A GASTRORETENTIVE DOSAGE SYSTEM AND PROCESS OF
PREPARATION THEREOF
Field of the Invention
The present invention relates to gastroretentive dosage systems, in particular, a
floating capsule which releases the drug without any lag time and which remains buoyant
for a sufficient period of time in the stomach. Further, the invention relates to the process
of preparation thereof.
Background of the Invention
Due to the ease of administration, patient compliance, and variability in
formulations, the oral route of administration remains the most preferred route of
administration. Amongst oral, a site specific drug delivery system remains the system of
choice in many circumstances. This system can also help in optimizing oral-controlled
delivery of drugs having an "absorption window" by continuously releasing the drug prior
to the absorption window, for a prolonged period of time thus causing optimal
bioavailability. Gastric emptying of dosage forms is an extremely variable process and the
ability to prolong and control the emptying time is a valuable asset for dosage forms,
which reside in the stomach for a longer period of time than conventional dosage forms.
Prolonged gastric residence time and controlled-release of drugs within the gastrointestinal
tract helps to reduce the dosing frequency and total dose, improve patient compliance and
convenience, and maintain a less fluctuating plasma level, as well as reduce GI side
effects. Prolonging of the gastric residence time of the therapeutic agents is thought to be
beneficial, especially under several circumstances such as for drugs acting topically on the
gastric region, for drugs with a narrow therapeutic window, for drugs with the major
absorption site in the upper GI tract and for drugs that are less soluble in or are degraded
by the alkaline pH of the upper GI tract.
The prior art discloses different approaches or systems to prolong the gastric
residence time, such as mucoadhesive or bioadhesive systems, high density systems,
expandable or swelling systems, and floating drug delivery systems.
The mucoadhesive systems are intended to extend the gastric residence time by
adhering the drug to the gastric mucous membrane. Bioadhesion on soft tissues of certain
natural or synthetic polymers has been exploited to control as well as to prolong the gastric
retention of the delivery system. Jackson et al, in "Comparative Scintigraphic
Assessment of the Intragastric Distribution and Residence of Cholestyramine, Carbopol
934P and sucralfate", Int. J. Pharm., 212(1):55-62(2001); U.S. Patent No. 6,207,197; and
U.S. Patent Application No. 2005/0064027 describe the mucoadhesive gastroretentive
system.
High density systems are intended to lodge in the rugae or folds of the stomach
withstanding the peristaltic movements. Systems with a density of 1.3g/ml or higher are
expected to be retained in the lower part of the stomach. Hampson et al. , "Alginate Rafts
and Their Characterization", Int. J. Pharm., 294( 1-2) :137-147 (2005) describe the high
density gastroretentive systems.
Expandable or swelling systems are easily swallowed and reach a significantly
larger size in the stomach due to swelling or unfolding processes that prolong their time in
the gastrointestinal tract. After drug-release, their dimensions are minimized with
subsequent evacuation from the stomach. Chavanpatil et al, "Development of Sustained
Release Gastroretentive Drug Delivery System for Ofloxacin: In vitro and in vivo
Evaluation", Int. J. Pharm., 304 1-2):178- 184 (2005) describe the swelling gastroretentive
system.
Floating drug delivery systems have a bulk density less than gastric fluids and so
remain buoyant in the stomach without affecting gastric emptying rate for a prolonged
period of time. While the system is floating on the gastric contents, the drug is released
slowly at the desired rate from the system. After release of the drug, the residual system is
emptied from the stomach. Arora et al, "Floating Drug Delivery Systems: A review",
AAPS PharmSciTech 6(3):E372-E390 (2005) describes the floating gatroretentive system.
The floating drug system can further be classified into effervescent systems such as gas
generating systems and non-effervervescent systems such as colloidal gel barrier systems,
microporous compartment system, floating microspheres and alginate floating beads.
Glumetza® GR, Cytotec®, Conviron®, Cifran OD, Madopar, and Valrelease® are
some of the marketed preparations based on gastroretentive dosage forms.
U.S. Patent No. 3,976,764 discloses solid therapeutic preparations floatable in the
gastric juice wherein the active ingredient is impregnated into a body of empty globular
shell or a small granular lump of a material having high buoyancy. The empty shells of
the invention are gelatin capsules coated with active ingredients. The invention also
discloses pop-corn or pop-rice type of materials coated with active ingredients.
