Description
The present invention discloses a press-coated tablet, comprising of a core
comprising one or more active substances and optionally along with one or more
pharmaceutically acceptable excipients, and a coating surrounding the said core,
wherein the said core is being disposed within said coating such that the coating
thickness around the horizontal edges of the core is less than or equal to the coating
thickness around the vertical edges of the core, wherein the dosage form delays the
release of the active substance from the core for a period of about 2h to 10h after
oral administration.
Circadian rhythms are physical, mental and behavioral changes that follow a roughly
24-hour cycle, responding primarily to light and darkness in an organism’s
environment. Circadian rhythms are produced by natural factors within the body, but
they are also affected by signals from the environment. Light is the main cue
influencing circadian rhythms, turning on or turning off genes that control an
organism’s internal clocks. Circadian rhythms can change sleep-wake cycles,
hormone release, body temperature and other important bodily functions. For
example, an asthmatic attack generally happens in the early morning, the stomach
pH decreases during the night and in some hypertension diseases the pressure
value is higher during the daytime, while a decrease occurs during the night.
The biological clocks that control circadian rhythms are groupings of interacting
molecules in cells throughout the body. A “master clock” in the brain coordinates all
the body clocks so that they are in synch. The master clock network is composed of
the paired suprachiasmatic nuclei (SCN) that are situated in the hypothalamus and
the pineal gland. This circadian clock is a combination of an input pathway
(photoreceptors and projections of retinal ganglion cells), circadian pacemakers
generating the circadian signal and an output pathway manifesting circadian
behaviors. Circadian rhythms in gastrointestinal, liver, kidney and other bodily
processes and functions are of great importance for therapeutics, for example, in
choosing when to administer medications in relation to rhythm influences on their
pharmacokinetics, effect-duration, efficacy, adverse effect and beneficial outcomes.
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Various circadian phase dependent patterns have been well documented in
conditions such as asthma, arthritis, epilepsy, migraine, allergic rhinitis,
cardiovascular disease (myocardial infarction, angina, stroke), chronic inflammation
and pain, such as rheumatoid arthritis (RA), polymyalgia rheumatica (PMR) and
peptic ulcer disease, with particular times where symptoms are more prominent
and/or exacerbated. Treating these conditions require different amounts of drug at
particular times which synchronize the circadian cycle and provide adequate relief.
Immediate release dosage forms may be impractical if the symptoms of the disease
are pronounced during the night or early morning. Therapy with modified release
dosage forms with zero order drug release theoretically leads to controlled and
constant levels of drug in plasma throughout the day and at times may not be
sufficient to synchronize the biological response i.e they do not provide extra
therapeutic levels at the time of pronounced symptoms. Further, the modified release
dosage forms may produce adverse effects with little therapeutic benefit due to
unwanted plasma drug concentration at other times of day.
To fulfill the specific therapeutic needs of such diseases, which depend on circadian
rhythmicity, new drug delivery systems are required for the time-programmed
administration of the active ingredients. Such dosage forms should release the drug
both at the rate and time, which is in sync with the circardian rhythm. For example,
the assumption in the evening of a dosage form able to start releasing the dose some
hours after ingestion at a proper rate could be a suitable therapeutic regimen for all
diseases, which show a night symptomatic recrudescence.
Various attempts have been made by several researchers for development of a
delivery system modifying the release of the active ingredient providing desired
therapeutic effect to overcome the symptoms that are linked to circadian fluctuations
and achieve better patient compliance.
Recently various chronopharmaceutical technologies have emerged, such as, Oros®
Technology, Ceform® Technology, Contin® Technology, Diffucaps® Technology,
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Chronotopic® Technology, Egalet® Technology, Codas® Technology, GeoClock®
Technology, Port® Technology, Three Dimensional Printing® (3DP) Technology,
TimeRx® Technology, Chronomodulated infusion pump and Controlled Release
Microchip.
Inorganic salt of calcium ion is available as Emcompress® (Edward mendell, USA), A
Tab® (Rhodia, USA), Di Tab® (Rhodia, USA), Fujicalin® (Fuji Chemical Industry,
Japan), Calstar (FMC Biopolymer) which contains dicalcium phosphate; Tricalcium
phosphate is available as Tri Tab® (Rhodia, USA); Calcium sulphate is available as
Delaflo® (JWS Delavau, USA); Calcium lactate pentahydrate is available as Puracal
DC® (Purac, USA); Calcium lactate trihydrate is available as Puracal TP® (Purac,
USA).
Dicalcium phosphate also known as calcium hydrogen orthophosphate dihydrate;
calcium monohydrogen phosphate dihydrate; Di-Cafos; dicalcium orthophosphate;
DI-TAB; E341; Emcompress; phosphoric acid calcium salt (1:1) dihydrate; secondary
calcium phosphate. Dicalcium phosphate is the most common inorganic salt used in
direct compression as a filler-binder. The milled material is typically used in wetgranulated,
roller-compacted or slugged formulations. The ‘unmilled’ or coarse-grade
material is typically used in direct-compression formulations. Dibasic calcium
phosphate dihydrate is nonhygroscopic and stable at room temperature. However,
under certain conditions of temperature and humidity, it can lose water of
crystallization below 1000C. This has implications for certain types of packaging and
aqueous film coating since the loss of water of crystallization appears to be initiated
by high humidity and by implication high moisture vapor concentrations in the vicinity
of the dibasic calcium phosphate dihydrate particles. However, dibasic calcium
phosphate dihydrate is abrasive and a lubricant is required for tableting. Water of
crystallization of dicalcium phosphate dihydrate could possible be released during
processing and thus chemically interact with hydrolysable drug.
It is also well known that, dicalcium phosphate is insoluble and very abrasive, which
generally leds to reduced tooling life due to wear on the equipment during tablet
5
manufacture. High levels of lubricants are required to overcome the abrasiveness,
but elevated levels of hydrophobic lubricants can impact the mechanical strength of
the tablets and disintegration/dissolution performance. Further, due to the propensity
of dicalcium phosphate towards brittleness, it tend to exhibit failure in a plane normal
to the compaction axis, i.e. experience tablet capping and lamination phenomena.
Properties of dicalcium phosphate has been modulated by the use of glyceryl
behenate. Such modified dicalcium phosphate has been used as an excipients in
immediate and non-immediate release dosage forms. Use of these excipients in
coating composition has not been explored.
Glyceryl dibehenate is a mixture of glycerol esters. It is also known as Compritol 888
ATO; 2,3-dihydroxypropyl docosanoate; docosanoic acid, 2,3-dihydroxypropyl ester;
E471; glycerol behenate; glyceroli dibehenas; glyceryl monobehenate. It is a mixture
of diacylglycerols, mainly dibehenoylglycerol, together with variable quantities of
mono- and triacylglycerols.
Glyceryl behenate is used in cosmetics, foods, and oral pharmaceutical formulations.
In pharmaceutical formulations, glyceryl behenate is mainly used as a lubricant in the
preparation of oral tablets and capsules. It has also been investigated for use in the
preparation of sustained-release tablets; as a matrix-forming agent for the controlled
release of water-soluble drugs; and it can also be used as a hot-melt coating agent
sprayed onto a powder or drug-loaded sugar beads and granules. It may also be
incorporated via extrusion/spheronization into pellets, which can be further
compressed into tablets.
