PHARMACEUTICAL COMPOSITION FOR CONTROLLED DRUG DELIVERY SYSTEM

COMPOSITION PHARMACEUTIQUE POUR SYSTEME A LIBERATION PROGRESSIVE DE MEDICAMENTS

English Abstract

The present invention describes a novel controlled release multilayer
composition that is capable of delivering a first active agent from one layer
immediately followed by continuous controlled delivery of second active agent
from matrix forming layer while the dosage form floats and is retained in the
fluid of the environment. The floating bilayer system comprises of immediate
release layer containing one active agent and a disintegrating agent whereas
second floating matrix forming layer comprises a gas generating component, a
gelling agent, and a second active agent. The present invention relates more
particularly to a controlled release fluoroquinolone compositions, which
maintain a therapeutically effective blood concentration of fluoroquinolone
for duration with once a day administration.

French Abstract

L'invention porte sur une nouvelle composition multicouche à libération progressive libérant un premier agent actif d'une couche immédiatement suivi de la libération progressive continue d'un deuxième agent actif provenant d'une couche formant une matrice, tandis que la forme posologique qui flotte et retenue dans le fluide environnant. Le système bicouche flottant comporte une couche à libération immédiate contenant un agent actif et un agent désintégrateur et une deuxième couche formant une matrice flottante comprenant un élément gazogène, un gélifiant, et un deuxième agent actif. L'invention porte plus particulièrement sur une composition à libération progressive de fluoroquinolone qui maintient une concentration sanguine efficace de fluoroquinolone permettant une administration quotidienne.

Claims

WHAT IS CLAIMED IS:
1. The solid pharmaceutical composition for oral administration containing
two
or more layers comprising of
a) At least one layer containing an active agent and disintegrating agent
intended for immediate delivery,
b) At least one second layer that includes an active agent for controlled drug
delivery, gas generating component, a matrix forming gelling agent which is
intended for controlled delivery of active agent to maintain therapeutic
effective concentrations with once a day administration in a human body and
also can be extended to veterinary use with appropriate modifications.
c) An optional third layer placed between the above two layers comprising an
inert excipients selected from lactose, mannitol, microcrystalline cellulose,
starch, dicalcium phosphate, the layer physically separates the other two
layers and facilitates delivery of two incompatible active agents.
2. The solid pharmaceutical composition for oral administration according to
claim 1, wherein the said composition on oral ingestion, comes in contact
with gastric fluid, the first layer disintegrates rapidly releasing the active
ingredient instantaneously, the second layer considerably swells and gels in
presence of fluid of the environment resulting in volume expansion
entrapping the gas generated by the reaction of gas generating component
and fluid of the environment, thus, releasing the active agent from second
layer which may be same or different, in a controlled manner while the
system floats in gastric environment.
3. The solid pharmaceutical composition for oral administration according to
claim 1, wherein composition is preferably a bilayer tablet and the layers are
differentiated by using different colors.
24

4. The solid pharmaceutical composition for oral administration according to
claim 1, wherein a first layer comprises of a disintegrating agent which can
be
selected from group of starch, sodium starch glycolate, pregelatinised starch,
crosslinked poly vinyl pyrrolidone, cross linked carboxy methyl cellulose, ion
exchange resin, the most preferred being sodium starch glycolate. Sodium
starch glycolate is present in an amount ranging from about 0.25% to 2.5%,
more preferably about 0.5 to 2.0% and most preferably is about 1% by weight
based on the total weight of the composition.
5. The second controlled release layer of the solid pharmaceutical composition
for oral administration according to claim 1, wherein gas generating
component can be selected from the group consisting of a water soluble
carbonates, sulphites, and bicarbonates such as sodium carbonate, sodium
bicarbonate, sodium metabisulphite, calcium carbonate, and combinations
thereof, which on contact with gastric fluid release carbon dioxide or sulphur
dioxide gas.
6. The solid pharmaceutical composition for oral administration according to
claim 1, wherein the gas generating component is sodium bicarbonate
present in an amount from about 2.0% to about 15.0%, preferably in an
amount from about 5.0% to 10% and the most preferred is about 7% by
weight based on the total weight of the composition.
7. The solid pharmaceutical composition for oral administration according to
claim 1, wherein the second controlled release layer contains one or more
matrix forming gelling agents selected from group consisting of hydroxypropyl
methylcellulose, methylcellulase, hydroxypropyl cellulose, carbomer, carboxy
methylcellulose, gum tragacanth, gum acacia, guar gum, pectin, modified
starch derivatives, xanthan gum, locusta bean gum, sodium alginate, the
most preferred being hydroxypropyl methylcellulose which on contact with
gastric fluid swells and gels, forming matrix structure that entraps the gas
released and also release the active agent in a controlled manner.
25

8. The solid pharmaceutical composition for oral administration according to
claim 1, wherein the matrix forming gelling agent is hydroxypropyl
methylcellulose i.e. Methocel® which has a viscosity in the range from
4,000
cps to about 100,000cps. Concentration of matrix forming polymer is from
about 5% to about 20.0%, preferably from 7.5% to 15% and the most
preferred is about 10% by weight based on the total weight of the
composition.
9. The solid pharmaceutical composition for oral administration according to
claim 1, wherein the most preferred combination of matrix forming gelling
agent contains combination of Methocel® K4M and Methocel® K100M.
10. The solid pharmaceutical composition for oral administration according to
claim 1, wherein the gas generating component is adapted to generate a gas
in contact with gastric fluid, wherein the gelling agent is adapted to form a
substantially gas-impermeable gel matrix in the presence of a fluid, and
thereby trapping the gas generated effectively causing the device to float in
the fluid while the second active agent is released slowly in a controlled
manner.
11. The solid pharmaceutical composition for oral administration according to
claim 1, wherein each layer of the said dosage form additionally comprises
an additive selected from the group consisting of magnesium stearate,
calcium stearate, zinc stearate, powdered stearic acid, hydrogenated
vegetable oils, talc, polyethylene glycol, mineral oil, an FD&C color,
modified
cellulose, lactose, gelatin, starch paste, acacia, tragacanth, povidone,
polyethylene glycol, colloidal silicon dioxide, talc, sodium lauryl sulfate,
quaternary ammonium salts, mannitol, sodium chloride, sodium sulfate,
sodium phosphate, magnesium chloride, magnesium sulfate, magnesium
phosphate, microcrystalline cellulose, sodium starch glycolate, lactose,
26

