Indian Patents. 269661:GASTRORETENTIVE FORMULATIONS AND MANUFACTURING PROCESS THEREOF

Title of Invention	GASTRORETENTIVE FORMULATIONS AND MANUFACTURING PROCESS THEREOF
Abstract	The present invention concerns gastroretentive formulation comprising an active substance granulated with a mixture of a weak gelling agent, a strong gelling agent, and a gas generating agent and process for manufact ring said formulation.

Full Text	WO 2007/010400 PCT/IB2006/002636 1 GASTRORETENTIVE FORMULATIONS AND MANUFACTURING PROCESS THEREOF The invention relates to gastroretentive formulations, in particular tablets, and to the process for manufacturing said formulations. An important factor affecting the absorption of orally administered drug through gastro-intestinal tract is transit time in gastrointestinal tract. Some active substances, for example metformin and ciprofloxacin, are known as being absorbed only from the stomach to the jejunum, i.e in the upper part of the gastrointestinal tract. Hence, to achieve maximum efficiency with a minimum of active substance, it would be beneficial that the formulation be retained during a prolonged time in the stomach and allows therein a sustained release of the active substance. Some attempts have already been done to achieve formulations with such a sustained release in the stomach, either thanks to the use of multilayer tablets such as in US 6,797,283 (Edgren et al.), US patent application 20030232081, or thanks to tablets which are sufficiently small to be ingested and which swell after ingestion such as in US6,635,280 (Shell et al.) and US 6,660,300 (Timmins et al.), and which further include disintegrating agent and effervescent agent, such as in US 6,261,601 (Talwar et al.). However, these formulations are not completely satisfactory and it still exists a need for formulations which are able to be retained in the higher part of the gastrointestinal tract and to release the active substance during several hours in the stomach. Unexpectedly and surprisingly, the inventors have found that those objectives are fulfilled with a WO 2007/010400 PCT/IB2006/002636 2 gastroretentive formulation comprising an active substance granulated with a mixture of a weak gelling agent, a strong gelling agent, and a gas generating agent. In the present invention, a "weak gelling agent" is a compound presenting a viscosity of less than 175 centipoise when it is in a form of a 2.6 % W/V aqueous dispersion at 25°C. A "strong gelling agent" is a compound presenting a viscosity of at least 600 centipoise when it is in the form of a 1 % W/V aqueous solution at 25° C. Without being linked by any theory, it is thought that the weak gelling agent helps the matrix to swell faster due to its fast wetting property and the effervescent agent, which liberate gas on reaction with the gastric medium, helps to keep the tablet floating in the stomach. Use of a strong gelling agent provides rigidity to the swollen tablet matrix and helps to entrap the liberated gas in the tablet matrix. In other words, as the acidic environment of the stomach enters in the core of the gelled matrix, it reacts with the gas liberating agent to liberate gas. The liberated gas gets entrapped in the gel matrix and releases slowly on the surface of the gelled matrix as the drug is diffused or delivered from the gelled matrix. The released gas gets adsorbed on the surface of the gelled matrix forming a bubbled layer on the surface and helps to control the dissolution or erosion of the gelled matrix in turn helping to control the release of the drug from the matrix. The composition remains in the stomach for long time releasing almost entire drug in the stomach for absorption. According to the present invention, the gastroretentive formulation is a monolithic pharmaceutical WO 2007/010400 PCT/IB2006/002636 3 composition with sustained release effect, which is retained in the stomach from where the drug has maximum absorption for better therapeutic effect thereby acting as site specific drug delivery system. The formulation is suitable for both highly soluble and/or partially soluble or poorly soluble drugs. Due to this specific delivery system, the formulation according to the invention, is particularly useful for antibacterial substances of the fluoroquinolone class such as ciprofloxacin, ofloxacin, pefloxacin, grepafloxacin, enoxacin, amifioxacin, fleroxacin, temafloxacin, lomefloxacin, norfloxacin, sparfloxacin, levofloxacin, gatifloxacin and moxifloxacin, amoxicillin and Cephalexin derivatives in the form of base or salt thereof and' also for antidiabetic substances such as metformin hydrochloride, Gliclazide, antihyertensive drugs such as diltiazem hydrochloride, metoprolol tartarate or succinate. The amount of active substance ranges from 10 to 90%, preferably from 20 to 80 % and even more preferably from 50 to 75 % by weight of the total weight of the formulation. The weak gelling agent is selected from the group comprising a co-processed material of microcrystalline cellulose and sodium carboxy methylcellulose, preferably the one sold under the trademark AVICEL® CL611, AVICEL® RC 581 and AVICEL® RC 591. The strong gelling agent, is selected from the group consisting of methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose with the. exclusion of low- substituted hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, xanthan gum, guar gum, carrageenan gum, locust bean gum, sodium alginate, agar-agar, gelatin, modified starches, co-polymers of WO 2007/010400 PCT/IB2006/002636 4 carboxyvinyl polymers, co-polymer of acrylates, co-polymers of oxyethylene and oxypropylene and mixtures thereof. The total amount of both weak and strong gelling agents ranges from 2 to 40% , preferably from 3 to 30 % and even more preferably from 5 to 25 % by weight of the total weight of the formulation. The ratio of the weak gelling agent to the strong gelling agent ranges between 1:1 to 1:10, preferably from 1:2 to 1:8 and even more preferably between 1:3 to 1:5. The ratio of the substance active to both weak and strong gelling agents ranges from 1:99 to 99:1, preferably from 1:1 to 20 :1, and even more preferably from 2:1 to 15 :1 The gas generating agent is a compound which generates gas when it is in contact with an acidic medium, such as gastric fluid. Said gas generating agent is selected from the group consisting in water soluble carbonates, sulfites and bicarbonates, such as sodium carbonate, sodium bicarbonate, sodium metabisulfite, calcium carbonate, and mixtures thereof. The amount of gas generating agent ranges from 5 to 30%, preferably from 10 to 25 % and even more preferably from 12 to 22% by weight of the total weight of the formulation. The gas generating agent may be present in the formulation according to the invention inside the granules of active substance or as an excipient of the formulation or