One of the major problem associated with press coated tablets is that they suffer
from the disadvantages that sometimes neither the minimum quantity of active
substance is released therefrom "in vitro" after fixed intervals (programmed-release
profile with indication of the minimum amount to be released at fixed intervals), nor
are they are immune to the influence and possible variations of the preparation
during the aging or storage thereof (stability of the programmed-release rate of the
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preparation over time). Moreover, lag phase in most of the press coated tablets is
dependent on geometry of dosage form such as tablet geometry or presence of weak
points in the tablet. This leads to uneven rupture of the coating, thus leading to
variation in drug release. Undesired batch to batch variation in release of active
ingredient is common with such type of dosage form. Prior art also discloses that the
core should be correctly located within the coating to ensure that a tablet has an
appropriate coating thickness. The coating thickness of the tablet directly affects the
lag time. Thus improper positioning of the core will lead to intra-subject and intersubject
variance in bioavailability.
Thus, a need exists for a dosage form which is independent of the geometry of the
tablet, free from lag phase variation and provides release of active substance at a
fixed duration.
U.S. Patent No. 7,364,755 discloses a modified calcium phosphate excipient with a
fatty acid wax in a weight ratio of 50:50 to 95:5. The patent discloses use of excipient
for formulating immediate and non-immediate release formulation, which can be
further coated.
U.S. Patent No. 7,776,358 discloses an extended release coated tablet comprising a
tablet core, which comprises at least 70% venlafaxine besylate; and a coating over
said tablet core which comprises an ammonio methacrylate copolymer component,
wherein said coating is in an amount within the range of 3% to 25% of the weight of
said tablet core.
U.S. Patent Application No. 20050048118 discloses an modified release tablet
having a core, which comprises a lipophilic matrix and an effective amount of
venlafaxine hydrochloride; and a water insoluble, permeable coating over said core.
PCT Patent Application No. 2005013953, discloses an extended release tablet
wherein the matrix material is co-processed with calcium phosphate and fatty acid
wax having a ratio within the range of 85: 15 to 65: 35, respectively.
7
U.S. Patent No. 5,422,123 discloses tablets with zero order controlled-rate of release
of the active substances, consisting of a core of defined geometrical form containing
the active substance, polymer substances which swell on contact with aqueous
liquids and polymer substances with gelling properties, and a support applied to said
core to partly cover its surface, the support consisting of polymer substances which
are slowly soluble and/or slowly gellable in aqueous liquids, plasticizing substances,
and possibly substances with an adjuvant function.
U.S. Patent No. 4,839,177 discloses a system for the controlled-rate release of active
substances, consisting of a deposit-core comprising the active substance and having
defined geometric form and a support-platform applied to said deposit-core. Said
deposit-core contains, mixed with the active substance, a polymeric material having a
high degree of swelling on contact with water or aqueous liquids, a gellable polymeric
material, said polymeric materials being replaceable by a single polymeric material
having both swelling and gelling properties, and other adjuvants able to provide the
mixture with suitable characteristics for its compression and for its intake of water.
U.S. Patent Application No. 20060057200 (‘200) discloses a pharmaceutical dosage
form with site and time-controlled gastrointestinal release of active ingredient. The
application discloses tablet composition wherein the ratio of the thickness of the
press coating on the sides of the tablet to the upper side or lower side is preferably
about 2.2-2.6mm (for side edges): about 1.2-1.6mm for the upper side and about 1.0-
1.4 mm for lower side of the tablet. The ‘200 application discloses the use of glyceryl
behenate, calcium phosphate and povidone in coating composition, by using wet
granulation process, for delaying the release of active substance.
U.S. Patent Application No. 20070110807 (‘807) discloses a press-coated tablet
comprising a core containing an drug substance, and a coating, the core being
disposed within the coating such that the coating has a first thickness about an axis
A-B and a thickness about an orthogonal axis X-Y, such that the coating about the
axis X-Y is thicker than the coating about the axis A-B, to provide a lag time of
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between about 2 to 6 hours. The ‘807 application discloses the use of glyceryl
behenate, calcium phosphate and povidone in coating composition, by using wet
granulation process, for delaying the release of active substance.
U.S. Patent Application No. 20100196427 (‘427) discloses a method for treatment of
a patient suffering from rheumatoid arthritis by administering a delayed-release
dosage form of a glucocorticoid to a subject in need thereof. The release of the active
substance is delayed for a time period of 2-10h after intake, preferably 2-6h, more
preferably 3-5h. The ‘427 application disclose the use of glyceryl behenate, calcium
phosphate and povidone in coating composition, by using wet granulation process,
for delaying the release of active substance.
U.S. Patent Application No. 20100222312 (‘312) and PCT Publication No.
2010084188 disclose a method for treatment of asthma by administering a delayedrelease
dosage form of a glucocorticoid to a subject in need thereof. The release of
the active substance is delayed for a time period of 2-10h after intake, preferably 2-
6h, more preferably 3-5h. The release of the active substance is delayed for a time
period of 2-10h after intake, preferably 2-6h, more preferably 3-5h. The ‘427
application disclose the use of glyceryl behenate, calcium phosphate and povidone in
coating composition, by using wet granulation process, for delaying the release of
active substance.
U.S. Patent Nos. 6,488,960 and 6,677,326 discloses a controlled release unit dose
formulation comprising 0.25 to 2 mg of a corticosteroid. This small dose can be used
to treat rheumatoid arthritis, especially if adapted to release at least 90% by weight of
the corticosteroid, 2 to 8 hours after administration. The patents does not disclose the
use of co-procesed glyceryl behenate and calcium phosphate in coating composition,
for delaying the release of active substance.
U.S. Patent No. 5,464,633 discloses a tablet for oral administration suitable to
release the active substance after a definite period of time, consisting essentially of, a
core containing the active substance to be released in the gastric or intestinal tract, a
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polymeric substance which swells and/or gels and/or erodes on contact with water or
aqueous liquids, a layer applied externally to said core by a compression process
said layer being suitable to allow the release of the active substance contained in the
core after a definite period of time i.e, after 2 to 3 hours.
U.S. Patent No. 5,279,832 and European Patent No. 0495349 discloses a delayed
release dosage form with a core, which contains the active substance and a coating.
The coating has selected areas which are thinner than the average thickness of the
coating and/or areas which are predetermined rupture sites.
U.S. Patent No. 6,365,185 discloses a osmotic drug delivery system, which delivers
the active agent in a substantially constant effective dose for the duration of the
transit through the stomach and small intestine, followed by accelerated release
when reaching the large intestine.
U.S. Patent No. 5,792,476 discloses a pharmaceutical composition for peroral
treatment of rheumatoid arthritis and a treatment method therefor are described,
wherein said composition comprises 2.5-7 mg of a glucocorticoid as active substance
with a regulated sustained release such that at least 90% by weight of the
glucocorticoid is released during a period of about 40-80 min, starting about 1-3 h
after the entry of said glucocorticoid into the small intestine of a mammal.
U.S. Patent No. RE39,239 discloses methods of treating early morning pathologies
using a time-specific controlled release dosage formulation which comprises a core
including the pharmaceutically active agent effective for the treatment of the early
morning pathology, and a swellable polymeric coating layer substantially surrounding
the core.
U.S. Patent Nos. 6,372,254 and 6,730,321 discloses a press coated, pulsatile drug
delivery system having an immediate-release compartment, which contains a
compressed blend of an active agent and one or more polymers, substantially
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enveloped by an extended-release compartment, which contains a compressed
blend of the active agent and hydrophilic and hydrophobic polymers.
U.S. Patent Application No. 20070243253 disclose a delayed release drug
formulation comprising a particle with a core and a coating for the core, the core
comprising a drug and the coating comprising a mixture of a first material which is
susceptible to attack by colonic bacteria and a second material which has a pH
threshold at about pH 5 or above, wherein the first material comprises at least one
polysaccharide.