microcrystalline cellulose, sucrose, glucose, mannitol, calcium carbonate,
colloidal anhydrous silica, polyethylene glycols, waxes, hydrogenated castor
oil, starch, PVP and a combination thereof.
12. The solid pharmaceutical composition for oral administration according to
claim 1, wherein active agent in Immediate Release layer and active agent in
Controlled Release layer may be same or different. The preferred
composition according to claim 1, comprises same active agent in both the
layers.
13. The solid pharmaceutical composition for oral administration according to
claim 1, wherein the total amount of active agent is in the range from about
5% to about 80% of an total active ingredient, more preferably about 25% to
75% and the most preferably about 72% by weight based on the total weight
of the composition.
14. The solid pharmaceutical composition for oral administration according to
claim 1, wherein the therapeutic agent is selected from the groups consisting
of ACE inhibitor, alcohol abuse preparation, alpha adrenergic agonist,
amoebicide, analgesics, anti-inflammatory agents, anthelmintics, anti-
arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants,
anti-depressants, anti-diabetics, anti-diuretics, anti-emetic, anti-
epileptics,
anti-flatulent, anti-viral, anti-fungal agents, anti-gout agents, anti-
hypertensive
agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-
neoplastic agents, anti-parkinson agents, anti-psychotic, anti-pyretic,
obesity
management agents, anti-asthematics, immunosuppressants, anti-protozoal
agents, anti-thyroid agents, anti-tussives, anxiolytic, sedatives, hypnotics,
neuroleptics, beta-Blockers, cardiac inotropic agents, corticosteriods,
diuretics, gastro-intestinal agents, histamine receptor antagonists,
norcotics,
NSAIDs, anorectics, anorexiants, antacid, blood modifiers, anti convulsant,
bone matabolism regulators, bronchial dialators, calcium channel blockers,
beta adregeneic blockers, diuretics, CNS agents, cough preparations, erectile
27

dysfunction therapeutic agent, lipid regulating agents, muscle relaxants, anti-
anginal agents, psychotherapeutic agents, osteoporosis preparations,
respiratory agents, nutritional agents, anti convulsant, smoking cessation
agents, thyroid preparation, sex hormones, stimulants, urinary tract agents,
uterine contractors, and mixtures thereof.
15. The solid pharmaceutical composition for oral administration according to
claim 1, wherein the active agent is preferably selected from group of
fluoroquinolone antibiotic such as ciprofloxacin, ofloxacin, pefloxacin,
grepafloxacin, enoxacin, amifioxacin, fleroxacin, temafloxacin, lomefloxacin,
norfloxacin, sparfloxacin, levofloxacin, gatifloxacin and moxifloxacin.
16. The solid pharmaceutical composition for oral administration according to
claim 1, wherein the most preferred active agents is ofloxacin.
17. The solid pharmaceutical composition for oral administration according to
claim 1, wherein the most preferred active agents is ciprofloxacin.
18. The solid pharmaceutical composition for oral administration according to
claim 1, wherein the system may be coated with a transparent polymeric film
merely to provide protection from moisture which doesn't retard the release.
The said coating polymer is selected from a group of hydroxypropyl
methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl
alcohol or methacrylic acid polymer, the most preferred being Eudragit E
100®.
19. The solid pharmaceutical composition for oral administration according to
claim 1, wherein the preferred polymer for coating is Eudragit® E 100 and
is
present in concentration from about 1% to about 5.0%, the most preferred is
about 2% by weight based on the total weight of the composition.
28

20. The process of manufacturing the solid pharmaceutical composition for oral
administration according to claim 1, is as described below
Preparation of Immediate release granule I:
a) The active agent, microcrystalline cellulose, colloidal anhydrous silica,
colour are sifted through 40# sieve and mixed in a suitable mixer for 10
minutes.
b) The blend is granulated with warm water ( 50-55°) by mechanical
means.
c) Granules are dried at 45-50°C till LOD is between 2-3%w/w.
d) Dried granules are mechanically sifted through 30# sieve.
e) The granules are lubricated with mixture of sodium starch glycolate,
colloidal anhydrous silica, colour, magnesium stearate (presifted through
40#) by mechanical mixing.
Preparation of Floating controlled release Granules II:
a) Active agent, Methocel® K 4M, Methocel® K100M, lactose are sifted
through 30# sieve and mixed by mechanical means in a area with a
controlled temperature and humidity.
b) The blend is granulated using water and granules are dried at 45-
50°C.
c) The dried granules are sifted through 30# sieve and lubricated with
sodium bicarbonate, talc and magnesium stearate( presifted through 40#
sieve).
Compression:
Granules I & II are compressed on bilayer tablet compression machine.
Coating:
Appropriate quantity of Eudragit® E 100 is dissolved in blend of Isopropyl
alcohol, dichloromethane water under stirring to get clear solution. The
solution is strained through 100# & used for film coating of bilayer tablets
21. The process of manufacturing the solid pharmaceutical composition for oral
administration according to claim 20, wherein the solid pharmaceutical
composition for oral administration comprises of two or more layers
containing
a) At least one layer containing an active agent and disintegrating agent
29

intended for immediate delivery,
b) at least one second layer that includes an active agent for controlled drug
delivery, gas generating component, a matrix forming gelling agent which is
intended for controlled delivery of active agent to maintain therapeutic
effective concentrations with once a day administration in a human body and
also can be extended to veterinary use with appropriate modifications.
c) An optional third layer placed between the above two layers comprising an
inert excipients selected from lactose, mannitol, microcrystalline cellulose,
starch, dicalcium phosphate, the layer physically separates the other two
layers and facilitates delivery of two incompatible active agents.
22. The process of manufacturing the solid pharmaceutical composition for oral
administration according to claim 20, wherein the said composition on oral
ingestion, comes in contact with gastric fluid, the first layer disintegrates
rapidly releasing the active ingredient instantaneously, the second layer
considerably swells and gels in presence of fluid of the environment resulting
in volume expansion entrapping the gas generated by the reaction of gas
generating component and fluid of the environment, thus, releasing the active
agent from second layer which may be same or different, in a controlled
manner while the system floats in gastric environment.
23. The process of manufacturing the solid pharmaceutical composition for oral
administration according to claim 20, wherein the solid pharmaceutical
composition for oral administration is preferably a bilayer tablet and the
layers
are differentiated by using different colors.
24. The process of manufacturing the solid pharmaceutical composition for oral
administration according to claim 20, wherein a first layer comprises of a
disintegrating agent which can be selected from group of starch, sodium
starch glycolate, pregelatinised starch, crosslinked poly vinyl pyrrolidone,
cross linked carboxy methylcellulose, ion exchange resin, the most preferred
being sodium starch glycolate. Sodium starch glycolate is present in an