Aerogels and foam materials have been used to produce floating systems. Due to
entrapped air and gases in their hollow spaces, they are inherently less dense and hence
float on the gastric fluids. U.S. Patent No. 5,626,876 discloses floatable oral therapeutic
systems which use microporous materials having a high void proportion for obtaining low
specific gravity. The materials used are thermoplastic polymers, natural polymers and
inorganic compounds such as glasses and ceramic materials. The invention relates to the
preparation of microporous materials by processes such as granulation, hot melting,
compression or molding. However, use of microporous materials tends to increase the
bulk of the systems. There is also less flexibility for designing the dosage form and
incorporating active ingredients. Such systems may also be complex and less
reproducible.
U.S. Patent No. 7,485,322 discloses a floating capsule dosage form having
prolonged gastric residence time, wherein the capsule body and cap are assembled such as
to encapsulate at least a tablet and granulate together with entrapped gas and is coated with
a coating which is substantially insoluble or poorly soluble in an acidic medium. In this
reference, the tablet and granulate comprise active and hydrophilic or lipophilic substances
which helps in controlling the release. The active-release is controlled by a dual
mechanism, one with the help of hydrophilic or lipophilic substances in the matrix of
tablet and granulates, and second with the help of an outer coating layer. This increases
the processing steps and also the complexity of the dosage form, as it would be critical to
control the amount of hydrophilic and lipophilic substances in the granulate and/or tablet
and to control the thickness of the coating. Further, a large amount of excipients would be
required resulting in high cost. The main disadvantage with this system in particular, and
with other known gastroretentive dosage systems, is that these systems release the drug
after some time and there always remains the initial lag time. This may not be acceptable
in instances where immediate drug-release would be required.
There is a need in the art to formulate a gastroretentive dosage system which is
simple, safe, cost-effective, easy to manufacture and is functionally reproducible.
We have now developed a gastroretentive dosage system which controls the
release of the active ingredient only with the help of coating, making it simple and costeffective.
Further, the gastroretentive dosage system is designed to start releasing the
active ingredient without any lag time. The gastroretentive dosage system can incorporate
high amount of active ingredient and therefore this system can be explored for high dose
active ingredients. Further, the system can be used for pulsatile drug delivery and
combination of active ingredients in particular, incompatible active ingredients.
Summary of the Invention
In one of the general aspects, there is provided a gastroretentive dosage system
comprising:
(a) a shell filled with the active ingredient in powder form; and
(b) an extended-release layer over the shell.
In another general aspect there is provided a gastroretentive dosage system
comprising:
(a) a shell filled with the active ingredient and one or more pharmaceutically
acceptable excipient(s) in powder form; and
(b) an extended-release layer over the shell.
In another general aspect, there is provided a gastroretentive dosage system
comprising:
(a) a shell filled with the active ingredient in powder form;
(b) an extended-release layer over the shell; and
(c) an immediate-release layer comprising the active ingredient over the
extended-release layer.
In another general aspect, there is provided a gastroretentive dosage system
comprising:
(a) a shell filled with the active ingredient and one or more pharmaceutically
acceptable excipient(s) in powder form;
(b) an extended-release layer over the shell; and
(c) an immediate-release layer comprising the active ingredient over the
extended-release layer.
In another general aspect, there is provided a gastroretentive dosage system
comprising:
(a) a shell filled with the active ingredient in powder form;
(b) an extended-release layer comprising one or more extended-release
polymer(s), one or more coating additive(s); and
(c) an immediate-release layer comprising the active ingredient, one or more
binder(s) and one or more coating additive(s).
In another general aspect, there is provided a gastroretentive dosage system
comprising:
(a) a shell filled with the active ingredient and one or more pharmaceutically
acceptable excipient(s) in powder form;
(b) an extended-release layer comprising one or more extended-release
polymer(s), one or more coating additive(s); and
(c) an immediate-release layer comprising the active ingredient, one or more
binder(s) and one or more coating additive(s).