The present inventors, while trying to develop press coated tablets, surprisingly found
that, by modifying the geometry of the press coated tablets which comprises of a core
and a coating comprising inorganic salts of calcium ions co-processed with glyceryl
behenate, is press coated on the core such that the thickness around the horizontal
edges of the core is less than or equal to the coating thickness around the vertical
edges of the core, delays the release of the active substances from the core for a
period of about 2h to 10h. When this press coated tablet is exposed into aqueous
media, the coating ruptures into two equal halves after a fixed time interval, thus
releasing the active substance contained in the core. The lag phase in the release of
the active substance from the core can be modulated by changing the ratio of
glyceryl behenate to inorganic salts of calcium ions in the coating composition. To
exemplify few, the present inventors found that when glyceryl behenate and
dicalcium phosphate were co-processed in a ratio of 30:70, with 1.5mm thickness
around the horizontal edge of the core and 1.75mm thickness around the vertical
edge of the core, a lag phase of about 4h to 5h was observed. Further, when glyceryl
behenate and dicalcium phosphate were co-processed in a ratio of 50:50, with
1.5mm thickness around both, the horizontal edge and the vertical edge of the core,
a lag phase of about 9h to 10h was observed. Present inventors have thus
surprisingly discovered that such a coating composition has reduced the batch to
batch variation, variations of the formulation during the aging or storage thereof, and
provides a consistent lag time with minimal variation. Further, the press coated
tablets did not required specialized tooling for preparation.
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Thus, the present inventors have now developed a press coated tablets comprising
various active ingredient, which helps to control initial burst release of the active
ingredient and achieves desirable dissolution profile and consistent release pattern
after a lag phase of about 2 to about 10h hours.
The term “dosage form” as used herein refers to a pharmaceutical preparation in
which dose or doses of one or more therapeutically active ingredients are included. It
may be in form of a tablet, capsule, tablet in tablet, tablet in capsule, bilayer tablet,
trilayer tablet, in-lay tablet, microsphers, coated pellets, Multiple Unit Pellet System or
combinations thereof.
In the present invention, “coating thickness around the vertical edges of the core” of
the tablet is used interchangbly with “length”. The term “length” of the tablet refers to
the thickness of the tablet, or the sides which comes in contact with the upper and
lower punch.
In the present invention, “coating thickness around the horizontal edges of the core”
of the tablet is used interchangbly with “width”. The term “width” refers to diameter of
the tablet, or the edges which are in contact to die while copmression.
The term “Programmed release” as used herein refers to the release of drug after a
certain lag phase. The drug relase may be monophasic or biphasic. The site of the
release may be programmed too.
“Modified release dosage forms” as used herein is defined (e.g. as by the United
States Pharmacopoeia “USP”) as those whose drug release characteristics of time
course and/or location are chosen to accomplish therapeutic or convenience
objectives not offered by conventional immediate release dosage forms. The USP
considers that the terms controlled release, prolonged release and sustained release
are interchangeable. Accordingly, the terms “modified-release”, controlled-release”,
“control-releasing”, “rate-controlled release”, “extended release”, “prolonged-release”,
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and “sustained-release” are used interchangeably herein, For the discussion herein,
the definition of the term “modified-release” encompasses the scope of the definitions
for the terms “extended release”, “enhanced-absorption”, “controlled release”,
“sustained release” and “delayed release”.
The term “delayed release” is defined as any formulation, wherein the release of the
drug is delayed for certain period of time. Conventional art known examples of such
delayed release systems may include, but are not limited to timed-release tablets
and capsules and enteric-coated tablets and beads.
“Lag time” is the time to disintegrate the tablet and to release the drug after
administration of the press coated tablets.
The term “Co-processing” as used herein refers to a combination of two or more
excipients by an appropriate process, which involves but is not limited to wet
granulation, melt granulation, etc.
The terms “pore former”, “pore forming agent”, and “pore forming additive” as used
herein are used interchangeably in this application, and are defined to mean an
excipient that can be added to a coating, wherein upon exposure to fluids in the
environment of use, the pore former dissolves or leaches from the coating to form
pores, channels or paths in the coating, that can fill with the environmental fluid and
allow the fluid to enter the core and cause core to disintegrate leading to open up of
the coating in two halves, and modify the release characteristics of the formulation.
The pore formers can be inorganic or organic, and include materials that can be
dissolved, extracted or leached from the coating in the environment of use.
The term “bioavailable” as used herein, includes, but is not limited to the rate and
extent to which the drug(s) become bioavailable to the site of action after
administration.
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The term "Cmax " is the highest plasma concentration of the drug attained within the
dosing interval.
The term "Tmax " is the time period, which elapses after administration of the dosage
form at which the plasma concentration of the drug attains the highest plasma
concentration of drug attained within the dosing interval.
The term "AUC0-t " as used herein, means area under plasma concentration-time
curve from drug administration to last observed concentration at time t.
The term "AUC0-a" as used herein, means area under the plasma concentration-time
curve extrapolated to infinite time.
The term "mean", when preceding a pharmacokinetic value (e.g. mean Tmax)
represents the mean value of the pharmacokinetic value taken from a population of
patients or healthy volunteers.
In one general aspect of the invention there is provided a press-coated tablet,
comprising of a core comprising one or more active substances and optionally along
with one or more pharmaceutically acceptable excipients, and a coating surrounding
the said core, wherein the said core is being disposed within said coating such that
the coating thickness around the horizontal edges of the core is less than or equal to
the coating thickness around the vertical edges of the core, wherein the dosage form
delays the release of the active substance from the core for a period of about 2h to
10h after oral administration.
A wide variety of active substances may be employed in the present invention, which
are incorporated by reference to U.S. Patent Application No. 20070110807 into the
specification of the present invention. Drugs for treating conditions the symptoms of
which result from nocturnal circadian rhythms are particularly suitable. Accordingly,
drugs for treating incontinence, sleep disorders, apnoea, asthma, epilepsy,
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bronchitis, parkinsonism, rheumatoid arthritis, allergic rhinitis and ischaemic heart
diseases, cluster and migraine headache, congestive heart failure, and depression
are particularly suitable for use in tablets according to the present invention. Further,
drug substances that are metabolized by cytochrome P450 are also particularly
suitable, they include: Amitriptyline, caffeine, clomipramine, clozapine, fluvoxamine,
haloperidol, imipramine, mexilitine, oestradiol, olanzepine, paracetamol, propranolol,
tacrine, theophylline, warfarin, Bupropion, Cyclophosphamide, Celecoxib, Diclofenac,
Flubiprofen, Ibuprofen, glimepirideindome, thacin, naproxen, phenytoin, piroxicam,
tenoxicam, citalopram, diazepam, lansoprazole, omeprazole, pantoprozole,
propanolol, topiramate, Alpranolol, chlorpromazine, clomipramine, codeine,
Desipramine, dextromethorphan, diphenhydramine, donepezil, flecainide, fluoxetine,
labetalol, Methadone, metoprolol, mianserin, nortripyline, ondansetron, oxprenolol,
oxycodone, paroxetine, perhehexilene, pethidine, promethazine, risperdone,
thioridazine, ticlopidine, timolol, trimipramine, paracetamol, alprazolam, amiodarone,
budesonide, buprenorphine, buspirone, Calcium Channel Blockers, carbamazepine,
cisapride, clarithromycin, clonazepam, cocaine, cortisol, cyclosporine,
dexamethasone, erythromycin, fentanyl, ketoconazole, losartan, miconazole,
midazolam, quinidine, sertraline, statins, tacrolimus, tamoxifen, TCAs, triamzolam,
zolpidem, or mixtures thereof.