both. Thus, according to a first embodiment, at least a part of the gas generating agent is present in the granules of the active substance, i.e. at least a part of the gas generating agent is granulated together with the active substance and the mixture of weak and strong gelling agents, optionally with the other granulating agents; the remaining part of the WO 2007/010400 PCT/IB2006/002636 5 gas generating agent being present with excipients of the formulation, i.e. not granulated with the active substance. According to a second embodiment, the whole amount of the gas generating agent is present with the excipients of the formulation, i.e. is not granulated with the active substance and the mixture of weak and strong gelling agents, optionally with the other granulating agents. The gastroretentive formulation according to the invention comprises an active substance granulated with a mixture of: (A) a weak gelling agent selected from the group comprising co-processed material of microcrystalline cellulose and sodium carboxy methylcellulose, and (B) at least one strong gelling agents selected from the group consisting of methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose with the exclusion of low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, xanthan gum, guar gum, carrageenan gum, locust bean gum, sodium alginate, agar-agar, gelatin, modified starches, co-polymers of carboxyvinyl polymers, co-polymer of acrylates, co- polymers of oxyethylene and oxypropylene and mixtures thereof, preferably it is xanthan gum, (C) optionally a binder selected from the group consisting in low viscosity HPMC ,PVP, polymethacrylic acid ccpolymer (Eudragit E 100 ) and mixtures thereof, the formulation also comprises a gas generating agent. According to a third embodiment of the invention, the active substance may also be granulated with at least one additive (D) selected from the group comprising diluent or anti-static agent such as colloidal silicon dioxide, or mixture thereof. WO 2007/010400 PCT/IB2006/002636 6 The amount of binder (C) ranges from 0 to 10 %, preferably from 0.5 to 5%, and even more preferably from 1 to 3% by weight of the total weight of the formulation. The granules used in the formulation of the present invention are prepared by wet granulation using a an alcoholic or hydro-alcoholic solution of said binder (C). Preferably, the alcohol used for granulation is ethyl alcohol or isopropyl alcohol. The formulation according to the invention can further comprises excipients selected from the group consisting of diluents, lubricating agents, wetting agents, sweeteners, flavours, colorants and mixtures thereof. Commonly used diluent may be lactose, dibasic calcium phosphate, microcrystalline cellulose and mixtures thereof. Lubricating agents are conventionally used ones, such as stearates, in particular magnesium stearate, glyceryl behanate, colloidal silicon dioxide, and mixtures thereof. Wetting agents may be polysorbates, sodium lauryl sulphates and mixtures thereof. Preferably, the formulation according to the invention is a tablet. The tablets may be film coated with suitable polymeric materials that are commonly used in the art of film coating. Film coating improves the appearance of the formulation, masks the unpleasant taste and/or improves the stability of the formulation by providing a protection from moisture and does not have any influence on the release rate of the drug from the composition. The invention further relates to the process for manufacturing the formulation according to the invention. According to a first embodiment, the prccess comprises the following steps: WO 2007/010400 PCT/IB2006/002636 7 (1) an active substance is dry mixed with a mixture of (A) a weak gelling agent and (B) a strong gelling agent and optionally at least one additive (D) selected from the group comprising diluent or anti- static agent or mixture thereof; (2) ' optionally the obtained dry mix is granulated with at least one binder (C) dissolved in alcohol or alcohol and water mixture, (3) the gas generating agent is dry mixed with granules obtained from step ( 2) optionally with excipients selected from the group comprising diluents, lubricating agents, wetting agents, sweetners, flavours, colorants and mixtures thereof, (4) the mixture is then compressed into tablets; (5) optionally the tablets are film coated. According to a second embodiment, the process comprises the following steps: (1) an active substance is dry mixed with a mixture of (A) a weak gelling agent and (B) a strong gelling agent and optionally at least one additive (D) selected from the group comprising diluent or anti-static agent or mixture thereof, and at least a part of a gas generating agent; (2) optionally the obtained dry mix is granulated with at least one binder (C) dissolved in alcohol or alcohol and water mixture, (3) the remaining part of the gas generating agent, if any, is dry mixed with granules obtained from step ( 2} optionally with excipients selected from the group comprising diluents, lubricating agents, wetting agents, sweetners, flavours, colorants and mixtures thereof, WO 2007/010400 PCT/IB2006/002636 8 (4) the mixture is then compressed into tablets; (5) optionally the tablets are film coated. The invention is further illustrated by the following examples. EXAMPLES Example 1 Ingredient Weight ( mg/tab) % w/w Metformin Hydrochloride 510.0 57.47 Avicel CL 611 30.00 3.45 Xanthan gum 145.00 16.67 PVP K 30 17.00 1.95 Sodium Bicarbonate 17 6.00 20.23 Magnesium Stearate 2.0 0.23 Metformin Hydrochloride( 2 % Extra quantity taken ), Avicel CL 611, xanthan gum were mixed together in a suitable mixer such as high shear mixer or planetory mixer. The blend was granulated with a solution of PVP K 30 in isopropyl alcohol and water. The wet mass was dried in a drier till a moisture content between 3.5 to 5.5 % was obtained. The dried mass was calibrated through 20 mesh screen and mixed with sodium bicarbonate and magnesium stearate in a suitable blender. The resultant blend was compressed into tablets using a rotary compression machine with 16 stations (Fette or Suvac type machine), at 880 mg tablet weight with tablet parameters as follows: machine speed: 25 to 27 rpm. Tablet shape -biconvex caplets Size - length 19 mm and width 9 mm Hardness - 120 to 160 N WO 2007/010400 PCT/IB2006/002636 9 The tablets were tested for dissolution in 0.1 N HCl using USP type II apparatus at 100 RPM. The dissolution results are as follows - Time in Hrs Cumulative release percentage (expressed by weight) 1 31.10 2 45.20 4 65.40 6 78.00 8 88.10 12 97.70 Example 2 Ingredient Weight ( mg/tab) % w/w Ciprofloxacin Base 500.0 72.99 Avicel CL 611 10.00 1.45 Xanthan gum 30.00 4.38 Colloidal Silicon Dioxide 25.00 3.65 PVP K 30 10.00 1.46 Sodium Bicarbonate 85.00 12.41 Magnesium Stearate 25.0 3.65 Ciprofloxacin, Avicel CL 611, Xanthan gum , Colloidal Silicon Dioxide and sodium bicarbonate were mixed together in a suitable mixer such as high shear mixer or planetory mixer. The blend was granulated with a solution of PVP K 30 in isopropyl alcohol. The wet mass was dried in a drier till a WO 2007/010400 PCT/IB2006/002636 10 moisture content between 1.5 to 3.0 % was obtained. The dried mass was calibrated through 20 mesh screen and mixed with magnesium stearate in a suitable blender. The resultant blend was compressed in to tablets using . a rotary tablet compression machine at 685 mg tablet weight with tablet parameters as follows: Tablet shape -biconvex caplets Size - length 16 mm and width 8 mm Hardness - 100 to 160 N The tablets were coated with a coating solution having the following composition: lactose monohydrate: 19.17 % Talc: . 