OSMOTIC FLOATING TABLETS
Field of the Invention
The present invention relates to osmotic floating tablets comprising: (i) an inner
core comprising a drug, one or more low density polymers, and one or more
pharmaceutically acceptable excipients; and (ii) an outer osmotic coating surrounding the
inner core that is substantially permeable to surrounding fluids and substantially
impermeable to the drug. The present invention also relates to processes for the
preparation of said tablets.
Background of the Invention
Oral administration is the most preferred and convenient route of administration
for various types of drugs. However, there are certain drugs that do not have uniform
absorption throughout the entire gastrointestinal tract and are predominantly absorbed
from the stomach and the upper part of the intestine. For such drugs, it is beneficial to
develop oral gastroretentive dosage forms that can remain in the gastric region for longer
periods of time so as to significantly prolong the gastric retention time. Such
gastroretentive dosage forms are also useful for drugs that are poorly soluble, degraded by
the higher pH of the intestine, or have an absorption which is modified by changes in
gastric emptying time. Gastroretentive dosage forms are also useful for local as well as
sustained drug delivery for certain disease states.
To formulate such stomach-specific gastroretentive dosage forms, several
techniques have been described in the prior art such as hydrodynamically balanced
systems (HBS)/floating drug delivery system, low density systems, bioadhesive or
mucoadhesive systems, high density systems, superporous hydrogels, and magnetic
systems.
U.S. Publication No. 2007/02695 11 discloses a pregabalin gastroretentive
formulation comprising a matrix forming agent and a swelling agent wherein the matrix
forming agent is polyvinyl acetate and polyvinylpyrrolidone, and the swelling agent is
cross-linked polyvinylpyrrolidone.
PCT Publication No. WO 201 1/151708 discloses a gastroretentive dosage form
comprising a GABA analog, at least one swelling agent, at least one non-swelling release
retardant, and at least one pharmaceutically acceptable excipient.
U.S. Publication No. 201 1/0135723 discloses once-daily pharmaceutical
compositions of pregabalin wherein the excipients include one or more water-insoluble
components or a combination of one or more water-insoluble components and one or more
water-soluble components.
U.S. Publication No. 2010/0255067 discloses pharmaceutical compositions
comprising pregabalin, a hydrophobic release-controlling agent, and other
pharmaceutically acceptable excipients.
PCT Publication No. WO 03/035029 discloses a gastric retentive dosage form
consisting of single polymer matrix comprising an active agent and hydrophilic polymers
such as hydroxypropyl methylcellulose and poly(ethylene oxide). U.S. Patent No.
6,207,197 discloses gastro-retentive controlled-release compositions comprising
microspheres containing a drug in an inner core, a rate-controlling layer of a hydrophilic
polymer, and an outer layer of bioadhesive cationic polymer.
However, administration of such dosage forms might result in fluctuating drug
levels in the plasma. In order to overcome this drawback, the inventors have now
developed an osmotic floating tablet comprising: (i) an inner core comprising a drug, one
or more low density polymers, and one or more pharmaceutically acceptable excipients;
and (ii) an outer osmotic coating surrounding the inner core that is substantially permeable
to the surrounding fluids and substantially impermeable to the drug. The incorporation of
such an osmotic coating on the floating inner core provides several advantages over
conventional gastroretentive dosage forms, such as reduction in the plasma level
fluctuations, zero order drug release, and resistance against alcohol-induced dose
dumping.
Summary of the Invention
The present invention relates to an osmotic floating tablet comprising: (i) an inner
core comprising a drug, one or more low density polymers, and one or more
pharmaceutically acceptable excipients; and (ii) an outer osmotic coating surrounding the
inner core that is substantially permeable to the surrounding fluids and substantially
impermeable to the drug. The present invention also includes processes for the preparation
of said osmotic floating tablet.