amount ranging from about 0.25% to 2.5%, more preferably about 0.5 to
2.0% and most preferably is about 1% by weight based on the total weight of
the composition.
25. The process of manufacturing the solid pharmaceutical composition for oral
administration according to claim 20, wherein the second controlled release
layer contains gas generating component which can be selected from the
group consisting of a water soluble carbonates, sulphites, and bicarbonates
such as sodium carbonate, sodium bicarbonate, sodium metabisulphite,
calcium carbonate, and combinations thereof, which on contact with gastric
fluid release carbon dioxide or sulphur dioxide gas.
26. The process of manufacturing the solid pharmaceutical composition for oral
administration according to claim 20, wherein the gas generating component
is sodium bicarbonate present in an amount from about 2.0% to about 15.0%,
more preferably from about 5% to 10% and the most preferred is about 7%
by weight based on the total weight of the composition.
27. The process of manufacturing the solid pharmaceutical composition for oral
administration according to claim 20, wherein the second controlled release
layer contains one or more matrix forming gelling agents selected from group
consisting of hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl
cellulose, carbomer, carboxy methylcellulose, gum tragacanth, gum acacia,
guar gum, pectin, modified starch derivatives, xanthan gum, locusta bean
gum, sodium alginate, the most preferred being hydroxypropyl
methylcellulose which on contact with gastric fluid swells and gels, forming
matrix structure that entraps the gas released and also release the active
agent in a controlled manner.
28. The process of manufacturing the solid pharmaceutical composition for oral
administration according to claim 20, wherein the matrix forming gelling agent
is hydroxypropyl methylcellulose i.e. Methocel® which has a viscosity in
the
31

range from 4,000 cps to about 100,000cps. Concentration of matrix forming
polymer is from about 5% to about 20.0%, preferably from 7.5% to 15% and
the most preferred is about 10% by weight based on the total weight of the
composition.
29. The process of manufacturing the solid pharmaceutical composition for oral
administration according to claim 20, wherein the most preferred combination
of matrix forming gelling agent contains combination of Methocel® K4M and
Methocel® K100M.
30. The process of manufacturing the solid pharmaceutical composition for oral
administration according to claim 20, wherein the gas generating component
is adapted to generate a gas in contact with gastric fluid, wherein the
gelling
agent is adapted to form a substantially gas-impermeable gel matrix in the
presence of a fluid, and thereby trapping the gas generated effectively
causing the device to float in the fluid while the second active agent is
released slowly in a controlled manner.
31. The process of manufacturing the solid pharmaceutical composition for oral
administration according to claim 20, wherein the floating bilayer system is
adapted to be taken into a person's gastric region and upper intestine by
being oral administered.
32. The process of manufacturing the solid pharmaceutical composition for oral
administration according to claim 20, wherein each layer of the said dosage
form additionally comprises an additive selected from the group consisting of
magnesium stearate, calcium stearate, zinc stearate, powdered stearic acid,
hydrogenated vegetable oils, talc, polyethylene glycol, mineral oil, an FD&C
color, modified cellulose, lactose, gelatin, starch paste, acacia, tragacanth,
povidone, polyethylene glycol, colloidal silicon dioxide, talc, sodium lauryl
sulfate, quaternary ammonium salts, mannitol, sodium chloride, sodium
sulfate, sodium phosphate, magnesium chloride, magnesium sulfate,
32

magnesium phosphate, microcrystalline cellulose, sodium starch glycolate,
lactose, microcrystalline cellulose, sucrose, glucose, mannitol, calcium
carbonate, colloidal anhydrous silica, polyethylene glycols, waxes,
hydrogenated castor oil, starch, PVP and a combination thereof.
33. The process of manufacturing the solid pharmaceutical composition for oral
administration according to claim 20, wherein active agent in Immediate
Release layer and active agent in Controlled Release layer may be same or
different. The preferred composition comprises same active agent in both the
layers.
34. The process of manufacturing the solid pharmaceutical composition for oral
administration according to claim 20, wherein the total amount of active agent
is in the range from about 5% to about 80% of an total active ingredient, more
preferably about 25% to 75% and the most preferably about 72% by weight
based on the total weight of the composition.
35. The process of manufacturing the solid pharmaceutical composition for oral
administration according to claim 20, wherein the active agent is selected
from ACE inhibitor, alcohol abuse preparation, alpha adrenergic agonist,
amoebicide, analgesics, anti-inflammatory agents, anthelmintics, anti-
arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants,
anti-depressants, anti-diabetics, anti-diuretics, anti-emetic, anti-
epileptics,
anti-flatulent, anti-viral, anti-fungal agents, anti-gout agents, anti-
hypertensive
agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-
neoplastic agents, anti-parkinson agents, anti-psychotic, anti-pyretic,
obesity
management agents, anti-asthematics, immunosuppressants, anti-protozoal
agents, anti-thyroid agents, anti-tussives, anxiolytic, sedatives, hypnotics,
neuroleptics, beta-Blockers, cardiac isotropic agents, corticosteriods,
diuretics, gastro-intestinal agents, histamine receptor antagonists,
norcotics,
NSAIDs, anorectics, anorexiants, antacid, blood modifiers, anti convulsant,
bone matabolism regulators, bronchial dialators, calcium channel blockers,
33

beta adregeneic blockers, diuretics, CNS agents, cough preparations, erectile
dysfunction therapeutic agent, lipid regulating agents, muscle relaxants, anti-
anginal agents, psychotherapeutic agents, osteoporosis preparations,
respiratory agents, nutritional agents, anti convulsant, smoking cessation
agents, thyroid preparation, sex hormones, stimulants, urinary tract agents,
uterine contractors, and mixtures thereof.
36. The process of manufacturing the solid pharmaceutical composition for oral
administration according to claim 20, wherein the active agent is preferably
selected from group of fluoroquinolone antibiotic such as ciprofloxacin,
ofloxacin, pefloxacin, grepafloxacin, enoxacin, amifioxacin, fleroxacin,
temafloxacin, lomefloxacin, norfloxacin, sparfloxacin, levofloxacin,
gatifloxacin and moxifloxacin.
37. The process of manufacturing the solid pharmaceutical composition for oral
administration according to claim 20, wherein the most preferred active
agents is ofloxacin.
38. The process of manufacturing the solid pharmaceutical composition for oral
administration according to claim 20, wherein the most preferred active gents
is Ciprofloxacin.
39. The process of manufacturing the solid pharmaceutical composition for oral
administration according to claim 20, wherein the system may be coated with
a polymeric film merely to provide protection from moisture which doesn't
retard the release. The said coating polymer is selected from a group of
hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl
pyrrolidone, polyvinyl alcohol or methacrylic acid polymer, the most preferred
being Eudragit E 100®.
40. The process of manufacturing the solid pharmaceutical composition for oral
administration according to claim 20, wherein the preferred polymer for
34

coating is Eudragit® E 100 and is present in concentration from about 1%
to
about 5.0%, the most preferred is about 2% by weight based on the total
weight of the composition.
35