2.87 % Titanium Dioxide: 1.43 % Polysorbate 80: 0.1 * water: 76.39% The coating was carried out between 1.50 to 2% of the core weight of the tablet formulation. The tablets were tested for dissolution in 0.1 N HC1 using USP type II apparatus at 50 RPM. The dissolution results are as follows - Time in Hrs Cumulative release percentage (expressed by weight) 1 37.18 2 56.09 4 77.14 6 92.59 8 98.26 WO 2007/010400 PCT/IB2006/002636 11 CLAIMS 1. Gastroretentive formulation comprising an active substance granulated with a mixture of a weak gelling agent which is a co-processed material of microcrystalline cellulose and sodium carboxy methylcellulose, a strong gelling agent and a gas generating agent. 2. Gastroretentive formulation according to claim 1, wherein the strong gelling agent is selected from the group consisting of methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose with the exclusion of low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, xanthan gum, guar gum, carrageenan gum, locust bean gum, sodium alginate, agar-agar, gelatin, modified starches, co-polymers of carboxyvinyl polymers, co-polymer of acrylates, co-polymers of oxyethylene and oxypropylene and mixtures thereof. 3. Gastroretentive formulation according to claim 1 or 2, wherein the active substance is also granulated with (C) a binder and optionally with (D) additives selected from the group comprising diluents, anti-static agents or mixtures thereof. 4. Gastroretentive formulation according to any one of claims 1 to 3, which further comprises excipients selected from the group consisiting of diluents, lubricating agents, wetting agents, sweeteners, flavours, colorants and mixtures thereof. WO 2007/010400 PCT/IB2006/002636 12 5. Gastroretentive formulation according to anyone of claims 1 to 4, wherein the gas generating agant is selected from the group consisting in water soluble carbonates, sulfites and bicarbonates, such as sodium carbonate, sodium bicarbonate, sodium metabisulfite, calcium carbonate, and mixtures thereof. 6. Gastroretentive formulation according to anyone of claims .1 to 5, wherein the binder is selected from the group consisting in low viscosity HPMC ,PVP, polymethacrylic acid copolymer ( Eudragit E 100 ) and mixtures thereof. 7. Gastroretentive formulation according to anyone of claims 1 to 6, wherein the amount of active substance ranges from 10 to 90%, preferably from 20 to 80% and even more preferably from 50 to 75% by weight of the total weight of the formulation. 8. Gastroretentive formulation according to anyone of claims 1 to 7, wherein the total amount of both weak and strong gelling agents ranges from 2 to 40%, preferably from 3 to 30 % and even more preferably from 5 to 25% by weight of the total weight of the formulation. 9. Gastroretentive formulation according to anyone of claims 1 to 8, wherein the ratio of the weak gelling agent to the strong gelling agent ranges between 1:1 to 1:10, preferably from 1:2 to 1:8 and even more preferably between 1:3 to 1:5. 10. Gastroretentive formulation according to anyone of claims 1 to 9, wherein the ratio of the substance active to both weak and strong gelling agents ranges from 1:99 to 99:1, WO 2007/010400 PCT/IB2006/002636 13 preferably from 1:1 to 20:1 and even more preferably from 2:1 to 15:1 11. Gastroretentive formulation according to anyone of claims 1 to 10, wherein the active substance is selected from antibacterial substances of the fluoroquinolone class such as ciprofloxacin, ofloxacin, pefloxacin, grepafloxacin, enoxacin, amifioxacin, fleroxacin, temafloxacin, lomefloxacin, norfloxacin, sparfloxacin, levofloxacin, gatifloxacin and ir.oxifloxacin, amoxicillin, cephalexin derivatives in the form of base or salt thereof and antidiabetic substances such as metformin hydrochloride , gliclazide , anti-hypertensive drugs such as diltiazem hydrochloride, metoprolol tartarate or succinate. 12. Process for manufacturing a formulation according to anyone of claims 1 to 11, comprising (1) dry mixing an active substance with a mixture of (A) a weak swelling agent which is a co-processed material of microcrystalline cellulose and sodium carboxy methylcellulose and (B) a strong gelling agent and optionally at least one additive (D) selected from the group comprising diluent or anti-static agents or mixtures thereof, gas generating agent with (C) a binder ; (2) optionally granulating the obtained dry mix with at least one binder (C) dissolved in alcohol or alcohol and water mixture, (3) dry mixing gas generating agent with the granules obtained from step (2) optionally with excipients selected from the group comprising diluents, lubricating agents, wetting agents, sweeteners, flavours, colorants and mixtures thereof, (4) compressing the mixture into tablets, WO 2007/010400 PCT/IB2006/002636 14 (5) optionally, film coating the tablets obtained in (4). 13. Process for manufacturing a formulation according to anyone of claims 1 to 11, comprising (1) ■ dry mixing an active substance with a mixture of (A) a weak gelling agent a which is a co-processed material of microcrystalline cellulose and sodium carboxy methylcellulose and (B) a strong gelling agent and optionally at least one additive (D) selected from the group comprising diluent or anti-static agent or mixture thereof, and at least a part of a gas generating agent; (2) optionally granulating the obtained dry mix with at least one binder (C) dissolved in alcohol or alcohol and water mixture, (3) dry mixing the remaining part of the gas generating agent, if any, with granules obtained from step ( 2) optionally with excipients selected from the group comprising diluents, lubricating agents, wetting agents, sweetners, flavours, colorants and mixtures thereof, (4) compressing the mixture into tablets; (5) optionally film coating the tablets. The present invention concerns gastroretentive formulation comprising an active substance granulated with a mixture of a weak gelling agent, a strong gelling agent, and a gas generating agent and process for manufact ring said formulation.

