, mefenamic acid, naproxen, propoxyphene,
cimetidine, ranitidine, albendazole, mebendazole, thiobendazole, pyrazinamide,
praziquantel, chlorpromazine, sumatriptan, bupropion, aminobenzoate,
pyridostigmine bromide, potassium chloride, niacin, tocainide, quetiapine,
fexofenadine, sertraline, chlorpheniramine, rifampin, methenamine, nefazodone,
modafinil, metaxalone, morphine, sevelamer, lithium carbonate, flecainide acetate,
simethicone, methyldopa, chlorthiazide, metyrosine, procainamide, entacapone,
metoprolol, propanolol hydrochloride, chlorzoxazone, tolmetin, tramadol, bepridil,
phenytoin, gabapentin, fluconazole, terbinafine, atorvastatin, doxepine, rifabutin,
mesalamine, etidronate, nitrofurantoin, choline magnesium trisalicylate,
theophylline, nizatidine, methocarbamol, mycophenolate mofetil, tolcapone,
ticlopidine, capecitabine, orlistat, colsevelam, meperidine, hydroxychloroquine,
guaifenesin, guanfacine, amiodarone, quinidine, atomoxetine, felbamate,
pseudoephedrine, carisoprodol, venlafaxine, etodolac, chondrotin, lansoprazole,
pantoprazole, esomeprazole, dexlansoprazole, dexmethylphenidate,
methylphenidate, sodium oxybate, or isotretinoin.
12. The extended release suspension composition of the claim 3, wherein the
suspension base further comprises one or more pharmaceutically acceptable
excipients selected from the group comprising suspending agents, anti-caking
agents, wetting agents, preservatives, buffering agents, flavoring agents, antioxidants,
and chelating agents.
13 . A process for t e preparation of t e extended release suspension composition of
claims 1 or 2 , wherein the process comprises the steps of:
(i) preparing cores comprising an active ingredient and one or more
pharmaceutically acceptable excipients;
(ii) dissolving/dispersing a release-controlling polymer and one or more
pharmaceutically acceptable coating additives in a suitable solvent;
(iii) applying the coating composition of step (ii) over the cores of step (i);
(iv) dissolving one or more osmogents and pharmaceutically acceptable excipients
into a pharmaceutically acceptable vehicle to form a suspension base; and
(v) dispersing the coated cores of step (iii) in the suspension base of step (iv) to
obtain the extended release suspension composition.
14. A process for the preparation of the extended release suspension composition of
claims 1 or 2 , wherein the process comprises the steps of:
(A) preparing a powder for suspension comprising the steps of:
(i) preparing cores comprising an active ingredient and one or more
pharmaceutically acceptable excipients;
(ii) dissolving/dispersing a release-controlling polymer and one or more
pharmaceutically acceptable coating additives in a suitable solvent;
(iii) applying the coating composition of step (ii) over the cores of step (i);
(iv) mixing one or more pharmaceutically acceptable excipients with the
coated cores of step (iii) to obtain the powder for suspension;
(B) preparing a suspension base by dissolving one or more osmogents and
pharmaceutically acceptable excipients into a pharmaceutically acceptable
vehicle; and
(C) reconstituting the powder for suspension of step (A) with a suspension base of
step (B) to obtain the extended release suspension composition.
15. A process for the preparation of t e extended release suspension composition of
claims 1 or 2, wherein the process comprises t e steps of:
(A) preparing a powder for suspension comprising the steps of:
(i) preparing cores comprising an active ingredient and one or more
pharmaceutically acceptable excipients;
(ii) dissolving/dispersing a release-controlling polymer and one or more
pharmaceutically acceptable coating additives in a suitable solvent;
(iii) applying the coating composition of step (ii) over the cores of step (i);
(iv) mixing one or more osmogents and one or more pharmaceutically
acceptable excipients with the coated cores of step (iii) to obtain the
powder for suspension; and
(B) reconstituting the powder for suspension of step (A) with a pharmaceutically
acceptable vehicle to obtain the extended release suspension composition.