In another general aspect, there is provided a gastroretentive dosage system
comprising:
(a) a shell comprising the active ingredient, one or more osmotic agent(s), and
one or more pharmaceutically acceptable excipient(s) in powder form;
(b) a semi-permeable layer comprising one or more semi-permeable membrane
forming polymer(s), one or more flux enhancer(s), and one or more coating
additive(s);
(c) an immediate-release layer comprising the active ingredient, one or more
binder(s), one or more coating additive(s); and
(d) optionally at least one passageway.
In one of the embodiments, the active ingredient present in the shell and the active
ingredient present in the immediate-release layer are similar.
In another embodiment, the active ingredient present in the shell and the active
ingredient present in the immediate-release layer are different.
In another general aspect there is provided a process for the preparation of
gastroretentive dosage system, wherein the process comprises the steps of:
(a) filling the empty shell with the active ingredient in powder form; and
(b) coating the shell with a solution or dispersion of one or more extendedrelease
polymer(s)and one or more coating additive(s).
In another general aspect, there is provided a process for the preparation of a
gastroretentive dosage system, wherein the process comprises the steps of:
(a) filling the empty shell with the blend of the active ingredient and one or more
pharmaceutically acceptable excipient(s) in powder form; and
(b) coating the shell with a solution or dispersion of one or more extendedrelease
polymer(s) and one or more coating additive(s).
In another general aspect, there is provided a process for the preparation of a
gastroretentive dosage system, wherein the process comprises the steps of:
(a) filling the empty shell with the active ingredient in powder form;
(b) coating the shell with a solution or dispersion of one or more extendedrelease
polymer(s) and one or more coating additive(s); and
(c) coating the above coated shells with a solution or dispersion of the active
ingredient, one or more binder(s) and one or more coating additive(s).
In another general aspect, there is provided a process for the preparation of a
gastroretentive dosage system, wherein the process comprises the steps of:
(a) filling the empty shell with the blend of the active ingredient and one or more
pharmaceutically acceptable excipient(s) in powder form;
(b) coating the shell with a solution or dispersion of one or more extendedrelease
polymer(s) and one or more coating additive(s); and
(c) coating the above-coated shells with a solution or dispersion of the active
ingredient, one or more binder(s) and one or more coating additive(s).
In another general aspect, there may be provided a process for the preparation of a
gastroretentive dosage system, wherein the process comprises the steps of:
(a) filling the empty shell with the active ingredient, one or more osmotic
agent(s), and one or more pharmaceutically acceptable excipient(s) in powder
form;
(b) coating the shell with a solution or dispersion of one or more semi-permeable
membrane forming polymer(s), one or more flux enhancer(s) and one or
more coating additive(s);
(c) coating the above coated shells with a solution or dispersion of the active
ingredient, one or more binder(s), and one or more coating additive(s); and
(d) optionally creating at least one passageway in the semi-permeable layer.
Detailed Description of the Invention
In the gastroretentive dosage system of the present invention, first the outermost
immediate-release layer comprising the active ingredient dissolves and releases the active
ingredient in the stomach. After that, the extended-release coating, due to insolubility or
poor solubility in an aqueous medium, prevents an influx of water into the shell for a
predetermined period of time and air entrapped in the shell helps in floating the shell. In
some of the aspects, the shell is filled with one or more osmotic agent(s) in addition to the
active ingredient that swells with the help of water, creating an osmotic pressure that helps
in complete and pH-independent release of the active ingredient. After the immediate
burst release, the release is only controlled by the composition and thickness of a coating.
Once the release process is initiated, the shell may still float or remain buoyant for a
certain period of time in the medium or it may sink and disintegrate. The gastroretentive
dosage system of the present invention remains floating for more than 1 hour, in particular
for more than 12 hours.
The term "shell", as used herein, refers to hard or soft gelatin capsules, wafers or
any aerogels or foam materials which are hollow and have a cavity inside which can
entrap air. These shells may be precoated with a dispersion (solution or suspension) of a
hydrophilic polymer, e.g., hydroxypropylmethylcellulose, hydroxypropylcellulose, or
hydroxyethylcellulose. This precoating may protect the shell from being degraded by
gastric juice, which can affect the floating performance in the stomach. It may also avoid
rupture of the shell or change of shape of the shell in the stomach for a longer period of
time.