Full Text

WO 2007/010400 PCT/IB2006/002636
1
GASTRORETENTIVE FORMULATIONS AND MANUFACTURING PROCESS
THEREOF
The invention relates to gastroretentive formulations,
in particular tablets, and to the process for manufacturing
said formulations.
An important factor affecting the absorption of orally
administered drug through gastro-intestinal tract is transit
time in gastrointestinal tract.
Some active substances, for example metformin and
ciprofloxacin, are known as being absorbed only from the
stomach to the jejunum, i.e in the upper part of the
gastrointestinal tract.
Hence, to achieve maximum efficiency with a minimum of
active substance, it would be beneficial that the formulation
be retained during a prolonged time in the stomach and allows
therein a sustained release of the active substance.
Some attempts have already been done to achieve
formulations with such a sustained release in the stomach,
either thanks to the use of multilayer tablets such as in US
6,797,283 (Edgren et al.), US patent application 20030232081,
or thanks to tablets which are sufficiently small to be
ingested and which swell after ingestion such as in
US6,635,280 (Shell et al.) and US 6,660,300 (Timmins et al.),
and which further include disintegrating agent and
effervescent agent, such as in US 6,261,601 (Talwar et al.).
However, these formulations are not completely
satisfactory and it still exists a need for formulations
which are able to be retained in the higher part of the
gastrointestinal tract and to release the active substance
during several hours in the stomach.
Unexpectedly and surprisingly, the inventors have
found that those objectives are fulfilled with a
WO 2007/010400 PCT/IB2006/002636
2
gastroretentive formulation comprising an active substance
granulated with a mixture of a weak gelling agent, a
strong gelling agent, and a gas generating agent.
In the present invention, a "weak gelling agent" is a
compound presenting a viscosity of less than 175 centipoise
when it is in a form of a 2.6 % W/V aqueous dispersion at
25°C.
A "strong gelling agent" is a compound presenting a
viscosity of at least 600 centipoise when it is in the
form of a 1 % W/V aqueous solution at 25° C.
Without being linked by any theory, it is thought
that the weak gelling agent helps the matrix to swell
faster due to its fast wetting property and the
effervescent agent, which liberate gas on reaction with
the gastric medium, helps to keep the tablet floating in
the stomach. Use of a strong gelling agent provides
rigidity to the swollen tablet matrix and helps to entrap
the liberated gas in the tablet matrix.
In other words, as the acidic environment of the
stomach enters in the core of the gelled matrix, it reacts
with the gas liberating agent to liberate gas. The
liberated gas gets entrapped in the gel matrix and
releases slowly on the surface of the gelled matrix as the
drug is diffused or delivered from the gelled matrix. The
released gas gets adsorbed on the surface of the gelled
matrix forming a bubbled layer on the surface and helps to
control the dissolution or erosion of the gelled matrix in
turn helping to control the release of the drug from the
matrix. The composition remains in the stomach for long
time releasing almost entire drug in the stomach for
absorption.
According to the present invention, the
gastroretentive formulation is a monolithic pharmaceutical
WO 2007/010400 PCT/IB2006/002636
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composition with sustained release effect, which is
retained in the stomach from where the drug has maximum
absorption for better therapeutic effect thereby acting as
site specific drug delivery system.
The formulation is suitable for both highly soluble
and/or partially soluble or poorly soluble drugs.
Due to this specific delivery system, the formulation
according to the invention, is particularly useful for
antibacterial substances of the fluoroquinolone class such as
ciprofloxacin, ofloxacin, pefloxacin, grepafloxacin,
enoxacin, amifioxacin, fleroxacin, temafloxacin,
lomefloxacin, norfloxacin, sparfloxacin, levofloxacin,
gatifloxacin and moxifloxacin, amoxicillin and Cephalexin
derivatives in the form of base or salt thereof and' also for
antidiabetic substances such as metformin hydrochloride,
Gliclazide, antihyertensive drugs such as diltiazem
hydrochloride, metoprolol tartarate or succinate.
The amount of active substance ranges from 10 to 90%,
preferably from 20 to 80 % and even more preferably from 50
to 75 % by weight of the total weight of the formulation.
The weak gelling agent is selected from the group
comprising a co-processed material of microcrystalline
cellulose and sodium carboxy methylcellulose, preferably the
one sold under the trademark AVICEL® CL611, AVICEL® RC 581
and AVICEL® RC 591.
The strong gelling agent, is selected from the group
consisting of methyl cellulose, hydroxypropyl methyl
cellulose, hydroxypropyl cellulose with the. exclusion of low-
substituted hydroxypropyl cellulose, hydroxyethyl cellulose,
ethyl cellulose, sodium carboxymethyl cellulose, xanthan gum,
guar gum, carrageenan gum, locust bean gum, sodium alginate,