Additional examples of drug classes and drugs that can be employed in tablets of the
present invention include:
Antihistamines (e.g., azatadine maleate, brompheniramine maleate, carbinoxamine
maleate, chlorpheniramine maleate, dexchlorpheniramine maleate, diphenhydramine
hydrochloride, doxylamine succinate, methdilazine hydrochloride, promethazine,
trimeprazine tartrate, tripelennamine citrate, tripelennamine hydrochloride and
triprolidine hydrochloride);
Antibiotics (e.g., penicillin V potassium, cloxacillin sodium, dicloxacillin sodium,
nafcillin sodium, oxacillin sodium, carbenicillin indanyl sodium, oxytetracycline
hydrochloride, tetracycline hydrochloride, clindamycin phosphate, clindamycin
15
hydrochloride, clindamycin palmitate HCL, lincomycin HCL, novobiocin sodium,
nitrofurantoin sodium, metronidazole hydrochloride); antituberculosis agents (e.g.,
isoniazid);
Cholinergic agents (e.g., ambenonium chloride, bethanecol chloride, neostigmine
bromide, pyridostigmine bromide);
Antimuscarinics (e.g., anisotropine methylbromide, clidinium bromide, dicyclomine
hydrochloride, glycopyrrolate, hexocyclium methylsulfate, homatropine
methylbromide, hyoscyamine sulfate, methantheline bromide, hyoscine
hydrobromide, oxyphenonium bromide, propantheline bromide, tridihexethyl
chloride);
Sympathomimetics (e.g., bitolterol mesylate, ephedrine, ephedrine hydrochloride,
ephedrine sulphate, orciprenaline sulphate, phenylpropanolamine hydrochloride,
pseudoephedrine hydrochloride, ritodrine hydrochloride, salbutamol sulphate,
terbutaline sulphate);
Sympatholytic agents (e.g., phenoxybenzamine hydrochloride); miscellaneous
autonomic drugs (e.g., nicotine);
Iron preparations (e.g., ferrous gluconate, ferrous sulphate);
Haemostatics (e.g., aminocaproic acid);
Cardiac drugs (e.g., acebutolol hydrochloride, disopyramide phosphate, flecainide
acetate, procainamide hydrochloride, propranolol hydrochloride, quinidine gluconate,
timolol maleate, tocainide hydrochloride, verapamil hydrochloride);
Antihypertensive agents (e.g., captopril, clonidine hydrochloride, hydralazine
hydrochloride, mecamylamine hydrochloride, metoprolol tartrate ); vasodilators (e.g.,
papaverine hydrochloride);
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Non-steroidal anti-inflammatory agents (e.g., choline salicylate, ibuprofen,
ketoprofen, magnesium salicylate, meclofenamate sodium, naproxen sodium,
tolmetin sodium);
Opiate agonists (e.g., codeine hydrochloride, codeine phosphate, codeine sulphate,
dextromoramide tartrate, hydrocodone bitartrate, hydromorphone hydrochloride,
pethidine hydrochloride, methadone hydrochloride, morphine sulphate, morphine
acetate, morphine lactate, morphine meconate, morphine nitrate, morphine
monobasic phosphate, morphine tartrate, morphine valerate, morphine
hydrobromide, morphine hydrochloride, propoxyphene hydrochloride);
Anticonvulsants (e.g., phenobarbital sodium, phenytoin sodium, troxidone,
ethosuximide, valproate sodium);
Tranquilizers (e.g., acetophenazine maleate, chlorpromazine hydrochloride,
fluphenazine hydrochloride, prochlorperazine edisylate, promethazine hydrochloride,
thioridazine hydrochloride, trifluoroperazine hydrochloride, lithium citrate, molindone
hydrochloride, thiothixine hydrochloride);
Chemotherapeutic agents (e.g., doxorubicin, cisplatin, floxuridine, methotrexate,
combinations thereof);
Lipid lowering agents (e.g., gemfibrozil, clofibrate, HMG-CoA reductase inhibitors,
such as for example, atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin,
simvastatin);
H2-antagonists (e.g., cimetidine, famotidine, nizatidine, ranitidine HCl);
Anti-coagulant and anti-platelet agents (e.g., warfarin, cipyridamole, ticlopidine);
Bronchodilators (e.g., albuterol, isoproterenol, metaproterenol, terbutaline);
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Stimulants (e.g., benzamphetamine hydrochloride, dextroamphetamine sulphate,
dextroamphetamine phosphate, diethylpropion hydrochloride, fenfluramine
hydrochloride, methamphetamine hydrochloride, methylphenidate hydrochloride,
phendimetrazine tartrate, phenmetrazine hydrochloride, caffeine citrate);
Barbiturates (e.g., amylobarbital sodium, butabarbital sodium, secobarbital sodium);
Sedatives (e.g., hydroxyzine hydrochloride, methprylon); expectorants (e.g.,
potassium iodide);
Antiemetics (e.g., benzaquinamide hydrochloride, metoclopropamide hydrochloride,
trimethobenzamide hydrochloride);
Gastrointestinal drugs (e.g., ranitidine hydrochloride); heavy metal antagonists (e.g.,
penicillamine, penicillamine hydrochloride);
Antithyroid agents (e.g., methimazole);
Genitourinary smooth muscle relaxants (e.g., flavoxate hydrochloride, oxybutynin
hydrochloride);
Vitamins (e.g., thiamine hydrochloride, ascorbic acid);
Steroids, particularly glucocorticoids (e.g., prednisolone, methylprednisolone,
prednisone, cortisone, hydrocortisone, methylprednisolone, betamethasone,
dexamethasone, triamcinolone).
Unclassified agents (e.g., amantadine hydrochloride, colchicine, etidronate disodium,
leucovorin calcium, methylene blue, potassium chloride, pralidoxime chloride).
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The core is composed of either an immediate release or controlled release
pharmaceutical composition consisting of the active ingredient in admixture with
suitable excipients. If necessary, the core can be protected by a water-soluble or
water-insoluble film before coating with the coating composition. The core may be
prepared by various techniques known in the art such as direct compression, dry
granulation, melt granulation, wet granulation.
Typically a core may contain 0.1 to 90% by weight of active substance.
Coating is prepared by co-processing glyceryl behenate and dicalcium phosphate
with one or more pharmaceutically acceptable excipients. The coating may be
polymeric film and/or compression coating.
The tablets may also be compressed in the form of two or more layer tablet or presscoated
in the form of tab-in-tab or tab-in-tab-in-tab.The penetration of aqueous fluid
takes place through pores formed due to solubilization of the pore forming agent. For
the purpose of present invention, pore forming agent include one or more inorganic
salts of calcium ion.
Inorganic salts of calcium ion comprises but not limited to calcium phosphate,
calcium phosphate dihydrate, calcium phosphate anhydrous, dibasic calcium
phosphate, dibasic calcium phosphate monohydrate, dibasic calcium phosphate
dihydrate, anhydrous dibasic calcium phosphate, monobasic calcium phosphate,
tribasic calcium phosphate, calcium acetate, calcium carbonate, calcium chloride,
calcium hydroxide, calcium pyrophosphate, calcium sulfate, calcium sulfate
anhydrous, calcium sulfate dihydrate, or calcium sulfate hemihydrate.
In another general aspect of the invention, there is provided a press-coated tablet,
comprising of a core comprising one or more active substances and optionally along
with one or more pharmaceutically acceptable excipients, and a coating surrounding
the said core, wherein the said core is being disposed within said coating such that
the coating thickness around the horizontal edges of the core is less than or equal to
19
the coating thickness around the vertical edges of the core, wherein one or more
inorganic salts of calcium ion are melt granulated with glyceryl behenate.
The coating composition of the present invention may further comprises one or more
hydrophilic polymer, hydrophobic polymer or non-polymeric rate controlling
excipients.