Description

CA 02486794 2004-11-19
WO 03/101431 PCT/IN02/00133
PHARMACEUTICAL COMPOSITION
FOR CONTROLLED DRUG DELIVERY SYSTEM
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention generally relates to novel pharmaceutical compositions for
oral administration. This invention relates in particular to such
compositions in the form of floating bilayer controlled release system for
delivery of one or more active agents.
This invention relates more particularly to immediate delivery of a first
active agent followed by continuous controlled delivery of a second agent,
which may be same or different from the first active agent, while the
system or dosage form floats in the fluid of the environment (e.g., the
stomach), thereby being retained in the environment of use for an
extended period of time.
2. Description of the Prior Art
Various proposals have been made to achieve controlled release
i5 pharmaceutical compositions to slow down the release rate of a drug from
preparations so that therapeutically active concentrations are maintained
in the body for longer time. In recent years, there have been numerous
developments in polymeric carriers and controlled release systems such
as films with the drug in a polymer matrix, monolithic devices, reservoir
device, microparticles, microspheres or nanoparticles in the form of
reservoir and matrix devices, osmotic pumps, pH dependant coatings,
soluble polymers with covalently attached 'pendant' drug molecules.
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Oral route is the most preferred route of administration for various types of
active agents however few active agents exhibit a "small absorption
window" in gastrointestinal tract i.e. they are more effectively absorbed
only from stomach, duodenum, and initial portion of small intestine. (e.g.
S methyl dopa, captopril) Hence, in case of such active agents to achieve
maximum absorption, it is mandatory to retain these drugs in stomach for
extended period of time.
Some active agents are intended for exerting a medical action at gastric
level e.g. antibiotics like ofloxacin, ciprofloxacin in the treatment of H.
to pylori infection, antacids, proton pump inhibitors and H2 receptor
antagonists. In order to achieve maximum therapeutic efficacy, it is
beneficial to maintain such drugs in close proximity to gastric mucosa.
There also exists a requirement of therapeutic cases wherein
administration (as acute/symptomatic treatment) of a first therapeutically
is effective dose of an active agent is required whereas in following steps,
slow administration of maintenance dose of the same or different drug is
necessary. These types of therapeutic needs result in complicated
dosage regimen that are not always correctly adhered to by the patients
especially the outpatients. Non compliance with dosage regimen is
z,d directly proportional to complexity and no. of daily doses.
The major concern 'with antibiotic therapy is development of resistance by
microorganisms. The variation in the antibiotic drug concentrations in the
body fluid after conventional drug therapy leads to development of
resistance by microorganisms. Many a times this problem is further
aggravated due to patient non-compliance due to missed doses.
Fluoroquinolones are one of the most widely used in the management of
infectious diseases. Their potent and broad spectrum of activity, efficacy
and relative safety make them useful for both community acquired and
2

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nosocomial infections. However, inappropriate prescribing and missed
posology can lead to antimicrobial resistance.
The candidates representing fluoroquinolone class are ciprofloxacin,
ofloxacin, pefloxacin, grepafloxacin, enoxacin, amifioxacin, fleroxacin,
temafloxacin, lomefloxacin, norfloxacin, sparfloxacin, levofloxacin,
gatifloxacin and moxifloxacin. Ciprofloxacin and ofloxacin have exhibited
wide spectrum of antimicrobial activity.
The present invention will be further elaborated with exemplifications with
ciprofloxacin and ofloxacin those being the representative candidates of
i a fluoroquinolone group but the scope of the invention is not limitative
thereof.
Ciprofloxacin is 1-cyclopropyl-6-fluoro-1, 4-drhydro-4-oxo-7-(1-
piperazinyl)-3-quinoline carboxylic acid. It is a faintly yellowish to light
yellow crystalline substance. Ciprofloxacin differs from other quinolones in
is that it has a fluorine atom at the 6-position, a piperazine moiety at the 7-
position, and a cyclopropyl ring at the 1-position. The recommended adult
dosage 500-mg every 12 hours. The usual duration of treatment is 7-14
days.
An important factor affecting the absorption of orally administered drug
zo through gastrointestinal tract is transit time in gastrointestinal tract.
Ciprofloxacin is absorbed only from the stomach to the jejunum. Hence to
achieve maximum efficacy it would be beneficial if the drug is retained in
stomach for extended period of time. This problem can be overcome by
developing a system that is retained in stomach for prolonged time and
zs can release active agent in a controlled manner.
Another widely used fluororquinolone candidate, ofloxacin is the
racemate, (~)-9- fluoro-2,3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl)-
7-oxo-7H- pyrido [1,2,3-de]-1,4-benzo-xazine -6- carboxylic acid.
3

CA 02486794 2004-11-19
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Ofloxacin is an off-white to pale yellow crystalline powder. The molecule
exists as a zwitterion at the pH conditions in the small intestine. The
relative solubility characteristics of ofloxacin at room temperature indicate
that ofloxacin is considered to be soluble in aqueous solutions with pH
S between 2 and 5. It is sparingly to slightly soluble in aqueous solutions
with pH 7 and freely soluble in aqueous solutions with pH above 9. The
usual dose of ofloxacin is 200mg to 400mg every 12 hours and the usual
duration of treatment is 7-10 days. Considering the maximum solubility of
drug, it would be more beneficial to retain the drug in stomach for
~o prolonged duration so as to achieve maximum absorption.
As described above and exemplified with the two leading fluoroquinolone
derivatives, the efficacy and patient compliance of the fluoroquinolones
and similar drugs can be improved by retaining the compositions in
stomach for longer time. To facilitate their longer duration of treatments
and to avoid variation in drug concentrations in the body (which occurs
with conventional therapy) it is further desirable to extend the release of
drug that would lead to better patient compliance and success of therapy.
Thus, in the view of the above discussion it can be concluded that to
achieve maximum efficacy of the fluoroquinolone derivatives it is desirable
,~.c to retain the active agents in stomach and acquire uniform continuous
release of the same in a controlled manner. It is also desirable to avoid
the initial lag time in the release of antibiotic from controlled release
composition hence the pharmaceutical composition of the present
invention is designed to have an initial loading dose as an immediate
t5 release form.
The concept of bilayer tablet is well known in the art which is generally
employed for various purposes such as stabilization (US pat. 6,287,600),
taste masking (US pat. 5,690,959) or delivering two drugs having
synergistic effects (US 6,319,519). Bastin described use of bilayer tablet
4