agar-agar, gelatin, modified starches, co-polymers of
WO 2007/010400 PCT/IB2006/002636
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carboxyvinyl polymers, co-polymer of acrylates, co-polymers
of oxyethylene and oxypropylene and mixtures thereof.
The total amount of both weak and strong gelling agents
ranges from 2 to 40% , preferably from 3 to 30 % and even
more preferably from 5 to 25 % by weight of the total weight
of the formulation.
The ratio of the weak gelling agent to the strong
gelling agent ranges between 1:1 to 1:10, preferably from 1:2
to 1:8 and even more preferably between 1:3 to 1:5.
The ratio of the substance active to both weak and
strong gelling agents ranges from 1:99 to 99:1, preferably
from 1:1 to 20 :1, and even more preferably from 2:1 to 15 :1
The gas generating agent is a compound which generates
gas when it is in contact with an acidic medium, such as
gastric fluid. Said gas generating agent is selected from the
group consisting in water soluble carbonates, sulfites and
bicarbonates, such as sodium carbonate, sodium bicarbonate,
sodium metabisulfite, calcium carbonate, and mixtures
thereof.
The amount of gas generating agent ranges from 5 to 30%,
preferably from 10 to 25 % and even more preferably from 12
to 22% by weight of the total weight of the formulation.
The gas generating agent may be present in the
formulation according to the invention inside the granules of
active substance or as an excipient of the formulation or
both.
Thus, according to a first embodiment, at least a part
of the gas generating agent is present in the granules of the
active substance, i.e. at least a part of the gas generating
agent is granulated together with the active substance and
the mixture of weak and strong gelling agents, optionally
with the other granulating agents; the remaining part of the
WO 2007/010400 PCT/IB2006/002636
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gas generating agent being present with excipients of the
formulation, i.e. not granulated with the active substance.
According to a second embodiment, the whole amount of
the gas generating agent is present with the excipients of
the formulation, i.e. is not granulated with the active
substance and the mixture of weak and strong gelling agents,
optionally with the other granulating agents.
The gastroretentive formulation according to the
invention comprises an active substance granulated with a
mixture of:
(A) a weak gelling agent selected from the group comprising
co-processed material of microcrystalline cellulose and
sodium carboxy methylcellulose, and
(B) at least one strong gelling agents selected from the
group consisting of methyl cellulose, hydroxypropyl
methyl cellulose, hydroxypropyl cellulose with the
exclusion of low-substituted hydroxypropyl cellulose,
hydroxyethyl cellulose, ethyl cellulose, sodium
carboxymethyl cellulose, xanthan gum, guar gum,
carrageenan gum, locust bean gum, sodium alginate,
agar-agar, gelatin, modified starches, co-polymers of
carboxyvinyl polymers, co-polymer of acrylates, co-
polymers of oxyethylene and oxypropylene and
mixtures thereof, preferably it is xanthan gum,
(C) optionally a binder selected from the group consisting
in low viscosity HPMC ,PVP, polymethacrylic acid ccpolymer
(Eudragit E 100 ) and mixtures thereof,
the formulation also comprises a gas generating agent.
According to a third embodiment of the invention, the
active substance may also be granulated with at least one
additive (D) selected from the group comprising diluent or
anti-static agent such as colloidal silicon dioxide, or
mixture thereof.
WO 2007/010400 PCT/IB2006/002636
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The amount of binder (C) ranges from 0 to 10 %,
preferably from 0.5 to 5%, and even more preferably from 1
to 3% by weight of the total weight of the formulation.
The granules used in the formulation of the present
invention are prepared by wet granulation using a an
alcoholic or hydro-alcoholic solution of said binder (C).
Preferably, the alcohol used for granulation is ethyl alcohol
or isopropyl alcohol.
The formulation according to the invention can further
comprises excipients selected from the group consisting of
diluents, lubricating agents, wetting agents, sweeteners,
flavours, colorants and mixtures thereof.
Commonly used diluent may be lactose, dibasic calcium
phosphate, microcrystalline cellulose and mixtures thereof.
Lubricating agents are conventionally used ones, such as
stearates, in particular magnesium stearate, glyceryl
behanate, colloidal silicon dioxide, and mixtures thereof.
Wetting agents may be polysorbates, sodium lauryl
sulphates and mixtures thereof.
Preferably, the formulation according to the
invention is a tablet.
The tablets may be film coated with suitable
polymeric materials that are commonly used in the art of
film coating. Film coating improves the appearance of the
formulation, masks the unpleasant taste and/or improves
the stability of the formulation by providing a protection
from moisture and does not have any influence on the
release rate of the drug from the composition.