Hydrophillic polymers is selected from the group consisting of one or more of
cellulose derivatives; polyhydric alcohols; saccharides, gums and derivatives thereof;
vinyl derivatives, polymers, copolymers or mixtures thereof; maleic acid copolymers;
polyalkylene oxides or copolymers thereof; acrylic acid polymers and acrylic acid
derivatives; or any combinations thereof.
Cellulose derivatives include, but are not limited to, ethyl cellulose, methylcellulose,
hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl
cellulose, hydroxymethyl cellulose, hydroxypropyl ethylcellulose, carboxymethylethyl
cellulose, carboxy- ethylcellulose, carboxymethyl hydroxyethylcellulose,
hydroxyethylmethyl carboxymethyl cellulose, hydroxyethyl methyl cellulose,
carboxymethyl cellulose (CMC), methylhydroxyethyl cellulose, methylhydroxypropyl
cellulose, carboxymethyl sulfoethyl cellulose, sodium carboxymethyl cellulose, or
combinations thereof.
Polyhydric alcohols include, but are not limited to, polyethylene glycol (PEG) or
polypropylene glycol; or any combinations thereof.
Saccharides, gums and their derivatives include, but are not limited to, dextrin,
polydextrin, dextran, pectin and pectin derivatives, alginic acid, sodium alginate,
polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropyl
starch, amylose and amylopectin, CMC agar; guar gum, locust bean gum, xanthan
gum, karaya gum, tragacanth, carrageenan, acacia gum, arabic gum or gellan gum
or the like; or any combinations thereof.
20
Vinyl derivatives, polymers, copolymers or mixtures thereof include, but are not
limited to, polyvinyl acetate, polyvinyl alcohol, mixture of polyvinyl acetate (8 parts
w/w) and polyvinylpyrrolidone (2 parts w/w) (Kollidon SR), copolymers of vinyl
pyrrolidone, vinyl acetate copolymers, polyvinylpyrrolidone (PVP); or combinations
thereof.
Polyalkylene oxides or copolymers thereof include, but are not limited to,
polyethylene oxide, polypropylene oxide, poly (oxyethylene)-poly (oxypropylene)
block copolymers (poloxamers) or combinations thereof.
Maleic acid copolymers include, but are not limited to, vinylacetate maleic acid
anhydride copolymer, styrene maleic acid anhydride copolymer, styrene maleic acid
monoester copolymer, vinylmethylether maleic acid anhydride copolymer, ethylene
maleic acid anhydride copolymer, vinylbutyiether maleic acid anhydride copolymer,
acrylonitrile methyl acrylate maleic acid anhydride copolymer, butyl acrylate, styrene
maleic acid anhydride copolymer or the like or any combinations thereof.
Suitable acrylic acid polymers include any suitable polyacrylic acid polymers or
carboxyvinyl polymers such as those available under the brand name carbopol.
Pharmaceutically acceptable acrylic polymer may be include one or more, but not
limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate
copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, aminoalkyl
methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid
alkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride),
methyl methacrylate, polymethacrylate, poly(methyl methacrylate), poly(methyl
methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer,
poly(methacrylic acid anhydride), and glycidyl methacrylate.
Hydrophobic polymer is selected from waxes, which are esters of fatty acids with long
chain monohydric alcohols natural waxes are often mixtures of such esters, and may
also contain hydrocarbons Waxes employed in the present invention include, but are
not limited to, natural waxes, such as animal waxes, vegetable waxes, and petroleum
21
waxes, paraffin waxes, microcrystalline waxes, petrolatum waxes, mineral waxes),
and synthetic waxes Specific examples include, but are not limited to spermaceti
wax, carnauba wax, Japan wax, bayberry wax, flax wax, beeswax, yellow wax,
Chinese wax, shellac wax, lanolin wax, sugarcane wax, candelilla wax, castor wax
paraffin wax, microcrystalline wax, petrolatum wax, carbowax, and the like, or
mixtures thereof.
Waxes are also monoglyceryl esters, diglyceryl esters, or; glyceryl esters (glycerides)
and derivatives and mixtures thereof formed from a fatty acid having from about 10 to
about 22 carbon atoms and glycerol, wherein one or more of the hydroxyl groups of
glycerol are substituted by a fatty acid. Glycerides employed in the present invention
include, but are not limited to, glyceryl monostearate, glyceryl distearate, glyceryl
tristearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monopalmitate, glyceryl
palmitostearate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl
didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl
monocaproate, glyceryl dicaproate, glyceryl tricaproate, glyceryl monomyristate,
glyceryl dimyristate, glyceryl trimyhstate, glyceryl monodecenoate, glyceryl
didecenoate, glyceryl tridecenoate, glyceryl behenate (compritol), polyglyceryl
diisostearate, lauroyl macrogolglycerides (Gelucire), oleoyl macrogolglycerides,
stearoyl macrogolglycerides, mixtures of monoglycerides and diglycerides of oleic
acid (Peceol), or combinations thereof.
Fatty acids include, but are not limited to, hydrogenated palm kernel oil,
hydrogenated peanut oil, hydrogenated palm oil, hydrogenated rapeseed oil,
hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated sunflower oil,
hydrogenated castor oil (Lubritab), hydrogenated cottonseed oil, and mixtures
thereof. Other fatty acids include, but are not limited to, decenoic acid, docosanoic
acid, stearic acid, palmitic acid, lauric acid, myristic acid, or the like, or mixtures
thereof.
22
Non-polymeric rate controlling excipients are selected from the group consisting of
fat, wax, fatty acid, fatty acid ester, long chain monohydric alcohol or their ester or
any combinations thereof.
In another general aspect of the invention, there is provided a press-coated tablet,
comprising of a core comprising one or more active substances and optionally along
with one or more pharmaceutically acceptable excipients, and a coating surrounding
the said core, wherein the said core is being disposed within said coating such that
the coating thickness around the horizontal edges of the core is less than or equal to
the coating thickness around the vertical edges of the core, wherein the ratio of width
of the tablet to the length of the tablet is less than the ratio of 1.33:1.
In another general aspect of the invention a press coated pharmaceutical
composition one or more active substances are selected from the group consisting of
prednisone, prednisolone, methylprednisolone, cortisone, hydrocortisone,
budesonide, dexamethasone, fludrocortisone, fluocortolone, cloprednole, deflazacort
and Triamcinolone.
In another general aspect of the invention, there is provided a press-coated tablet,
comprising of a core comprising one or more active substances and optionally along
with one or more pharmaceutically acceptable excipients, and a coating surrounding
the said core, wherein the said core is being disposed within said coating such that
the coating thickness around the horizontal edges of the core is less than or equal to
the coating thickness around the vertical edges of the core, wherein the
pharmaceutically acceptable excipients comprise one or more of diluents, fillers,
binders, disintegrant, lubricants, glidants and colorant.
Examples of suitable diluents include but are not limited to one or more of lactose,
lactose monohydrate, mannitol, sucrose, maltodextrin, dextrin, maltitol, sorbitol,
xylitol, powdered cellulose, cellulose gum, microcrystalline cellulose, starch, calcium
phosphate, or metal carbonate.
23
Examples of suitable binders include, but are not limited to, starch, gums,
pregelatinized starch, polyvinyl prrolidone (PVP), copovidone, cellulose derivatives,
such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and
carboxymethyl cellulose (CMC) and their salts.
Suitable lubricants include but are not limited to one or more talc, magnesium
stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic
acid, sodium stearyl fumarate, talc and sodium benzoate.
Compositions of the present invention may include a glidant such as, but not limited
to, colloidal silica, silica gel, precipitated silica, or combinations thereof.
Suitable disintegrant may include but are not limited to one or more of starch,
croscarmellose sodium, crospovidone, and sodium starch glycolate.