In another embodiment, the shell comprises solely the active ingredient in the form
of a powder.
In another embodiment, the shell comprises the active ingredient and one or more
pharmaceutically acceptable excipient(s) in powder form.
In yet another embodiment, the shell comprises the active ingredient, one or more
osmotic agent(s), and one or more pharmaceutically acceptable excipient(s) in powder
form.
The term "active ingredient", as used herein, includes, but is not limited to drugs
which are mainly absorbed in the stomach, drugs having higher solubility in the stomach
than in the intestine, drugs which are poorly absorbed or degraded in the intestine, drugs
requiring local effect in the stomach, etc. Specific examples include, but are not limited
to, active nucleic acids or amino acids and their derivatives, peptidomimetic substances,
antiulcer agents, some analgesics, antipsychotics, antidepressants, antiepileptics,
cytostatics, antimigraine agents, antiviral substances, antibiotics, anti-inflammatory
agents, sedatives, antidiabetic agents, antihistamines, therapeutic ions, vitamins,
bronchodilators, antihypertensives, diuretics, hypolipemic agents, and antiobesity agents.
Specific examples of active ingredients include, but are not limited to, acyclovir,
gabapentin, pregabalin, trimetazidine, feropenem, 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, valacyclovir, azithromycin, inosine, didanosine, pranobex,
tribavirin, vidarabine, simvastatin, pravastatin, atorvastatin, lovastatin, selegiline,
midazolam, lithium carbonate, cimetidine, ranitidine, famotidine, nizatidine, bifentidine,
nifentidine, roxatidine, omeprazole, lansoprazole, pantoprazole, antacids such as
magnesium carbonate, aluminum carbonate, aluminum hydroxide, magnesium oxide and
sucralfate, carbenoloxalone, misoprostol, pirenzepine, telenzepine, bismuth salts,
metronidazole, ciprofloxacin, clarithromycin, amoxicillin, cephalexin, ascorbic acid, folic
acid, vitamin E, furosemide, topiramide, hydrochlorothiazide, orlistat, and
pharmaceutically acceptable salts, esters or prodrugs thereof. The dose of any active
ingredient would depend on the individual active substance. The invention particularly
can be used for active ingredients where the dose is high, e.g., more than 500 mg.
The active ingredient present in the shell and the active ingredient present in the
immediate layer of the dosage form are either similar or different. The active ingredients
may belong to a similar therapeutic class or to a different therapeutic class. The active
ingredients may be incompatible or a combination of high and low-dose active ingredients.
When both the shell and immediate-release layers comprise similar active
ingredients, pulsatile-release can be achieved. First, there is a burst of immediate-release
from the outer active layer, and after a predetermined time interval there is release of the
active ingredient from the shell resulting in a pulsatile delivery. Also the system may
provide the initial burst-release which provides the appropriate active concentration at the
initial stage, followed by a constant drug-release without any lag, thereby maintaining the
stable plasma concentration.
Extended-release polymers used in the present invention include polymers which
are insoluble in an aqueous medium or a combination of polymers which are insoluble in
an aqueous medium with water-soluble polymers. The amount of extended-release
polymer used may vary from about 1% to about 20% w/w based on the total dosage form.
Specific examples of extended-release polymers which are insoluble in an aqueous
medium include, but are not limited to, cellulose acetate phthalate, cellulose acetate
mellitate, cellulose acetate succinate, cellulose acetate, hydroxypropylmethylcellulose
phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylcellulose ether,
polyvinylacetate phthalate, polyester of styrene and maleic acid copolymer, polyester of
vinylether and maleic acid copolymer, vinylacetate and crotonic acid copolymer,
copolymers of methacrylic acid and ethylacrylate, copolymers of methacrylic acid and
methacrylate (e.g., Eudragit® LI00, Eudragit® LI00-55, Eudragit® L 30 D-55, and
Eudragit® SI 00), ethylcellulose, copolymers of
methacrylate/trimethylamonioethylmethacrylate (e.g., Eudragit® RL PO, Eudragit® RL
100, Eudragit® RL 30D, Eudragit® RS PO, Eudragit® RS 100, and Eudragit® RS 30D),
neutral polymers of methacrylate (e.g., Eudragit® NE 30 D and Eudragit® NE 40 D) and
mixtures thereof.