The invention further relates to the process for
manufacturing the formulation according to the invention.
According to a first embodiment, the prccess comprises
the following steps:
WO 2007/010400 PCT/IB2006/002636
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(1) an active substance is dry mixed with a mixture of
(A) a weak gelling agent and (B) a strong gelling
agent and optionally at least one additive (D)
selected from the group comprising diluent or anti-
static agent or mixture thereof;
(2) ' optionally the obtained dry mix is granulated with at
least one binder (C) dissolved in alcohol or alcohol
and water mixture,
(3) the gas generating agent is dry mixed with granules
obtained from step ( 2) optionally with excipients
selected from the group comprising diluents,
lubricating agents, wetting agents, sweetners,
flavours, colorants and mixtures thereof,
(4) the mixture is then compressed into tablets;
(5) optionally the tablets are film coated.
According to a second embodiment, the process comprises the
following steps:
(1) an active substance is dry mixed with a mixture of
(A) a weak gelling agent and (B) a strong gelling agent
and optionally at least one additive (D) selected from
the group comprising diluent or anti-static agent or
mixture thereof, and at least a part of a gas
generating agent;
(2) optionally the obtained dry mix is granulated with
at least one binder (C) dissolved in alcohol or alcohol
and water mixture,
(3) the remaining part of the gas generating agent, if
any, is dry mixed with granules obtained from step ( 2}
optionally with excipients selected from the group
comprising diluents, lubricating agents, wetting
agents, sweetners, flavours, colorants and mixtures
thereof,
WO 2007/010400 PCT/IB2006/002636
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(4) the mixture is then compressed into tablets;
(5) optionally the tablets are film coated.
The invention is further illustrated by the following
examples.
EXAMPLES
Example 1
Ingredient Weight ( mg/tab) % w/w
Metformin Hydrochloride 510.0 57.47
Avicel CL 611 30.00 3.45
Xanthan gum 145.00 16.67
PVP K 30 17.00 1.95
Sodium Bicarbonate 17 6.00 20.23
Magnesium Stearate 2.0 0.23
Metformin Hydrochloride( 2 % Extra quantity taken ), Avicel
CL 611, xanthan gum were mixed together in a suitable mixer
such as high shear mixer or planetory mixer.
The blend was granulated with a solution of PVP K 30 in
isopropyl alcohol and water. The wet mass was dried in a
drier till a moisture content between 3.5 to 5.5 % was
obtained.
The dried mass was calibrated through 20 mesh screen and
mixed with sodium bicarbonate and magnesium stearate in a
suitable blender.
The resultant blend was compressed into tablets using a
rotary compression machine with 16 stations (Fette or Suvac
type machine), at 880 mg tablet weight with tablet
parameters as follows:
machine speed: 25 to 27 rpm.
Tablet shape -biconvex caplets
Size - length 19 mm and width 9 mm
Hardness - 120 to 160 N
WO 2007/010400 PCT/IB2006/002636
9
The tablets were tested for dissolution in 0.1 N HCl using
USP type II apparatus at 100 RPM. The dissolution results are
as follows -
Time in Hrs Cumulative release percentage
(expressed by weight)
1 31.10
2 45.20
4 65.40
6 78.00
8 88.10
12 97.70
Example 2
Ingredient Weight ( mg/tab) % w/w
Ciprofloxacin Base 500.0 72.99
Avicel CL 611 10.00 1.45
Xanthan gum 30.00 4.38
Colloidal Silicon Dioxide 25.00 3.65
PVP K 30 10.00 1.46
Sodium Bicarbonate 85.00 12.41
Magnesium Stearate 25.0 3.65
Ciprofloxacin, Avicel CL 611, Xanthan gum , Colloidal Silicon
Dioxide and sodium bicarbonate were mixed together in a
suitable mixer such as high shear mixer or planetory mixer.
The blend was granulated with a solution of PVP K 30 in
isopropyl alcohol. The wet mass was dried in a drier till a
WO 2007/010400 PCT/IB2006/002636
10
moisture content between 1.5 to 3.0 % was obtained. The dried
mass was calibrated through 20 mesh screen and mixed with
magnesium stearate in a suitable blender. The resultant blend
was compressed in to tablets using . a rotary tablet
compression machine at 685 mg tablet weight with tablet
parameters as follows:
Tablet shape -biconvex caplets
Size - length 16 mm and width 8 mm
Hardness - 100 to 160 N
The tablets were coated with a coating solution having the
following composition:
lactose monohydrate: 19.17 %
Talc: . 2.87 %
Titanium Dioxide: 1.43 %
Polysorbate 80: 0.1 *
water: 76.39%
The coating was carried out between 1.50 to 2% of the core
weight of the tablet formulation.
The tablets were tested for dissolution in 0.1 N HC1 using
USP type II apparatus at 50 RPM. The dissolution results are
as follows -
Time in Hrs Cumulative release percentage
(expressed by weight)
1 37.18
2 56.09
4 77.14
6 92.59
8 98.26
WO 2007/010400 PCT/IB2006/002636
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CLAIMS
1. Gastroretentive formulation comprising an active substance
granulated with a mixture of a weak gelling agent which is a
co-processed material of microcrystalline cellulose and
sodium carboxy methylcellulose, a strong gelling agent and a
gas generating agent.
2. Gastroretentive formulation according to claim 1,