Moreover, the composition of the invention optionally include usual auxiliaries known
in the art such as saliva stimulating agents like citric acid, lactic acid, malic acid,
succinic acid, ascorbic acid, adipic acid, fumaric acid, tartaric acids; cooling sensation
agents like maltitol, monomenthyl succinate, ultracool; stabilizers like gums, agar;
taste masking agents like acrylic polymers, copolymers of acrylates, celluloses,
resins; coloring agents like titanium dioxide, natural food colors, dyes suitable for
food, drug and cosmetic applications or ascorbic acid palmitate or effervescing
agents like citric acid, tartaric acid, sodium bicarbonate, sodium carbonate and the
like.
In another general aspect of the invention, there is provided a press-coated tablet,
wherein shape of the dosage form comprise one or more of square, rectangular,
circular, oval, donut, cylindrical, pentagonal, hexagonal, heptagonal, octagonal,
pillowed shaped or a centrally notched round tablet.
In another general aspect of the invention, there is provided a press-coated tablet,
comprising of a core comprising one or more active substances and optionally along
24
with one or more pharmaceutically acceptable excipients, and a coating surrounding
the said core, wherein the said core is being disposed within said coating such that
the coating thickness around the horizontal edges of the core is less than or equal to
the coating thickness around the vertical edges of the core, used for treating
circadian phase dependent pathologies such as asthma, arthritis, epilepsy, migraine,
allergic rhinitis, cardiovascular disease, chronic inflammation, pain, rheumatoid
arthritis, polymyalgia rheumatica and peptic ulcer.
In another aspect, composition of the present invention is administered to host
comprising human patients suffering from circadian phase dependent pathologies.
In another general aspect of the invention a press coated pharmaceutical
composition in form of tablet, capsule, tablet in tablet, tablet in capsule, bilayer tablet,
trilayer tablet, in-lay tablet, microsphers, coated pellets, multiple unit pellet system,
granules, particles or combinations thereof.
The present invention is further illustrated by the following examples which are
provided merely to be exemplary of the invention and do not limit the scope of the
invention. Certain modifications and equivalents will be apparent to those skilled in
the art and are intended to be included within the scope of the present invention.
Examples
Example 1: Prednisone MR Tablets-1, 2 and 5 mg
Wet granulation process
Coating material composition
Core Shell Unit composition
Sr.
No.
Ingredients/Grade %w/w
Intragranular Ingredients
25
1. Calcium hydrogen phosphate
dihydrate (Calipharm D)
70-80
2. Microcrystalline Cellulose
(Avicel PH 101)
3.2-3.6
3. Glycerol dibehenate
(Compritol 888 ATO)
10-20
4. Povidone K29/32 3-7
5. Purified Water q.s
6. Colloidal Anhydrous Silica 0.5-1.0
7. Magnesium Stearate 0.5-1.0
Procedure:
Intragranular ingredients were taken together and sifted. The sifted material was
transferred to rapid mixer granulator. The sifted material in rapid mixer granulator
was granulated using the prepared binder solution. The granules obtained were dried
and then mixed with colloidal anhydrous silica and magnesium stearate.
Example 2: Core Tablet Unit Composition
Core Tablet Unit Composition
Sr.
No.
Ingredient/Grade %w/w
Intragranular Ingredients
1. Prednisone 1-10
2. Microcrystalline Cellulose
(Avicel PH 101)
15-25
3. Lactose Monohydrate
(Pharmatose 200 M)
65-75
4. Red Ferric Oxide E172 0.1-0.7
26
Binder Solution
5. Povidone (PVP K-30) 2-8
6. Purified Water q.s
Extragranular Ingredients
7. Croscarmellose Sodium
(Ac-Di-Sol)
4-8
8. Colloidal Silicon Dioxide
(Aerosil 200)
0.3-1.0
9. Magnesium Stearate 0.2-1.0
Procedure:
Intragranular ingredients were taken together and sifted except Red Ferric Oxide
which was sifted seperately. All the ingredients were transferred into suitable rapid
mixer granulator and dry mixed with impeller at a low speed. Wet granulation was
carried out using the binder solution. The granules obtained were dried and collected
in a pre-labeled container. Extragranular material were taken together, sifted and
collected in a pre-labeled container. This mixture was then transferred into low shear
blender and prelubrication was done.
Example 3:
Compression: (1mg Strength)
Tooling: 5.0mm round standard concave plain on both sides
Avg.Wt: 60.6 mg
Uniformity of Weight: 58.3-62.4 mg
Hardness: 40-43N
Thickness: 2.70-2.83 mm
Disintegration time: 1 min 12 sec
Friability: 0.07% w/w
Compression of Prednisone MR Tablets-1 mg
27
Tooling: 8.0 mm round Flat Faced Beveled Edges debossed with ‘45’ on one side
and plain on other side.
Avg.Wt.: 457-461 mg
Uniformity of Weight: 458.3-463.2 mg
Hardness: 55-65 N
Thickness: 5.92-5.98 mm
Example 4: Dissolution Conditions:
Sr.
No.
Time
points
(h)
6.8 pH
Phosphate
Buffer
% RSD
1 2 0 0
2 3 54 29.63
3 4 84 19.05
4 5 86 15.12
5 6 90 8.89
Example 5: Prednisone MR Tablets-1, 2 and 5 mg
Melt granulation process
Coating material composition
Core Shell Unit composition
Sr. No. Ingredient/Grade %w/w
Intragranular Ingredients
1.
Calcium hydrogen phosphate
dihydrate
(Calipharm D)
55-75
2.
Glycerol dibehenate
(Compritol 888 ATO)
15-35
Extragranular Ingredients
28
3. Yellow ferric oxide 0.05-0.2
4. Povidone K29/32 2-8
5.
Colloidal Silicon Dioxide
(Aerosil 200)
0.5-1.0
Lubricants
6. Magnesium Stearate 0.5-2
Procedure:
Accurately weighed quantity of Glyceryl dibehenate was melted in SS vessel at a
temperature of 65-750C to form a true liquefied wax. Calcium hydrogen phosphate
dihydrate was sifted and added to melted glyceryl dibehenate. The mixture was then
granulated while hot with vigorous mixing. The obtained material was then cooled.
This was then passed through mesh and collected in a pre-labeled container. Yellow
ferric oxide was sifted and collected in a pre-labeled container. Granules of glyceryl
behenate and calcium hydrogen phosphate dihydrate along with yellow ferric oxide,
povidone, Magnesium Stearate and colloidal silicon dioxide were transferred into
double cone blender and prelubricated. Blend was unloaded and compressed.
Example 6: Core Tablet Unit Composition
Core Tablet Unit Composition
Sr.
No.
Ingredient/Grade %w/w
Intragranular Ingredients
1. Prednisone 1-10
2. Microcrystalline Cellulose
(Avicel PH 101)
15-25
3. Lactose Monohydrate
(Pharmatose 200 M)
65-75
4. Red Ferric Oxide E172 0.1-0.7
29
5. Maize Starch
(Unipure FL)
5-15
Binder Solution
6. Purified Water q.s.
Extragranular Ingredients
7. Magnesium Stearate 0.2-1.0
Procedure:
All Intragranular ingredients were taken together and sifted except Red Ferric Oxide
which was sifted seperately. All the ingredients were transferred into suitable rapid
mixer granulator and dry mixed with impeller at a low speed. Wet granulation was
carried out using the binder solution. The granules obtained were dried and collected
in a pre-labeled container. Extragranular material were taken together, sifted and
collected in a pre-labeled container. This mixture was then transferred into low shear
blender and prelubrication was done.