Detailed Description of the Invention
A first aspect of the present invention provides an osmotic floating tablet
comprising:
(i) an inner core comprising a drug, one or more low density polymers, and one
or more pharmaceutically acceptable excipients; and
(ii) an outer osmotic coating surrounding the inner core that is substantially
permeable to surrounding fluids and substantially impermeable to the drug.
According to one embodiment of the above aspect, there is provided an osmotic
floating tablet comprising:
(i) an inner core comprising a drug, one or more low density polymers, and one
or more pharmaceutically acceptable excipients; and
(ii) an outer osmotic coating surrounding the inner core that is substantially
permeable to surrounding fluids and substantially impermeable to the drug
wherein one or more low density polymers are selected from the group comprising
polyvinyl alcohol-polyethylene glycol graft copolymer, acrylic acid polymer, methacrylic
acid copolymers, polyvinyl alcohol, polyvinyl acetate, polysaccharides, cellulose based
polymers, or their combinations.
According to another embodiment of the above aspect, there is provided an
osmotic floating tablet comprising:
(i) an inner core comprising a drug, one or more low density polymers, and one
or more pharmaceutically acceptable excipients; and
(ii) an outer osmotic coating surrounding the inner core that is substantially
permeable to surrounding fluids and substantially impermeable to the drug
wherein the outer osmotic coating comprises one or more semi-permeable membrane
forming polymers, one or more pore-forming agents, and one or more plasticizers.
A second aspect of the present invention provides an osmotic floating tablet
comprising:
(i) an inner core comprising a drug, one or more low density polymers, and one
or more pharmaceutically acceptable excipients; and
(ii) an outer osmotic coating surrounding the inner core that is substantially
permeable to surrounding fluids, and substantially impermeable to the drug
wherein the tablet further comprises a subcoat layer located between the inner tablet core
and the outer osmotic coating.
According to one embodiment of the above aspect, the subcoat layer comprises one
or more polymers and one or more lubricants.
A third aspect of the present invention provides a process for the preparation of an
osmotic floating tablet wherein the process comprises the steps of:
(i) blending the drug with one or more low density polymers and one or more
pharmaceutically acceptable excipients;
(ii) directly compressing the blend of step (i) to form the inner tablet core;
(iii) dissolving/dispersing one or more semi-permeable membrane-forming
polymers, one or more pore-forming agents, and one or more plasticizers in a
suitable solvent; and
(iv) applying the coating composition of step (iii) over the tablet core of step (ii)
to form the osmotic floating tablet.
A fourth aspect of the present invention provides a process for the preparation of
an osmotic floating tablet wherein the process comprises the steps of:
(i) blending the drug with one or more low density polymers and one or more
pharmaceutically acceptable excipients;
(ii) directly compressing the blend of step (i) to form the inner tablet core;
(iii) dissolving one or more polymers in a suitable solvent followed by dispersion
of the lubricant to form a subcoat dispersion;
(iv) applying the subcoat dispersion of step (iii) over the tablet core of step (ii);
(v) dissolving/dispersing one or more semi-permeable membrane-forming
polymers, one or more pore-forming agents, and one or more plasticizers in a
suitable solvent; and
(vi) applying the coating composition of step (v) over the subcoated tablet core of
step (iv) to form the osmotic floating tablet.
The term "osmotic floating tablet", as used herein, represents a tablet designed in
such a way so that it is retained in the stomach for a prolonged period of time and is
intended to provide zero order drug-release. While the osmotic floating tablet floats over
the gastric contents, the drug is released slowly at a desired rate, resulting in an increased
gastric retention time. The outer osmotic coating controls the drug-release from the tablet.