wherein the strong gelling agent is selected from the
group consisting of methyl cellulose, hydroxypropyl methyl
cellulose, hydroxypropyl cellulose with the exclusion of
low-substituted hydroxypropyl cellulose, hydroxyethyl
cellulose, ethyl cellulose, sodium carboxymethyl
cellulose, xanthan gum, guar gum, carrageenan gum, locust
bean gum, sodium alginate, agar-agar, gelatin, modified
starches, co-polymers of carboxyvinyl polymers, co-polymer
of acrylates, co-polymers of oxyethylene and oxypropylene
and mixtures thereof.
3. Gastroretentive formulation according to claim 1 or 2,
wherein the active substance is also granulated with (C) a
binder and optionally with (D) additives selected from the
group comprising diluents, anti-static agents or mixtures
thereof.
4. Gastroretentive formulation according to any one of
claims 1 to 3, which further comprises excipients selected
from the group consisiting of diluents, lubricating agents,
wetting agents, sweeteners, flavours, colorants and mixtures
thereof.
WO 2007/010400 PCT/IB2006/002636
12
5. Gastroretentive formulation according to anyone of
claims 1 to 4, wherein the gas generating agant is selected
from the group consisting in water soluble carbonates,
sulfites and bicarbonates, such as sodium carbonate, sodium
bicarbonate, sodium metabisulfite, calcium carbonate, and
mixtures thereof.
6. Gastroretentive formulation according to anyone of
claims .1 to 5, wherein the binder is selected from the group
consisting in low viscosity HPMC ,PVP, polymethacrylic acid
copolymer ( Eudragit E 100 ) and mixtures thereof.
7. Gastroretentive formulation according to anyone of
claims 1 to 6, wherein the amount of active substance ranges
from 10 to 90%, preferably from 20 to 80% and even more
preferably from 50 to 75% by weight of the total weight of
the formulation.
8. Gastroretentive formulation according to anyone of claims
1 to 7, wherein the total amount of both weak and strong
gelling agents ranges from 2 to 40%, preferably from 3 to 30
% and even more preferably from 5 to 25% by weight of the
total weight of the formulation.
9. Gastroretentive formulation according to anyone of claims
1 to 8, wherein the ratio of the weak gelling agent to the
strong gelling agent ranges between 1:1 to 1:10, preferably
from 1:2 to 1:8 and even more preferably between 1:3 to 1:5.
10. Gastroretentive formulation according to anyone of claims
1 to 9, wherein the ratio of the substance active to both
weak and strong gelling agents ranges from 1:99 to 99:1,
WO 2007/010400 PCT/IB2006/002636
13
preferably from 1:1 to 20:1 and even more preferably from 2:1
to 15:1
11. Gastroretentive formulation according to anyone of claims
1 to 10, wherein the active substance is selected from
antibacterial substances of the fluoroquinolone class such as
ciprofloxacin, ofloxacin, pefloxacin, grepafloxacin,
enoxacin, amifioxacin, fleroxacin, temafloxacin,
lomefloxacin, norfloxacin, sparfloxacin, levofloxacin,
gatifloxacin and ir.oxifloxacin, amoxicillin, cephalexin
derivatives in the form of base or salt thereof and
antidiabetic substances such as metformin hydrochloride ,
gliclazide , anti-hypertensive drugs such as diltiazem
hydrochloride, metoprolol tartarate or succinate.
12. Process for manufacturing a formulation according to
anyone of claims 1 to 11, comprising
(1) dry mixing an active substance with a mixture of (A) a
weak swelling agent which is a co-processed material of
microcrystalline cellulose and sodium carboxy
methylcellulose and (B) a strong gelling agent and
optionally at least one additive (D) selected from the
group comprising diluent or anti-static agents or mixtures
thereof, gas generating agent with (C) a binder ;
(2) optionally granulating the obtained dry mix with at
least one binder (C) dissolved in alcohol or alcohol and
water mixture,
(3) dry mixing gas generating agent with the granules
obtained from step (2) optionally with excipients selected
from the group comprising diluents, lubricating agents,
wetting agents, sweeteners, flavours, colorants and
mixtures thereof,
(4) compressing the mixture into tablets,
WO 2007/010400 PCT/IB2006/002636
14
(5) optionally, film coating the tablets obtained in (4).
13. Process for manufacturing a formulation according to
anyone of claims 1 to 11, comprising
(1) ■ dry mixing an active substance with a mixture of
(A) a weak gelling agent a which is a co-processed
material of microcrystalline cellulose and sodium
carboxy methylcellulose and (B) a strong gelling agent
and optionally at least one additive (D) selected from
the group comprising diluent or anti-static agent or
mixture thereof, and at least a part of a gas
generating agent;
(2) optionally granulating the obtained dry mix with at
least one binder (C) dissolved in alcohol or alcohol
and water mixture,
(3) dry mixing the remaining part of the gas generating
agent, if any, with granules obtained from step ( 2)
optionally with excipients selected from the group
comprising diluents, lubricating agents, wetting
agents, sweetners, flavours, colorants and mixtures
thereof,
(4) compressing the mixture into tablets;
(5) optionally film coating the tablets.