Specific examples of the combination include a combination of polymers which
are insoluble in an aqueous medium with water-soluble polymers such as a combination of
ethylcellulose or methacrylate/trimethylammonioethylmethacrylate copolymers (e.g.,
Eudragit® RL PO, Eudragit® RL 100, Eudragit® RL 30 D, Eudragit® RS PO, Eudragit®
RS 100, and Eudragit® RS 30 D) or neutral methacrylate polymers (e.g., Eudragit® NE
30 D and Eudragit® NE 40D) with water-soluble polymers such as
hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose,
methylcellulose and polyvinylpyrrolidone.
The thickness of the coating is critical for controlling the release of the active
ingredient. The extended-release coating is applied until there is a weight gain of 3% to
15% w/w based on the total weight of the dosage form.
The term "osmotic agent", as used herein, includes all pharmaceutically acceptable
inert water-soluble compounds. Examples of compounds suitable as osmotic agents
include, but are not limited to, water-soluble salts of inorganic acids such as magnesium
chloride or magnesium sulfate, lithium chloride, sodium chloride, potassium chloride,
lithium hydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate,
lithium dihydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen
phosphate; water-soluble salts of organic acids such as sodium acetate, potassium acetate,
magnesium succinate, sodium benzoate, sodium citrate, and sodium ascorbate; non-ionic
organic compounds with high water-solubility, e.g., carbohydrates such as mannitol,
sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose,
lactose, and raffinose; water-soluble amino acids such as glycine, leucine, alanine, or
methionine; urea and urea derivatives; and mixtures thereof. The amount of osmotic agent
used may vary from about 5% to about 20% w/w based on the total dosage form.
The semi-permeable layer of the present invention comprises one or more semi
permeable membrane-forming polymer(s), one or more flux enhancer(s), and one or more
coating additive(s). A semi-permeable layer allows movement of water molecules through
it, but does not allow contents of the shell to pass through.
Semi-permeable membrane-forming polymers are those which are not metabolized
in the gastrointestinal tract, i.e., are ejected unchanged from the body in feces. Examples
of semi-permeable membrane- forming polymers include, but are not limited to, cellulose
derivatives such as cellulose acetate, ethyl cellulose, cellulose triacetate, agar acetate,
amylose acetate, cellulose acetate ethyl carbamate, cellulose acetate phthalate, cellulose
acetate methyl carbamate, cellulose acetate succinate, cellulose acetate
dimethylaminoacetate, cellulose acetate ethyl carbonate, cellulose acetate chioroacetate,
cellulose acetate ethyl oxalate, cellulose acetate methyl sulphonate, cellulose acetate butyl
sulphonate, cellulose acetate propionate, cellulose acetate diethylamino-acetate, cellulose
acetate octate, cellulose acetate laurate, cellulose acetate p-toluenesulphonate, and
cellulose acetate butyrate; polymeric epoxides; copolymers of alkylene oxides and alkyl
glycidyl ethers; polyglycols or polylactic acid derivatives; copolymers of acrylic acid ethyl
ester and methacrylic acid methyl ester; and mixtures thereof. Controlling semi
permeable membrane thickness also helps to control the permeability of the membrane,
which generally may vary from about 3% to about 15% weight build up over the shell.
Flux enhancers are water-soluble substances which aid in drawing water from the
surrounding media and are thereby helpful in manipulating the semi-permeable
membrane's permeability. Specific examples of flux enhancers include, but are not limited
to, hydroxymethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol,
hydroxypropylcellulose, propylene glycol, polyvinylpyrrolidone, and mixtures thereof.
The immediate-release layer of the present invention comprises the active
ingredient, one or more binder(s), one or more film forming polymer(s), and one or more
coating additive(s).
Specific examples of binders include, but are not limited to, povidone, methyl
cellulose, ethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose,
hydroxypropyl methyl cellulose, and mixtures thereof.