Examples of drugs that can be incorporated in the osmotic floating tablet of the
present invention include, but are not limited to, pregabalin, losartan, cefuroxime axetil,
metformin, trimetazidine dihydrochloride, faropenem, carbidopa, levodopa, methyldopa,
verapamil, propranolol, carvedilol, atenolol, albuterol, pirbuterol, nifedipine, nimodipine,
nicardipine, amlodipine, prazosin, guanabenz, allopurinol, metoprolol, oxprenolol,
baclofen, sumatriptan, benazepril, enalapril, lisinopril, captopril, quinapril, moxipril,
indolapril, olindapril, retinapril, spirapril, cilazapril, perindopril, ramipril, zofenopril,
fosinopril, nitrofurantoin, acyclovir, valacyclovir, zidovudine, inosine, didanosine,
pranobex, tribavirin, vidarabine, simvastatin, pravastatin, atorvastatin, lovastatin,
selegiline, midazolam, lithium carbonate, lithium citrate, cimetidine, ranitidine,
famotidine, nizatidine, bifentidine, nifentidine, roxatidine, omeprazole, lansoprazole,
pentoprazole, magnesium carbonate, aluminum carbonate, aluminum hydroxide,
magnesium oxide, sucralfate, carbenoloxalone, misoprostol, pirenzepine, telenzepine,
bismuth salts, ciprofloxacin, clarithromycin, amoxicillin, cephalexin, and
pharmaceutically acceptable salts, esters, or prodrugs thereof. The dose of any drug is in a
therapeutically effective amount to treat a disease or condition.
The term "low density polymers", as used herein, includes polymers that have low
bulk density so as to cause the tablet to float, and are non-swelling in nature. Non-swelling
behavior can be pH-dependent or pH-independent. Suitable low density polymers include
polyvinyl alcohol-polyethylene glycol graft copolymers such as Kollicoat®Protect; acrylic
acid polymers such as Carbopol®; methacrylic acid copolymers such as Eudragit®L100,
Eudragit® SI00, and Eudragit®E PO; polyvinyl alcohol; polyvinyl acetate;
polysaccharides such as inulin and pullulan; cellulose based polymers such as
hypromellose phthalate, hypromellose succinate, and ethyl cellulose; or combinations
thereof.
The core of the present invention comprises one or more pharmaceutically
acceptable excipients that are routinely used in pharmaceutical tablets, and are selected
from the group comprising diluents, binders, disintegrants, lubricants, glidants, or
combinations thereof.
Suitable diluents are selected from the group comprising microcrystalline
cellulose, silicified microcrystalline cellulose, microfine cellulose, lactose, starch,
pregelatinized starch, calcium carbonate, calcium sulfate, sugar, mannitol, sorbitol,
dextrates, dextrin, maltodextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic
calcium phosphate, magnesium carbonate, magnesium oxide, or combinations thereof.
Suitable binders are selected from the group comprising polyvinylpyrrolidone,
cross-linked polyvinylpyrrolidone, cellulose gums (e.g. carboxymethyl cellulose,
hydroxypropyl methylcellulose, and hydroxypropyl cellulose), pregelatinized starch,
acacia, guar gum, alginic acid, carbomer, dextrin, maltodextrin, or combinations thereof.
Suitable disintegrants are selected from the group comprising mannitol, alginic
acid, carboxymethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose,
croscarmellose sodium, povidone, crospovidone, magnesium aluminum silicate,
methylcellulose, sodium alginate, starches, modified starches, or combinations thereof.
Suitable lubricants are selected from the group comprising magnesium stearate,
zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, vegetable oil, mineral
oil, or combinations thereof.
Suitable glidants are selected from the group comprising talc, colloidal silicon
dioxide, corn starch, or combinations thereof.
The term "outer osmotic coating", as used herein, refers to a semi-permeable
membrane that is substantially permeable to the passage of fluid from the environment to
the core allowing water or solvent to pass into the core, and is substantially impermeable
to the passage of drug from the inner core. The outer osmotic coating comprises one or
more semi-permeable membrane-forming polymers, one or more pore-forming agents, and
one or more plasticizers.
Suitable semi-permeable membrane-forming polymers are selected from the group
comprising cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate
butyrate, cellulose tri-mallitate, ethyl cellulose, methyl methacrylate, or combinations
thereof.