The present invention concerns gastroretentive formulation comprising an active substance granulated with a mixture
of a weak gelling agent, a strong gelling agent, and a gas generating agent and process for manufact ring said formulation.

Documents:

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Patent Number

269661

Indian Patent Application Number

239/KOLNP/2008

PG Journal Number

45/2015

Publication Date

06-Nov-2015

Grant Date

30-Oct-2015

Date of Filing

17-Jan-2008

Name of Patentee

ETHYPHARM

Applicant Address

21, RUE SAINT MATTHIEU, 78550 HOUDAN

Inventors:

#	Inventor's Name	Inventor's Address
1	CHAUDHARI MAHENDRA	601 KONARK TOWER, OP. SAIBABA MANDIR, GHANTALI ROAD, NAUPADA THANA (WEST), MAHARASHTRA 400602
2	YELEGAONKAR RAJASHREE S.	BHALCHANDRA SOCIETY A-WING, BLDG. NO. 9, BADLAPUR (E) DIST. THANE, MAHARASHTRA 421503
3	CHANDWANI OMPRAKASH D.	CHANDWANI NIWAS, PLOT NO. 365, OT SECTION, ULHASNAGAR(W) DIST. THANE, MAHARASHTRA 421003

PCT International Classification Number

A61K 9/16, A61K 9/22

PCT International Application Number

PCT/IB2006/002636

PCT International Filing date

2006-07-19

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	05291542.8	2005-07-19	EUROPEAN UNION