Specific examples of film-forming polymers include, but are not limited to,
hydroxypropyl methylcellulose, hydroxypropylcellulose, ethylcellulose, methylcellulose,
carboxymethyl cellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose
acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose
acetate trimellitate; waxes such as polyethylene glycol; methacrylic acid polymers such as
Eudragit®; polyvinyl pyrrolidone; and mixtures thereof.
The term "pharmaceutically acceptable excipients" includes all the excipients used
conventionally in the dosage forms, in particularly fillers.
Specific examples of fillers include, but not are limited to, talc, lactose, mannitol,
colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, and mixtures
thereof.
Coating additives may be selected from the group consisting of fillers, plasticizers,
opacifiers, coloring agents, lubricants/glidants, and mixtures thereof.
Specific examples of plasticizers include, but are not limited to, triethylcitrate,
dibutylsebacate, acetylated triacetin, tributylcitrate, glyceroltributyrate, diacetylated
monoglyceride, rape oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate,
glycerin sorbitol, diethyloxalate, diethyl phthalate, diethylmalate, diethylfumarate,
dibutylsuccinate, diethylmalonate, dioctylphthalate, and mixtures thereof.
Specific examples of opacifiers include, but are not limited to, titanium dioxide,
manganese dioxide, iron oxide, silicon dioxide, and mixtures thereof.
Coating may be performed by applying the coating composition as a
solution/suspension/blend using any conventional coating technique known in the prior art
such as spray coating in a conventional coating pan or fluidized bed processor; dip
coating; or compression coating.
Examples of solvents used for preparing the solution/dispersion of coating
substances include methylene chloride, isopropyl alcohol, acetone, methanol, ethanol,
water, and mixtures thereof.
The term "passageway", as used herein, covers any suitable means for releasing
the active ingredient present in the shell into the surrounding media. The term includes
passages, apertures, bores, holes, openings and the like, that are created through the semi
permeable layer and form a connection between the shell and the surrounding media. The
passageway may be created by mechanical drilling or laser drilling, or be formed in
response to the osmotic pressure acting on the drug delivery system. Based on the nature
of the desired drug-release profile, the number and diameter of the passageways may be
adjusted. However, the diameter of the passageway should not be large enough to allow
body fluids to enter the drug delivery system by the process of convection.
The invention may be further illustrated by the following examples, which are for
illustrative purposes only and should not be construed as limiting the scope of the
invention in any way.
Examples 1-8 :
Process:
Pregabalin was filled into capsules and the capsules were locked.
A 10% w/w gelatin solution was prepared and the capsules were band sealed
using it.
Acetone and purified water were mixed together.
Triacetin and Polyethylene Glycol 400 were added to the solution of step 3.
5. Polyethylene Glycol 3350 was dissolved in the solution of step 4 under
continuous stirring.
6. Cellulose acetate was dissolved in the solution of step 5 under continuous
stirring.
7. The coating solution of step 6 was used to coat the capsules of step 2 in a
coating pan.
Example 9 :
Trimetazidine dihydrochloride was filled into capsules and the capsules were
locked.
A 10% w/w gelatin solution was prepared and the capsules were band sealed
using it.
Acetone and purified water were mixed together.
4. Triacetin and Polyethylene Glycol 400 were added to the solution of step 3.
5. Polyethylene Glycol 3350 was dissolved in the solution of step 4 under
continuous stirring.
6. Cellulose acetate was dissolved in the solution of step 5 under continuous
stirring.
7. The coating solution of step 6 was used to coat the capsules of step 2 in a
coating pan.
8. Ethanol and purified water were mixed together.
9. Trimetazidine dihydrochloride was dissolved in the solution of step 8.
10. Hydroxypropylmethyl cellulose was dissolved in the solution of step 9 under
continuous stirring.
11. The solution of step 10 was used to coat the capsules of step 7 in a coating
pan.
Example 10 :
Pregabalin, mannitol and talc were sifted and mixed together and then filled
into capsules and the capsules were locked.
A 10% w/w gelatin solution was prepared and the capsules were band sealed
using it.
Ethylcellulose was dissolved in ethanol under continuous stirring.
Triethyl citrate was added to the solution of step 3.
Polyvinylpyrrolidone (PVP K-30) was dissolved in the solution of step 4
under continuous stirring.