Pore-forming agents help to draw water from the surrounding medium into the
core, and are selected from the group comprising polyethylene glycol, hydroxymethyl
cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, propylene glycol,
polyvinylpyrrolidone, micronized sugar, sodium chloride, mannitol, sorbitol, or
combinations thereof.
Suitable plasticizers are selected from the group comprising triacetin, acetylated
triacetin, triethyl citrate, dibutyl sebacate, tributyl citrate, glycerol tributyrate, diacetylated
monoglyceride, rapeseed oil, olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl
citrate, glycerin sorbitol, diethyl oxalate, diethyl phthalate, diethyl malate, diethyl
fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, or combinations thereof.
The osmotic floating tablet, as described herein, may further comprise a subcoat
layer located between the inner core and the outer osmotic coating. The subcoat layer
comprises one or more polymers and one or more lubricants.
Suitable polymers in the subcoat layer are selected from the group comprising
hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose,
polyvinyl pyrrolidone, polyvinyl acetate, or combinations thereof.
Suitable lubricants in the subcoat layer are selected from the group comprising
magnesium stearate, calcium stearate, zinc stearate, glyceryl monosterate, sodium stearyl
fumarate, polyoxyethylene monostearate, sucrose monolaurate, sodium lauryl sulfate,
magnesium lauryl sulfate, magnesium dodecyl sulfate, or combinations thereof.
Examples of solvents used for granulation or coating include purified water and
organic solvents such as acetone, ethanol, isopropyl alcohol, methylene chloride, or
combinations thereof.
The inner tablet core may be prepared by conventional techniques known in the art
such as such as direct compression, wet granulation, or dry granulation. The resultant
blends/granules can be compressed into a tablet using a conventional tableting process.
Preferably, the inner tablet core is prepared by the technique of direct compression.
Coating may be performed by applying the coating composition as a
solution/suspension/blend using any conventional coating technique known in the art such
as spray coating in a conventional coating pan, a fluidized bed processor, dip coating, or
compression coating.
The outer osmotic coating layer of the tablets may additionally comprise one or
more orifices that is created through the semi-permeable membrane and allows the inner
tablet core to communicate with the surrounding media. The orifice may be created by
mechanical perforation, laser perforation, or formed in response to the osmotic pressure
acting on the tablet.
The following examples represent various embodiments according to the present
invention. The examples are given solely for the purpose of illustration and are not to be
construed as limitations of the present invention, as many variations thereof are possible
without departing from the spirit and scope of the invention.
Examples 1-3:
Procedure:
1. Pregabalin was blended with Kollicoat® Protect and Carbopol®/Ethyl
cellulose/Eudragit® E PO for 15 minutes.
2. Magnesium stearate was mixed with the blend of step 1.
3. The blend of step 2 was directly compressed using suitable tooling to form an inner
tablet core.
4. Hydroxypropyl cellulose was dissolved in ethanol under continuous stirring followed
by dispersion of magnesium stearate to form a subcoat dispersion.
5. The tablet core of step 3 was coated with the subcoat dispersion of step 4. .
6. Cellulose acetate was dissolved in a mixture of acetone and water.
7. Polyethylene glycol 6000, polyethylene glycol 400, and triacetin were dissolved in
the solution of step 6 to form the osmotic coating solution.
8. The subcoated tablets of step 5 were coated with the osmotic coating solution of step
7 until the desired tablet weight was obtained.
Example 4:
Procedure:
1. Losartan potassium was blended with Kollicoat® Protect, Eudragit® E PO, Pearlitol®
200SD, and silicon dioxide for 15 minutes.
2. Magnesium stearate was mixed with the blend of step 1.
3. The blend of step 2 was directly compressed using suitable tooling to form an inner
tablet core.
4. Hydroxypropyl cellulose was dissolved in ethanol under continuous stirring followed
by dispersion of magnesium stearate to form a subcoat dispersion.
5. The tablet core of step 3 was coated with the subcoat dispersion of step 4. .
6. Cellulose acetate was dissolved in a mixture of acetone and water.
7. Polyethylene glycol 6000, polyethylene glycol 400, and triacetin were dissolved in
the solution of step 6 to form the osmotic coating solution.