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WO 03/101431 PCT/IN02/00133
for administration of drugs prone to abuse where the drug layer and
gelling layer are separate and the concentration of gelling agent is such
that it doesn't retard release of active agent but facilitates drug release
similar to that of conventional tablet. Blume (US pat. 6,372,252) discloses
s guaifenesin sustained release bilayer tablet offering bioavailability of
drug
for 12 hours where first portion is of immediate release and second is for
controlled release. The release is not site specific.
Several literatures describe buoyant dosage forms which improve gastric
residence time. Most of the patents disclose monolithic systems (US
to 4,126,672 and US 4,167,558). US patents 4,814,178 and 4,814,179
describe non-complexed sustained release floating tablets including
hydrocolloid gelling agent, oil, selected therapeutic agent, water and have
multitudes of air holes with density less than 1. These systems are not
restricted to floating in gastric fluid. US patent 4,140,755 discloses two
r.s layered buoyant tablet containing antacid where one layer is formulated to
immediately release the active and other to obtain density lower than
gastric fluid and provide controlled release of drug. Franz (US pat.
5,232,704) discloses sustained release bilayer formulation where one
layer is drug release layer and other is a floating layer which releases all
zo the drug over a extended period in stomach. Conte et al (Us pat
5,681,583) disclosed pharmaceutical multilayered tablet which exhibited
high volume increase in contact with biological fluid, increasing volume of
tablet and retaining the dosage form in stomach. Dennis (US pat
5,169,638) described buoyant controlled release powder formulation
comprising basic active agent, salt of alginic acid and hydrocarbon gelling
agent. Alza corporation (US pat. 4,036,228, 4,847,093, 4,344,929)
describe osmotic device containing gas generating agent and releasing
drug as a effervescent generated fine dispersion over osmotic gradient.
Us patent 4,777,033 discloses oral compositions containing sodium
3o bicarbonate as gas generating agent along with hydrocolloid polymer

CA 02486794 2004-11-19
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which offers buoyancy to the system and releasing drug in a controlled
manner but not specific to stomach.
All the above systems describe either bilayer tablets or gastro-retentive
compositions or combined bilayer gastro-retentive formulation which are
either intended for immediate release, or only for controlled delivery of
drugs which pose problems of bioavailibility fluctuations. To overcome
these insufficiencies, the inventors of the present invention have come out
with a novel pharmaceutical composition of floating bilayer system
wherein the first layer is designed to release active agent immediately
to avoiding lag time in the therapy and the matrix forming second layer that
releases drug in a controlled manner while the system floats in gastric
environment.
The present invention relates to a controlled release fluoroquinolone
formulation for oral administration and methods of its manufacture. In
~g particular, it relates to a controlled release fluoroquinolone formulation
which maintains a therapeutically effective blood concentration of
fluoroquinolone with once a day administration. The present invention
further relates to a modified release bi-layer fluoroquinolone tablet which
demonstrates a maximum serum concentration equivalent to an
2o immediate release tablet yet maintains a therapeutically effective blood
concentration with once a day administration.
SUMMARY OF THE INVENTION
It is an object of this invention to provide a novel solid pharmaceutical
composition for oral administration in the form of floating bilayer system
2s that allows immediate delivery of one active agent followed by release of
second active agent from specialized matrix forming layer which causes
the system to float.
6

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It is another object of the present invention to provide a drug delivery
system that exhibits immediate release of one active ingredient present in
one layer followed by controlled release of second active agent
incorporated in second layer which can be same or different than the first
one.
It is also an object of the invention to provide a drug delivery system for
delivering fluoroquinolone derivatives that floats and thereby is retained in
the stomach
It is a further object of the present invention to provide such a
o composition, which releases active agent from one layer instantaneously
due to rapid disintegration of the layer in the fluid of the environment of
use.
It is yet another object of the present invention to develop a bilayer
system where a gas generating component of a second layer produces
I5 gas which gets entrapped by swollen gelled hydrophilic matrix thus
causing the system to float, retain in the stomach and release the active
agent in a controlled manner from the matrix.
It is yet another object of the present invention to develop a floating
bilayer system for delivering fluoroquinolone derivatives that maintains
zo therapeutically active concentrations of fluoroquinolones with once a day
administration thus leading to better patient compliance.
Thus, the pharmaceutical bilayer composition as described in the present
invention is effective for immediate release of active agent from one layer
followed by continuous, controlled delivery of active agent present in
~s second layer which is capable of acting locally in gastrointestinal tract
or
acting systemically by absorption via stomach and upper part of the
intestine which can be same or different than the first active. The rate at
7