Example 7: Core Compression: (5 mg Strength)
Tooling: 5.0mm round standard concave plain on both sides
Avg.Wt: 60.6 mg
Uniformity of Weight: 59.6-61.4 mg
Hardness: 25-35
Thickness: 2.3-2.4 mm
Disintegration time: 20 sec
Friability: 0.07% w/w
Compression of Prednisone MR Tablets- 5 mg (Finished Product)
Tooling: 8.0 mm round FFBE embossed with W5 on one side and plain on other side.
Description: Round, yellow colored, press/compression coated FFBE debossed with
W5 on one side and plain on other side.
Average Weight: 460.0 mg.
Layer-I: 200.0 mg, Layer-II 200.0 mg and Core tablet Weight: 60.0 mg
30
Thickness: 5.70-6.10 mm
Hardness: 45-80N
Friability: 0.021%w/w (At optimum Hardness)
Disintegration Time: 4 hrs 05 min in water
4 hrs 30 min in pH 6.8 Phosphate Buffer
Example 8: Dissolution Profile
No. of Units 6 24
Dissolution
media
6.8 pH phosphate buffer 6.8 pH phosphate buffer
Apparatus USP -II ,Paddle USP -II ,Paddle
Speed 50 RPM 50 RPM
Volume 900 mL 900 mL
Lag Phase 3 h 35 min to 4 h 01 min
(for optimum hardness- 50-
60N)
3 h 58 min to 4 h 52 min
(for high hardness-70-75 N)
3 h 47 min to 5 h 04 min
(for optimum hardness-
50-60N)
Example 9: Ondansetron MR Tablets- 4 and 8 mg
Melt granulation process
Coating material composition
Procedure:
Coating material composition was prepared as described in Example 5 using melt
granulation process.
Example 10: Core Tablet Unit Composition
Core Tablet Unit Composition
31
Sr.
No.
Ingredient/Grade %w/w
Intragranular Ingredients
1. Ondansetron hydrochloride dihydrate
equivalent to Ondansetron hydrochloride
1-10
2. Anhydrous Lactose
(DCL 21)
65-75
3. Microcrystalline cellulose (Avicel PH102) 6-10
4. Prezelatinized Starch 10-14
5. Colloidal silicon dioxide (Aerosil 200) 2-4
Binder Solution
6. Purified Water q.s
7. Magnesium Stearate 0.5-1
Procedure:
All Intragranular ingredients were taken together and sifted except Red Ferric Oxide
which was sifted seperately. All the ingredients were transferred into suitable rapid
mixer granulator and dry mixed with impeller at a low speed. Wet granulation was
carried out using the binder solution. The granules obtained were dried and collected
in a pre-labeled container. Extragranular material were taken together, sifted and
collected in a pre-labeled container. This mixture was then transferred into low shear
blender and prelubrication was done.
.
Example 11: Core Compression: (4 mg Strength)
Tooling: 5.0mm round standard concave plain on both sides
Avg.Wt: 60.3 mg
Uniformity of Weight: 59.5-61.3 mg
Hardness: 25-35
Thickness: 2.3-2.4 mm
Disintegration time: 20 sec
Friability: 0.06% w/w
32
Compression of Ondansetron Tablets- 4 mg (Finished Product)
Tooling: 8.0 mm round FFBE embossed with W5 on one side and plain on other side.
Description: Round, press/compression coated FFBE debossed with W5 on one side
and plain on other side.
Average Weight: 460.0 mg.
Layer-I: 200.0 mg, Layer-II 200.0 mg and Core tablet Weight: 60.0 mg
Thickness: 5.70-6.10 mm
Hardness: 45-80N
Friability: 0.022%w/w (At optimum Hardness)
Disintegration Time: 4 hrs 10 min in water
4 hrs 40 min in pH 6.8 Phosphate Buffer
Example 12: Dissolution Profile
No. of Units 6 24
Dissolution
media
6.8 pH phosphate buffer 6.8 pH phosphate buffer
Apparatus USP -II ,Paddle USP -II ,Paddle
Speed 50 RPM 50 RPM
Volume 900 mL 900 mL
Lag Phase 3 h 40 min to 4 h 10 min (for
optimum hardness-50-60N)
3h 58 min to 4 h 52 min
(for high hardness-70-75 N)
3 h 53 min to 4 h 50 min
(for optimum hardness -
50-60N)
Example 13: Alprazolam MR Tablets- 0.5 and 1 mg
Melt granulation process
Coating material composition
Procedure:
33
Coating material composition was prepared as described in Example 5 using melt
granulation process.
Example 14: Core Tablet Unit Composition
Core Tablet Unit Composition
Sr. No. Ingredient/Grade %w/w
Intragranular Ingredients
1. Alprazolam 0.1-5
2. Mannitol (Pearlitol SD 200) 70-80
3. Microcrystalline cellulose (Avicel
PH102)
10-20
4. FD&C Yellow No. 6 Aluminum
Lake
0.2-0.7
5. Colloidal silicon dioxide (Aerosil
200)
2-5
Extragranular Ingredients
6. Magnesium Stearate 0.1-1
Procedure:
All intragranular material were taken together and sifted except colorant which was
sifted seperately. All the ingredients were transferred into suitable rapid mixer
granulator and dry mixing was carried out with impeller slow speed. Extragranular
material magnesium stearate were sifted and collected in a pre-labeled container
separately. Sifted magnesium stearate was then transferred into low shear blender
and lubrication was done.
Example 15: Core Direct Compression: (0.5 mg Strength)
Tooling: 5.0mm round standard concave plain on both sides
Avg.Wt: 60.5 mg
34
Uniformity of Weight: 59.8-61.1 mg
Hardness: 25-35
Thickness: 2.3-2.4 mm
Disintegration time: 20 sec
Friability: 0.06% w/w
Compression of Alprazolam Tablets- 0.5 mg (Finished Product)
Tooling: 8.0 mm round FFBE embossed with W5 on one side and plain on other side.
Description: Round, yellow colored, press/compression coated FFBE debossed with
W5 on one side and plain on other side.
Average Weight: 460.0 mg.
Layer-I: 200.0 mg, Layer-II 200.0 mg and Core tablet Weight: 60.0 mg
Thickness: 5.70-6.10 mm
Hardness: 45-80N
Friability: 0.022%w/w (At optimum Hardness)
Disintegration Time: 4 hrs 15 min in water
4 hrs 40 min in pH 6.8 Phosphate Buffer
Example 16: Dissolution Profile
No. of Units 6 24
Dissolution
media
6.8 pH phosphate buffer 6.8 pH phosphate buffer
Apparatus USP -II ,Paddle USP -II ,Paddle
Speed 50 RPM 50 RPM
Volume 900 mL 900 mL
Lag Phase 3 h 45 min to 4 h 15 min (for
optimum hardness -50-60N)
3hrs 58 min to 4 hrs 52 min
(for high hardness-70-75 N)
3 h 58 min to 4 h 43 min
(for optimum-50-60N
hardness)
35
Example 17: Albuterol MR Tablets- 2 and 4 mg
Melt granulation process
Coating material composition
Procedure:
Coating material composition was prepared as described in Example 5 using melt
granulation process.
Example 18: Core Tablet Unit Composition
Core Tablet Unit Composition
Sr.
No.