The coating solution of step 5 was used to coat the capsules of step 2 in a
coating pan.
Example 11:
1. Pregabalin, mannitol and talc were sifted and mixed together and then filled
into capsules and the capsules were locked.
A 10% w/w gelatin solution was prepared and the capsules were band sealed
using it.
Ethanol, acetone and water were mixed together.
Triacetin was added to the solution of step 3.
Eudragit® RL PO was dissolved in the solution of step 4 under continuous
stirring.
The coating solution of step 5 was used to coat the capsules of step 2 in a
coating pan.
We Claim:
1. A gastroretentive dosage system comprising:
(a) a shell filled with the active ingredient in powder form; and
(b) an extended-release layer over the shell.
2. A gastroretentive dosage system comprising:
(a) a shell filled with the active ingredient in powder form;
(b) an extended-release layer over the shell; and
(c) an immediate-release layer comprising the active ingredient over the
extended-release layer.
3. The gastroretentive dosage system of claim 2, wherein the active ingredient present
in the shell and active ingredient present in the immediate-release layer are similar or
different.
4. The gastroretentive dosage system of claims 1 and 2, wherein the shell further
comprises one or more pharmaceutically acceptable excipients.
5. The gastroretentive dosage system of claims 1 and 2, wherein the active ingredient
is selected from the group consisting of acyclovir, gabapentin, pregabalin, trimetazidine,
feropenem, 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,
valacyclovir, azithromycin, inosine, didanosine, pranobex, tribavirin, vidarabine,
simvastatin, pravastatin, atorvastatin, lovastatin, selegiline, midazolam, lithium carbonate,
cimetidine, ranitidine, famotidine, nizatidine, bifentidine, nifentidine, roxatidine,
omeprazole, lansoprazole, pantoprazole, antacids such as magnesium carbonate, aluminum
carbonate, aluminum hydroxide, magnesium oxide and sucralfate, carbenoloxalone,
misoprostol, pirenzepine, telenzepine, bismuth salts, metronidazole, ciprofloxacin,
clarithromycin, amoxicillin, cephalexin, ascorbic acid, folic acid, vitamin E, furosemide,
topiramide, hydrochlorothiazide, orlistat and pharmaceutically acceptable salts, esters or
prodrugs thereof.
6. The gastroretentive dosage system of claims 1 and 2, wherein the extended-release
layer comprises one or more extended-release polymer(s) and one or more coating
additive(s).
7. The gastroretentive dosage system of claim 6, wherein the extended-release
polymer is selected from the group consisting of cellulose acetate phthalate, cellulose
acetate mellitate, cellulose acetate succinate, cellulose acetate,
hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate,
carboxymethylcellulose ether, polyvinylacetate phthalate, polyester of styrene and maleic
acid copolymer, polyester of vinylether and maleic acid copolymer, vinylacetate and
crotonic acid copolymer, copolymers of methacrylic acid and ethylacrylate, copolymers of
methacrylic acid and methacrylate, ethylcellulose, copolymers of
methacrylate/trimethylamonioethylmethacrylate, neutral polymers of methacrylate and a
combination of ethylcellulose or methacrylate/trimethylammonioethylmethacrylate
copolymers or neutral methacrylate polymers with water soluble polymers such as
hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose,
methylcellulose and polyvinylpyrrolidone.
8. The gastroretentive dosage system of claim 6, wherein the coating additive is
selected from the group consisting of fillers, plasticizers, opacifiers, coloring agents,
lubricants/glidants, and mixtures thereof.
9. A process for the preparation of a gastroretentive dosage system, wherein the
process comprises the steps of:
(a) filling the empty shell with the active ingredient in powder form; and
(b) coating the shell with a solution or dispersion of one or more extendedrelease
polymer(s) and one or more coating additive(s).
10. A process for the preparation of a gastroretentive dosage system, wherein the
process comprises the steps of:
(a) filling the empty shell with the active ingredient in powder form;
(b) coating the shell with a solution or dispersion of one or more extendedrelease
polymer(s) and one or more coating additive(s); and
(c) coating the above coated shells with a solution or dispersion of the active
ingredient, one or more binder(s) and one or more coating additive(s).