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which the drug from the second matrix forming controlled release layer is
released depends on the rate of diffusion of the active agent through
swollen polymeric matrix.
Other features, advantages and objectives of this invention and its
preferred embodiments will become apparent from the detailed
description and accompanying claims, which follow.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is a novel solid pharmaceutical composition in the
form of a floating bilayer system for oral administration that is adapted to
o deliver a first active agent from an first layer immediately upon reaching
the gastrointestinal tract, and deliver a second active agent from a second
layer which may be same or different, in a controlled manner over a
specific time period. The second layer is also adapted to provide
buoyancy for the device, thereby making the device effectively float and
cs remain in the stomach.
The present invention provides a solid pharmaceutical composition for
oral administration containing two or more layers comprising of
a) At least one layer containing an active agent and disintegrating agent
intended for immediate delivery,
o b) at least one second layer that includes an active agent for controlled
drug delivery, gas generating component, a matrix forming gelling agent
which is intended for controlled delivery of active agent to maintain
therapeutic effective concentrations with once a day administration in
human body and also be administered to veterinary class with appropriate
s5 modifications.
c) An optional third layer placed between the above two layers comprising
an inert excipients selected from lactose, mannitol, microcrystalline
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cellulose, starch, dicalcium phosphate, the layer physically separates the
other two layers and facilitates delivery of finro incompatible active agents.
The said composition of the present invention on oral ingestion, comes in
contact with gastric fluid, the first layer disintegrates rapidly releasing
the
5- active ingredient instantaneously, the second layer considerably swells
and gels in presence of fluid of the environment resulting in volume
expansion entrapping the gas generated by the reaction of gas generating
component and fluid of the environment, thus, releasing the active agent
from second layer which may be same or different, in a controlled manner
io while the system floats in gastric environment.
The preferred embodiment of the present invention wherein solid
pharmaceutical composition is preferably a bilayer tablet and two layers
are distinguished by different colors.
A preferred embodiment of the present invention comprises about 5% to
cs about 80% of an total active ingredient, more preferably about 25% to
75% and the most preferably about 72% of the total active agent by
weight based on the total weight of the composition.
The active agent preferably present in the first layer is in the range of
about 2% to 20%, more preferably between 5% to 17% and most
zo preferably about 10% of the active agent by weight based on the total
weight of the composition.
The preferred ratio of active agent in immediate layer to that in controlled
release layer is in the range of 1:1 to about 1:12 and more preferably from
about 1:3 to about 1:10.
ZS A first layer of the preferred embodiment of the present invention
comprises of a disintegrating agent which can be selected from group of
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starch, sodium starch glycolate, pregelatinised starch, crosslinked poly
vinyl pyrrolidone, Gross linked carboxy methyl cellulose, ion exchange
resin, the most preferred being sodium starch glycolate. Sodium starch
glycolate helps in rapid disintegration of the first layer as the system
comes in contact with the fluid of the environment thus releasing the
active agent instantaneously. Sodium starch glycolate is present in an
amount ranging from about 0.25% to 2.5%, more preferably 0.5 to 2.0%
and most preferably is about 1 % by weight based on the total weight of
the composition.
~o The second layer of the preferred embodiment of the present invention
comprises about 45% to about 75% of an active ingredient, more
preferably about 50% to 70% and most preferably is about 62% by weight
based on the total weight of the composition along with about 2% to about
15% of a gas generating material, about 5% to about 20% of a gelling
,5 agent. As used herein, percentage amounts for an ingredient are the
percent weights of the ingredients based on the total weight of the
composition, which may be abbreviated as "% w/w."
The active agent as described in the present invention comprises
therapeutic compounds which can be formulated into the present floating
so bilayer system include ACE inhibitor, alcohol abuse preparation, alpha
adrenergic agonist, amoebicide, analgesics, anti-inflammatory agents,
anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral
agents, anti-coagulants, anti-depressants, anti-diabetics, anti-diuretics,
anti-emetic, anti-epileptics, anti-flatulent, anti-viral, anti-fungal agents,
z5 anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine
agents, anti-muscarinic agents, anti-neoplastic agents, anti-Parkinson
agents, anti-psychotic, anti-pyretic, obesity management agents, anti-
asthematics, immunosuppressants, anti-protozoal agents, anti-thyroid
agents, anti-tussives, anxiolytic, sedatives, hypnotics, neuroleptics, beta-
Blockers, cardiac inotropic agents, corticosteriods, diuretics, gastro-