8. The subcoated tablets of step 5 were coated with the osmotic coating solution of step
7 until the desired tablet weight was obtained.
Example 5:
Procedure:
1. Cefuroxime axetil was blended with Kollicoat® Protect, Eudragit® E PO, Pearlitol®
200SD, ferric oxide red, and silicon dioxide for 15 minutes.
2. Magnesium stearate was mixed with the blend of step 1.
3. The blend of step 2 was directly compressed using suitable tooling to form an inner
tablet core.
4. Hydroxypropyl cellulose was dissolved in ethanol under continuous stirring followed
by dispersion of magnesium stearate to form a subcoat dispersion.
5. The tablet core of step 3 was coated with the subcoat dispersion of step 4. .
6. Cellulose acetate was dissolved in a mixture of acetone and water.
7. Polyethylene glycol 6000, polyethylene glycol 400, and triacetin were dissolved in
the solution of step 6 to form the osmotic coating solution.
8. The subcoated tablets of step 5 were coated with the osmotic coating solution of step
7 until the desired tablet weight was obtained.
Example 6:
Procedure:
1. Metformin was blended with Kollicoat® Protect, Eudragit® E PO, Pearlitol®200SD,
and silicon dioxide for 15 minutes.
2. Magnesium stearate was mixed with the blend of step 1.
3. The blend of step 2 was directly compressed using suitable tooling to form an inner
tablet core.
4. Hydroxypropyl cellulose was dissolved in ethanol under continuous stirring followed
by dispersion of magnesium stearate to form a subcoat dispersion.
5. The tablet core of step 3 was coated with the subcoat dispersion of step 4. .
6. Cellulose acetate was dissolved in a mixture of acetone and water.
7. Polyethylene glycol 6000, polyethylene glycol 400, and triacetin were dissolved in
the solution of step 6 to form the osmotic coating solution.
8. The subcoated tablets of step 5 were coated with the osmotic coating solution of step
7 until the desired tablet weight was obtained.
Example 7:
Procedure:
1. Trimetazidine dihydrochloride was blended with Kollicoat® Protect, Eudragit® E PO,
Pearlitol®200SD, ferric oxide red, and silicon dioxide for 15 minutes.
2. Magnesium stearate was mixed with the blend of step 1.
3. The blend of step 2 was directly compressed using a suitable tooling to form an inner
tablet core.
4. Hydroxypropyl cellulose was dissolved in ethanol under continuous stirring followed
by dispersion of magnesium stearate to form a subcoat dispersion.
5. The tablet core of step 3 was coated with the subcoat dispersion of step 4. .
6. Cellulose acetate was dissolved in a mixture of acetone and water.
7. Polyethylene glycol 6000, polyethylene glycol 400, and triacetin were dissolved in
the solution of step 6 to form the osmotic coating solution.
8. The subcoated tablets of step 5 were coated with the osmotic coating solution of step
7 until the desired tablet weight was obtained.
In-Vitro Studies
The tablets prepared according to Examples 4-7 were subjected to dissolution
studies in 900 mL of 0.1N HCl using a USP type II apparatus with a paddle speed at 50
rpm. The results of the release studies are represented in Table 1 below.
Table 1: Percentage (%) of In-Vitro Drug Release in USP Type II Apparatus (Media:
900 mL of 0.1N HCl at 50 rpm) from Tablets Prepared According to Examples 4-7

We Claim:
1. An osmotic floating tablet comprising:
(i) an inner core comprising a drug, one or more low density polymers, and one
or more pharmaceutically acceptable excipients; and
(ii) an outer osmotic coating surrounding the inner core that is substantially
permeable to surrounding fluids and substantially impermeable to the drug.