Ingredient/Grade %w/w
Intragranular Ingredients
1. Albuterol 1-10
2. Lactose Monohydrate
(Pharmatose 200 M)
60-80
3. Pregelatinized starch
(Starch 1500)
10-20
4. Sodium lauryl sulfate 2-5
Binder Solution
5. Purified Water q.s
Extragranular Ingredients
6. Pregelatinized starch
(Starch 1500)
3-7
7. Sodium lauryl sulfate 3-7
8. Magnesium Stearate 0.5-1.5
Procedure:
All intragranular material were sifted and transferred into suitable rapid mixer
granulator. Dry mixing was carried out with impeller on slow speed. Wet granulation
36
was performed using the binder solution. Resultant granules were dried and collected
in a pre-labeled container. Extragranular material magnesium stearate was sifted and
collected in a pre-labeled container separately. Sifted magnesium stearate was then
transferred into low shear blender and lubrication was done.
Example 19: Core Compression: (0.5 mg Strength)
Tooling: 5.0mm round standard concave plain on both sides
Avg.Wt: 60.5 mg
Uniformity of Weight: 59.8-61.1 mg
Hardness: 25-35
Thickness: 2.3-2.4 mm
Disintegration time: 20 sec
Friability: 0.06% w/w
Compression of Albuterol Tablets- 0.5 mg (Finished Product)
Tooling: 8.0 mm round FFBE embossed with W5 on one side and plain on other side.
Description: Round, press/compression coated FFBE debossed with W5 on one side
and plain on other side.
Average Weight: 460.0 mg.
Layer-I: 200.0 mg, Layer-II 200.0 mg and Core tablet Weight: 60.0 mg
Thickness: 5.70-6.10 mm
Hardness: 45-80N
Friability: 0.022%w/w (At optimum Hardness)
Disintegration Time: 4 hrs 15 min in water
4 hrs 40 min in pH 6.8 Phosphate Buffer
Example 20: Dissolution Profile
No. of Units 6 24
Dissolution
media
6.8 pH phosphate buffer 6.8 pH phosphate buffer
37
Apparatus USP -II ,Paddle USP -II ,Paddle
Speed 50 RPM 50 RPM
Volume 900 mL 900 mL
Lag Phase 3 h 38 min to 4 h 02 min (for
optimum hardness-50-60N)
3h 58 min to 4 h 52 min
(for high hardness-70-75 N)
3 h 45 min to 4 h 35
min (for optimum-50-
60N hardness)
Example 21: Budesonide MR Tablets- 3 mg
Melt granulation process
Coating material composition
Procedure:
Coating material composition was prepared as described in Example 5 using melt
granulation process.
Example 22: Core Tablet Unit Composition
Core Tablet Unit Composition
Sr.
No.
Ingredient/Grade %w/w
Intragranular Ingredients
1. Budesonide 1-5
2. Lactose monohydrate
(Pharmatose 200 M)
60-70
3. Crospovidone (PPXL 10) 5-15
Binder Solution
4. Povidone (PVP K-30) 1-5
5. Purified Water q.s
Extragranular Ingredients
38
6. Crospovidone (PPXL 10) 7-13
7. Colloidal Silicon Dioxide 1-5
8. Magnesium Stearate 1-3
Procedure:
All intragranular material were sifted and transferred into suitable rapid mixer
granulator. Dry mixing was carried out with impeller on slow speed. Wet granulation
was performed using the binder solution. Resultant granules were dried and collected
in a pre-labeled container. Extragranular material magnesium stearate was sifted and
collected in a pre-labeled container separately. Sifted magnesium stearate was then
transferred into low shear blender and lubrication was done.
Example 23: Core Compression: (0.5 mg Strength)
Tooling: 5.0mm round standard concave plain on both sides
Avg. Wt: 60.1 mg
Uniformity of Weight: 59.5-60.8 mg
Hardness: 25-35
Thickness: 2.4-2.5 mm
Disintegration time: 20 sec
Friability: 0.05% w/w
Compression of Budesonide Tablets- 0.5 mg (Finished Product)
Tooling: 8.0 mm round FFBE embossed with W5 on one side and plain on other side.
Description: Round, press/compression coated FFBE debossed with W5 on one side
and plain on other side.
Average Weight: 460.0 mg.
Layer-I: 200.0 mg, Layer-II 200.0 mg and Core tablet Weight: 60.0 mg
Thickness: 5.80-6.30 mm
Hardness: 45-80N
Friability: 0.025%w/w (At optimum Hardness)
Disintegration Time: 4 hrs 10 min in water
39
4 hrs 35 min in pH 6.8 Phosphate Buffer
Example 24: Dissolution Profile
No. of Units 6 24
Dissolution
media
6.8 pH phosphate buffer 6.8 pH phosphate buffer
Apparatus USP -II ,Paddle USP -II ,Paddle
Speed 50 RPM 50 RPM
Volume 900 mL 900 mL
Lag Phase 3 h 46 min to 4 h 15 min (for
optimum hardness-50-60N)
3h 58 min to 4 h 52 min
(for high hardness-70-75 N)
3 h 55 min to 4 h 45
min (for optimum-50-
60N hardness)
40
We Claim-
1. A press-coated tablet, comprising of
a core comprising one or more active substances and optionally along with
one or more pharmaceutically acceptable excipients, and
a coating surrounding the said core, wherein the said core is being disposed
within said coating such that the coating thickness around the horizontal edges
of the core is less than or equal to the coating thickness around the vertical
edges the core,
wherein the dosage form delays the release of the active substance from the
core for a period of about 2h to 10h after oral administration.
2. The press-coated tablet of claim 1, wherein the coating composition comprises
one or more inorganic salts of calcium ion co-processed with glyceryl
behenate.
3. The press-coated tablet of claim 2, wherein inorganic salts of calcium ion
comprises one or more of calcium phosphate, calcium phosphate dihydrate,
calcium phosphate anhydrous, dibasic calcium phosphate, dibasic calcium
phosphate monohydrate, dibasic calcium phosphate dihydrate, anhydrous
dibasic calcium phosphate, monobasic calcium phosphate, tribasic calcium
phosphate, calcium acetate, calcium carbonate, calcium chloride, calcium
hydroxide, calcium pyrophosphate, calcium sulfate, calcium sulfate anhydrous,
calcium sulfate dihydrate or calcium sulfate hemihydrate.
4. The press-coated tablet as claimed in the preceding claims, wherein one or
more inorganic salts of calcium ion are melt granulated with glyceryl behenate.
5. The press-coated tablet as claimed in the preceding claims, wherein coating
composition further comprises hydrophilic or hydrophobic polymer.
41
6. The press-coated tablet as claimed in the preceding claims, wherein the ratio
of width of the tablet to the length of the tablet is less than the ratio of 1.33:1.
7. The press-coated tablet as claimed in the preceding claims, wherein one or
more active substances are selected from the group consisting of
ondansetron, alprazolam, albuterol sulphate, budesonide, dexamethasone,
prednisone, prednisolone, methylprednisolone, cortisone, hydrocortisone,
budesonide, dexamethasone, fludrocortisone, fluocortolone, cloprednole,
deflazacort or triamcinolone.
8. The press-coated tablet as claimed in the preceding claims, wherein the
pharmaceutically acceptable excipients comprise one or more of diluents,
fillers, binders, disintegrant, lubricants, glidants and colorant.
9. A method of treating circadian phase dependent pathologies such as asthma,
arthritis, epilepsy, migraine, allergic rhinitis, cardiovascular disease, chronic
inflammation, pain, rheumatoid arthritis, polymyalgia rheumatica and peptic
ulcer wherein the method comprises administering a press-coated tablet as
claimed in claim 1 to a host in need of said treatment.
10. The press-coated tablet as claimed in claim 1, wherein the composition is in
form of tablet, capsule, tablet in tablet, tablet in capsule, bilayer tablet, trilayer
tablet, in-lay tablet, microsphers, coated pellets, multiple unit pellet system,
granules, particles or combinations thereof.

Dated 18th day of August, 2011

For Wockhardt Limited

(Mandar Kodgule)
Authorized Signatory