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intestinal agents, histamine receptor antagonists, norcotics, NSAIDs,
anorectics, anorexiants, antacid, blood modifiers, anti convulsant, bone
matabolism regulators, bronchial dialators, calcium channel blockers, beta
adregeneic blockers, diuretics, CNS agents, cough preparations, erectile
dysfunction therapeutic agent, lipid regulating agents, muscle relaxants,
anti-anginal agents, psychotherapeutic agents, osteoporosis preparations,
respiratory agents, nutritional agents, anti convulsant, smoking cessation
agents, thyroid preparation, sex hormones, stimulants, urinary tract
agents, uterine contractors, and mixtures thereof. The pharmaceutical
tQ composition as described in the present invention can be employed for
any new active ingredients for human as well as veterinary use which
would be invented in future, with appropriate modifications and not limited
only to the catagories mentioned above.
The preferred embodiment of the present invention comprising the active
is agent for controlled delivery and the active agent for immediate delivery
may exhibit small absorption window in gastrointestinal tract.
The active ingredient present in the first immediate layer and the active
ingredient present in the second controlled release layer of the floating
bilayer system of the present invention may be same or different. In case
.zo of the preferred embodiments of the present invention both the drugs are
the same.
The preferred embodiment of the present invention comprising the active
agent is preferably selected from group of fluoroquinolone antibiotic such
as ciprofloxacin, ofloxacin, pefloxacin, grepafloxacin, enoxacin,
sr...s amifioxacin, fleroxacin, temafloxacin, lomefloxacin, levofloxacin,
norfloxacin, sparfloxacin, trovafloxacin, gatifloxacin and moxifloxacin.
The second layer of the pharmaceutical composition of the present
invention comprises gas generating component which generates gas on
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contact with gastric fluid and is selected from group of water soluble
carbonates, sulfites and bicarbonates such as sodium carbonate, sodium
bicarbonate, sodium metabisulfite, calcium carbonate. The most
preferred being sodium bicarbonate and is present in an amount from
about 2% to 15%, preferably from about 5.0% to 10.0% and the most
preferred is about 7% by weight based on the total weight of the
composition. The gas generating coi'nponent upon interaction with gastric
fluid generates carbon dioxide or sulfur dioxide that gets entrapped within
hydrated gel matrix of the gelling agent. The amount of gas generating
o component present is at least 7.5% of the concentration of the active
agent present in the second layer and more preferably about 10%.
The second controlled release layer of the pharmaceutical composition of
the present invention contains one or more matrix forming gelling agents
selected from group consisting of hydroxypropyl methylcellulose,
~5 methylcellulose, hydroxypropyl cellulose, carbomer, carboxy
methylcellulose, gum tragacanth, gum acacia, guar gum, pectin, modified
starch derivatives, xanthan gum, locusta bean gum, sodium alginate, the
most preferred being hydroxypropyl methylcellulose i.e. Methocel~ which
on contact with gastric fluid swells and gels, forming matrix structure that
~o entraps the gas released and also release the active agent in a controlled
manner.
The most preferred matrix forming gelling agent of the present invention is
hydroxypropyl methylcellulose which has a viscosity in the range from
4,OOOcps to about 100,OOOcps. Concentration of matrix forming gelling
~5 agent is from about 5% to about 20.0% more preferred being 7.5% to
15% and the most preferred being 10% by weight based on the total
weight of the composition. The preferred embodiment of the present
invention contains a combination of matrix forming gelling agent
comprising of Methocel~ K4M and Methocel~ K100M. The ratio between
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concentration of Methocel~ K 4 M to Methocel~ K 100M is in the range of
1:0.25 to about 1:5.
The pharmaceutical composition of the present invention can also
comprise any other suitable ingredient well known to those skilled in the
art, such as adsorbents, fillers, antioxidants, buffering agents, colorants,
flavorants, sweetening agents, tablet antiadherents, lubricants, tablet
binders, diluents, tablet direct compression excipients, tablet
disintegrants, tablet glidants, polishing agents, and other equivalent
excipients selected from the group consisting of magnesium stearate,
io calcium stearate, zinc stearate, powdered stearic acid, hydrogenated
vegetable oils, talc, polyethylene glycol, mineral oil, an FD&C color,
modified cellulose, lactose, gelatin, starch paste, acacia, tragacanth,
povidone, polyethylene glycol, colloidal silicon dioxide, talc, sodium lauryl
sulfate, quaternary ammonium salts, mannitol, sodium chloride, sodium
i5 sulfate, sodium phosphate, magnesium chloride, magnesium sulfate,
magnesium phosphate, microcrystalline cellulose, sodium starch
glycolate, lactose, microcrystalline cellulose, sucrose, glucose, mannitol,
calcium carbonate, colloidal anhydrous silica, polyethylene glycols,
waxes, hydrogenated castor oil, starch, polyvinyl pyrrolidone and a
2o combination thereof.
Furthermore preferred embodiments of the present invention may be
coated with a polymeric film merely to provide protection from moisture.
The said coating polymer is selected from a group of hydroxypropyl
methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl
.z5 alcohol or methacrylic acid polymer, the most preferred being Eudragit E
100~. The said coating is transparent, soluble in fluid of the environment
i.e. soluble in acidic pH and does not retard the release of active agent.
The coating imparts moisture barrier properties to increase stability.
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The solid pharmaceutical composition of the present invention is coated
and the most preferred polymer for coating is Eudragit~ E 100 which is
present in concentration from about 1 % to about 5.0%, the most preferred
is about 2% by weight based on the total weight of the composition.
The pharmaceutical composition as described by the present invention is
prepared by process as described below:
Preparation of immediate release granule I:
The granules can be prepared either by process A or B as described
below.
t o Process A:
a) The active agent, microcrystallline cellulose, colloidal anhydrous silica,
colour are sifted through 40# sieve and mixed in a suitable mixer for 10
minutes.
b) The blend is granulated with warm water (50-55°) by mechanical
t5 means.
c) Granules are dried at 45-50°C till LOD is between 2-3%wlw.
d) Dried granules are mechanically sifted through 30# sieve.
e) The granules are lubricated with mixture of sodium starch glycolate,
colloidal anhydrous silica, colour, magnesium stearate (presifted through
Zo. 40#) by mechanical mixing.
Process B:
a) The active agent, microcrystallline cellulose, colloidal anhydrous silica,
colour, sodium starch glycolate, colloidal anhydrous silica, colour,
magnesium stearate are sifted through 40# sieve and mixed in a suitable
25 mixer for 10 minutes.
b) The blend is slugged on rotary compression machine or compacted
using roll compactor
c) The slugs or compacts are sifted through 30# sieve to obtain fine
granules.
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c) The granules are further lubricated with part of the magnesium stearate
(presifted through 40#) by mechanical mixing.
Preparation of Floating controlled release Granules II:
The granules can, be prepared either by process A or B as described
below.
Process A:
a) Active agent, Methocel~ K 4M, Methocel~ K100M, lactose are sifted
through 30# sieve and mixed by mechanical means in a area with a
controlled temperature and humidity.
to b) The blend is granulated using water and granules are dried at 45-
50°C.
c) The dried granules are sifted through 30# sieve and lubricated with
sodium bicarbonate, talc and magnesium stearate( presifted through
40# sieve).
Process B:
a) Active agent, Methocel~ K 4M, Methocel~ K100M, lactose, sodium
bicarbonate, talc and magnesium stearate are sifted through 30# sieve
and mixed by mechanical means in a area with a controlled
temperature and humidity.
b) The blend is dry granulated and sifted through 20# sieve.
Compression:
Granules I & II are compressed on bilayer tablet compression machine.
Coatin
Appropriate quantity of Eudragit~ E 100 is dissolved in blend of Isopropyl
alcohol, dichloromethane water under stirring to get clear solution. The
solution is strained through 100# & used for film coating of bilayer tablets