2. The osmotic floating tablet of claim 1, wherein the drug is selected from the group
comprising pregabalin, losartan, cefuroxime axetil, metformin, trimetazidine
dihydrochloride, faropenem, carbidopa, levodopa, methyldopa, verapamil, propranolol,
carvedilol, atenolol, albuterol, pirbuterol, nifedipine, nimodipine, nicardipine, amlodipine,
prazosin, guanabenz, allopurinol, metoprolol, oxprenolol, baclofen, sumatriptan,
benazepril, enalapril, lisinopril, captopril, quinapril, moxipril, indolapril, olindapril,
retinapril, spirapril, cilazapril, perindopril, ramipril, zofenopril, fosinopril, nitrofurantoin,
acyclovir, valacyclovir, zidovudine, inosine, didanosine, pranobex, tribavirin, vidarabine,
simvastatin, pravastatin, atorvastatin, lovastatin, selegiline, midazolam, lithium carbonate,
lithium citrate, cimetidine, ranitidine, famotidine, nizatidine, bifentidine, nifentidine,
roxatidine, omeprazole, lansoprazole, pentoprazole, magnesium carbonate, aluminum
carbonate, aluminum hydroxide, magnesium oxide, sucralfate, carbenoloxalone,
misoprostol, pirenzepine, telenzepine, bismuth salts, ciprofloxacin, clarithromycin,
amoxicillin, cephalexin, and pharmaceutically acceptable salts, esters, or prodrugs thereof.
3. The osmotic floating tablet of claim 1, wherein one or more low density polymers
are selected from the group comprising polyvinyl alcohol- polyethylene glycol graft
copolymers, acrylic acid polymers, methacrylic acid copolymers, polyvinyl alcohol,
polyvinyl acetate, polysaccharides, cellulose based polymers, or combinations thereof.
4. The osmotic floating tablet of claim 1, wherein the one or more pharmaceutically
acceptable excipients in the inner tablet core are selected from the group comprising
diluents, binders, disintegrants, lubricants, glidants, or combinations thereof.
5. The osmotic floating tablet of claim 1, wherein the outer osmotic coating
comprises one or more semi-permeable membrane-forming polymers, one or more poreforming
agents, and one or more plasticizers.
6. The osmotic floating tablet of claim 1, wherein the semi-permeable membraneforming
polymer is selected from the group comprising cellulose acetate, cellulose
diacetate, cellulose triacetate, cellulose acetate butyrate, cellulose tri-mallitate, ethyl
cellulose, methyl methacrylate, or combinations thereof.
7. The osmotic floating tablet of claim 5, wherein one or more pore-forming agents
are selected from the group comprising polyethylene glycol, hydroxymethyl cellulose,
hydroxypropyl methylcellulose, hydroxypropyl cellulose, propylene glycol,
polyvinylpyrrolidone, micronized sugar, sodium chloride, mannitol, sorbitol, or
combinations thereof.
8. The osmotic floating tablet of claim 5, wherein one or more plasticizers are
selected from the group comprising triacetin, acetylated triacetin, triethylcitrate,
dibutylsebacate, tributylcitrate, glyceroltributyrate, diacetylated monoglyceride, rapeseed
oil, olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, glycerin sorbitol,
diethyl oxalate, diethyl phthalate, diethyl malate, diethyl fumarate, dibutyl succinate,
diethyl malonate, dioctyl phthalate, or combinations thereof.
9. The osmotic floating tablet of claim 1, wherein the tablet further comprises a
subcoat layer comprising one or more polymers and one or more lubricants.
10. A process for the preparation of an osmotic floating tablet of claim 1, wherein the
process comprises the steps of:
(i) blending the drug with one or more low density polymers and one or more
pharmaceutically acceptable excipients;
(ii) directly compressing the blend of step (i) to form an inner tablet core;
(iii) dissolving/dispersing one or more semi-permeable membrane-forming
polymers, one or more pore-forming agents, and one more plasticizers in a
suitable solvent; and
(iv) applying the coating composition of step (iii) over the tablet core of step (ii)
to form the osmotic floating tablet.