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The most preferred process being process A for preparation of immediate
release and controlled release granules.
The invention will be more fully understood from the following
examples. These examples are to be constructed as illustrative of the
invention and not limitative thereof
Example 1 - Ofloxacin
Example 1 discloses a floating bilayer system according to the present
invention wherein the active agent is Ofloxacin, which is required for the
treatment of local action on H. pylori in the stomach.
t o 1. Ingredients of Immediate lacer % w/w
Ofloxacin 7.0
Microcrystalline cellulose 1.5
Anhydrous Colloidal Silica 1.0
Color iron oxide yellow 1.0
Sodium starch glycolate 1.0
Magnesium stearate 0.5
2. Ingredients of Controlled release layer % w/w
Ofloxacin 63.0
Methocel~ K 100M 6.0
Methocel~ K 4M 4.0
Sodium bicarbonate 7.0
Lactose 4.0
Talc 1.0
Magnesium stearate 1.0
25 3. Coating % w/w
Eudragit~ E 100 2.0
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The tablet of Example 1 is prepared by following process
Preparation of Immediate release granule I:
a) Ofloxacin, microcrystalline cellulose, colloidal anhydrous silica, colour
are sifted through 40# sieve and mixed in a suitable mixer for 10 minutes.
b) The blend is granulated with warm water (50-55°) by mechanical
means.
c) Granules are dried at 45-50°C till LOD is between 2-3%w/w.
d) Dried granules are mechanically sifted through 30# sieve.
e) The granules are lubricated with mixture of sodium starch glycolate,
colloidal anhydrous silica, colour, magnesium stearate (presifted through
40#) by mechanical mixing.
Preparation of Floating controlled release Granules II:
a) Ofloxacin, Methocel~ K 4M, Methocel~ K100M, lactose are sifted
through 30# sieve and mixed by mechanical means in a area with a
$ controlled temperature and humidity.
b) The blend is granulated using water and granules are dried at 45-
50°C.
c) The dried granules are sifted through 30# sieve and lubricated with
sodium bicarbonate, talc and magnesium stearate( presifted through
40# sieve).
Compression:
Granules I & II are compressed on Manesty bilayer tablet compression
machine.
Coating:
Appropriate quantity of Eudragit~ E 100 is dissolved in blend of Isopropyl
alcohol, dichloromethane water under stirring to get clear solution. The
solution is strained through 100# & used for film coating of bilayer tablets
The tablet of Example 1 was tested for dissolution in 0.1 N HCI using USP
apparatus 1 at 100 rpm. The release profile is as follows:
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Ofloxacin released
Time (hrs.) (cumulative
%)
1 24.25
2 33.22
4 50.0
8 67.72
16 94.30
Example 2
Example 2 discloses a floating bilayer system according to the present
,o invention wherein the active agent is ciprofloxacin, which is required for
systemic action and absorbed only from the upper part of gastrointestinal
tract.
1. Ingredients of Immediate layer % w/w
Ciprofloxacin base 15.0
Microcrystalline cellulose 2.0
Anhydrous Colloidal Silica 0.95
Color iron oxide yellow 1.0
Crosslinked polyvinyl pyrrolidone 0.89
Starch 1500 1.0
zo Magnesium stearate 0.4
2. Ingredients of Controlled release layer % w/w
Ciprofloxacin base 60.0
Methocel~ K 100M 3.5
Methocel~ K 4M 3.5
ss Sodium bicarbonate 7.5
Lactose 1.0
Talc
0.5
Magnesium stearate 1.0
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3. Coating % W/W
Eudragit~ E 100 2.0
The tablet of Example 2 is prepared by following process
Pre~~aration of Immediate release granule I:
a) Ciprofloxacin, microcrystalline cellulose, colloidal anhydrous silica,
colour are sifted through 40# sieve and mixed in a suitable mixer for 10
minutes.
b) The blend is granulated using aqueous solution of starch 1500 (50-
55°)
by mechanical means.
c) Granules are dried at 45-50°C till LOD is between 2-3%w/w.
d) Dried granules are mechanically sifted through 30# sieve.
e) The granules are lubricated with mixture of croslinked polyvinyl
pyrrolidone, colloidal anhydrous silica, colour, magnesium stearate
(presifted through 40#) by mechanical mixing.
Preparation of Floating controlled release Granules II:
a) Ciprofloxacin, Methocel~ K 4M, Methocel~ K100M, lactose are sifted
through 30# sieve and mixed by mechanical means in a area with a
controlled temperature and humidity.
b) The blend is granulated using water and granules are dried at 45-
50°C.
c) The dried granules are sifted through 30# sieve and lubricated with
sodium bicarbonate, talc and magnesium stearate( presifted through
40# sieve).
Compression:
~> Granules I & II are compressed on Manesty bilayer tablet compression
machine.
Coatin
Appropriate quantity of Eudragit~ E 100 is dissolved in blend of Isopropyl
alcohol, dichloromethane water under stirring to get clear solution. The
solution is strained through 100# & used for film coating of bilayer tablets
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The tablet of Example 2 was tested for dissolution in 0.1 N HCI using USP
apparatus 1 at 100 rpm. The release profile is as follows:
ciprofloxacin, released
Time (hrs.) (cumulative %)
1 21.39
2 39.30
4 52.02
8 72.80
16 89.50
!o Example 3
Example 3 discloses a floating bilayer system according to the present
invention wherein the active agent is levofloxacin.
1. Ingredients of Immediate I~er % w/w
Levofloxacin 6.5
15 Microcrystalline cellulose 2.5
Anhydrous Colloidal Silica 1.0
Color iron oxide yellow 1.0
Sodium starch glycolate 1.2
Magnesium stearate 0.4
.Zo 2. Ingredients of Controlled release layer
Levofloxacin 62.5
Methocel~ K 100M 5.0
Methocel~ K 4M 3.3
Sodium bicarbonate 7.5
Lactose 5.0
Talc 1.1

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Magnesium stearate 1.0
3. Coatin
Eudragit~ E 100 2.0
The tablet of Example 3 is prepared by following process
Preparation of Immediate release granule I:
a) Levofloxacin, microcrystalline cellulose, colloidal anhydrous silica,
colour are sifted through 40# sieve and mixed in a suitable mixer for 10
minutes.
b) The blend is granulated with warm water (50-55°) by mechanical
means.
c) Granules are dried at 45-50°C till LOD is between 2-3%w/w
d) Dried granules are mechanically sifted through 30# sieve.
e) The granules are lubricated with mixture of sodium starch glycolate,
colloidal anhydrous silica, colour, magnesium stearate (presifted through
40#) by mechanical mixing.
Preparation of Floating controlled release Granules II:
a) Levofloxacin, Methocel~ K 4M, Methocel~ K100M, lactose, sodium
bicarbonate, talc and stearic acid are sifted through 30# sieve and
mixed by mechanical means in a area with a controlled temperature
,t 0 and humidity.
b) The blend is dry granulated and sifted through 20# sieve.
Compression:
Granules I & II are compressed on Manesty bilayer tablet compression
machine.
2s Coating:
Appropriate quantity of Eudragit~ E 100 is dissolved in blend of Isopropyl
alcohol, dichloromethane water under stirring to get clear solution. The
solution is strained through 100# & used for film coating of bilayer tablets
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The tablet of Example 3 was tested for dissolution in 0.1 N HCI using USP
apparatus 1 at 100 rpm. The release profile is as follows:
levofloxacin released
Time (hrs.) (cumulative
%)
1 25.65
2 37.84
4 47.75
8 68.22
16 95.87
Thus, compositions according to the present invention do not only provide
gastric-retentive dosage forms which release active agents in a controlled
manner through an floating bilayer system but also provides initial
instantaneous release of active agent avoiding delay in antimicrobial
action.
~S Compositions according to the present invention have an advantage that
they may release part of the active agent immediately avoiding lag time
and then the compositions may be retained for a long period of time in the
stomach of a mammal, thereby delivering an active agent over a period of
time that is significant for the clinical need with ince a day administration
which offers better patient compliance. Also compositions according to
the present invention have the advantage that they may provide gastric
retention in order to improve the absorption of the active agents which are
absorbed only from the stomach to jejunum, and also to offer local
treatment in the stomach.
It is to be understood that the examples and embodiments described
hereinabove are for the purposes of providing a description of the present
invention by way of examples and are not to be viewed as limiting the
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present invention in any way. Modification that may be made to that
described in above examples by those of ordinary skill in the art is also
contemplated by the present invention and is to be included within the
spirit.
23